Organic Aldehyde_Isothiocyanate chemistry

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Organic Aldehyde/Isothiocyanate chemistry PDF generated using the open source mwlib toolkit. See http://code.pediapress.com/ for more information. PDF generated at: Sun, 02 Dec 2012 18:52:55 UTC Contents Articles Nucleophilic addition Tetrahedral carbonyl addition compound Nucleophilic substitution Nucleophilic acyl substitution Addition reaction Condensation reaction Substitution reaction Elimination reaction Leaving group Reductive amination Aldol condensation SN1 reaction SN2 reaction Alkylimino-de-oxo-bisubstitution Schotten–Baumann reaction Mannich reaction Edman degradation Carbocation Organocatalysis Double bond Functional group Nucleophile Electrophile Sigma bond Pi bond Alkane Amine Amide Imine Schiff base Aldehyde Racemic mixture Aldimine Acid anhydride 1 3 12 15 22 23 25 27 31 32 34 39 43 46 49 50 54 55 59 63 65 74 78 82 84 86 101 109 114 117 118 125 127 128 Carboxylic acid Carbonyl Cyanide Alkoxide Acyl halide Acetyl chloride Haloalkane Hemiaminal Carboximidate Enol Hydroxylamine Oxime Nitrile Hydrogen cyanide Ethyl chloroformate Dithiocarbamate Isothiocyanate Glucosinolate Thiourea Urea Allyl isothiocyanate Methyl isothiocyanate Ethyl carbamate Carbamate Sodium diethyldithiocarbamate Thiocarbamate Pyridoxal phosphate 130 136 139 146 149 151 154 159 160 161 165 170 174 181 188 189 189 192 195 200 209 211 213 218 221 223 224 References Article Sources and Contributors Image Sources, Licenses and Contributors 227 232 Article Licenses License 241 Nucleophilic addition 1 Nucleophilic addition In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new σ bonds by the addition of a nucleophile.[1] Addition reactions are limited to chemical compounds that have multiple-bonded atoms: • molecules with carbon – hetero multiple bonds like carbonyls, imines or nitriles • molecules with carbon – carbon double bonds or triple bonds. Addition to carbon – hetero double bonds Addition reactions of a nucleophile to carbon – hetero double bonds such as C=O or CN triple bond show a wide variety. These bonds are polar (have a large difference in electronegativity between the two atoms) consequently carbon carries a partial positive charge. This makes this atom the primary target for the nucleophile. This type of reaction is also called a 1,2 nucleophilic addition. The stereochemistry of this type of nucleophilic attack is not an issue, when both alkyl substituents are dissimilar and there are not any other controlling issues such as chelation with a Lewis acid, the reaction product is a racemate. Addition reactions of this type are numerous. When the addition reaction is accompanied by an elimination the reaction type is nucleophilic acyl substitution or an addition-elimination reaction. Carbonyls With a carbonyl compound as an electrophile, the nucleophile can be: • • • • • • • • • • water in hydration to a geminal diol (hydrate) an alcohol in acetalisation to an acetal a hydride in reduction to an alcohol an amine with formaldehyde and a carbonyl compound in the Mannich reaction an enolate ion in an aldol reaction or Baylis–Hillman reaction an organometallic nucleophile in the Grignard reaction or the related Barbier reaction or a Reformatskii reaction ylides such as a Wittig reagent or the Corey–Chaykovsky reagent or α-silyl carbanions in the Peterson olefination a phosphonate carbanion in the Horner–Wadsworth–Emmons reaction a pyridine zwitterion in the Hammick reaction an acetylide in the Favorskii reaction. Nucleophilic addition 2 Nitriles With nitrile electrophiles nucleophilic addition take place by: • • • • hydrolysis of a nitrile to an amide or a carboxylic acid organozinc nucleophiles in the Blaise reaction alcohols in the Pinner reaction. the (same) nitrile α-carbon in the Thorpe reaction. The intramolecular version is called the Thorpe–Ziegler reaction. Addition to carbon – carbon double bonds The driving force for the addition to alkenes is the formation of a nucleophile X− that forms a covalent bond with an electron-poor unsaturated system -C=C- (step 1). The negative charge on X is transferred to the carbon – carbon bond. In step 2 the negatively charged carbanion combines with (Y) that is electron-poor to form the second covalent bond. Ordinary alkenes are not susceptible to a nucleophilic attack (apolar bond). Styrene reacts in toluene with sodium to 1,3-diphenylpropane [2] through the intermediate carbanion: Another exception to the rule is found in the Varrentrapp reaction. Fullerenes have unusual double bond reactivity and additions such has the Bingel reaction are more frequent. When X is a carbonyl group like C=O or COOR or a cyanide group (CN), the reaction type is a conjugate addition reaction. The substituent X helps to stabilize the negative charge on the carbon atom by its inductive effect. In addition when Y-Z is an active hydrogen compound the reaction is known as a Michael reaction. Nucleophilic addition Perfluorinated alkenes (alkenes that have all hydrogens replaced by fluorine) are highly prone to nucleophilic addition, for example by fluoride ion from caesium fluoride or silver(I) fluoride to give a perfluoroalkyl anion. 3 References [1] March Jerry; (1985). Advanced Organic Chemistry reactions, mechanisms and structure (3rd ed.). New York: John Wiley & Sons, inc. ISBN 0-471-85472-7 [2] Sodium-catalyzed Side Chain Aralkylation of Alkylbenzenes with Styrene Herman Pines, Dieter Wunderlich J. Am. Chem. Soc.; 1958; 80(22)6001–6004. doi:10.1021/ja01555a029 Tetrahedral carbonyl addition compound Tetrahedral intermediate is a reaction intermediate in which the bond arrangement around an initially double-bonded carbon atom has been transformed from trigonal to tetrahedral.[1] Tetrahedral intermediates result from nucleophilic addition to a carbonyl group. The stability of tetrahedral intermediate depends on the ability of the groups attached to the new tetrahedral carbon atom to leave with the negative charge. Tetrahedral intermediates are very significant in organic syntheses and biological systems as a key intermediate in esterification, transesterification, ester hydrolysis, formation and hydrolysis of amides and peptides, hydride reductions, and other chemical reactions. Tetrahedral carbonyl addition compound 4 History One of the earliest accounts of the tetrahedral intermediate came from Rainer Ludwig Claisen in 1887.[2] In the reaction of benzyl benzoate with sodium methoxide, and methyl benzoate with sodium benzyloxide, he observed a white precipitate which under acidic conditions yields benzyl benzoate, methyl benzoate, methanol, and benzyl alcohol. He named the likely common intermediate “aditionelle Verbidung.” Victor Grignard assumed the existence of unstable tetrahedral intermediate in 1901, while investigating the reaction of esters with organomagnesium reagents.[3] The first evidence for tetrahedral intermediates in the substitution reactions of carboxylic derivatives was provided by Myron L. Bender in 1951.[4] He labeled carboxylic acid derivatives with oxygen isotope O18 and reacted these derivatives with water to make labeled carboxylic acids. At the end of the reaction he found that the remaining starting material had a decreased proportion of labeled oxygen, which is consistent with the existence of the tetrahedral intermediate. Reaction Mechanism The nucleophilic attack on the carbonyl group proceeds via Bürgi-Dunitz trajectory. The angle between the line of nucleophilic attack and the C-O bond is greater than 90˚. This due to a better orbital overlap between the HOMO of the nucleophile and the π* LUMO of the C-O double bond. Burgi-Dunitz trajectory Tetrahedral carbonyl addition compound 5 Structure of Tetrahedral Intermediates General Features Although the tetrahedral intermediates are usually transient intermediates, many compounds of this general structures are known. The reactions of aldehydes, ketones, and their derivatives frequently have a detectable tetrahedral intermediate, while for the reactions of derivatives of carboxylic acids this is not the case. At the oxidation level of carboxylic acid derivatives, the groups such as OR, OAr, NR2, or Cl are conjugated with the carbonyl group, which means that addition to the carbonyl group is thermodynamically less favored than addition to corresponding aldehyde or ketone. Stable tetrahedral intermediates of carboxylic acid derivatives do exist and they usually possess at least one of the following four structural features: 1) polycyclic structures (e.g.tetrodotoxin)[5] 2) compounds with a strong electron-withdrawing group attached to the acyl carbon (e.g.N,N-dimethyltrifluoroacetamide)[6] 3) compounds with donor groups that are poorly conjugated with the potential carbonyl group (e.g.cyclol)[7] 4) compounds with sulfur atoms bonded to the anomeric centre (e.g.S-acylated-1,8-Naphtalenedithiol)[8] These compounds were used to study the kinetics of tetrahedral intermediate decomposition into its respective carbonyl species, and to measure the IR, UV, and NMR spectra of the tetrahedral adduct. Tetrodotoxin X-Ray Crystal Structure Determination The first x-ray crystal structures of tetrahedral intermediates were obtained from the porcine trypsin crystallized with soybean tripsin inhibitor in 1974, and the bovine trypsin crystallized with bovine pancreatic trypsin inhibitor in 1973.[9][10] In both cases the tetrahedral intermediate is stabilized in the active sites of enzymes, which have evolved to stabilize the transition state of peptide hydrolysis. Some insight into the structure of tetrahedral intermediate can be obtained from the crystal structure of N-brosylmitomycin A, crystallized in 1967.[11] The tetrahedral carbon C17 forms a 136.54pm bond with O3, which is shorter than C8-O3 bond (142.31pm). In contrast, C17-N2 bond (149.06pm) is longer than N1-C1 bond (148.75pm) and N1-C11 bond (147.85pm) due to donation of O3 lone pair into σ* orbital of C17-N2. This model however is forced into tetracyclic sceleton, and tetrahedral O3 is methylated which makes it a poor model overall. Tetrahedral carbonyl addition compound 6 The more recent x-ray crystal structure of 1-aza-3,5,7-trimethyladamantan-2-one is a good model for cationic tetrahedral intermediate.[12] The C1-N1 bond is rather long [155.2(4)pm], and C1-O1(2) bonds are shortened [138.2(4)pm]. The protonated nitrogen atom N1 is a great amine leaving group. In 2002 David Evans et al. observed a very stable neutral tetrahedral intermediate in the reaction of N-acylpyrroles with organometallic compounds, followed by protonation with ammounium chloride producing a carbinol.[13] The C1-N1 bond [147.84(14) pm] is longer than the usual Csp3-Npyrrole bond which range from 141.2-145.8 pm. In contrast, the C1-O1 bond [141.15(13) pm] is shorter than the average Csp3-OH bond which is about 143.2 pm. The elongated C1-N1, and shortened C1-O1 bonds are explained with an anomeric effect resulting from the interaction of the oxygen lone pairs with the σ*C-N orbital. Similarly, an interaction of an oxygen lone pair with σ*C-C orbital should be responsible for the lengthened C1-C2 bond [152.75(15) pm] compared to the average Csp2-Csp2 bonds which are 151.3 pm. Also, the C1-C11 bond [152.16(17) pm] is slightly shorter than the average Csp3-Csp3 bond which is around 153.0 pm. Tetrahedral carbonyl addition compound 7 Stability of Tetrahedral Intermediates Acetals and Hemiacetals Hemiacetals and acetals are essentially tetrahedral intermediates. They form when nucleophiles add to a carbonyl group, but unlike tetrahedral intermediates they can be very stable and used as protective groups in synthetic chemistry. A very well known reaction occurs when acetaldehyde is dissolved in methanol, producing a hemiacetal. Most hemiacetals are unstable with respect to their parent aldehydes and alcohols. For example, the equilibrium constant for reaction of acetaldehyde with simple alcohols is about 0.5, where the equilibrium constant is defined as K=[hemiacetal]/[aldehyde][alcohol]. Hemiacetals of ketones (sometimes called hemiketals) are even less stable than those of aldehydes. However, cyclic hemiacetals and hemiacetals bearing electron withdrawing groups are stable. Electronwithdrawing groups attached to the carbonyl atom shift the equilibrium constant toward the hemiacetal. They increase the polarization of the carbonyl group, which already has a positively polarized carbonyl carbon, and make it even more prone to attack by a nucleophile. The chart below shows the extent of hydration of some carbonyl compounds. Hexafluoroacetone is probably the most hydrated carbonyl compound possible. Formaldehyde reacts with water so readily because its substituents are very small- a purely steric effect.[14] [15] Cyclopropanones- three-membered ring ketones- are also hydrated to a significant extent. Since three-membered rings are very strained (bond angles forced to be 60˚), sp3 hybridization is more favorable than sp2 hybridization. For the sp3 hybridized hydrate the bonds have to be distorted by about 49˚, while for the sp2 hybridized ketone the bond Tetrahedral carbonyl addition compound angle distortion is about 60˚. So the addition to the carbonyl group allows some of the strain inherent in the small ring to be released, which is why cyclopropanone and cyclobutanone are very reactive electrophiles. For larger rings, where the bond angles are not as distorted, the stability of the hemiacetals is due to entropy and the proximity of the nucleophile to the carbonyl group. Formation of an acyclic acetal involves a decrease in entropy because two molecules are consumed for every one produced. In contrast, the formation of cyclic hemiacetals involves a single molecule reacting with itself, making the reaction more favorable. Another way to understand the stability of cyclic hemiacetals is to look at the equilibrium constant as the ratio of the forward and backward reaction rate. For a cyclic hemiacetal the reaction is intramolecular so the nucleophile is always held close to the carbonyl group ready to attack, so the forward rate of reaction is much higher than the backward rate. Many biologically relevant sugars, such as glucose, are cyclic hemiacetals. 8 In the presence of acid, hemiacetals can undergo an elimination reaction, losing the oxygen atom that once belonged to the parent aldehyde’s carbonyl group. These oxonium ions are powerful electrophiles, and react rapidly with a second molecule of alcohol to from new, stable compounds, called acetals. The whole mechanism of acetal formation from hemiacetal is drawn bellow. Tetrahedral carbonyl addition compound 9 Acetals, as already pointed out, are stable tetrahedral intermediates so they can be used as protective groups in organic synthesis. Acetals are stable under basic conditions, so they can be used to protect ketones from a base. Acetal group is hydrolyzed under acidic conditions. An example with dioxolane protecting group is given below. Weinreb Amides Weinreb amides are N-methoxy-Nmethyl-carboxylic acid amides.[16] Weinreb amides are reacted with organometallic compounds togive, on protonation, ketones (see Weinreb ketone synthesis). It is generally accepted that the high yields of ketones are due to the high stability of the five-membered ring- chelated intermediate. Quantum mechanical calculations have shown that thetrahedral adduct is formed easily and it is fairly stable, in agreement with the experimental results.[17] The very facile reaction of Weinreb amides with organolithium and Grignard reagents results from the chelate stabilization in the tetrahedral adduct and, more importantly, the transition state leading to the adduct. The tetrahedral adducts are shown below. Tetrahedral carbonyl addition compound 10 Applications in Biomedicine Drug Design A solvated ligand that binds the protein of interest is likely to exist as an equilibrium mixture of several conformers. Likewise the solvated protein also exists as several conformers in equilibrium. Formation of protein-ligand complex includes displacement of the solvent molecules that occupy the binding site of the ligand, to produce a solvated complex. Because this necessarily means that the interaction is entropically disfavored, highly favorable enthalpic contacts between the protein and the ligand must compensate for the entropic loss. The design of new ligands is usually based on the modification of known ligands for the target proteins. Proteases are enzymes that catalyze hydrolysis of a peptide bond. These proteins have evolved to recognize and bind the transition state of peptide hydrolysis reaction which is a tetrahedral intermediate. Therefore, the main protease inhibitors are tetrahedral intermediate mimics having an alcohol or a phosphate group. Examples are saquinavir, ritonavir, pepstatin, etc.[18] Enzymatic Activity Stabilization of tetrahedral intermediates inside of the enzyme active site has been investigated using tetrahedral intermediate mimics. The specific binding forces involved in stabilizing the trasition state have been describe crystallographycally. In the mammalian serine proteases, trypsin and chymotrypsin, two peptide NH groups of the polypeptide backbone form the so-called oxyanion hole by donating hydrogen bonds to the negatively charged oxygen atom of the tetrahedral intermediate.[19] A simple diagram describing the interaction is shown below. Tetrahedral carbonyl addition compound 11 References [1] "IUPAC Gold Book definition" (http:/ / goldbook. iupac. org/ T06289. html). . [2] Claisen, Ludwig (1887). Chem. Ber. 20: 646–650. doi:10.1002/cber.188702001148. [3] Grignard, Victor (1901). Ann. Chim. Phys. 24: 433–490. [4] Bender, Myron (1951). J. Am. Chem. Soc. 73: 1626–1629. doi:10.1021/ja01148a063. [5] Woodward, R.B.; Gougoutas J. Z. (1964). J. Am. Chem. Soc. 86: 5030. [6] Gideon, Fraenkel; Watson Debra (1975). J. Am. Chem. Soc. 97: 231–232. doi:10.1021/ja00834a063. [7] Cerrini, S.; Fedeli W., Mazza F. (1971). Chem. Commun.: 1607–1608. doi:10.1039/C29710001607. [8] Tagaki, M.; Ishahara R., Matsudu T. (1977). Bull. Chem. Soc. Jpn. 50: 2193–2194. doi:10.1246/bcsj.50.2193. [9] Sweet, R.M.; Wright H.T., Clothia C.H., Blow D.M. (1974). Biochemistry 13: 4212–4228. doi:10.1021/bi00717a024. PMID 4472048. [10] Ruhlmann, A.; Kukla D., Schwager P., Bartels K., Huber R. (1973). J. Mol. Biol. 77 (3): 417–436. [11] Tulinsky, A.; Van den Hende J.H. (1967). J. Am. Chem. Soc. 89: 2905–2911. [12] Kirby, A. J.; Komarov I.V., Feeder N. (1998). J. Am. Chem. Soc. 120: 7101–7102. doi:10.1021/ja980700s. [13] Evans, D. A.; G. Borg, K. A. Scheidt (2002). Angewandte Chemie 114 (17): 3320–23. [14] Bell, R. P. (1966). Adv. Phys. Org. Chem. 4 (1). [15] Clayden J., Greeves N., Warren S., and Wothers P. (2001). Organic Chemistry. Oxford University Press. [16] Nahm, S.; Weinreb S. M. (1981). Tetrahedron Lett. 22: 3815–18. doi:10.1016/s0040-4039(01)91316-4. [17] Adler, M.; Adler S., Boche G. (2005). J. Phys. Org. Chem. 18: 193–209. doi:10.1002/poc.807. [18] Babine, R. E.; Bender S. L. (1997). Chem. Rev. 97: 1359–1472. doi:10.1021/cr960370z. PMID 11851455. [19] Bryan, P.; Pantoliano M. W., Quill S. G., Hsiao H. Y., Poulos T. (1986). Proc. Natl. Acad. Sci. USA 83: 3743–5. Nucleophilic substitution 12 Nucleophilic substitution In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive atom is referred to as an electrophile.[1][2] The most general form for the reaction may be given as Nuc: + R-LG → R-Nuc + LG: The electron pair (:) from the nucleophile (Nuc) attacks the substrate (R-LG) forming a new bond, while the leaving group (LG) departs with an electron pair. The principal product in this case is R-Nuc. The nucleophile may be electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged. An example of nucleophilic substitution is the hydrolysis of an alkyl bromide, R-Br, under alkaline conditions, where the attacking nucleophile is the OH− and the leaving group is Br-. R-Br + OH− → R-OH + Br− Nucleophilic substitution reactions are commonplace in organic chemistry, and they can be broadly categorised as taking place at a saturated aliphatic carbon or at (less often) a saturated aromatic or other unsaturated carbon centre.[3] Nucleophilic substitution at saturated carbon centres SN1 and SN2 reactions In 1935, Edward D. Hughes and Sir Christopher Ingold studied nucleophilic substitution reactions of alkyl halides and related compounds. They proposed that there were two main mechanisms at work, both of them competing with each other. The two main mechanisms are the SN1 reaction and the SN2 reaction. S stands for chemical substitution, N stands for nucleophilic, and the number represents the kinetic order of the reaction.[4] In the SN2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously. SN2 occurs where the central carbon atom is easily accessible to the nucleophile. By contrast the SN1 reaction involves two steps. SN1 reactions tend to be important when the A graph showing the relative reactivities of the different alkyl halides towards SN1 central carbon atom of the substrate is and SN2 reactions (also see Table 1). surrounded by bulky groups, both because such groups interfere sterically with the SN2 reaction (discussed above) and because a highly substituted carbon forms a stable carbocation. An example of a substitution reaction taking place by a so-called borderline mechanism as originally studied by Hughes and Ingold [5] is the reaction of 1-phenylethyl chloride with sodium methoxide in methanol. Nucleophilic substitution 13 The reaction rate is found to the sum of SN1 and SN2 components with 61% (3,5 M, 70°C) taking place by the latter. Nucleophilic substitution at carbon SN1 mechanism SN2 mechanism Table 1. Nucleophilic substitutions on RX (an alkyl halide or equivalent) Factor Kinetics Primary alkyl Rate = k[RX] Never unless additional stabilising groups present Moderate Excellent SN1 SN2 Rate = k[RX][Nuc] Good unless a hindered nucleophile is used Moderate Never Elimination likely if heated or if strong base used For halogens, I > Br > Cl >> F Comments Secondary alkyl Tertiary alkyl Leaving group Important Important Nucleophilicity Preferred solvent Stereochemistry Rearrangements Eliminations Unimportant Polar protic Important Polar aprotic Racemisation (+ partial inversion possible) Common Common, especially with basic nucleophiles Inversion Rare Only with heat & basic nucleophiles Side reaction Side reaction esp. if heated Nucleophilic substitution reactions There are many reactions in organic chemistry that involve this type of mechanism. Common examples include • Organic reductions with hydrides, for example R-X → R-H using LiAlH4   (SN2) • hydrolysis reactions such as R-Br + OH− → R-OH + Br− (SN2) or R-Br + H2O → R-OH + HBr   (SN1) • Williamson ether synthesis R-Br + OR'− → R-OR' + Br−   (SN2) • The Wenker synthesis, a ring-closing reaction of aminoalcohols. Nucleophilic substitution • The Finkelstein reaction, a halide exchange reaction. Phosphorus nucleophiles appear in the Perkow reaction and the Michaelis–Arbuzov reaction. • The Kolbe nitrile synthesis, the reaction of alkyl halides with cyanides. 14 Other mechanisms Besides SN1 and SN2, other mechanisms are known, although they are less common. The SNi mechanism is observed in reactions of thionyl chloride with alcohols, and it is similar to SN1 except that the nucleophile is delivered from the same side as the leaving group. Nucleophilic substitutions can be accompanied by an allylic rearrangement as seen in reactions such as the Ferrier rearrangement. This type of mechanism is called an SN1' or SN2' reaction (depending on the kinetics). With allylic halides or sulphonates, for example, the nucleophile may attack at the γ unsaturated carbon in place of the carbon bearing the leaving group. This may be seen in the reaction of 1-chloro-2-butene with sodium hydroxide to give a mixture of 2-buten-1-ol and 1-buten-3-ol: The Sn1CB mechanism appears in inorganic chemistry. Competing mechanisms exist.[6][7] In organometallic chemistry the nucleophilic abstraction reaction occurs with a nucleophilic substitution mechanism. CH3CH=CH-CH2-Cl → CH3CH=CH-CH2-OH + CH3CH(OH)-CH=CH2 Nucleophilic substitution at unsaturated carbon centres Nucleophilic substitution via the SN1 or SN2 mechanism does not generally occur with vinyl or aryl halides or related compounds. Under certain conditions nucleophilic substitutions may occur, via other mechanisms such as those described in the nucleophilic aromatic substitution article. When the substitution occurs at the carbonyl group, the acyl group may undergo nucleophilic acyl substitution. This is the normal mode of substitution with carboxylic acid derivatives such as acyl chlorides, esters and amides. References [1] J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992. [2] R. A. Rossi, R. H. de Rossi, Aromatic Substitution by the SRN1 Mechanism, ACS Monograph Series No. 178, American Chemical Society, 1983. [ISBN 0-8412-0648-1]. [3] L. G. Wade, Organic Chemistry, 5th ed., Prentice Hall, Upper Saddle RIver, New Jersey, 2003. [4] S. R. Hartshorn, Aliphatic Nucleophilic Substitution, Cambridge University Press, London, 1973. [ISBN 0-521-09801-7] [5] 253. Reaction kinetics and the Walden inversion. Part II. Homogeneous hydrolysis, alcoholysis, and ammonolysis of -phenylethyl halidesEdward D. Hughes, Christopher K. Ingold and Alan D. Scott, J. Chem. Soc., 1937, 1201 doi:10.1039/JR9370001201 [6] N.S.Imyanitov. Electrophilic Bimolecular Substitution as an Alternative to Nucleophilic Monomolecular Substitution in Inorganic and Organic Chemistry. J. Gen. Chem. USSR (Engl. Transl.) 1990; 60 (3); 417-419. [7] Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov. SciTecLibrary (http:/ / sciteclibrary. ru/ eng/ catalog/ pages/ 9330. html) Nucleophilic acyl substitution 15 Nucleophilic acyl substitution Nucleophilic acyl substitution describe a class of substitution reactions involving nucleophiles and acyl compounds. In this type of reaction, a nucleophile - such as an alcohol, amine, or enolate - displaces the leaving group of an acyl derivative - such as an acid halide, anhydride, or ester. The resulting product is a carbonyl-containing compound in which the nucleophile has taken the place of the leaving group present in the original acyl derivative. Because acyl derivatives react with a wide variety of nucleophiles, and because the product can depend on the particular type of acyl derivative and nucleophile involved, nucleophilic acyl substitution reactions can be used to synthesize a variety of different products. Reaction mechanism Carbonyl compounds react with nucleophiles via an addition mechanism: the nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. This reaction can be accelerated by acidic conditions, which make the carbonyl more electrophilic, or basic conditions, which provide a more anionic and therefore more reactive nucleophile. The tetrahedral intermediate itself can be an alcohol or alkoxide, depending on the pH of the reaction. The tetrahedral intermediate of an acyl compound contains a substituent attached to the central carbon that can act as a leaving group. After the tetrahedral intermediate forms, it collapses, recreating the carbonyl C=O bond and ejecting the leaving group in an elimination reaction. As a result of this two-step addition/elimination process, the nucleophile takes the place of the leaving group on the carbonyl compound by way of an intermediate state that does not contain a carbonyl. Both steps are reversible and as a result, nucleophilic acyl substitution reactions are equilibrium processes.[1] Because the equilibrium will favor the product containing the best nucleophile, the leaving group must be a comparatively poor nucleophile in order for a reaction to be practical. Acidic conditions Under acidic conditions, the carbonyl group of the acyl compound 1 is protonated, which activates it towards nucleophilic attack. In the second step, the protonated carbonyl (2) is attacked by a nucleophile (H–Z) to give tetrahedral intermediate 3. Proton transfer from the nucleophile (Z) to the leaving group (X) gives 4, which then collapses to eject the protonated leaving group (H–X), giving protonated carbonyl compound 5. The loss of a proton gives the substitution product, 6. Because the last step involves the loss of a proton, nucleophilic acyl substitution reactions are considered catalytic in acid. Also note that under acidic conditions, a nucleophile will typically exist in its protonated form (i.e. H–Z instead of Z–). Basic conditions Under basic conditions, a nucleophile (Nuc) attacks the carbonyl group of the acyl compound 1 to give tetrahedral alkoxide intermediate 2. The intermediate collapses and expels the leaving group (X) to give the substitution product 3. While nucleophilic acyl substitution reactions can be catalytic in base, they will not be if the leaving group is a weaker base than the nucleophile. Unlike acid-catalyzed processes, both the nucleophile and the leaving group exist as anions under basic conditions. Nucleophilic acyl substitution 16 This mechanism is supported by isotope labeling experiments. When ethyl propionate with an oxygen-18-labeled ethoxy group is treated with sodium hydroxide (NaOH), the oxygen-18 label is completely absent from propionic acid and is found exclusively in the ethanol.[2] Reactivity trends There are five main types of acyl derivatives. Acid halides are the most reactive towards nucleophiles, followed by anhydrides, esters, and amides. Carboxylate ions are essentially unreactive towards nucleophilic substitution, since they possess no leaving group. It is interesting to note the reactivity of these five classes of compounds covers a broad range; the relative reaction rates of acid chlorides and amides differ by a factor of 1013.[3] A major factor in determining the reactivity of acyl derivatives is leaving group ability, which is related to acidity. Weak bases are better leaving groups than strong bases; a species with a strong conjugate acid (e.g. hydrochloric acid) will be a better leaving group than a species with a weak conjugate acid (e.g. acetic acid). Thus, chloride ion is a better leaving group than acetate ion. The reactivity of acyl compounds towards nucleophiles decreases as the basicity of the leaving group increases, as the table shows.[4] Compound Name Acetyl chloride Structure Leaving Group pKa of Conjugate Acid -7 Acetic anhydride 4.76 Ethyl acetate 15.9 Nucleophilic acyl substitution 17 38 Acetamide Acetate anion N/a N/a Another factor that plays a role in determining the reactivity of acyl compounds is resonance. Amides exhibit two main resonance forms. Both are major contributors to the overall structure, so much so that the amide bond between the carbonyl carbon and the amide nitrogen has significant double bond The two major resonance forms of an amide. character. The energy barrier for rotation about an amide bond is 75 to 85 kJ/mol (18 to 20 kcal/mol), much larger than values observed for normal single bonds. For example, the C–C bond in ethane has an energy barrier of only 12 kJ/mol (3 kcal/mol).[3] Once a nucleophile attacks and a tetrahedral intermediate is formed, the energetically favorable resonance effect is lost. This helps explain why amides are one of the least reactive acyl derivatives.[4] Esters exhibit less resonance stabilization than amides, so the formation of a tetrahedral intermediate and subsequent loss of resonance is not as energetically unfavorable. Anhydrides experience even weaker resonance stabilization, since the resonance is split between two carbonyl groups, and are more reactive than esters and amides. In acid halides, there is very little resonance, so the energetic penalty for forming a tetrahedral intermediate is small. This helps explain why acid halides are the most reactive acyl derivatives.[4] Reactions of acyl derivatives Many nucleophilic acyl substitution reactions involve converting one acyl derivative into another. In general, conversions between acyl derivatives must proceed from a relatively reactive compound to a less reactive one in order to be practical; an acid chloride can easily be converted to an ester, but converting an ester directly to an acid chloride is essentially impossible. When converting between acyl derivatives, the product will always be more stable than the starting compound. Nucleophilic acyl substitution reactions that do not involve interconversion between acyl derivatives are also possible. For example, amides and carboxylic acids react with Grignard reagents to produce ketones. An overview of the reactions that each type of acyl derivative can participate in is presented here. Acid halides Acid halides are the most reactive acyl derivatives, and can easily be converted into any of the others. Acid halides will react with carboxylic acids to form anhydrides. If the structure of the acid and the acid chloride are different, the product is a mixed anhydride. First, the carboxylic acid attacks the acid chloride (1) to give tetrahedral intermediate 2. The tetrahedral intermediate collapses, ejecting chloride ion as the leaving group and forming oxonium species 3. Deprotonation gives the mixed anhydride, 4, and an equivalent of HCl. Nucleophilic acyl substitution 18 Alcohols and amines react with acid halides to produce esters and amides, respectively, in a reaction formally known as the Schotten-Baumann reaction.[5] Acid halides hydrolyze in the presence of water to produce carboxylic acids, but this type of reaction is rarely useful, since carboxylic acids are typically used to synthesize acid halides. Most reactions with acid halides are carried out in the presence of a non-nucleophilic base, such as pyridine, to neutralize the hydrohalic acid that is formed as a byproduct. Acid halides will react with carbon nucleophiles, such as Grignards and enolates, though mixtures of products can result. While a carbon nucleophile will react with the acid halide first to produce a ketone, the ketone is also susceptible to nucleophilic attack, and can be converted to a tertiary alcohol. For example, when benzoyl chloride (1) is treated with two equivalents of a Grignard reagent, such as methyl magnesium bromide (MeMgBr), 2-phenyl-2-propanol (3) is obtained in excellent yield. Although acetophenone (2) is an intermediate in this reaction, it is impossible to isolate because it reacts with a second equivalent of MeMgBr rapidly after being formed.[6] Unlike most other carbon nucleophiles, lithium dialkylcuprates - often called Gilman reagents - can add to acid halides just once to give ketones. The reaction between an acid halide and a Gilman reagent is not a nucleophilic acyl substitution reaction, however, and is thought to proceed via a radical pathway.[2] The Weinreb ketone synthesis can also be used to convert acid halides to ketones. In this reaction, the acid halide is first converted to an N-methoxy-N-methylamide, known as a Weinreb amide. A Weinreb amide. When a carbon nucleophile - such as a Grignard or organolithium reagent - adds to a Weinreb amide, the metal is chelated by the carbonyl and N-methoxy oxygens, preventing further nucleophilic additions.[7] In the Friedel-Crafts acylation, acid halides act as electrophiles for electrophilic aromatic substitution. A Lewis acid such as zinc chloride (ZnCl2), iron(III) chloride (FeCl3), or aluminum chloride (AlCl3) - coordinates to the halogen on the acid halide, activating the compound towards nucleophilic attack by an activated aromatic ring. For especially electron-rich aromatic rings, the reaction will proceed without a Lewis acid.[8] Anhydrides The chemistry of acid halides and anhydrides is similar. While anhydrides cannot be converted to acid halides, they can be converted to the remaining acyl derivatives. Anhydrides also participate in Schotten-Baumann-type reactions to furnish esters and amides from alcohols and amines, and water can hydrolyze anhydrides to their corresponding acids. As with acid halides, anhydrides can also react with carbon nucleophiles to furnish ketones and/or tertiary alcohols, and can participate in both the Friedel-Crafts acylation and the Weinreb ketone synthesis.[8] Unlike acid halides, however, anhydrides do not react with Gilman reagents.[2] Nucleophilic acyl substitution The reactivity of anhydrides can be increased by using a catalytic amount of N,N-dimethylaminopyridine, or DMAP. Pyridine can also be used for this purpose, and acts via a similar mechanism.[5] 19 First, DMAP (2) attacks the anhydride (1) to form a tetrahedral intermediate, which collapses to eliminate a carboxylate ion to give amide 3. This intermediate amide is more activated towards nucleophilic attack than the original anhydride, because dimethylaminopyridine is a better leaving group than a carboxylate. In the final set of steps, a nucleophile (Nuc) attacks 3 to give another tetrahedral intermediate. When this intermediate collapses to give the product 4, the pyridine group is eliminated and its aromaticity is restored - a powerful driving force, and the reason why the pyridine compound is a better leaving group than a carboxylate ion. Esters Esters are less reactive than acid halides and anhydrides. As with more reactive acyl derivatives, they can react with ammonia and primary and secondary amines to give amides, though this type of reaction is not often used, since acid halides give better yields. Esters can be converted to other esters in an process known as transesterification. Transesterification can be either acid- or base-catalyzed, and involves the reaction of an ester with an alcohol. Unfortunately, because the leaving group is also an alcohol, the forward and reverse reactions will often occur at similar rates. Using a large excess of the reactant alcohol or removing the leaving group alcohol (e.g. via distillation) will drive the forward reaction towards completion, in accordance with Le Chatelier's principle.[9] Acid-catalyzed hydrolysis of esters is also an equilibrium process - essentially the reverse of the Fischer esterification reaction. Because an alcohol (which acts as the leaving group) and water (which acts as the nucleophile) have similar pKa values, the forward and reverse reactions compete with each other. As in transesterification, using a large excess of reactant (water) or removing one of the products (the alcohol) can promote the forward reaction. Basic hydrolysis of esters, known as saponification, is not an equilibrium process; a full equivalent of base is consumed in the reaction, which produces one equivalent of alcohol and one equivalent of a carboxylate salt. The saponification of esters of fatty acids is an industrially important process, used in the production of soap.[9] Estes can undergo a variety of reactions with carbon nucleophiles. As with acid halides and anhyrides, they will react with an excess of a Grignard reagent to give tertiary alcohols. Esters also react readily with enolates. In the Claisen condensation, an enolate of one ester (1) will attack the carbonyl group of another ester (2) to give tetrahedral intermediate 3. The intermediate collapses, forcing out an alkoxide (R'O-) and producing β-keto ester 4. Nucleophilic acyl substitution 20 Crossed Claisen condensations, in which the enolate and nucleophile are different esters, are also possible. An intramolecular Claisen condensation is called a Dieckmann condensation or Dieckmann cyclization, since it can be used to form rings. Esters can also undergo condensations with ketone and aldehyde enolates to give β-dicarbonyl compounds.[10] A specific example of this is the Baker-Venkataraman rearrangement, in which an aromatic ortho-acyloxy ketone undergoes an intramolecular nucleophilic acyl substitution and subsequent rearrangement to form an aromatic β-diketone.[11] The Chan rearrangement is another example of a rearrangement resulting from an intramolecular nucleophilic acyl substitution reaction. Amides Because of their low reactivity, amides do not participate in nearly as many nucleophilic substitution reactions as other acyl derivatives do. Amides are stable to water, and are roughly 100 times more stable towards hydrolysis than esters.[3] Amides can, however, be hydrolyzed to carboxylic acids in the presence of acid or base. The stability of amide bonds has biological implications, since the amino acids that make up proteins are linked with amide bonds. Amide bonds are resistant enough to hydrolysis to maintain protein shape and structure in aqueous environments, but are susceptible enough that they can be broken when necessary.[3] Primary and secondary amides do not react favorably with carbon nucleophiles. Grignard reagents and organolithiums will act as bases rather than nucleophiles, and will simply deprotonate the amide. Tertiary amides do not experience this problem, and react with carbon nucleophiles to give ketones; the amide anion (NR2-) is a very strong base and thus a very poor leaving group, so nucleophilic attack only occurs once. When reacted with carbon nucleophiles, N,N-dimethylformamide, or DMF, can be used to introduce a formyl group.[12] Here, phenyllithium (1) attacks the carbonyl group of DMF (2), giving tetrahedral intermediate 3. Because the dimethylamide anion is a poor leaving group, the intermediate does not collapse and another nucleophilic addition does not occur. Upon acidic workup, the alkoxide is protonated to give 4, then the amine is protonated to give 5. Elimination of a neutral molecule of dimethylamine and loss of a proton give benzaldehyde, 6. Carboxylic acids Carboxylic acids are not especially reactive towards nucleophilic substitution, though they can be converted to other acyl derivatives. Converting a carboxylic acid to an amide is possible, but not straightforward. Instead of acting as a nucleophile, an amine will react as a base in the presence of a carboxylic acid to give the ammonium carboxylate salt. Heating the salt to above 100 °C will drive off water and lead to the formation of the amide. This method of synthesizing amides is industrially important, and has laboratory applications as well.[13] In the presence of a strong acid catalyst, carboxylic acids can condense to form acid anhydrides. The condensation produces water, however, which can hydrolyze the anhydride back to the starting carboxylic acids. Thus, the formation of the anhydride via Nucleophilic acyl substitution condensation is an equilibrium process. Under acid-catalyzed conditions, carboxylic acids will react with alcohols to form esters via the Fischer esterification reaction, which is also an equilibrium process. Alternatively, diazomethane can be used to convert an acid to an ester. While esterification reactions with diazomethane often give quantitative yields, diazomethane is only useful for forming methyl esters.[13] Thionyl chloride can be used to convert carboxylic acids to their corresponding acid chlorides. First, carboxylic acid 1 attacks thionyl chloride, and chloride ion leaves. The resulting oxonium ion 2 is activated towards nucleophilic attack and has a good leaving group, setting it apart from a normal carboxylic acid. In the next step, 2 is attacked by chloride ion to give tetrahedral intermediate 3, a chlorosulfite. The tetrahedral intermediate collapses with the loss of sulfur dioxide and chloride ion, giving protonated acid chloride 4. Chloride ion can remove the proton on the carbonyl group, giving the acid chloride 5 with a loss of HCl. 21 Phosphorus(III) chloride (PCl3) and phosphorus(IV) chloride (PCl5) will also convert carboxylic acids to acid chlorides, by a similar mechanism. One equivalent of PCl3 can react with three equivalents of acid, producing one equivalent of H3PO3, or phosphorus acid, in addition to the desired acid chloride. PCl5 reacts with carboxylic acids in a 1:1 ratio, and produces phosphorus(V) oxychloride, POCl3, as a byproduct. Carboxylic acids react with Grignard reagents and organolithiums to form ketones. The first equivalent of nucleophile acts as a base and deprotonates the acid. A second equivalent will attack the carbonyl group to create a geminal alkoxide dianion, which is protonated upon workup to give the hydrate of a ketone. Because most ketone hydrates are unstable relative to their corresponding ketones, the equilibrium between the two is shifted heavily in favor of the ketone. For example, the equilibrium constant for the formation of acetone hydrate from acetone is only 0.002.[14] References [1] [2] [3] [4] [5] Wade 2010, pp. 996-997. McMurry, John (1996). Organic Chemistry (4th ed.). Pacifc Grove, CA: Brooks/Cole Publishing Company. pp. 820–821. ISBN 0534238327. Carey, Francis A. (2006). Organic Chemistry (6th ed.). New York: McGraw-Hill. pp. 866–868. ISBN 0072828374. Wade 2010, pp. 998-999. Kürti, László; Barbara Czakó (2005). Strategic Applications of Named Reactions in Organic Synthesis. London: Elsevier Academic Press. p. 398. ISBN 0124297854. [6] McMurry 1996, pp. 826-827. [7] Kürti and Czakó 2005, p. 478. [8] Kürti and Czakó 2005, p. 176. [9] Wade 2010, pp. 1005-1009. [10] Carey 2006, pp. 919-924. [11] Kürti and Czakó 2005, p. 30. [12] Katritzky, Alan R.; Meth-Cohn, Otto; Rees, Charles W., eds. (1995). Comprehensive Organic Functional Group Transformations. 3 (1st ed.). Oxford: Pergamon Press. p. 90. ISBN 0080423248. [13] Wade 2010, pp. 964-965. [14] Wade 2010, p. 838. Nucleophilic acyl substitution 22 External links • Reaction of acetic anhydride with acetone in Organic Syntheses Coll. Vol. 3, p. 16; Vol. 20, p. 6 Article (http:// www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0016) Addition reaction An addition reaction, in organic chemistry, is in its simplest terms an organic reaction where two or more molecules combine to form a larger one.[1][2] Addition of chlorine to ethylene Addition reactions are limited to chemical compounds that have multiple bonds, such as molecules with carbon-carbon double bonds (alkenes), or with triple bonds (alkynes). Molecules containing carbon—hetero double bonds like carbonyl (C=O) groups, or imine (C=N) groups, can undergo addition as they too have double bond character. An addition reaction is the opposite of an elimination reaction. For instance the hydration reaction of an alkene and the dehydration of an alcohol are addition-elimination pairs. There are two main types of polar addition reactions: electrophilic addition and nucleophilic addition. Two non-polar addition reaction exists as well called free radical addition and cycloadditions. Addition reactions are also encountered in polymerizations and called addition polymerization. Addition reactions general overview. Top to bottom: electrophilic addition to alkene, nucleophilic addition of nucleophile to carbonyl and free radical addition of halide to alkene Addition-elimination reaction In the related addition-elimination reaction an addition reaction is followed by an elimination reaction. In the majority of reactions it involves addition of nucleophiles to carbonyl compounds in what is called nucleophilic acyl substitution.[3] Other addition-elimination reactions are the reaction of an aliphatic amine to an imine and an aromatic amine to a Schiff base in alkylimino-de-oxo-bisubstitution. The hydrolysis of nitriles to carboxylic acids is also a form of addition-elimination. Addition reaction 23 References [1] Morrison, R. T.; Boyd, R. N. (1983). Organic Chemistry (4th ed.). Boston: Allyn and Bacon. ISBN 0-205-05838-8. [2] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7 [3] Reaction-Map of Organic Chemistry Murov, Steven. J. Chem. Educ. 2007, 84, 1224 Abstract (http:/ / jchemed. chem. wisc. edu/ Journal/ Issues/ 2007/ Jul/ abs1224. html) Condensation reaction A condensation reaction is a chemical reaction in which two molecules or moieties (functional groups) combine to form one single molecule, together with the loss of a small molecule.[1] When this small molecule is water, it is The condensation of two amino acids to form a peptide bond (red) with expulsion of water (blue) known as a dehydration reaction; other possible small molecules lost are hydrogen chloride, methanol, or acetic acid. The word "condensation" suggests a process in which two or more things are brought "together" (Latin "con") to form something "dense", like in condensation from gaseous to liquid state of matter; this does not imply, however, that condensation reaction products have greater density than reactants. When two separate molecules react, the condensation is termed intermolecular. A simple example is the condensation of two amino acids to form the peptide bond characteristic of proteins. This reaction example is the opposite of hydrolysis, which splits a chemical entity into two parts through the action of the polar water molecule, which itself splits into hydroxide and hydrogen ions. If the union is between atoms or groups of the same molecule, the reaction is termed intramolecular condensation, and in many cases leads to ring formation. An example is the Dieckmann condensation, in which the two ester groups of a single diester molecule react with each other to lose a small alcohol molecule and form a β-ketoester product. Dieckmann condensation reaction Condensation reaction 24 Mechanism Many condensation reactions follow a nucleophilic acyl substitution or an aldol condensation reaction mechanism. Other condensations, such as the acyloin condensation are triggered by radical or single electron transfer conditions. Condensation reactions in polymer chemistry In one type of polymerization reaction, a series of condensation steps take place whereby monomers or monomer chains add to each other to form longer chains. This is termed 'condensation polymerization' or 'step-growth polymerization', and occurs for example in the synthesis of polyesters or nylons. It may be either a homopolymerization of a single monomer A-B with two different end groups that condense or a copolymerization of two co-monomers A-A and B-B. Small molecules are usually liberated in these condensation steps, in contrast to polyaddition reactions with no liberation of small molecules. In general, condensation polymers form more slowly than addition polymers, often requiring heat. They are generally lower in molecular weight. Monomers are consumed early in the reaction; the terminal functional groups remain active throughout and short chains combine to form longer chains. A high conversion rate is required to achieve high molecular weights as per Carothers' equation. Bifunctional monomers lead to linear chains (and therefore thermoplastic polymers), but, when the monomer functionality exceeds two, the product is a branched chain that may yield a thermoset polymer. Applications This type of reaction is used as a basis for the making of many important polymers, for example: nylon, polyester, and other condensation polymers and various epoxies. It is also the basis for the laboratory formation of silicates and polyphosphates. The reactions that form acid anhydrides from their constituent acids are typically condensation reactions. Many biological transformations are condensation reactions. Polypeptide synthesis, polyketide synthesis, terpene syntheses, phosphorylation, and glycosylations are a few examples of this reaction. A large number of such reactions are used in synthetic organic chemistry. Other examples include: • • • • • • • • • • • • • • Acyloin condensation Aldol condensation Benzoin condensation (this is not technically a condensation, but is called so for historical reasons)[1] Claisen condensation Claisen-Schmidt condensation Darzens condensation (glycidic ester condensation) Dieckmann condensation Guareschi-Thorpe condensation Knoevenagel condensation Michael condensation Pechmann condensation Rap-Stoermer condensation Self-condensation or symmetrical aldol condensation Ziegler condensation See named reactions Condensation reaction 25 References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "Condensation Reaction" (http:/ / goldbook. iupac. org/ C01238. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.C01238. ISBN 0-9678550-9-8. . Substitution reaction In a substitution reaction, a functional group in a particular chemical compound is replaced by another group.[1][2] In organic chemistry, the electrophilic and nucleophilic substitution reactions are of prime importance. Organic substitution reactions are classified in several main organic reaction types depending on whether the reagent that brings about the substitution is considered an electrophile or a nucleophile, whether a reactive intermediate involved in the reaction is a carbocation, a carbanion or a free radical or whether the substrate is aliphatic or aromatic. Detailed understanding of a reaction type helps to predict the product outcome in a reaction. It also is helpful for optimizing a reaction with regard to variables such as temperature and choice of solvent. A good example of a substitution reaction is the photochemical chlorination of methane forming methyl chloride. chlorination of methane by chlorine Nucleophilic substitution Nucleophilic substitution happens when the reagent is a nucleophile, which means, an atom or molecule with free electrons. A nucleophile reacts with an aliphatic substrate in a nucleophilic aliphatic substitution reaction. These substitutions can be produced by two different mechanisms: unimolecular nucleophilic substitution (SN1) and bimolecular nucleophilic substitution (SN2). The SN1 mechanism has two steps. In the first step, the leaving group departs, forming a carbocation. In the second step, the nucleophilic reagent attacks the carbocation and forms a sigma bond. This mechanism can result in either inversion or retention of configuration. An SN2 reaction has just one step. The attack of the reagent and the expulsion of the leaving group happen simultaneously. This mechanism always results in inversion of configuration. When the substrate is an aromatic compound the reaction type is nucleophilic aromatic substitution. Carboxylic acid derivatives react with nucleophiles in nucleophilic acyl substitution. This kind of reaction can be useful in preparing compouds. Substitution reaction 26 Electrophilic substitution Electrophiles are involved in electrophilic substitution reactions and particularly in electrophilic aromatic substitutions. Electrophilic aromatic substitution Electrophilic reactions to other unsaturated compounds than arenes generally lead to electrophilic addition rather than substitution. Radical substitution A radical substitution reaction involves radicals. An example is the Hunsdiecker reaction. Organometallic substitution Coupling reactions are a class of metal-catalyzed reactions involving an organometallic compound RM and an organic halide R'X that together react to a compound of the type R-R' with formation of a new carbon-carbon bond. Examples are the Heck reaction and the Ullmann reaction. Many variations exist.[3] Substituted compounds Substituted compounds are chemical compounds where one or more hydrogen atoms of a core structure have been replaced with a functional group like alkyl, hydroxy, or halogen. For example benzene is a simple aromatic ring and substituted benzenes are a heterogeneous group of chemicals with a wide spectrum of uses and properties: compound general formula general structure Benzene C6H6 Toluene C6H5-CH3 o-Xylene C6H4(-CH3)2 Substitution reaction 27 Mesitylene C6H3(-CH3)3 Phenol C6H5-OH Just a few substituted benzene compounds References [1] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7 [2] Imyanitov, Naum S. (1993). "Is This Reaction a Substitution, Oxidation-Reduction, or Transfer?". J. Chem. Educ. 70 (1): 14–16. Bibcode 1993JChEd..70...14I. doi:10.1021/ed070p14. [3] Elschenbroich, C.; Salzer, A. (1992). Organometallics: A Concise Introduction (2nd ed.). Weinheim: Wiley-VCH. ISBN 3-527-28165-7. Elimination reaction An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism.[2] The one-step mechanism is known as the E2 reaction, and the two-step mechanism is known as the E1 reaction. The numbers do not have to do with the number of steps in the mechanism, Elimination reaction of cyclohexanol to [1] but rather the kinetics of the reaction, bimolecular and unimolecular cyclohexene with sulfuric acid and heat respectively. In most organic elimination reactions, at least one hydrogen is lost to form the double bond: the unsaturation of the molecule increases. It is also possible that a molecule undergoes reductive elimination, by which the valence of an atom in the molecule decreases by two. An important class of elimination reactions are those involving alkyl halides, with good leaving groups, reacting with a Lewis base to form an alkene. Elimination may be considered the reverse of an addition reaction. When the substrate is asymmetric, regioselectivity is determined by Zaitsev's rule. E2 mechanism During the 1920s, Sir Christopher Ingold proposed a model to explain a peculiar type of chemical reaction; the E2 mechanism. E2 stands for bimolecular elimination. The fundamental elements of the reaction are as follows: • One step mechanism in which carbon-hydrogen and carbon-halogen bonds break to form a double bond. C=C Pi bond. Specificities • E2 is a one-step process of elimination with a single transition state. • Typically undergone by primary or secondary substituted alkyl halides • The reaction rate, influenced by both the alkyl halide and the base (bimolecular), is second order. • Because E2 mechanism results in formation of a pi bond, the two leaving groups (often a hydrogen and a halogen) need to be antiperiplanar. An antiperiplanar transition state has staggered conformation with lower energy than a synperiplanar transition state which is in eclipsed conformation with higher energy. The reaction mechanism involving staggered conformation is more favorable for E2 reactions (unlike E1 reactions). Elimination reaction • E2 typically uses a strong base, It needs a chemical strong enough to pull off a weakly acidic hydrogen. • In order for the pi bond to be created, the hybridization of carbons need to be lowered from sp3 to sp2. • The C-H bond is weakened in the rate determining step and therefore a primary deuterium isotope effect much larger than 1 (commonly 2-6) is observed. • E2 is very similar to the SN2 reaction mechanism. 28 An example of this type of reaction in scheme 1 is the reaction of isobutylbromide with potassium ethoxide in ethanol. The reaction products are isobutylene, ethanol and potassium bromide. E1 mechanism E1 is a model to explain a particular type of chemical elimination reaction. E1 stands for unimolecular elimination and has the following specificities. • It is a two-step process of elimination: ionization and deprotonation. • Ionization: the carbon-halogen bond breaks to give a carbocation intermediate. • Deprotonation of the carbocation. E1 typically takes place with tertiary alkyl halides, but is possible with some secondary alkyl halides. The reaction rate is influenced only by the concentration of the alkyl halide because carbocation formation is the slowest step aka rate-determining step. Therefore first-order kinetics apply (unimolecular). Reaction usually occurs in complete absence of base or presence of only a weak base (acidic conditions and high temperature). E1 reactions are in competition with SN1 reactions because they share a common carbocationic intermediate. A secondary deuterium isotope effect of slightly larger than 1 (commonly 1 - 1.5) is observed. No antiperiplanar requirement. An example is the pyrolysis of a certain sulfonate ester of menthol: • • • • • • Elimination reaction Only reaction product A results from antiperiplanar elimination, the presence of product B is an indication that an E1 mechanism is occurring.[3] • Accompanied by carbocationic rearrangement reactions 29 An example in scheme 2 is the reaction of tert-butylbromide with potassium ethoxide in ethanol. E1 eliminations happen with highly substituted alkyl halides due to 2 main reasons. • Highly substituted alkyl halides are bulky, limiting the room for the E2 one-step mechanism; therefore, the two-step E1 mechanism is favored. • Highly substituted carbocations are more stable than methyl or primary substituted cations. Such stability gives time for the two-step E1 mechanism to occur. • If SN1 and E1 pathways are competing, the E1 pathway can be favored by increasing the heat. Specific features : 1 . Rearrangement possible 2 . Independent of concentration and basicity of base E2 and E1 elimination final notes The reaction rate is influenced by halogen's reactivity; iodide and bromide being favored. Fluoride is not a good leaving group. There is a certain level of competition between elimination reaction and nucleophilic substitution. More precisely, there are competitions between E2 and SN2 and also between E1 and SN1. Substitution generally predominates and elimination occurs only during precise circumstances. Generally, elimination is favored over substitution when • • • • • steric hindrance increases basicity increases temperature increases the steric bulk of the base increases (such as in Potassium tert-butoxide) the nucleophile is poor In one study [4] the kinetic isotope effect (KIE) was determined for the gas phase reaction of several alkyl halides with the chlorate ion. In accordance with an E2 elimination the reaction with t-butyl chloride results in a KIE of 2.3. The methyl chloride reaction (only SN2 possible) on the other hand has a KIE of 0.85 consistent with a SN2 reaction because in this reaction type the C-H bonds tighten in the transition state. The KIE's for the ethyl (0.99) and isopropyl (1.72) analogues suggest competition between the two reaction modes. Elimination reaction 30 Specific elimination reactions The E1cB elimination reaction is a special type of elimination reaction involving carbanions. In an addition-elimination reaction elimination takes place after an initial addition reaction and in the Ei mechanism both substituents leave simultaneously in a syn addition. In each of these elimination reactions the reactants have specific leaving groups: • • • • • • • • • • dehydrohalogenation, leaving group a halide. the dehydration reaction is one where the leaving group is water. the Bamford-Stevens reaction with a tosylhydrazone leaving group assisted by alkoxide the Cope reaction with an amine oxide leaving group the Hofmann elimination with quaternary amine leaving group the Chugaev reaction with a methyl xanthate leaving group the Grieco elimination with a selenoxide leaving group the Shapiro reaction with a tosylhydrazone leaving group assisted by alkyllithium Hydrazone iodination with a hydrazone leaving group assisted by iodine A Grob fragmentation with degree of unsaturation increasing in one of the leaving groups. • the Kornblum–DeLaMare rearrangement (elimination over a (H)C-O(OR) bond) with an alcohol leaving group forming a ketone • the Takai olefination with two bulky chromium groups. References [1] Organic Syntheses I:185 http:/ / orgsynth. org/ orgsyn/ pdfs/ CV1P0183. pdf [2] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7 [3] Nash, J. J.; Leininger, M. A.; Keyes, K. (April 2008). "Pyrolysis of Aryl Sulfonate Esters in the Absence of Solvent: E1 or E2? A Puzzle for the Organic Laboratory". Journal of Chemical Education 85 (4): 552. Bibcode 2008JChEd..85..552N. doi:10.1021/ed085p552. [4] Stephanie M. Villano, Shuji Kato, and Veronica M. Bierbaum (2006). "Deuterium Kinetic Isotope Effects in Gas-Phase SN2 and E2 Reactions: Comparison of Experiment and Theory". J. Am. Chem. Soc. 128 (3): 736–737. doi:10.1021/ja057491d. PMID 16417360. Leaving group 31 Leaving group In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate ("tosylate", TsO−). Common neutral molecule leaving groups are water (H2O), and ammonia. In this SN2 reaction, bromide (Br−) acts as the leaving group and hydroxide (OH−) as the nucleophile. The ability of a leaving group to depart is correlated with the pKa of the conjugate acid, with lower pKa being associated with better leaving group ability. The correlation is not perfect because leaving group ability is a kinetic phenomenon, relating to a reaction's rate, whereas pKa is a thermodynamic phenomenon, describing the position of an equilibrium. Nevertheless, it is a general rule that more highly stabilized anions act as better leaving groups. Consistent with this rule, strong bases such as alkoxide (RO−), hydroxide (HO−), and amide (R2N−) are poor leaving groups. Leaving groups ordered approximately in decreasing ability to leave *R-N2+ R-OR'2+ R-OSO2C4F9 R-OSO2CF3 R-OSO2F R-OTs, R-OMs, etc. R-I R-Br R-OH2+ R-Cl R-OHR'+ diazonium salts oxonium ions nonaflates triflates fluorosulfonates tosylates, mesylates, and similar iodides bromides (Conjugate acid of an alcohol) chlorides, and acyl chloride when attached to carbonyl carbon Conjugate acid of an ether [1] R-ONO2, R-OPO(OH)2 nitrates, phosphates, and other inorganic esters R-SR'2+ R-NR'3+ R-F R-OCOR R-NH3+ tetraalkylammonium salts fluorides esters, and acid anhydrides when attached to carbonyl carbon ammonium salts Leaving group 32 R-OAr R-OH R-OR phenoxides alcohols, and carboxylic acids when attached to carbonyl carbon ethers, and esters when attached to carbonyl carbon It is uncommon for groups such as H- (hydrides), R3C- (alkyl anions, R=alkyl or H), or R2N- (amides, R=alkyl or H) to depart with a pair of electrons because of the instability of these bases. However, the requirement for a good leaving group is relaxed in the case of E1cb mechanisms, such as the elimination step in the addition-elimination mechanism of nucleophilic acyl substitutions. Here, alkoxides and even amides can act as leaving groups due to the entropic favorability of having one molecule split into two. References [1] Smith, March. Advanced Organic Chemistry 6th ed. (501-502) Reductive amination Reductive amination (also known as reductive alkylation) is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. Reaction process In this organic reaction, the amine first reacts with the carbonyl group to form a hemiaminal species, which subsequently loses one molecule of water in a reversible manner by alkylimino-de-oxo-bisubstitution, to form the imine. The equilibrium between aldehyde/ketone and imine can be shifted toward imine formation by removal of the formed water through physical or chemical means. This intermediate imine can then be isolated and reduced with a suitable reducing agent (e.g., sodium borohydride). This is indirect reductive amination. However, it is also possible to carry out the same reaction simultaneously, with the imine formation and reduction occurring concurrently. This is known as direct reductive amination, and is carried out with reducing agents that are more reactive toward protonated imines than ketones, and that are stable under moderately acidic conditions. These include sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OCOCH3)3).[1] This reaction has in recent years been performed in an aqueous environment casting doubt on the necessity of forming the imine.[2] This is because the loss of the water molecule is thermodynamically disfavoured by the presence of a large amount of water in its environment, as seen in the work of Turner et al.[3] Therefore, this suggests that in some cases the reaction proceeds via direct reduction of the hemiaminal species.[4] Reductive amination 33 Variations and related reactions This reaction is related to the Eschweiler-Clarke reaction in which amines are methylated to tertiary amines, the Leuckart-Wallach reaction with formic acid and to other amine alkylation methods as the Mannich reaction and the Petasis reaction. A classic named reaction is the Mignonac Reaction (1921) [5] involving reaction of a ketone with ammonia over a nickel catalyst for example in a synthesis of 1-phenylethylamine starting from acetophenone:[6] In industry, tertiary amines such as triethylamine and diisopropylethylamine are formed directly from ketones with a gaseous mixture of ammonia and hydrogen and a suitable catalyst. Biochemistry A step in the biosynthesis of many α-amino acids is the reductive amination of an α-ketoacid, usually by a transaminase enzyme. The process is catalyzed by pyridoxamine phosphate, which is converted into pyridoxal phosphate after the reaction. The initial step entails formation of an imine, but the hydride equivalents are supplied by a reduced pyridine to give an aldimine, which hydrolyzes to the amine.[7] The sequence from keto-acid to amino acid can be summarized as follows: HO2CC(O)R → HO2CC(=NCH2-X)R → HO2CCH(N=CH-X)R → HO2CCH(NH2)R. References [1] Ellen W. Baxter and Allen B. Reitz, Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents, Organic Reactions, 1, 59, 2002 ( Review (http:/ / www. mrw2. interscience. wiley. com/ ordb/ articles/ or059. 01/ abstract-fs. html)) [2] Shinya Sato, Takeshi Sakamoto, Etsuko Miyazawa and Yasuo Kikugawa, One-Pot Reductive Amination of Aldehydes and Ketones with α-Picoline Borane in Methanol, in Water, and in Neat Conditions, Tetrahedron, 7899-7906, 60, 2004, doi:10.1016/j.tet.2004.06.045 [3] Colin J. Dunsmore, Reuben Carr, Toni Fleming and Nicholas J. Turner, A Chemo-Enzymatic Route to Enantiomerically Pure Cyclic Tertiary Amines, J Am Chem Soc, 2224-2225, 128(7), 2006 [4] V. A. Tarasevich and N. G. Kozloz, Reductive Amination of Oxygen-Containing Organic Compounds, Russian Chemical Reviews, 68(1), 55-72, 1999 [5] Nouvelle méthodegénérale de préparation des amines à partir des aldéhydes ou des cétones. (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k3125x/ f37. chemindefer) M. Georges Mignonac, Compt. rend., 172, 223 (1921). [6] John C. Robinson, Jr. and H. R. Snyder (1955), "α-Phenylethylamine" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv3p0717), Org. Synth., ; Coll. Vol. 3: 717 [7] Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6. External links • Current methods for reductive amination (http://www.organic-chemistry.org/synthesis/C1N/amines/ reductiveamination.shtm) • Industrial Reductive amination at BASF (http://www2.basf.de/en/intermed/nbd/technology/amination. htm?id=V00-mR-a29Q3ebw20L7) Aldol condensation 34 Aldol condensation An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone. Aldol condensations are important in organic synthesis, providing a good way to form carbon–carbon bonds. The Robinson annulation reaction sequence features an aldol condensation; the Wieland-Miescher ketone product is an important starting material for many organic syntheses. Aldol condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms.[1][2][3] In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals.[4][5][6] The name aldol condensation is also commonly used, especially in biochemistry, to refer to just the first (addition) stage of the process—the aldol reaction itself—as catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small molecule. The reactions between a ketone and a carbonyl compound lacking an alpha-Hydrogen(Cross Aldol condensation) is called Claisen-Schmidt condensation. These reactions are named after two of its pioneering investigators Rainer Ludwig Claisen and J. G. Schmidt, who independently published on this topic in 1880 and 1881.[7][8][9] An example is the synthesis of dibenzylideneacetone. Aldol condensation 35 Mechanism The first part of this reaction is an aldol reaction, the second part a dehydration—an elimination reaction(Involves removal of a water molecule or an alcohol molecule). Dehydration may be accompanied by decarboxylation when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong base like potassium t-butoxide, potassium hydroxide or sodium hydride in an enolate mechanism,[10] or in an acid-catalyzed enol mechanism. : Aldol condensation 36 Condensation types It is important to distinguish the aldol condensation from other addition reactions to carbonyl compounds. • When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a Knoevenagel condensation. • In a Perkin reaction the aldehyde is aromatic and the enolate generated from an anhydride. • A Claisen condensation involves two ester compounds. • A Dieckmann condensation involves two ester groups in the same molecule and yields a cyclic molecule • A Henry reaction involves an aldehyde and an aliphatic nitro compound. • A Robinson annulation involves a α,β-unsaturated ketone and a carbonyl group, which first engage in a Michael reaction prior to the aldol condensation. • In the Guerbet reaction, an aldehyde, formed in situ from an alcohol, self-condenses to the dimerized alcohol. • In the Japp-Maitland condensation water is removed not by an elimination reaction but by a nucleophilic displacement Aldox process In industry the Aldox process developed by Royal Dutch Shell and Exxon, converts propylene and syngas directly to 2-Ethylhexanol via hydroformylation to butyraldehyde, aldol condensation to 2-ethylhexenal and finally hydrogenation.[11] In one study crotonaldehyde is directly converted to 2-ethylhexanal in a palladium / Amberlyst / supercritical carbon dioxide system [12]: Scope Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.[13] The synthetic procedure [14] is typical for this type of reactions. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in decarboxylation. Ethyl glyoxylate 2 and diethyl 2-methylglutaconate 1 react to isoprenetricarboxylic acid 3 (isoprene skeleton) with sodium ethoxide. This reaction product is very unstable with initial loss of carbon dioxide and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the carboxylic Aldol condensation group in the cis-dienoid structure.[15] 37 Occasionally an aldol condensation is buried in a multistep reaction or in catalytic cycle such as the one sketched below:[16] In this reaction an alkynal 1 is converted into a cycloalkene 7 with a ruthenium catalyst and the actual condensation takes place with intermediate 3 through 5. Support for the reaction mechanism is based on isotope labeling.[17] The reaction between menthone and anisaldehyde is complicated due to steric shielding of the ketone group. The solution is use of a strong base such as potassium hydroxide and a very polar solvent such as DMSO in the reaction below [18]: Aldol condensation 38 Due to epimerization through a common enolate ion (intermediate A) the reaction product has (R,R) cis configuration and not (R,S) trans as in the starting material. Because it is only the cis isomer that precipitates from solution this product is formed exclusively. References [1] Wade, L. G. (2005). Organic Chemistry (6th ed.). Upper Saddle River, NJ: Prentice Hall. pp. 1056–1066. ISBN 0-13-236731-9. [2] Smith, M. B.; March, J. (2001). Advanced Organic Chemistry (5th ed.). New York: Wiley Interscience. pp. 1218–1223. ISBN 0-471-58589-0. [3] Mahrwald, R. (2004). Modern Aldol Reactions. 1, 2. Weinheim, Germany: Wiley-VCH. pp. 1218–1223. ISBN 3-527-30714-1. [4] Heathcock, C. H. (1991). Additions to C-X π-Bonds, Part 2. Comprehensive Organic Synthesis. Selectivity, Strategy and Efficiency in Modern Organic Chemistry. 2. Oxford: Pergamon. pp. 133–179. ISBN 0-08-040593-2. [5] Mukaiyama T. (1982). "The Directed Aldol Reaction". Organic Reactions 28: 203–331. doi:10.1002/0471264180.or028.03. [6] Paterson, I. (1988). "New Asymmetric Aldol Methodology Using Boron Enolates". Chemistry and Industry (London: Paterson Group) 12: 390–394. [7] Claisen, L.; Claparède, A. (1881). "Condensationen von Ketonen mit Aldehyden" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k906939/ f871. chemindefer). Berichte der Deutschen Chemischen Gesellschaft 14 (1): 2460–2468. doi:10.1002/cber.188101402192. . [8] Schmidt, J. G. (1881). "Ueber die Einwirkung von Aceton auf Furfurol und auf Bittermandelöl in Gegenwart von Alkalilauge" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k90692z/ f1461. chemindefer). Berichte der Deutschen Chemischen Gesellschaft 14 (1): 1459–1461. doi:10.1002/cber.188101401306. . [9] March, J. (1985). Advanced Organic Chemistry: Reactions, Mechanisms and Structure (3rd ed.). Wiley Interscience. ISBN 0-471-85472-7. [10] Nielsen, A. T.; Houlihan., W. J. (1968). "The Aldol Condensation". Organic Reactions 16: 1–438. doi:10.1002/0471264180.or016.01. [11] For example BG 881979 (http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=BG881979) [12] Seki, T.; Grunwaldt, J.-D.; Baiker, A. (2007). "Continuous catalytic "one-pot" multi-step synthesis of 2-ethylhexanal from crotonaldehyde". Chemical Communications 2007 (34): 3562–3564. doi:10.1039/b710129e. [13] Badía, C.; Castro, J. M.; Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Nogueras, M.; Sánchez, A. (2004). "(E)-6-(2,2,3-Trimethyl-cyclopent-3-enyl)-hex-4-en-3-one" (http:/ / www. mdpi. com/ 1422-8599/ 2004/ 1/ M388/ pdf) (pdf). Molbank 2004 (1): M388. doi:10.3390/M388. . [14] Ethyl 2-methylacetoacetate (2) is added to a stirred solution of sodium hydride in dioxane. Then campholenic aldehyde (1) is added and the mixture refluxed for 15 h. Then 2N hydrochloric acid is added and the mixture extracted with diethyl ether. The combined organic layers are washed with 2N hydrochloric acid, saturated sodium bicarbonate and brine. The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield a residue that was purified by vacuum distillation to give 3 (58%). [15] Goren, M. B.; Sokoloski, E. A.; Fales, H. M. (2005). "2-Methyl-(1Z,3E)-butadiene-1,3,4-tricarboxylic Acid, "Isoprenetricarboxylic Acid"". Journal of Organic Chemistry 70 (18): 7429–7431. doi:10.1021/jo0507892. PMID 16122270. Aldol condensation [16] Varela, J. A.; Gonzalez-Rodriguez, C.; Rubin, S. G.; Castedo, L.; Saa, C. (2006). "Ru-Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes". Journal of the American Chemical Society 128 (30): 9576–9577. doi:10.1021/ja0610434. PMID 16866480. [17] The ruthenium catalyst, [CpRu(CH3CN)3]PF6, has a cyclopentadienyl ligand, three acetonitrile ligands and a phosphorus hexafluoride counterion; the acidic proton in the solvent (acetic acid) is replaced by deuterium for isotopic labeling. Reaction conditions: 90°C, 24 hrs. 80% chemical yield. The first step is formation of the Transition metal carbene complex 2. Acetic acid adds to this intermediate in a nucleophilic addition to form enolate 3 followed by aldol condensation to 5 at which stage a molecule of carbon monoxide is lost to 6. The final step is reductive elimination to form the cycloalkene. [18] Vashchenko, V.; Kutulya, L.; Krivoshey, A. (2007). "Simple and Effective Protocol for Claisen-Schmidt Condensation of Hindered Cyclic Ketones with Aromatic Aldehydes". Synthesis 2007 (14): 2125–2134. doi:10.1055/s-2007-983746. 39 SN1 reaction The SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic substitution and the "1" represents the fact that the rate-determining step is unimolecular.[1][2] Thus, the rate equation is often shown as having first-order dependence on electrophile and zero-order dependence on nucleophile. This relationship holds for situations where the amount of nucleophile is much greater than that of the carbocation intermediate. Instead, the rate equation may be more accurately described using steady-state kinetics. The reaction involves a carbocation intermediate and is commonly seen in reactions of secondary or tertiary alkyl halides under strongly basic conditions or, under strongly acidic conditions, with secondary or tertiary alcohols. With primary alkyl halides, the alternative SN2 reaction occurs. In inorganic chemistry, the SN1 reaction is often known as the dissociative mechanism. This dissociation pathway is well-described by the cis effect. A reaction mechanism was first proposed by Christopher Ingold et al. in 1940.[3] This reaction does not take account much on the strength of the nucleophile unlike the SN2 mechanism. Mechanism An example of a reaction taking place with an SN1 reaction mechanism is the hydrolysis of tert-butyl bromide with water forming tert-butanol: This SN1 reaction takes place in three steps: • Formation of a tert-butyl carbocation by separation of a leaving group (a bromide anion) from the carbon atom: this step is slow and reversible.[4] • Nucleophilic attack: the carbocation reacts with the nucleophile. If the nucleophile is a neutral molecule (i.e. a solvent) a third step is required to complete the reaction. When the solvent is water, the intermediate is an oxonium ion. This reaction step is fast. SN1 reaction 40 • Deprotonation: Removal of a proton on the protonated nucleophile by water acting as a base forming the alcohol and a hydronium ion. This reaction step is fast. Scope of the reaction The SN1 mechanism tends to dominate when the central carbon atom is surrounded by bulky groups because such groups sterically hinder the SN2 reaction. Additionally, bulky substituents on the central carbon increase the rate of carbocation formation because of the relief of steric strain that occurs. The resultant carbocation is also stabilized by both inductive stabilization and hyperconjugation from attached alkyl groups. The Hammond-Leffler postulate suggests that this too will increase the rate of carbocation formation. The SN1 mechanism therefore dominates in reactions at tertiary alkyl centers and is further observed at secondary alkyl centers in the presence of weak nucleophiles. An example of a reaction proceeding in a SN1 fashion is the synthesis of 2,5-dichloro-2,5-dimethylhexane from the corresponding diol with concentrated hydrochloric acid [5]: As the alpha and beta substitutions increase with respect to leaving groups the reaction is diverted from SN2 to SN1. Stereochemistry The carbocation intermediate formed in the reaction's rate limiting step is an sp2 hybridized carbon with trigonal planar molecular geometry. This allows two different avenues for the nucleophilic attack, one on either side of the planar molecule. If neither avenue is preferentially favored, these two avenues occur equally, yielding a racemic mix of enantiomers if the reaction takes place at a stereocenter.[6] This is illustrated below in the SN1 reaction of S-3-chloro-3-methylhexane with an iodide ion, which yields a racemic mixture of 3-iodo-3-methylhexane: SN1 reaction 41 However, an excess of one stereoisomer can be observed, as the leaving group can remain in proximity to the carbocation intermediate for a short time and block nucleophilic attack. This stands in contrast to the SN2 mechanism, which is a stereospecific mechanism where stereochemistry is always inverted as the nucleophile comes in from the rear side of the leaving group. Side reactions Two common side reactions are elimination reactions and carbocation rearrangement. If the reaction is performed under warm or hot conditions (which favor an increase in entropy), E1 elimination is likely to predominate, leading to formation of an alkene. At lower temperatures, SN1 and E1 reactions are competitive reactions and it becomes difficult to favor one over the other. Even if the reaction is performed cold, some alkene may be formed. If an attempt is made to perform an SN1 reaction using a strongly basic nucleophile such as hydroxide or methoxide ion, the alkene will again be formed, this time via an E2 elimination. This will be especially true if the reaction is heated. Finally, if the carbocation intermediate can rearrange to a more stable carbocation, it will give a product derived from the more stable carbocation rather than the simple substitution product. Solvent effects Since the SN1 reaction involves formation of an unstable carbocation intermediate in the rate-determining step, anything that can facilitate this will speed up the reaction. The normal solvents of choice are both polar (to stabilize ionic intermediates in general) and protic (to solvate the leaving group in particular). Typical polar protic solvents include water and alcohols, which will also act as nucleophiles and the process is known as solvolysis. The Y scale correlates solvolysis reaction rates of any solvent (k) with that of a standard solvent (80% v/v ethanol/water) (k0) through with m a reactant constant (m = 1 for tert-butyl chloride) and Y a solvent parameter.[7] For example 100% ethanol gives Y = −2.3, 50% ethanol in water Y = +1.65 and 15% concentration Y = +3.2.[8] SN1 reaction 42 References [1] L. G. Wade, Jr., Organic Chemistry, 6th ed., Pearson/Prentice Hall, Upper Saddle River, New Jersey, USA, 2005 [2] March, J. (1992). Advanced Organic Chemistry (4th ed.). New York: Wiley. ISBN 0-471-60180-2. [3] Leslie C. Bateman, Mervyn G. Church, Edward D. Hughes, Christopher K. Ingold and Nazeer Ahmed Taher (1940). "188. Mechanism of substitution at a saturated carbon atom. Part XXIII. A kinetic demonstration of the unimolecular solvolysis of alkyl halides. (Section E) a general discussion". Journal of the Chemical Society (Resumed): 979. doi:10.1039/JR9400000979. [4] Peters, K. S. (2007). "Nature of Dynamic Processes Associated with the SN1 Reaction Mechanism". Chem. Rev. 107 (3): 859–873. doi:10.1021/cr068021k. PMID 17319730. [5] Synthesis of 2,5-Dichloro-2,5-dimethylhexane by an SN1 Reaction Carl E. Wagner and Pamela A. Marshall , J. Chem. Educ., 2010, 87 (1), pp 81–83 doi:10.1021/ed8000057 [6] Sorrell, Thomas N. "Organic Chemistry, 2nd Edition" University Science Books, 2006 [7] Ernest Grunwald and S. Winstein (1948). "The Correlation of Solvolysis Rates". J. Am. Chem. Soc. 70 (2): 846. doi:10.1021/ja01182a117. [8] Arnold H. Fainberg and S. Winstein (1956). "Correlation of Solvolysis Rates. III.1 t-Butyl Chloride in a Wide Range of Solvent Mixtures". J. Am. Chem. Soc. 78 (12): 2770. doi:10.1021/ja01593a033. Further reading • Electrophilic Bimolecular Substitution as an Alternative to Nucleophilic Monomolecular Substitution in Inorganic and Organic Chemistry / N.S.Imyanitov. J. Gen. Chem. USSR (Engl. Transl.) 1990; 60 (3); 417-419. • Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov. SciTecLibrary (http://sciteclibrary.ru/ eng/catalog/pages/9330.html) External links • Diagrams (http://www.chemhelper.com/sn1.html): Frostburg State University • Exercise (http://www.usm.maine.edu/~newton/Chy251_253/Lectures/Sn1/Sn1FS.html): the University of Maine • Study Organic Chemistry (http://www.study-organic-chemistry.com), Resources for Success in Organic Chemistry SN2 reaction 43 SN2 reaction The SN2 reaction (also known as bimolecular nucleophilic substitution) is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step. Since two reacting species are involved in the slow, rate-determining step of the reaction, this leads to the name bimolecular nucleophilic substitution, or SN2. Among inorganic chemists, the SN2 reaction is often known as the interchange mechanism. Reaction mechanism The reaction most often occurs at an aliphatic sp3 carbon center with an electronegative, stable leaving group attached to it - 'X' - frequently a halide atom. The breaking of the C-X bond and the formation of the new C-Nu bond occur simultaneously to form a transition state in which the carbon under nucleophilic attack is pentacoordinate, and approximately sp2 hybridised. The nucleophile attacks the carbon at 180° to the leaving group, since this provides the best overlap between the nucleophile's lone pair and the C-X σ* antibonding orbital. The leaving group is then pushed off the opposite side and the product is formed. If the substrate under nucleophilic attack is chiral, this can lead, although not necessarily, to an inversion of stereochemistry called a Walden inversion (the nucleophile attacks the electrophilic carbon center, inverting the tetrahedron, much like an umbrella turning inside out in the wind). In an example of the SN2 reaction, the attack of OH− (the nucleophile) on a bromoethane (the electrophile) results in ethanol, with bromide ejected as the leaving group: Ball-and-stick representation of the SN2 reaction of CH3SH with CH3I Structure of the SN2 transition state SN2 reaction of bromoethane with hydroxide ion. SN2 attack occurs if the backside route of attack is not sterically hindered by substituents on the substrate. Therefore this mechanism usually occurs at an unhindered primary carbon centre. If there is steric crowding on the substrate near the leaving group, such as at a tertiary carbon centre, the substitution will involve an SN1 rather than an SN2 mechanism, (an SN1 would also be more likely in this case because a sufficiently stable carbocation intermediary could be formed.) In coordination chemistry, associative substitution proceeds via a similar mechanism as SN2. SN2 reaction 44 Factors affecting the rate of the reaction Four factors affect the rate of the reaction: • Substrate. The substrate plays the most important part in determining the rate of the reaction. This is because the nucleophile attacks from the back of the substrate, thus breaking the carbon-leaving group bond and forming the carbon-nucleophile bond. Therefore, to maximise the rate of the SN2 reaction, the back of the substrate must be as unhindered as possible. Overall, this means that methyl and primary substrates react the fastest, followed by secondary substrates. Tertiary substrates do not participate in SN2 reactions, because of steric hindrance. Moreover, compounds like '1-chloro 1-ethene' too do not undergo nucleophillic substitution easily because the carbon to chlorine bond is said to be of partial double bond character, thus is harder to break. Another factor leading to an SN2 reaction due to substrate involves the stability and ease by which the carbocation is formed after removing the leaving group. This means the more stable the carbocation is after removing the leaving group, the more likely it is an SN1 reaction will occur instead of an SN2. Among the stabilization methods to be considered are: resonance stabilization, hyper-conjugative stabilization, inductive effect stabilization, or the formation of an aromatic ring molecule (as in the case of 7-chloro cyclohept-1, 3, 5-triene, as it will form a tropolium carbocation which is aromatic). • Nucleophile. Like the substrate, steric hindrance affects the nucleophile's strength. The methoxide anion, for example, is both a strong base and nucleophile because it is a methyl nucleophile, and is thus very much unhindered. tert-Butoxide, on the other hand, is a strong base, but a poor nucleophile, because of its three methyl groups hindering its approach to the carbon. Nucleophile strength is also affected by charge and electronegativity: nucleophilicity increases with increasing negative charge and decreasing electronegativity. For example, OH- is a better nucleophile than water, and I- is a better nucleophile than Br- (in polar protic solvents). In a polar aprotic solvent, nucleophilicity increases up a column of the periodic table as there is no hydrogen bonding between the solvent and nucleophile; in this case nucleophilicity mirrors basicity. I- would therefore be a weaker nucleophile than Br- because it is a weaker base. Verdict - A strong/anionic nucleophile always favours SN2 manner of nucleophillic substitution. • Solvent. The solvent affects the rate of reaction because solvents may or may not surround a nucleophile, thus hindering or not hindering its approach to the carbon atom. Polar aprotic solvents, like tetrahydrofuran, are better solvents for this reaction than polar protic solvents because polar protic solvents will be solvated by the solvent hydrogen bonding to the nucleophile and thus hindering it from attacking the carbon with the leaving group. A polar aprotic solvent with low dielectric constant or a hindered dipole end will favour SN2 manner of nucleophillic substitution reaction. Examples-DMSO,DMF,acetone etc. In polar aprotic solvent, nucleophilicity parallels basicity. • Leaving group. The leaving group affects the rate of reaction because the more stable it is, the more likely that it will take the two electrons of its carbon-leaving group bond with it when the nucleophile attacks the carbon. Therefore, the weaker the leaving group is as a conjugate base, and thus the stronger its corresponding acid, the better the leaving group. Examples of good leaving groups are therefore the halides (except fluoride) and tosylate, whereas HO- and H2N- are not. SN2 reaction 45 Reaction kinetics The rate of an SN2 reaction is second order, as the rate-determining step depends on the nucleophile concentration, [Nu−] as well as the concentration of substrate, [RX]. r = k[RX][Nu−] This is a key difference between the SN1 and SN2 mechanisms. In the SN1 reaction the nucleophile attacks after the rate-limiting step is over, whereas in SN2 the nucleophile forces off the leaving group in the limiting step. In other words, the rate of SN1 reactions depend only on the concentration of the substrate while the SN2 reaction rate depends on the concentration of both the substrate and nucleophile. In cases where both mechanisms are possible (for example at a secondary carbon centre), the mechanism depends on solvent, temperature, concentration of the nucleophile or on the leaving group. SN2 reactions are generally favored in primary alkyl halides or secondary alkyl halides with an aprotic solvent. They occur at a negligible rate in tertiary alkyl halides due to steric hindrance. It is important to understand that SN2 and SN1 are two extremes of a sliding scale of reactions, it is possible to find many reactions which exhibit both SN2 and SN1 character in their mechanisms. For instance, it is possible to get a contact ion pairs formed from an alkyl halide in which the ions are not fully separated. When these undergo substitution the stereochemistry will be inverted (as in SN2) for many of the reacting molecules but a few may show retention of configuration. Sn2 reactions are more common than Sn1 reactions . E2 competition A common side reaction taking place with SN2 reactions is E2 elimination: the incoming anion can act as a base rather than as a nucleophile, abstracting a proton and leading to formation of the alkene. This is more common when the incoming ion is sterically hindered in which case abstracting a proton is much easier. This effect can be demonstrated in the gas-phase reaction between a sulfonate and a simple alkyl bromide taking place inside a mass spectrometer:[1][2] With ethyl bromide, the reaction product is predominantly the substitution product. As steric hindrance around the electrophilic center increases, as with isobutyl bromide, substitution is disfavored and elimination is the predominant reaction. Other factors favoring elimination are the strength of the base. With the less basic benzoate substrate, isopropyl bromide reacts with 55% substitution. In general, gas phase reactions and solution phase reactions of this type follow the same trends, even though in the first, solvent effects are eliminated. SN2 reaction 46 Roundabout mechanism A development attracting attention in 2008 concerns a SN2 roundabout mechanism observed in a gas-phase reaction between chloride ions and methyl iodide with a special technique called crossed molecular beam imaging. When the chloride ions have sufficient velocity, the energy of the resulting iodide ions after the collision is much lower than expected, and it is theorized that energy is lost as a result of a full roundabout of the methyl group around the iodine atom before the actual displacement takes place.[3][4][5] References [1] Gas Phase Studies of the Competition between Substitution and Elimination Reactions Scott Gronert Acc. Chem. Res.; 2003; 36(11) pp 848 857; (Article) doi:10.1021/ar020042n [2] The technique used is electrospray ionization and because it requires charged reaction products for detection the nucleophile is fitted with an additional sulfonate anionic group, non-reactive and well separated from the other anion. The product ratio of substitution and elimination product can be measured from the intensity their relative molecular ions [3] Imaging Nucleophilic Substitution Dynamics J. Mikosch, S. Trippel, C. Eichhorn, R. Otto, U. Lourderaj, J. X. Zhang, W. L. Hase, M. Weidemüller, and R. Wester Science 11 January 2008 319: 183-186 doi: 10.1126/science.1150238 (in Reports) [4] PERSPECTIVES CHEMISTRY: Not So Simple John I. Brauman (11 January 2008) Science 319 (5860), 168. doi:10.1126/science.1152387 [5] Surprise From SN2 Snapshots Ion velocity measurements unveil additional unforeseen mechanism Carmen Drahl Chemical & Engineering News January 14, 2008 Volume 86, Number 2 p. 9 http:/ / pubs. acs. org/ cen/ news/ 86/ i02/ 8602notw1. html , video included Alkylimino-de-oxo-bisubstitution Alkylimino-de-oxo-bisubstitution in organic chemistry is the organic reaction of carbonyl compounds with amines to imines.[2] The reaction name is based on the IUPAC Nomenclature for Transformations. The reaction is acid catalyzed and the reaction type is nucleophilic addition of the amine to the carbonyl compound followed by transfer of a proton from nitrogen to oxygen to a stable carbinolamine. With primary amines water is lost in an elimination reaction to an imine. With aryl amines especially stable Schiff bases are formed. Reaction of cyclohexylamine with acetaldehyde forming an imine. Sodium sulfate [1] removes water Reaction mechanism The reaction steps are reversible reactions and the reaction is driven to completion by removal of water by azeotropic distillation, molecular sieves or titanium tetrachloride. Primary amines react through an unstable hemiaminal intermediate which then splits of water. Alkylimino-de-oxo-bisubstitution Secondary amines do not lose water easily because they do not have a proton available and instead they often react further to an aminal: 47 or when an α-carbonyl proton is present to an enamine: In acidic environment the reaction product is an iminium salt by loss of water. This reaction type is found in many Heterocycle preparations for example the Povarov reaction and the Friedländer-synthesis to quinolines. Because both components are so reactive a molecule does not carry an aldehyde and an amine group at the same time unless the amine group is fitted with a protective group. As a further demonstration of reactivity one study [3] explored the properties of an α-formyl aziridine which was found to dimerize as an oxazolidine on formation from the corresponding ester by organic reduction with DIBAL [4]: Iminium ion formation is prohibited in this molecule because the azirine group and the formyl group are said to be orthogonal. Alkylimino-de-oxo-bisubstitution 48 Scope In one potential application [5] a particular electron-rich cinnamaldehyde is able to differentiate between cysteine and homocysteine. With cysteine, a buffered water solution of the aldehyde changes from yellow to colorless due to a secondary ring closing reaction of the imine. Homocysteine is unable to give ring closure and the color does not change. References [1] Organic Syntheses, Coll. Vol. 6, p.901 (1988); Vol. 50, p.66 (1970). Article (http:/ / www. orgsyn. org/ orgsyn/ prep. asp?prep=cv6p0901) [2] March Jerry; (1985). Advanced Organic Chemistry reactions, mechanisms and structure (3rd ed.). New York: John Wiley & Sons, inc. ISBN 0-471-85472-7 [3] Readily Available Unprotected Amino Aldehydes Ryan Hili and Andrei K. Yudin J. Am. Chem. Soc.; 2006; 128(46) pp 14772 - 14773; (Communication) doi:10.1021/ja065898s [4] The dimer reacts with sodium borohydride through the monomer it is in equilibrium with to the aziridine alcohol [5] Detection of Homocysteine and Cysteine Weihua Wang, Oleksandr Rusin, Xiangyang Xu, Kyu Kwang Kim, Jorge O. Escobedo, Sayo O. Fakayode, Kristin A. Fletcher, Mark Lowry, Corin M. Schowalter, Candace M. Lawrence, Frank R. Fronczek, Isiah M. Warner, and Robert M. Strongin J. Am. Chem. Soc.; 2005; 127(45) pp 15949 - 15958; (Article) doi:10.1021/ja054962n External links • reaction of benzaldehyde and methylamine in Organic Syntheses Coll. Vol. 10, p. 312 (2004); Vol. 76, p. 23 (1999). Online article (http://www.orgsyn.org/orgsyn/prep.asp?prep=v76p0023) • reaction of methylbenzylamine with 2-methylcyclohexanone in Organic Syntheses, Coll. Vol. 9, p. 610 (1998); Vol. 70, p. 35 (1992). Article (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv9p0610) • Reaction of acetophenone with methylamine in Organic Syntheses, Coll. Vol. 6, p. 818 (1988); Vol. 54, p. 93 (1974). Article (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0818) • Chiral Schiff base in Molbank 2005, M435 Article (http://www.mdpi.net/molbank/molbank2005/m435.htm) SchottenBaumann reaction 49 Schotten–Baumann reaction The Schotten–Baumann reaction is a method to synthesise amides from amines and acid chlorides: Sometimes the name for this reaction An example of a Schotten-Baumann reaction. Benzylamine reacts with acetyl chloride is also used to indicate the reaction under Schotten-Baumann conditions to form N-benzyl acetamide. between an acid chloride and a alcohol to form an ester. The reaction was first described in 1883 by German chemists Carl Schotten and Eugen Baumann.[1][2][3][4] Reaction mechanism In the first step an acid chloride reacts with an amine so that an amide is formed, together with a proton and a chloride ion. Addition of a base is required to absorb this acidic proton, or the reaction will not proceed. Often, an aqueous solution of a base is slowly added to the reaction mixture. The name "Schotten-Baumann reaction conditions" is often used to indicate the use of a two-phase solvent system, consisting of water and an organic solvent. The base within the water phase neutralizes the acid, generated in the reaction, while the starting materials and product remain in the organic phase, often dichloromethane or diethyl ether. Applications The Schotten–Baumann reaction or reaction conditions are widely used today in organic chemistry. Examples include: • • • • synthesis of N-vanillyl nonanamide, also known as synthetic capsaicin synthesis of benzamide from benzoyl chloride and a phenethylamine acylation of a benzylamine with acetyl chloride (acetic anhydride is an alternative) in the Fischer peptide synthesis (Hermann Emil Fischer, 1903)[5][6] an α-chloro acid chloride is condensed with the ester of an amino acid. The ester is then hydrolyzed and the acid converted to the acid chloride enabling the extension of the peptide chain by another unit. In a final step the chloride atom is replaced by an amino group completing the peptide synthesis. References [1] W Pötsch. Lexikon bedeutender Chemiker (VEB Bibliographisches Institut Leipzig, 1989) (ISBN 3-323-00185) [2] M B Smith, J March. March's Advanced Organic Chemistry (Wiley, 2001) (ISBN 0-471-58589-0) [3] Schotten, C. (1884). "Ueber die Oxydation des Piperidins". Berichte der deutschen chemischen Gesellschaft 17: 2544. doi:10.1002/cber.188401702178. [4] Baumann, E. (1886). "Ueber eine einfache Methode der Darstellung von Benzoësäureäthern". Berichte der deutschen chemischen Gesellschaft 19: 3218. doi:10.1002/cber.188601902348. [5] Emil Fischer (1903). "Synthese von Polypeptiden". Berichte der deutschen chemischen Gesellschaft 36 (3): 2982–2992. doi:10.1002/cber.19030360356. [6] Fischer Peptide Synthesis (http:/ / www. drugfuture. com/ OrganicNameReactions/ ONR135. htm) Mannich reaction 50 Mannich reaction The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base.[1] Reactions between aldimines and α-methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes. The reaction is named after chemist Carl Mannich.[2][3] The Mannich reaction is an example of nucleophilic addition of an amine to a carbonyl group followed by dehydration to the Schiff base. The Schiff base is an electrophile which reacts in the second step in a electrophilic addition with a compound containing an acidic proton(which is, or had become an enol). The Mannich reaction is also considered a condensation reaction. In the Mannich reaction, ammonia or primary or secondary amines are employed for the activation of formaldehyde. Tertiary amines lack an N-H proton to form the intermediate imine. α-CH-acidic compounds (nucleophiles) include carbonyl compounds, nitriles, acetylenes, aliphatic nitro compounds, α-alkyl-pyridines or imines. It is also possible to use activated phenyl groups and electron-rich heterocycles such as furan, pyrrole, and thiophene. Indole is a particularly active substrate; the reaction provides gramine derivatives. Reaction mechanism The mechanism of the Mannich reaction starts with the formation of an iminium ion from the amine and the formaldehyde. The compound with the carbonyl functional group (in this case a ketone) can tautomerize to the enol form, after which it can attack the iminium ion. Mannich reaction 51 Asymmetric Mannich reactions Progress has been made towards asymmetric Mannich reactions. When properly functionalized the newly formed ethylene bridge in the Mannich adduct has two prochiral centers giving rise to two diastereomeric pairs of enantiomers. The first asymmetric Mannich reaction with an unmodified aldehyde was carried with (S)-proline as a naturally occurring chiral catalyst.[4] The reaction taking place is between a simple aldehyde such as propionaldehyde and an imine derived from ethyl glyoxylate and p-methoxyaniline (PMP = paramethoxphenyl) catalyzed by (S)-proline in dioxane at room temperature. The reaction product is diastereoselective with a preference for the syn-Mannich reaction 3:1 when the alkyl substituent on the aldehyde is a methyl group or 19:1 when the alkyl group the much larger pentyl group. Of the two possible syn adducts (S,S) or (R,R) the reaction is also enantioselective with a preference for the (S,S) adduct with enantiomeric excess larger than 99%. This stereoselectivity is explained in the scheme below. Mannich reaction 52 Proline enters a catalytic cycle by reacting with the aldehyde to form an enamine. The two reactants (imine and enamine) line up for the Mannich reaction with Si facial attack of the imine by the Si-face of the enamine-aldehyde. Relief of steric strain dictates that the alkyl residue R of the enamine and the imine group are antiperiplanar on approach which locks in the syn mode of addition. The enantioselectivity is further controlled by hydrogen bonding between the proline carboxylic acid group and the imine. The transition state for the addition is a nine-membered ring with chair conformation with partial single bonds and double bonds. The proline group is converted back to the aldehyde and a single S,S isomer is formed. By modification of the proline catalyst to it is also possible to obtain anti-Mannich adducts.[5] Mannich reaction 53 An additional methyl group attached to proline forces a specific enamine approach and the transition state now is a 10-membered ring with addition in anti-mode. The diastereoselectivity is at least anti:syn 95:5 regardless of alkyl group size and the S,R enantiomer is preferred with at least 97% ee. Applications The Mannich-Reaction is employed in the organic synthesis of natural compounds such as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone). Other applications are in agro chemicals such as plant growth regulators,[6] paint- and polymer chemistry, catalysts and main mechanism of formalin tissue crosslinking. The Mannich reaction is also used in the synthesis of medicinal compounds e.g. rolitetracycline (Mannich base of tetracycline), fluoxetine (antidepressant), tramadol, and tolmetin (anti-inflammatory drug). References [1] Original translated from German Wiki [2] Mannich, C.; Krösche, W. (1912). "Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin". Archiv der Pharmazie 250: 647–667. doi:10.1002/ardp.19122500151. [3] Blicke, F. F. Org. React. 1942, 1. [4] Córdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas Cf, 3. (2002). "A highly enantioselective route to either enantiomer of both alphaand beta-amino acid derivatives". Journal of the American Chemical Society 124 (9): 1866–1867. doi:10.1021/ja017833p. PMID 11866595. [5] Mitsumori, S.; Zhang, H.; Ha-Yeon Cheong, P.; Houk, K.; Tanaka, F.; Barbas Cf, 3. (2006). "Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid". Journal of the American Chemical Society 128 (4): 1040–1041. doi:10.1021/ja056984f. PMC 2532695. PMID 16433496. [6] da Rosa F. A. F., Rebelo R. A., Nascimento II M. G. (2003). "Synthesis of new indolecarboxylic acids related to the plant hormone indoleacetic acid" (http:/ / www. scielo. br/ scielo. php?script=sci_arttext& pid=S0103-50532003000100003). Journal of the Brazilian Chemical Society 14: 11. doi:10.1590/S0103-50532003000100003. . Mannich reaction 54 External links • "Mechanism In Motion: Mannich reaction" (http://www.youtube.com/watch?v=HUVQ3SNz7m0). Edman degradation Edman degradation, developed by Pehr Edman, is a method of sequencing amino acids in a peptide.[1] In this method, the amino-terminal residue is labeled and cleaved from the peptide without disrupting the peptide bonds between other amino acid residues. Mechanism Phenylisothiocyanate is reacted with an uncharged terminal amino group, under mildly alkaline conditions, to form a cyclical phenylthiocarbamoyl derivative. Then, under acidic conditions, this derivative of the terminal amino acid is cleaved as a thiazolinone derivative. The thiazolinone amino acid is then selectively extracted into an organic solvent and treated with acid to form the more stable phenylthiohydantoin (PTH)- amino acid derivative that can be identified by using chromatography or electrophoresis. This procedure can then be repeated again to identify the next amino acid. A major drawback to this technique is that the peptides being sequenced in this manner cannot have more than 50 to 60 residues (and in practice, under 30). The peptide length is limited due to the cyclical derivatization not always going to completion. The derivatization problem can be resolved by cleaving large peptides into smaller peptides before proceeding with the reaction. It is able to accurately sequence up to 30 amino acids with modern machines capable of over 99% efficiency per amino acid. An advantage of the Edman degradation is that it only uses 10 - 100 pico-moles of peptide for the sequencing process. Edman degradation reaction is automated to speed up the process.[2] Edman degradation 55 Limitations Because the Edman degradation proceeds from the N-terminus of the protein, it will not work if the N-terminal amino acid has been chemically modified or if it is concealed within the body of the protein. It also requires the use of either guesswork or a separate procedure to determine the positions of disulfide bridges, and concentrations of 1 picomole of peptide or above for discernible results. Coupled analysis Following 2D SDS PAGE the proteins can be transferred to a polyvinylidene difluoride (PVDF) blotting membrane for further analysis. Edman degradations can be performed directly from a PVDF membrane. N-terminal residue sequencing resulting in five to ten amino acid may be sufficient to identify a Protein of Interest (POI). References [1] Edman, P.; Högfeldt, Erik; Sillén, Lars Gunnar; Kinell, Per-Olof (1950). "Method for determination of the amino acid sequence in peptides". Acta Chem. Scand. 4: 283–293. doi:10.3891/acta.chem.scand.04-0283. [2] Niall HD (1973). "Automated Edman degradation: the protein sequenator". Meth. Enzymol.. Methods in Enzymology 27: 942–1010. doi:10.1016/S0076-6879(73)27039-8. ISBN 978-0-12-181890-6. PMID 4773306. Carbocation A carbocation (  /ˌkɑrbɵˈkætaɪ.ɒn/) is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability (octet rule). Therefore carbocations are often reactive, seeking to fill the octet of valence electrons as well as regain a neutral charge. One could reasonably assume a carbocation to have sp3 hybridization with an empty sp3 orbital giving positive charge. However, the reactivity of a carbocation more closely resembles sp2 hybridization with a trigonal planar molecular geometry. An example is the methyl cation, CH3+. Carbenium ion of methane Definitions A carbocation was previously often called a carbonium ion but questions arose on the exact meaning.[1] In present day chemistry a carbocation is any positively charged carbon atom. Two special types have been suggested: carbenium ions (protonated carbenes, hence the name) are trivalent and carbonium ions (protonated alkanes) are pentavalent or hexavalent. University level textbooks only discuss carbocations as if they are carbenium ions,[2] or discuss carbocations with a fleeting reference to the older phrase of carbonium ion[3] or carbenium and carbonium ions.[4] One textbook to this day clings on to the older name of carbonium ion for carbenium ion and reserves the phrase hypervalent carbenium ion for CH5+.[5] tert-butyl cation, demonstrating planar geometry and sp2 hybridization Carbocation 56 History The history of carbocations dates back to 1891 when G. Merling[6] reported that he added bromine to tropylidene (cycloheptatriene) and then heated the product to obtain a crystalline, water soluble material, C7H7Br. He did not suggest a structure for it; however Doering and Knox[7] convincingly showed that it was tropylium (cycloheptatrienylium) bromide. This ion is predicted to be aromatic by Hückel's rule. In 1902, Norris and Kehrman independently discovered that colorless triphenylmethanol gave deep yellow solutions in concentrated sulfuric acid. Triphenylmethyl chloride similarly formed orange complexes with aluminium and tin chlorides. In 1902, Adolf von Baeyer recognized the salt-like character of the compounds formed. Carbonium ion of methane He dubbed the relationship between color and salt formation halochromy of which malachite green is a prime example. Carbocations are reactive intermediates in many organic reactions. This idea, first proposed by Julius Stieglitz in 1899[8] was further developed by Hans Meerwein in his 1922 study[9][10] of the Wagner-Meerwein rearrangement. Carbocations were also found to be involved in the SN1 reaction, the E1 reaction, and in rearrangement reactions such as the Whitmore 1,2 shift. The chemical establishment was reluctant to accept the notion of a carbocation and for a long time the Journal of the American Chemical Society refused articles that mentioned them. The first NMR spectrum of a stable carbocation in solution was published by Doering et al.[11] in 1958. It was the heptamethylbenzenium ion, made by treating hexamethylbenzene with methyl chloride and aluminium chloride. The stable 7-norbornadienyl cation was prepared by Story et al. in 1960[12] by reacting norbornadienyl chloride with silver tetrafluoroborate in sulfur dioxide at −80 °C. The NMR spectrum established that it was non-classically bridged (the first stable non-classical ion observed). In 1962, Olah directly observed the tert-butyl carbocation by nuclear magnetic resonance as a stable species on dissolving tert-butyl fluoride in magic acid. The NMR of the norbornyl cation was first reported by Schleyer et al.[13] and it was shown to undergo proton-scrambling over a barrier by Saunders et al.[14] Carbocation 57 Properties In organic chemistry, a carbocation is often the target of nucleophilic attack by nucleophiles like hydroxide (OH−) ions or halogen ions. Carbocations are classified as primary, secondary, or tertiary depending on the number of carbon atoms bonded to the ionized carbon. Primary carbocations have one or zero carbons attached to the ionized carbon, secondary carbocations have two carbons attached to the ionized carbon, and tertiary carbocations have three carbons attached to the ionized carbon. Order of stability of examples of tertiary (III), secondary (II), and primary (I) alkylcarbenium ions, as well as the methyl cation (far right). Stability of the carbocation increases with the number of alkyl groups bonded to the charge-bearing carbon. Tertiary carbocations are more stable (and form more readily) than secondary carbocations; primary carbocations are highly unstable because, while ionized higher-order carbons are stabilized by hyperconjugation, unsubstituted (primary) carbons are not. Therefore, reactions such as the SN1 reaction and the E1 elimination reaction normally do not occur if a primary carbocation would be formed. An exception to this occurs when there is a carbon-carbon double bond next to the carbon to be ionized, as the double bond in such a system will stabilize the carbocation by resonance. Such cations as allyl cation CH2=CH–CH2+ and benzyl cation C6H5–CH2+ are more stable than most other carbocations. Molecules which can form allyl or benzyl carbocations are especially reactive. Carbocations undergo rearrangement reactions from less stable structures to equally stable or more stable ones with rate constants in excess of 109/sec. This fact complicates synthetic pathways to many compounds. For example, when 3-pentanol is heated with aqueous HCl, the initially formed 3-pentyl carbocation rearranges to a statistical mixture of the 3-pentyl and 2-pentyl. These cations react with chloride ion to produce about 1/3 3-chloropentane and 2/3 2-chloropentane. Some carbocations such as the norbornyl cation exhibit more or less symmetrical three centre bonding. Cations of this sort have been referred to as non-classical ions. The energy difference between "classical" carbocations and "non-classical" isomers is often very small, and there is generally little, if any activation energy involved in the transition between "classical" and "non-classical" structures. The "non-classical" form of the 2-butyl carbocation is essentially 2-butene with a proton directly above the centre of what would be the carbon-carbon double bond. "Non-classical" carbocations were once the subject of great controversy. One of George Olah's greatest contributions to chemistry was resolving this controversy.[15] Specific carbocations Cyclopropylcarbinyl cations can be studied by NMR:[16][17] In the NMR spectrum of a dimethyl derivative, two nonequivalent signals are found for the two methyl groups indicating that the molecular conformation of this cation not perpendicular (as in A) but is bisected (as in B) with the empty p-orbital and the cyclopropyl ring system in the same plane: Carbocation 58 In terms of bent bond theory, this preference is explained by assuming favorable orbital overlap between the filled cyclopropane bent bonds and the empty p-orbital.[18] References [1] [2] [3] [4] Gold Book definition carbonium ion (http:/ / goldbook. iupac. org/ C00839. html) PDF (http:/ / www. iupac. org/ goldbook/ C00839. pdf) Organic chemistry 5th Ed. John McMurry ISBN 0-534-37617-7 Organic Chemistry, Fourth Edition Paula Yurkanis Bruice ISBN 0-13-140748-1 Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2001). Organic Chemistry (1st ed.). Oxford University Press. ISBN 978-0-19-850346-0. [5] Organic Chemistry by Marye Anne Fox and James K. Whitesell ISBN 0-7637-0413-X [6] Chem. Ber. 24, 3108 1891 [7] The Cycloheptatrienylium (Tropylium) Ion W. Von E. Doering and L. H. Knox J. Am. Chem. Soc.; 1954; 76(12) pp 3203 - 3206; doi:10.1021/ja01641a027 [8] On the Constitution of the Salts of Imido-Ethers and other Carbimide Derivatives; Am. Chem. J. 21, 101; ISSN: 0096-4085 [9] H. Meerwein and K. van Emster, Berichte, 1922, 55, 2500. [10] Rzepa, H. S.; Allan, C. S. M. (2010). "Racemization of Isobornyl Chloride via Carbocations: A Nonclassical Look at a Classic Mechanism". Journal of Chemical Education 87 (2): 221. Bibcode 2010JChEd..87..221R. doi:10.1021/ed800058c. [11] The 1,1,2,3,4,5,6-heptamethylbenzenonium ion W. von E. Doering and M. Saunders H. G. Boyton, H. W. Earhart, E. F. Wadley and W. R. Edwards G. Laber Tetrahedron Volume 4, Issues 1-2 , 1958, Pages 178-185 doi:10.1016/0040-4020(58)88016-3 [12] The 7-norbornadienyl carbonium ion Paul R. Story and Martin Saunders J. Am. Chem. Soc.; 1960; 82(23) pp 6199 - 6199; doi:10.1021/ja01508a058 [13] Stable Carbonium Ions. X.1 Direct Nuclear Magnetic Resonance Observation of the 2-Norbornyl Cation Paul von R. Schleyer, William E. Watts, Raymond C. Fort, Melvin B. Comisarow, and George A. Olah J. Am. Chem. Soc.; 1964; 86(24) pp 5679 - 5680; doi:10.1021/ja01078a056 [14] Stable Carbonium Ions. XI.1 The Rate of Hydride Shifts in the 2-Norbornyl Cation Martin Saunders, Paul von R. Schleyer, and George A. Olah J. Am. Chem. Soc.; 1964; 86(24) pp 5680 - 5681; doi:10.1021/ja01078a057 [15] George A. Olah - Nobel Lecture (http:/ / nobelprize. org/ chemistry/ laureates/ 1994/ olah-lecture. html) [16] Nuclear magnetic double resonance studies of the dimethylcyclopropylcarbinyl cation. Measurement of the rotation barrier David S. Kabakoff, , Eli. Namanworth J. Am. Chem. Soc. 1970, 92 (10), pp 3234–3235 doi:10.1021/ja00713a080 [17] Stable Carbonium Ions. XVII.1a Cyclopropyl Carbonium Ions and Protonated Cyclopropyl Ketones Charles U. Pittman Jr., George A. Olah J. Am. Chem. Soc., 1965, 87 (22), pp 5123–5132 doi:10.1021/ja00950a026 [18] F.A. Carey, R.J. Sundberg Advanced Organic Chemistry Part A 2nd Ed. External links • Press Release (http://nobelprize.org/nobel_prizes/chemistry/laureates/1994/press.html?print=1) The 1994 Nobel Prize in Chemistry". Nobelprize.org.9 Jun 2010 Organocatalysis 59 Organocatalysis In organic chemistry, the term Organocatalysis (a concatenation of the terms "organic" and "catalyst") refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds.[3][4][5][6][7][8] Because of their similarity in composition and description, they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved. Justus von Liebig's synthesis of oxamide from dicyan and water represents the first organocatalytic reaction, with acetaldehyde further identified as the first discovered pure "organocatalyst", which act similarly to the then-named [1][2] "ferments", now known as enzymes. Organocatalysts which display secondary amine functionality can be described as performing either enamine catalysis (by forming catalytic quantities of an active enamine nucleophile) or iminium catalysis (by forming catalytic quantities of an activated iminium electrophile). This mechanism is typical for covalent organocatalysis. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20-30 mol%). Noncovalent interactions such as hydrogen-bonding facilitates low catalyst loadings (down to 0.001 mol%). Organocatalysis offers several advantages. There is no need for metal-based catalysis thus making a contribution to green chemistry. In this context, simple organic acids have been used as catalyst for the modification of cellulose in water on multi-ton scale.[9] When the organocatalyst is chiral an avenue is opened to asymmetric catalysis, for example the use of proline in aldol reactions, Introduction Regular achiral organocatalysts are based on nitrogen such as piperidine used in the Knoevenagel condensation,[10] DMAP used in esterfications and DABCO used in the Baylis-Hillman reaction. Thiazolium salts are employed in the Stetter reaction. These catalysts and reactions have a long history but current interest in organocatalysis is focused on asymmetric catalysis with chiral catalysts and this particular branch is called asymmetric organocatalysis or enantioselective organocatalysis . A pioneering reaction developed in the 1970s is called the Hajos–Parrish–Eder–Sauer–Wiechert reaction: In this reaction, naturally occurring chiral proline is the chiral catalyst in an Aldol reaction. The starting material is an achiral triketone and it requires just 3% of proline to obtain the reaction product, a ketol in 93% enantiomeric excess. This is the first example of an amino acid-catalyzed asymmetric aldol reaction.[11][12] Organocatalysis The asymmetric synthesis of the Wieland-Miescher ketone (1985) is also based on proline and another early application was one of the transformations in the total synthesis of Erythromycin by Robert B. Woodward (1981).[13] Many chiral organocatalysts are an adaptation of chiral ligands (which together with a metal center also catalyze asymmetric reactions) and both concepts overlap to some degree. 60 Organocatalyst classes Organocatalysts for asymmetric synthesis can be grouped in several classes: • Biomolecules: notably proline, phenylalanine. Secondary amines in general.[14] The cinchona alkaloids, certain oligopeptides. • Synthetic catalysts derived from biomolecules. • Hydrogen bonding catalysts, including TADDOLS, derivatives of BINOL such as NOBIN, and organocatalysts based on thioureas • Triazolium salts as next-generation Stetter reaction catalysts Examples of asymmetric reactions involving organocatalysts are: • Asymmetric Diels-Alder reactions • Asymmetric Michael reactions • Asymmetric Mannich reactions • Shi epoxidation • Organocatalytic transfer hydrogenation Imidazolidinone organocatalysis A certain class of imidazolidinone compounds (also called MacMillan organocatalysts) are suitable catalysts for many asymmetric reactions such as asymmetric Diels-Alder reactions. The original such compound was derived from the biomolecule phenylalanine in two chemical steps (amidation with methylamine followed by condensation reaction with acetone) which leave the chirality intact:[15] This catalyst works by forming a iminium ion with carbonyl groups of α,β-unsaturated aldehydes (enals) and enones in a rapid chemical equilibrium. This iminium activation is similar to activation of carbonyl groups by a Lewis acid and both catalysts lower the substrate's LUMO:[16] Organocatalysis 61 The transient iminium intermediate is chiral which is transferred to the reaction product via chiral induction. The catalysts have been used in Diels-Alder reactions, Michael additions, Friedel-Crafts alkylations, transfer hydrogenations and epoxidations. One example is the asymmetric synthesis of the drug warfarin (in equilibrium with the hemiketal) in a Michael addition of 4-hydroxycoumarin and benzylideneacetone:[17] A recent exploit is the vinyl alkylation of crotonaldehyde with an organotrifluoroborate salt:[18] For other examples of its use: see organocatalytic transfer hydrogenation and asymmetric Diels-Alder reactions. Organocatalysis 62 Thiourea organocatalysis A large group of organocatalysts incorporate the urea or the thiourea moiety. These catalytically effective (thio)urea derivatives termed (thio)urea organocatalysts provide explicit double hydrogen-bonding interactions to coordinate and activate H-bond accepting substrates. References [1] Justus von Liebig, Justus (1860). "Ueber die Bildung des Oxamids aus Cyan". Annalen der Chemie und Pharmacie 113 (2): 246–247. doi:10.1002/jlac.18601130213. [2] W. Langenbeck (1929). "Über organische Katalysatoren. III. Die Bildung von Oxamid aus Dicyan bei Gegenwart von Aldehyden". Liebigs Ann. 469: 16. doi:10.1002/jlac.19294690103. [3] Berkessel, A., Groeger, H. (2005). Asymmetric Organocatalysis. Weinheim: Wiley-VCH. ISBN 3-527-30517-3. [4] Special Issue: List, Benjamin (2007). "Organocatalysis". Chem. Rev. 107 (12): 5413–5883. doi:10.1021/cr078412e. [5] Peter I. Dalko; Lionel Moisan (2004). "In the Golden Age of Organocatalysis". Angew. Chem. Int. Ed. 43 (39): 5138–5175. doi:10.1002/anie.200400650. [6] Matthew J. Gaunt; Carin C.C. Johansson; Andy McNally; Ngoc T. Vo (2007). "Enantioselective organocatalysis". Drug Discovery Today 12 (1/2): 8–27. doi:10.1016/j.drudis.2006.11.004. [7] Dieter Enders; Christoph Grondal; Matthias R. M. Hüttl (2007). "Asymmetric Organocatalytic Domino Reactions". Angew. Chem. Int. Ed. 46 (10): 1570–1581. doi:10.1002/anie.200603129. [8] Peter I. Dalko; Lionel Moisan (2001). "Enantioselective Organocatalysis". Angew. Chem. Int. Ed. 40 (20): 3726–3748. doi:10.1002/1521-3773(20011015)40:203.0.CO;2-D. [9] International Patent WO 2006068611 A1 20060629 “ Direct Homogeneous and Heterogeneous Organic Acid and Amino Acid-Catalyzed Modification of Amines and Alcohols” Inventors: Armando Córdova, Stockholm, Sweden; Jonas Hafrén, Stockholm, Sweden. [10] List, B. (2010). "Emil Knoevenagel and the Roots of Aminocatalysis". Angewandte Chemie (International ed. in English) 49 (10): 1730–1734. doi:10.1002/anie.200906900. PMID 20175175. [11] Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971 [12] Zoltan G. Hajos; David R. Parrish (1974). "Asymmetric synthesis of bicyclic intermediates of natural product chemistry". J. Org. Chem. 39 (12): 1615–1621. doi:10.1021/jo00925a003. [13] R. B. Woodward; E. Logusch; K. P. Nambiar; K. Sakan; D. E. Ward; B. W. Au-Yeung; P. Balaram; L. J. Browne et al. (1981). "Asymmetric total synthesis of erythromcin. 1. Synthesis of an erythronolide A secoacid derivative via asymmetric induction". J. Am. Chem. Soc. 103 (11): 3210–3213. doi:10.1021/ja00401a049. [14] Organocatalysis—after the gold rush Søren Bertelsen and Karl Anker Jørgensen Chem. Soc. Rev., 2009, 38, 2178–2189 doi:10.1039/b903816g [15] Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. (2000). "New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction". J. Am. Chem. Soc. 122 (17): 4243–4244. doi:10.1021/ja000092s. [16] Gérald Lelais; David W. C. MacMillan (2006). "Modern Strategies in Organic Catalysis: The Advent and Development of Iminium Activation" (http:/ / www. sigmaaldrich. com/ etc/ medialib/ docs/ Aldrich/ Acta/ al_acta_39_3. pdf). Aldrichimica Acta 39 (3): 79. . [17] Nis Halland; Tore Hansen; Karl Anker Jørgensen (2003). "Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl Compounds and α,β-Unsaturated Ketones - A Highly Atom-Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant". Angew. Chem. Int. Ed. 42 (40): 4955–4957. doi:10.1002/anie.200352136. PMID 14579449. [18] Sandra Lee; David W. C. MacMillan (2007). "Organocatalytic Vinyl and Friedel-Crafts Alkylations with Trifluoroborate Salts". J. Am. Chem. Soc. 129 (50): 15438–15439. doi:10.1021/ja0767480. PMID 18031044. Double bond 63 Double bond A double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in a carbonyl group with a carbon atom and an oxygen atom. Other common double bonds are found in azo compounds (N=N), imines (C=N) and sulfoxides (S=O). In skeletal formula the double bond is drawn as two parallel lines (=) between the two connected atoms; typographically, the equals sign is used for this.[1][2] Double bonds are stronger than single bonds and double bonds are also shorter. The bond order is two. Double bonds are also electron-rich, which makes them reactive. ethylene Common chemical compounds with double bonds acetone dimethyl sulfoxide Bonding The type of bonding can be explained in terms of orbital hybridization. In ethylene each carbon atom has three sp2 orbitals and one p-orbital. The three sp2 orbitals lie in a plane with 120° angles. The p-orbital is perpendicular to this plane. When the carbon atoms approach each other, two of the sp2 orbitals overlap to form a sigma bond. At the same time, the two p-orbitals approach (again in the same plane) and together they form a pi-bond. For maximum overlap, the p-orbitals have to remain parallel, and, therefore, rotation around the central bond is not possible. This property gives rise to cis-trans isomerism. Double bonds are shorter than single bonds because p-orbital overlap is maximized. 2 sp2 orbitals (total of 3 such orbitals) approach to form a sp2-sp2 sigma Two p-orbitals overlap to form a pi-bond in a plane parallel to the sigma plane bond With 133 pm, the C=C bond length is shorter than the C−C length in ethane with 154 pm. The double bond is also stronger, 636 (KJ/mol) versus 368 kJ/mole but not twice as much as the pi-bond is weaker than the sigma bond due to less effective pi-overlap. In an alternative representation, the double bond results from two overlapping sp3 orbitals as in a bent bond.[3] Double bond 64 Types of double bonds between atoms C O N imine S thioketone, thial C alkene carbonyl group O N S dioxygen nitroso compound sulfoxide, sulfone, sulfinic acid, sulfonic acid azo compound disulfur Variations In molecules with alternating double bonds and single bonds, p-orbital overlap can exist over multiple atoms in a chain, giving rise to a conjugated system. Conjugation can be found in systems such as dienes and enones. In cyclic molecules, conjugation can lead to aromaticity. In cumulenes two double bonds are adjacent. Double bonds are common for period 2 elements carbon, nitrogen, and oxygen, and less common with elements of higher periods. Metals, too, can engage in multiple bonding in a metal ligand multiple bond. References [1] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7. [2] Organic Chemistry 2nd Ed. John McMurry. [3] Advanced Organic Chemistry Carey, Francis A., Sundberg, Richard J. 5th ed. 2007. • Pyykkö, Pekka; Riedel, Sebastian; Patzschke, Michael (2005). "Triple-Bond Covalent Radii". Chemistry - A European Journal 11 (12): 3511–20. doi:10.1002/chem.200401299. PMID 15832398. Functional group 65 Functional group In organic chemistry, functional groups are lexicon-specific groups of atoms or bonds within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction(s) regardless of the size of the molecule it is a part of.[1][2] However, its relative reactivity can be modified by nearby functional groups. The word moiety (  /ˈmɔɪəti/) is often used synonymously with "functional Benzyl acetate has an ester functional group (in red), an acetyl moiety (circled group," but, according to the IUPAC definition,[3] a moiety is a part of a with green) and a benzyloxy moiety molecule that may include either whole functional groups or parts of (circled with orange). Other divisions can functional groups as substructures. For example, an ester (RCOOR') has an be made. ester functional group (COOR) and is composed of an alkoxy moiety (-OR') and an acyl moiety (RCO-), or, equivalently, it may be divided into carboxylate (RCOO-) and alkyl (-R') moieties. Each moiety may contain additional functional groups--for example, methyl para-hydroxybenzoate contains a phenol functional group within the acyl moiety. Combining the names of functional groups with the names of the parent alkanes generates a powerful systematic nomenclature for naming organic compounds. The atoms of functional groups are linked to each other and to the rest of the molecule by covalent bonds. When the group of covalently bound atoms bears a net charge, the group is referred to more properly as a polyatomic ion or a complex ion. Any subgroup of atoms of a compound also may be called a radical, and if a covalent bond is broken homolytically, the resulting fragment radicals are referred as free radicals. The first carbon atom after the carbon that attaches to the functional group is called the alpha carbon; the second, beta carbon, the third, gamma carbon, etc. If there is another functional group at a carbon, it may be named with the Greek letter, e.g., the gamma-amine in gamma-aminobutanoic acid is on the third carbon of the carbon chain attached to the carboxylic acid group. Synthetic chemistry for all Organic reactions are facilitated and controlled by the functional groups of the reactants. In general, alkyls are unreactive and difficult to get to react selectively at the desired positions, with few exceptions. In contrast, unsaturated carbon functional groups, and carbon-oxygen and carbon-nitrogen functional groups have a more diverse array of reactions that are also selective. It may be necessary to create a functional group in the molecule to make it react. For example, to synthesize iso-octane (the 8-carbon ideal gasoline) from the unfunctionalized alkane isobutane (a 4-carbon gas), isobutane is first dehydrogenated into isobutene. This contains the alkene functional group and can now dimerize with another isobutene to give iso-octene, which is then catalytically hydrogenated to iso-octane using pressured hydrogen gas. Functional group 66 Crystallography The International Union of Crystallography in its Crystallographic Information File dictionary defines "moiety" to represent discrete non-bonded components. Thus, Na2SO4 would contain 3 moieties (2 Na+ and one SO42-). The dictionary defines "chemical formula moiety": "Formula with each discrete bonded residue or ion shown as a separate moiety". Functionalization Functionalization is the addition of functional groups onto the surface of a material by chemical synthesis methods. The functional group added can be subjected to ordinary synthesis methods to attach virtually any kind of organic compound onto the surface. Functionalization is employed for surface modification of industrial materials in order to achieve desired surface properties such as water repellent coatings for automobile windshields and non-biofouling, hydrophilic coatings for contact lenses. In addition, functional groups are used to covalently link functional molecules to the surface of chemical and biochemical devices such as microarrays and microelectromechanical systems. Catalysts can be attached to a material that has been functionalized. For example, silica is functionalized with an alkyl silicone, wherein the alkyl contains an amine functional group. A ligand such as an EDTA fragment is synthesized onto the amine, and a metal cation is complexed into the EDTA fragment. The EDTA is not adsorbed onto the surface, but connected by a permanent chemical bond. Functional groups are also used to covalently link molecules such as fluorescent dyes, nanoparticles, proteins, DNA, and other compounds of interest for a variety of applications such as sensing and basic chemical research. Table of common functional groups The following is a list of common functional groups. In the formulas, the symbols R and R' usually denote an attached hydrogen, or a hydrocarbon side chain of any length, but may sometimes refer to any group of atoms. Hydrocarbons Functional groups, called hydrocarbyls, that contain only carbon and hydrogen, but vary in the number and order of π bonds. Each one differs in type (and scope) of reactivity. Chemical class Alkane Group Alkyl Formula R(CH2)nH Structural Formula Prefix alkylSuffix -ane Example Ethane Alkene Alkenyl R2C=CR2 alkenyl-ene Ethylene (Ethene) Alkyne Alkynyl RC≡CR' alkynyl-yne Acetylene (Ethyne) Functional group 67 Phenyl RC6H5 RPh phenyl-benzene Benzene derivative Cumene (2-phenylpropane) Toluene derivative Benzyl RCH2C6H5 RBn benzyl- 1-(substituent)toluene Benzyl bromide (α-Bromotoluene) There are also a large number of branched or ring alkanes that have specific names, e.g., tert-butyl, bornyl, cyclohexyl, etc. Hydrocarbons may form charged structures: positively charged carbocations or negative carbanions. Carbocations are often named -um. Examples are tropylium and triphenylmethyl cations and the cyclopentadienyl anion. Groups containing halogens Haloalkanes are a class of molecule that is defined by a carbon-halogen bond. This bond can be relatively weak (in the case of an iodoalkane) or quite stable (as in the case of a fluoroalkane). In general, with the exception of fluorinated compounds, haloalkanes readily undergo nucleophilic substitution reactions or elimination reactions. The substitution on the carbon, the acidity of an adjacent proton, the solvent conditions, etc. all can influence the outcome of the reactivity. Chemical class Group Formula Structural Formula Prefix haloalkane halo RX haloSuffix alkyl halide Chloroethane (Ethyl chloride) fluoroalkane fluoro RF fluoro- alkyl fluoride Example Fluoromethane (Methyl fluoride) chloroalkane chloro RCl chloro- alkyl chloride Chloromethane (Methyl chloride) bromoalkane bromo RBr bromo- alkyl bromide Bromomethane (Methyl bromide) Functional group 68 iodoalkane iodo RI iodoalkyl iodide Iodomethane (Methyl iodide) Groups containing oxygen Compounds that contain C-O bonds each possess differing reactivity based upon the location and hybridization of the C-O bond, owing to the electron-withdrawing effect of sp hybridized oxygen (carbonyl groups) and the donating effects of sp2 hybridized oxygen (alcohol groups). Chemical class Group Formula Structural Formula Prefix Suffix Example Alcohol Hydroxyl ROH hydroxy- -ol Methanol Ketone Carbonyl RCOR' -oyl- (-COR') or oxo- (=O) -one Butanone (Methyl ethyl ketone) Aldehyde Aldehyde RCHO formyl- (-COH) or oxo- (=O) -al Ethanal (Acetaldehyde) Acyl halide Haloformyl RCOX carbonofluoridoylcarbonochloridoylcarbonobromidoylcarbonoiodidoyl-oyl halide Acetyl chloride (Ethanoyl chloride) Carbonate Carbonate ester ROCOOR (alkoxycarbonyl)oxyalkyl carbonate Triphosgene (bis(trichloromethyl) carbonate) Carboxylate Carboxylate RCOO− carboxy-oate Sodium acetate (Sodium ethanoate) Carboxylic acid Carboxyl RCOOH carboxy-oic acid Acetic acid (Ethanoic acid) Functional group 69 Ester RCOOR' alkanoyloxyor alkoxycarbonyl methoxyhydroperoxyalkyl hydroperoxide Methyl ethyl ketone peroxide alkyl alkanoate Ethyl butyrate (Ethyl butanoate) Ester Methoxy Hydroperoxide Methoxy Hydroperoxy ROCH3 ROOH Peroxide Peroxy ROOR peroxy- alkyl peroxide Di-tert-butyl peroxide Ether Ether ROR' alkoxyalkyl ether Diethyl ether (Ethoxyethane) Hemiacetal Hemiacetal RCH(OR')(OH) alkoxy -ol -al alkyl hemiacetal -one alkyl hemiketal -al dialkyl acetal Hemiketal Hemiketal RC(ORʺ)(OH)R' alkoxy -ol Acetal Acetal RCH(OR')(OR") dialkoxy- Ketal (or Acetal) Orthoester Ketal (or Acetal) Orthoester RC(ORʺ)(OR‴)R' dialkoxy- -one dialkyl ketal RC(OR')(ORʺ)(OR‴) trialkoxy- Orthocarbonate ester Orthocarbonate C(OR)(OR')(ORʺ)(OR″) ester tetralkoxy- tetraalkyl orthocarbonate Groups containing nitrogen Compounds that contain nitrogen in this category may contain C-O bonds, such as in the case of amides. Chemical class Amide Group Formula Structural Formula Prefix Suffix Example Carboxamide RCONR2 carboxamidoor carbamoyl- -amide Acetamide (Ethanamide) Functional group 70 Primary amine RNH2 amino-amine Amines Methylamine (Methanamine) Secondary amine R2NH amino-amine Dimethylamine Tertiary amine R3N amino-amine Trimethylamine 4° ammonium ion R4N+ ammonio-ammonium Choline Imine Primary ketimine RC(=NH)R' imino-imine Secondary ketimine RC(=NR)R' imino- -imine Primary aldimine RC(=NH)H imino- -imine Ethanimine Secondary aldimine RC(=NR')H imino-imine Imide Imide (RCO)2NR' imido- -imide Succinimide (Pyrrolidine-2,5-dione) Azide Azide RN3 azidoalkyl azide Phenyl azide (Azidobenzene) Functional group 71 Azo (Diimide) RN2R' azo-diazene Azo compound Methyl orange (p-dimethylamino-azobenzenesulfonic acid) Cyanates Cyanate ROCN cyanatoalkyl cyanate Methyl cyanate Isocyanate RNCO isocyanatoalkyl isocyanate Methyl isocyanate Nitrate Nitrate RONO2 nitrooxy-, nitroxyalkyl nitrate Amyl nitrate (1-nitrooxypentane) Nitrile Nitrile RCN cyanoalkanenitrile alkyl cyanide Benzonitrile (Phenyl cyanide) Isonitrile RNC isocyanoalkaneisonitrile alkyl isocyanide Methyl isocyanide Nitrite Nitrosooxy RONO nitrosooxyalkyl nitrite Isoamyl nitrite (3-methyl-1-nitrosooxybutane) Nitro compound Nitro RNO2 nitro- Nitromethane Nitroso compound Nitroso RNO nitroso(Nitrosyl-) Nitrosobenzene Pyridine derivative Pyridyl RC5H4N 4-pyridyl (pyridin-4-yl) 3-pyridyl (pyridin-3-yl) 2-pyridyl (pyridin-2-yl) -pyridine Nicotine Functional group 72 Groups containing sulfur Compounds that contain sulfur exhibit unique chemistry due to their ability to form more bonds than oxygen, their lighter analogue on the periodic table. Substitutive nomenclature (marked as prefix in table) is preferred over functional class nomenclature (marked as suffix in table) for sulfides, disulfides, sulfoxides, sulfones, and negroz. Chemical class Thiol Group Formula Structural Formula Prefix Suffix Example Sulfhydryl RSH sulfanyl(-SH) substituent sulfanyl(-SR') -thiol Ethanethiol Sulfide (Thioether) Sulfide RSR' di(substituent) sulfide (Methylsulfanyl)methane (prefix) or Dimethyl sulfide (suffix) Disulfide Disulfide RSSR' substituent disulfanyl(-SSR') di(substituent) disulfide (Methyldisulfanyl)methane (prefix) or Dimethyl disulfide (suffix) Sulfoxide Sulfinyl RSOR' -sulfinyl(-SOR') di(substituent) sulfoxide (Methanesulfinyl)methane (prefix) or Dimethyl sulfoxide (suffix) Sulfone Sulfonyl RSO2R' -sulfonyl(-SO2R') di(substituent) sulfone (Methanesulfonyl)methane (prefix) or Dimethyl sulfone (suffix) Sulfinic acid Sulfino RSO2H sulfino(-SO2H) sulfo(-SO3H) -sulfinic acid 2-Aminoethanesulfinic acid -sulfonic acid Sulfonic acid Sulfo RSO3H Benzenesulfonic acid Thiocyanate Thiocyanate RSCN thiocyanato(-SCN) substituent thiocyanate Phenyl thiocyanate Isothiocyanate RNCS isothiocyanato(-NCS) substituent isothiocyanate Allyl isothiocyanate Thione Carbonothioyl RCSR' -thioyl(-CSR') or sulfanylidene(=S) methanethioyl(-CSH) or sulfanylidene(=S) -thione Diphenylmethanethione (Thiobenzophenone) -thial Thial Carbonothioyl RCSH Functional group 73 Groups containing phosphorus Compounds that contain phosphorus exhibit unique chemistry due to their ability to form more bonds than nitrogen, their lighter analogues on the periodic table. Chemical class Phosphine (Phosphane) Phosphonic acid Group Formula Structural Formula Prefix Suffix Example Phosphino R3P phosphanyl- -phosphane Methylpropylphosphane Phosphono RP(=O)(OH)2 phosphono- substituent phosphonic acid Benzylphosphonic acid Phosphate Phosphate ROP(=O)(OH)2 phosphonooxyor O-phosphono- (phospho-) substituent phosphate Glyceraldehyde 3-phosphate (suffix) O-Phosphonocholine (prefix) (Phosphocholine) Phosphodiester Phosphate HOPO(OR)2 [(alkoxy)hydroxyphosphoryl]oxydi(substituent) DNA or hydrogen phosphate O-[(alkoxy)hydroxyphosphoryl]or O‑[(2‑Guanidinoethoxy)hydroxyphosphoryl]‑l‑serine (prefix) phosphoric acid (Lombricine) di(substituent) ester Groups containing boron Compounds containing boron exhibit unique chemistry due to their having partially filled octets and therefore acting as Lewis acids. Chemical Group Formula class Boronic acid Borono RB(OH)2 Structural Formula Boronosubstituent boronic acid Prefix Suffix Example Bortezomib ([(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid) Boronic ester Boronate RB(OR)2 O-[bis(alkoxy)alkylboronyl]- substituent boronic acid di(substituent) ester Borinic acid Borino R2BOH Hydroxyborinodi(substituent) borinic acid Functional group 74 O-[alkoxydialkylboronyl]di(substituent) borinic acid substituent ester Borinic ester Borinate R2BOR References [1] Compendium of Chemical Terminology (IUPAC "Gold Book") http:/ / goldbook. iupac. org/ F02555. html [2] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7 [3] IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). XML on-line corrected version: http:/ / goldbook. iupac. org (2006-) created by M. Nic, J. Jirat, B. Kosata; updates compiled by A. Jenkins. ISBN 0-9678550-9-8 doi:10.1351/goldbook.M03968 http:/ / goldbook. iupac. org/ M03968. html External links • IUPAC Blue Book (organic nomenclature) (http://www.acdlabs.com/iupac/nomenclature/) • IUPAC ligand abbreviations (http://www.iupac.org/reports/provisional/abstract04/RB-prs310804/ TableVII-3.04.pdf) (pdf) • _chemical_formula_moiety in CIF dictionary (http://www.iucr.org/__data/iucr/cifdic_html/1/cif_core.dic/ Ichemical_formula_moiety.html) • Functional group synthesis (http://www.organic-reaction.com/organic-synthesis/functional-group-synthesis/) from organic-reaction.com Nucleophile A nucleophile is a chemical species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases. Nucleophilic describes the affinity of a nucleophile to the nuclei. Nucleophilicity, sometimes referred to as nucleophile strength, refers to a substance's nucleophilic character and is often used to compare the affinity of atoms. Neutral nucleophilic reactions with solvents such as alcohols and water are named solvolysis. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge. History The terms nucleophile and electrophile were introduced by Christopher Kelk Ingold in 1929,[1] replacing the terms cationoid and anionoid proposed earlier by A. J. Lapworth in 1925.[2] The word nucleophile is derived from nucleus and the Greek word φιλος, philos for love. Properties In general, in a row across the periodic table, the more basic the ion (the higher the pKa of the conjugate acid) the more reactive it is as a nucleophile. In a given group, polarizability is more important in the determination of the nucleophilicity: The easier it is to distort the electron cloud around an atom or molecule the more readily it will react; e.g., the iodide ion (I−) is more nucleophilic than the fluoride ion (F−). Nucleophile 75 Nucleophilicity scales Many schemes attempting to quantify relative nucleophilic strength have been devised. The following empirical data have been obtained by measuring reaction rates for a large number of reactions involving a large number of nucleophiles and electrophiles. Nucleophiles displaying the so-called alpha effect are usually omitted in this type of treatment. Swain-Scott equation The first such attempt is found in the Swain–Scott equation[3][4] derived in 1953: This free-energy relationship relates the pseudo first order reaction rate constant (in water at 25 °C), k, of a reaction, normalized to the reaction rate, k0, of a standard reaction with water as the nucleophile, to a nucleophilic constant n for a given nucleophile and a substrate constant s that depends on the sensitivity of a substrate to nucleophilic attack (defined as 1 for methyl bromide). This treatment results in the following values for typical nucleophilic anions: acetate 2.7, chloride 3.0, azide 4.0, hydroxide 4.2, aniline 4.5, iodide 5.0, and thiosulfate 6.4. Typical substrate constants are 0.66 for ethyl tosylate, 0.77 for β-propiolactone, 1.00 for 2,3-epoxypropanol, 0.87 for benzyl chloride, and 1.43 for benzoyl chloride. The equation predicts that, in a nucleophilic displacement on benzyl chloride, the azide anion reacts 3000 times faster than water. Ritchie equation The Ritchie equation, derived in 1972, is another free-energy relationship:[5][6][7] where N+ is the nucleophile dependent parameter and k0 the reaction rate constant for water. In this equation, a substrate-dependent parameter like s in the Swain–Scott equation is absent. The equation states that two nucleophiles react with the same relative reactivity regardless of the nature of the electrophile, which is in violation of the Reactivity–selectivity principle. For this reason this equation is also called the constant selectivity relationship. In the original publication the data were obtained by reactions of selected nucleophiles with selected electrophilic carbocations such as tropylium cations: or diazonium cations: or (not displayed) ions based on Malachite green. Many other reaction types have since been described. Typical Ritchie N+ values (in methanol) are: 0.5 for methanol, 5.9 for the cyanide anion, 7.5 for the methoxide anion, 8.5 for the azide anion, and 10.7 for the thiophenol anion. The values for the relative cation reactivities are -0.4 for the malachite green cation, +2.6 for the benzenediazonium cation, and +4.5 for the tropylium cation. Nucleophile Mayr-Patz equation In the Mayr-Patz equation (1994):[8] 76 The second order reaction rate constant k at 20°C for a reaction is related to a nucleophilicity parameter N, an electrophilicity parameter E, and a nucleophile-dependent slope parameter s. The constant s is defined as 1 with 2-methyl-1-pentene as the nucleophile. Many of the constants have been derived from reaction of so-called benzhydrylium ions as the electrophiles:[9] and a diverse collection of π-nucleophiles: . Typical E values are +6.2 for R = chlorine, +5.90 for R = hydrogen, 0 for R = methoxy and -7.02 for R = dimethylamine. Typical N values with s in parenthesis are -4.47 (1.32) for electrophilic aromatic substitution to toluene (1), -0.41 (1.12) for electrophilic addition to 1-phenyl-2-propene (2), and 0.96 (1) for addition to 2-methyl-1-pentene (3), -0.13 (1.21) for reaction with triphenylallylsilane (4), 3.61 (1.11) for reaction with 2-methylfuran (5), +7.48 (0.89) for reaction with isobutenyltributylstannane (6) and +13.36 (0.81) for reaction with the enamine 7.[10] The range of organic reactions also include SN2 reactions:[11] With E = -9.15 for the S-methyldibenzothiophenium ion, typical nucleophile values N (s) are 15.63 (0.64) for piperidine, 10.49 (0.68) for methoxide, and 5.20 (0.89) for water. In short, nucleophilicities towards sp2 or sp3 centers follow the same pattern. Unified equation In an effort to unify the above described equations the Mayr equation is rewritten as:[11] with sE the electrophile-dependent slope parameter and sN the nucleophile-dependent slope parameter. This equation can be rewritten in several ways: • with sE = 1 for carbocations this equation is equal to the original Mayr-Patz equation of 1994, • with sN = 0.6 for most n nucleophiles the equation becomes or the original Scott-Swain equation written as: • with sE = 1 for carbocations and sN = 0.6 the equation becomes: Nucleophile 77 or the original Ritchie equation written as: Types of nucleophiles Examples of nucleophiles are anions such as Cl−, or a compound with a lone pair of electrons such as NH3 (ammonia). In the example below, the oxygen of the hydroxide ion donates an electron pair to bond with the carbon at the end of the bromopropane molecule. The bond between the carbon and the bromine then undergoes heterolytic fission, with the bromine atom taking the donated electron and becoming the bromide ion (Br−), because a SN2 reaction occurs by backside attack. This means that the hydroxide ion attacks the carbon atom from the other side, exactly opposite the bromine ion. Because of this backside attack, SN2 reactions result in a reversal of the configuration of the electrophile. If the electrophile is chiral, it typically maintains its chirality, though the SN2 product's configuration is flipped as compared to that of the original electrophile. An ambident nucleophile is one that can attack from two or more places, resulting in two or more products. For example, the thiocyanate ion (SCN−) may attack from either the S or the N. For this reason, the SN2 reaction of an alkyl halide with SCN− often leads to a mixture of RSCN (an alkyl thiocyanate) and RNCS (an alkyl isothiocyanate). Similar considerations apply in the Kolbe nitrile synthesis. Carbon nucleophiles Carbon nucleophiles are alkyl metal halides found in the Grignard reaction, Blaise reaction, Reformatsky reaction, and Barbier reaction, organolithium reagents, and anions of a terminal alkyne. Enols are also carbon nucleophiles. The formation of an enol is catalyzed by acid or base. Enols are ambident nucleophiles, but, in general, nucleophilic at the alpha carbon atom. Enols are commonly used in condensation reactions, including the Claisen condensation and the aldol condensation reactions. Oxygen nucleophiles Examples of oxygen nucleophiles are water (H2O), hydroxide anion, alcohols, alkoxide anions, hydrogen peroxide, and carboxylate anions Sulfur nucleophiles Of sulfur nucleophiles, hydrogen sulfide and its salts, thiols (RSH), thiolate anions (RS−), anions of thiolcarboxylic acids (RC(O)-S−), and anions of dithiocarbonates (RO-C(S)-S−) and dithiocarbamates (R2N-C(S)-S−) are used most often. In general, sulfur is very nucleophilic because of its large size, which makes it readily polarizable, and its lone pairs of electrons are readily accessible. Nucleophile 78 Nitrogen nucleophiles Nitrogen nucleophiles include ammonia, azide, amines, and nitrites. References [1] Ingold, C. K. Recl. TraV. Chim. Pays-Bas 1929 [2] Lapworth, A. Nature 1925, 115, 625 [3] Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides C. Gardner Swain, Carleton B. Scott J. Am. Chem. Soc.; 1953; 75(1); 141-147. Abstract (http:/ / pubs. acs. org/ cgi-bin/ abstract. cgi/ jacsat/ 1953/ 75/ i01/ f-pdf/ f_ja01097a041. pdf) [4] Gold Book definition (Swain-Scott) Link (http:/ / www. iupac. org/ goldbook/ S06201. pdf) [5] Gold Book definition (Ritchie) Link (http:/ / www. iupac. org/ goldbook/ R05402. pdf) [6] Nucleophilic reactivities toward cations Calvin D. Ritchie Acc. Chem. Res.; 1972; 5(10); 348-354. Abstract (http:/ / pubs. acs. org/ cgi-bin/ abstract. cgi/ achre4/ 1972/ 5/ i10/ f-pdf/ f_ar50058a005. pdf) [7] Cation-anion combination reactions. XIII. Correlation of the reactions of nucleophiles with esters Calvin D. Ritchie J. Am. Chem. Soc.; 1975; 97(5); 1170-1179. Abstract (http:/ / pubs. acs. org/ cgi-bin/ abstract. cgi/ jacsat/ 1975/ 97/ i05/ f-pdf/ f_ja00838a035. pdf) [8] Scales of Nucleophilicity and Electrophilicity: A System for Ordering Polar Organic and Organometallic Reactions Angewandte Chemie International Edition in English, Vol. 33, No. 9, P. 938-957 doi:10.1002/anie.199409381 [9] Reference Scales for the Characterization of Cationic Electrophiles and Neutral NucleophilesHerbert Mayr, Thorsten Bug, Matthias F. Gotta, Nicole Hering, Bernhard Irrgang, Brigitte Janker, Bernhard Kempf, Robert Loos, Armin R. Ofial, Grigoriy Remennikov, and Holger Schimmel J. Am. Chem. Soc.; 2001; 123(39) pp 9500 - 9512; (Article) doi:10.1021/ja010890y [10] An internet database for reactivity parameters maintained by the Mayr group is available at http:/ / www. cup. uni-muenchen. de/ oc/ mayr/ [11] Towards a General Scale of Nucleophilicity? Thanh Binh Phan, Martin Breugst, Herbert Mayr, Angewandte Chemie International Edition Volume 45, Issue 23 , Pages 3869 - 3874 2006 doi:10.1002/anie.200600542 Electrophile In general, electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile (literally electron-lover) is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids (see acid-base reaction theories). Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons. The electrophiles attack the most electron-populated part of one nucleophile. The electrophiles frequently seen in the organic syntheses are cations such as H+ and NO+, polarized neutral molecules such as HCl, alkyl halides, acyl halides, and carbonyl compounds, polarizable neutral molecules such as Cl2 and Br2, oxidizing agents such as organic peracids, chemical species that do not satisfy the octet rule such as carbenes and radicals, and some lewis acids such as BH3 and DIBAL. Electrophile 79 Electrophiles in organic chemistry Alkenes Electrophilic addition is one of the three main forms of reaction concerning alkenes. • Hydrogenation by the addition of hydrogen over the double bond • Electrophilic addition reactions with halogens and sulfuric acid • Hydration to form alcohols. Addition of halogens These occur between alkenes and electrophiles, often halogens as in halogen addition reactions. Common reactions include use of bromine water to titrate against a sample to deduce the number of double bonds present. For example, ethene + bromine → 1,2-dibromoethane: This takes the form of 3 main steps shown below;[1] C2H4 + Br2 → BrCH2CH2Br 1. Forming of a π-complex The electrophilic Br-Br molecule interacts with electron-rich alkene molecule to form a π-complex 1. 2. Forming of a three-membered bromonium ion The alkene is working as an electron donor and bromine as an electrophile. The three-membered bromonium ion 2 consisted with two carbon atoms and a bromine atom forms with a release of Br−. 3. Attacking of bromide ion The bromonium ion is opened by the attack of Br− from the back side. This yields the vicinal dibromide with an antiperiplanar configuration. When other nucleophiles such as water or alcohol are existing, these may attack 2 to give an alcohol or an ether. This process is called AdE2 mechanism. Iodine (I2), chlorine (Cl2), sulfenyl ion (RS+), mercury cation (Hg2+), and dichlorocarbene (:CCl2) also react through similar pathways. The direct conversion of 1 to 3 will appear when the Br− is large excess in the reaction medium. A β-bromo carbenium ion intermediate may be predominant instead of 3 if the alkene has a cation-stabilizing substituent like phenyl group. There is an example of the isolation of the bromonium ion 2.[2] Addition of hydrogen halides Hydrogen halides such as hydrogen chloride (HCl) adds to alkenes to give alkyl halide in hydrohalogenation. For example, the reaction of HCl with ethylene furnishes chloroethane. The reaction proceeds with a cation intermediate, being different from the above halogen addition. An example is shown below: Electrophile 1. Proton (H+) adds (by working as an electrophile) to one of the carbon atoms on the alkene to form cation 1. 2. Chloride ion (Cl−) combines with the cation 1 to form the adducts 2 and 3. In this manner, the stereoselectivity of the product, that is, from which side Cl− will attack relies on the types of alkenes applied and conditions of the reaction. At least, which of the two carbon atoms will be attacked by H+ is usually decided by Markovnikov's rule. Thus, H+ attacks the carbon atom that carries fewer substituents so as the more stabilized carbocation (with the more stabilizing substituents) will form. This process is called A-SE2 mechanism. Hydrogen fluoride (HF) and hydrogen iodide (HI) react with alkenes in a similar manner, and Markovnikov-type products will be given. Hydrogen bromide (HBr) also takes this pathway, but sometimes a radical process competes and a mixture of isomers may form. 80 Hydration One of the more complex hydration reactions utilises sulfuric acid as a catalyst. This reaction occurs in a similar way to the addition reaction but has an extra step in which the OSO3H group is replaced by an OH group, forming an alcohol: C2H4 + H2O → C2H5OH As can be seen, the H2SO4 does take part in the overall reaction, however it remains unchanged so is classified as a catalyst. This is the reaction in more detail: 1. The H-OSO3H molecule has a δ+ charge on the initial H atom. This is attracted to and reacts with the double bond in the same way as before. 2. The remaining (negatively charged) −OSO3H ion then attaches to the carbocation, forming ethyl hydrogensulphate (upper way on the above scheme). 3. When water (H2O) is added and the mixture heated, ethanol (C2H5OH) is produced. The "spare" hydrogen atom from the water goes into "replacing" the "lost" hydrogen and, thus, reproduces sulfuric acid. Another pathway in which water molecule combines directly to the intermediate carbocation (lower way) is also possible. This pathway become predominant when aqueous sulfuric acid is used. Overall, this process adds a molecule of water to a molecule of ethene. This is an important reaction in industry, as it produces ethanol, whose purposes include fuels and starting material for other chemicals. Electrophilicity scale Electrophile 81 Electrophilicity index Fluorine Chlorine Bromine Iodine Hypochlorite Sulfur dioxide Carbon disulfide Benzene Sodium Some selected values 3.86 3.67 3.40 3.09 2.52 2.01 1.64 1.45 0.88 [3] (no dimensions) [4] Several methods exist to rank electrophiles in order of reactivity with the electrophilicity index ω given as: and one of them is devised by Robert Parr [3] with power: the electronegativity and chemical hardness. This equation is related to classical equation for electrical where is the resistance (Ohm or Ω) and is voltage. In this sense the electrophilicity index is a kind of electrophilic power. Correlations have been found between electrophilicity of various chemical compounds and reaction rates in biochemical systems and such phenomena as allergic contact dermititis. An electrophilicity index also exists for free radicals.[5] Strongly electrophilic radicals such as the halogens react with electron-rich reaction sites, and strongly nucleophilic radicals such as the 2-hydroxypropyl-2-yl and tert-butyl radical react with a preference for electron-poor reaction sites. Superelectrophiles Superelectrophiles are defined as cationic electrophilic reagents with greatly enhanced reactivities in the presence of superacids. These compounds were first described by George A. Olah.[6] Superelectrophiles form as a doubly electron deficient superelectrophile by protosolvation of a cationic electrophile. As observed by Olah, a mixture of acetic acid and boron trifluoride is able to remove a hydride ion from isobutane when combined with hydrofluoric acid via the formation of a superacid from BF3 and HF. The responsible reactive intermediate is the CH3CO2H3 dication. Likewise, methane can be nitrated to nitromethane with nitronium tetrafluoroborate NO BF only in presence of a strong acid like fluorosulfuric acid. In gitionic (gitonic) superelectrophiles, charged centers are separated by no more than one atom, for example, the protonitronium ion O=N+=O+—H (a protonated nitronium ion). And, in distonic superelectrophiles, they are separated by 2 or more atoms, for example, in the fluorination reagent F-TEDA-BF4[7] Electrophile 82 References [1] [2] [3] [4] [5] Lenoir, D.; Chiappe, C. Chem. Eur. J. 2003, 9, 1036. Brown, R. S. Acc. Chem. Res. 1997, 30, 131. Electrophilicity Index Parr, R. G.; Szentpaly, L. v.; Liu, S. J. Am. Chem. Soc.; (Article); 1999; 121(9); 1922-1924. doi:10.1021/ja983494x Electrophilicity Index Chattaraj, P. K.; Sarkar, U.; Roy, D. R. Chem. Rev.; (Review); 2006; 106(6); 2065-2091. doi:10.1021/cr040109f Electrophilicity and Nucleophilicity Index for Radicals Freija De Vleeschouwer, Veronique Van Speybroeck, Michel Waroquier, Paul Geerlings, and Frank De Proft Org. Lett.; 2007; 9(14) pp 2721 - 2724; (Letter) doi:10.1021/ol071038k [6] Electrophilic reactions at single bonds. XVIII. Indication of protosolvated de facto substituting agents in the reactions of alkanes with acetylium and nitronium ions in superacidic media George A. Olah, Alain Germain, Henry C. Lin, David A. Forsyth J. Am. Chem. Soc.; 1975; 97(10); 2928-2929. doi: 10.1021/ja00843a067 [7] Knorr Cyclizations and Distonic Superelectrophiles Kiran Kumar Solingapuram Sai, Thomas M. Gilbert, and Douglas A. Klumpp J. Org. Chem. 2007, 72, 9761-9764 doi:10.1021/jo7013092 Sigma bond In chemistry, sigma bonds (σ bonds) are the strongest type of covalent chemical bond.[1] They are formed by head-on overlapping between atomic orbitals. Sigma bonding is most clearly defined for diatomic molecules using the language and tools of symmetry groups. In this formal approach, a σ-bond is symmetrical with respect to rotation about the bond axis. By this definition, common forms of sigma bonds are s+s, σ bond between two atoms : localization of electron density. pz+pz, s+pz and dz2+dz2 (where z is defined as the axis of the bond).[2] Quantum theory also indicates that molecular orbitals (MO) of identical symmetry actually mix. As a practical consequence of this mixing of diatomic molecules, the wavefunctions s+s and pz+pz molecular orbitals become blended. The extent of this mixing (or blending) depends on the relative energies of the like-symmetry MO's. For homodiatomics, bonding σ orbitals have no nodal planes between the bonded atoms. The corresponding antibonding, or σ* orbital, is defined by the presence of a nodal plane between these two bonded atoms. Sigma bonds are the strongest type of covalent bonds due to the direct overlap of orbitals, and the electrons in these bonds are sometimes referred to as sigma electrons.[3] The symbol σ is the Greek letter sigma (s). When viewed down the bond axis, a σ MO resembles an s atomic orbital. Sigma bond 83 Sigma bonds in polyatomic compounds They are obtained by head-on overlapping of atomic shells. The concept of sigma bonding is extended, albeit loosely, to describe bonding interactions involving overlap of a single lobe of one orbital with a single lobe of another. For example, propane is described as consisting of ten sigma bonds, one each for the two C-C bonds and one each for the eight C-H bonds. The σ bonding in such a polyatomic molecule is highly delocalized, which conflicts with the two-orbital, one-bond concept. Despite this complication, the concept of σ bonding is extremely powerful and therefore pervasive. Sigma bonds in multiple-bonded species Top: atomic orbitals. Bottom: molecular orbitals with the sigma bond of two s-orbitals, a sigma bond of two p-orbitals, and a Pi Bond Compounds that feature multiple bonds, such as the dihydrogen complex, have sigma bonds between the multiple bonded atoms. These sigma bonds can be supplemented with other bonding interactions, such as by π-back donation, e.g. in the case of W(CO)3(PCy3)2(H2), and even δ-bonds, e.g. in the case of chromium(II) acetate.[4] Sigma bonds in organic molecules Organic molecules are often made up of one cyclic compound or more, such as benzene, and are often made up of many sigma bonds along with pi bonds. According to the sigma bond rule, the number of sigma bonds in a molecule is equivalent to the number of atoms plus the number of rings minus one. Nb σ = Nb atoms + Nb rings - 1 This can easily be concluded by realizing that the creation of bonds between atoms that are not connected in a ring requires the same number of atoms minus one (such as in hydrogen gas, H2, where there is only one sigma bond, or ammonia, NH3, where there are only 3 sigma bonds), and that rings do not obey this rule (such as benzene rings, which have 6 sigma bonds within the ring for 6 carbon atoms). References [1] Moore, John; Stanitski, Conrad L.; Jurs, Peter C.. Principles of Chemistry: The Molecular Science (http:/ / books. google. co. in/ books?id=ZOm8L9oCwLMC& pg=PA324& lpg=PA324& dq=sigma+ bond+ stronger+ than+ pi& source=bl& ots=ps9tk8CuCx& sig=phaUUfoNHzSp3XN1MWR7YENyVBE& hl=en& sa=X& ei=lRaqT9PMA8bprAfu3pXsAQ& ved=0CGsQ6AEwBTgU#v=onepage& q=sigma bond stronger than pi& f=false). . [2] Clayden, Jonathan; Greeves, Nick; Warren, Stuart (March 2012) [2002]. Organic Chemistry (http:/ / www. amazon. co. uk/ Organic-Chemistry-Jonathan-Clayden/ dp/ 0199270295/ ref=sr_1_1?ie=UTF8& qid=1331750521& sr=8-1) (2nd ed.). Oxford: OUP Oxford. pp. 101–136. ISBN 978-0199270293. . [3] Keeler, James; Wothers, Peter (May 2008). Chemical Structure and Reactivity (http:/ / www. amazon. co. uk/ Organic-Chemistry-Jonathan-Clayden/ dp/ 0199270295/ ref=sr_1_1?ie=UTF8& qid=1331750521& sr=8-1) (1st ed.). Oxford: OUP Oxford. pp. 27–46. ISBN 978-0199289301. . [4] Kubas, Gregory (2002). "Metal Dihydrogen and σ-Bond Complexes: Structure, Theory, and Reactivity" (http:/ / pubs. acs. org/ doi/ abs/ 10. 1021/ ja0153417?prevSearch=kubas& searchHistoryKey=). JCAS 14: 3799–3800. doi:10.1021/ja0153417. . Sigma bond 84 External links • IUPAC-definition (http://goldbook.iupac.org/S05434.html) Pi bond In chemistry, pi bonds (π bonds) are covalent chemical bonds where two lobes of one involved atomic orbital overlap two lobes of the other involved atomic orbital. These orbitals share a nodal plane which passes through both of the involved nuclei. Electron atomic and molecular orbitals, showing a pi bond at the bottom right of the picture. The Greek letter π in their name refers to p orbitals, since the orbital symmetry of the pi bond is the same as that of the p orbital when seen down the bond axis. P orbitals usually engage in this sort of bonding. D orbitals also engage in pi bonding, and form part of the basis for metal-metal multiple bonding. Pi bonds are usually weaker than sigma bonds. From the perspective of quantum mechanics, this bond's weakness is explained by significantly less overlap between the component p-orbitals due to their parallel Two p-orbitals forming a π-bond. orientation. Pi bonds result from overlap of atomic orbitals that are in contact through two areas of overlap. Pi-bonds are more diffuse bonds than the sigma bonds. Electrons in pi bonds are sometimes referred to as pi electrons. Molecular fragments joined by a pi bond cannot rotate about that bond without breaking the pi bond, because rotation involves destroying the parallel orientation of the constituent p orbitals. For homonuclear diatomic molecules, bonding π molecular orbitals have no nodal planes that pass between the bonded atoms. The corresponding antibonding, or π* ("pi-star") molecular orbital, is defined by the presence of an additional nodal plane between these two bonded atoms. Pi bond 85 Multiple bonds A typical double bond consists of one sigma bond and one pi bond; for example, the C=C double bond in ethylene. A typical triple bond, for example in acetylene, consists of one sigma bond and two pi bonds in two mutually perpendicular planes containing the bond axis. Two pi bonds are the maximum that can exist between a given pair of atoms. Quadruple bonds are extremely rare and can be formed only between transition metal atoms, and consist of one sigma bond, two pi bonds and one delta bond. A pi bond is weaker than a sigma bond, but the combination of pi and sigma bond is stronger than either bond by itself. The enhanced strength of a multiple bond versus a single (sigma bond) is indicated in many ways, but most obviously by a contraction in bond lengths. For example in organic chemistry, carbon–carbon bond lengths are 154 pm in ethane, 134 pm in ethylene and 120 pm in acetylene. More bonds make the total bond shorter and stronger. Comparison of carbon–carbon bond-lengths in simple structures ethane (1 σ bond) ethylene (1 σ bond + 1 π bond) acetylene (1 σ bond + 2 π bonds) Special cases Pi bonds do not necessarily connect a pair of atoms that are also sigma-bonded. In certain metal complexes, pi interactions between a metal atom and alkyne and alkene pi antibonding orbitals form pi-bonds. In some cases of multiple bonds between two atoms, there is no sigma bond at all, only pi bonds. Examples include diiron hexacarbonyl (Fe2(CO)6), dicarbon (C2), and the borane B2H2. In these compounds the central bond consists only of pi bonding, and in order to achieve maximum orbital overlap the bond distances are much shorter than expected.[1] References [1] Bond length and bond multiplicity: σ-bond prevents short π-bonds Eluvathingal D. Jemmis, Biswarup Pathak, R. Bruce King, Henry F. Schaefer III Chemical Communications, 2006, 2164–2166 Abstract (http:/ / dx. doi. org/ 10. 1039/ b602116f) Alkane 86 Alkane Alkanes (also known as paraffins or saturated hydrocarbons) are chemical compounds that consist only of hydrogen and carbon atoms and are bonded exclusively by single bonds (i.e., they are saturated compounds) without any cycles (or loops; i.e., cyclic structure). With the general chemical formula CnH2n+2, alkanes belong to a homologous series of organic compounds in which the members differ by a constant relative molecular mass of 14. They have two main commercial sources: crude oil and natural gas. Each carbon atom has 4 bonds (either C-H or C-C bonds), and each hydrogen atom is joined to a carbon atom (H-C bonds). A series of linked carbon atoms is known as the carbon skeleton or carbon backbone. The number of carbon atoms is used to define the size of the alkane (e.g., C2-alkane). Chemical structure of methane, the simplest alkane An alkyl group, generally abbreviated with the symbol R, is a functional group or side-chain that, like an alkane, consists solely of single-bonded carbon and hydrogen atoms, for example a methyl or ethyl group. The simplest possible alkane (the parent molecule) is methane, CH4. There is no limit to the number of carbon atoms that can be linked together, the only limitation being that the molecule is acyclic, is saturated, and is a hydrocarbon. Saturated oils and waxes are examples of larger alkanes where the number of carbons in the carbon backbone is greater than 10. Alkanes are not very reactive and have little biological activity. Alkanes can be viewed as a molecular tree upon which can be hung the more biologically active/reactive portions (functional groups) of the molecule. Structure classification Saturated hydrocarbons can be: • linear (general formula CnH2n + 2) wherein the carbon atoms are joined in a snake-like structure • branched (general formula CnH2n + 2, n > 3) wherein the carbon backbone splits off in one or more directions • cyclic (general formula CnH2n, n > 2) wherein the carbon backbone is linked so as to form a loop. According to the definition by IUPAC, the former two are alkanes, whereas the third group is called cycloalkanes.[1] Saturated hydrocarbons can also combine any of the linear, cyclic (e.g., polycyclic) and branching structures, and they are still alkanes (no general formula) as long as they are acyclic (i.e., having no loops).They also have single covalent bonds between their carbons. Alkane 87 Isomerism Alkanes with more than three carbon atoms can be arranged in various different ways, forming structural isomers. The simplest isomer of an alkane is the one in which the carbon atoms are arranged in a single chain with no branches. This isomer is sometimes called the n-isomer (n for "normal", although it is not necessarily the most common). However the chain of carbon atoms may also be branched at one or more points. The number of possible isomers increases rapidly with the number of carbon atoms (sequence A000602 in OEIS). For example: • C1: no isomers: methane • C2: no isomers: ethane • C3: no isomers: propane • C4: 2 isomers: n-butane & isobutane • C5: 3 isomers: pentane, isopentane, neopentane • C6: 5 isomers: hexane, 2-Methylpentane, 3-Methylpentane, 2,3-Dimethylbutane & 2,2-Dimethylbutane • C12: 355 isomers • C32: 27,711,253,769 isomers • C60: 22,158,734,535,770,411,074,184 isomers, many of which are not stable. Different C4-alkanes and -cycloalkanes (left to right): n-butane and isobutane are the two C4H10 isomers; cyclobutane and methylcyclopropane are the two C4H8 isomers. Bicyclo[1.1.0]butane is the only C4H6 compound and has no isomer; tetrahedrane (not shown) is the only C4H4 compound and has also no isomer. Branched alkanes can be chiral. For example 3-methylhexane and its higher homologues are chiral due to their stereogenic center at carbon atom number 3. In addition to these isomers, the chain of carbon atoms may form one or more loops. Such compounds are called cycloalkanes. Nomenclature The IUPAC nomenclature (systematic way of naming compounds) for alkanes is based on identifying hydrocarbon chains. Unbranched, saturated hydrocarbon chains are named systematically with a Greek numerical prefix denoting the number of carbons and the suffix "-ane".[2] August Wilhelm von Hofmann suggested systematizing nomenclature by using the whole sequence of vowels a, e, i, o and u to create suffixes -ane, -ene, -ine (or -yne), -one, -une, for the hydrocarbons. The first three name hydrocarbons with single, double and triple bonds; "-one" represents a ketone; "-ol" represents an alcohol or OH group; "-oxy-" means an ether and refers to oxygen between two carbons, so that methoxy-methane is the IUPAC name for dimethyl ether. It is difficult or impossible to find compounds with more than one IUPAC name. This is because shorter chains attached to longer chains are prefixes and the convention includes brackets. Numbers in the name, referring to which carbon a group is attached to, should be as low as possible, so that 1- is implied and usually omitted from names of organic compounds with only one side-group. Symmetric compounds will have two ways of arriving at the same name. Alkane 88 Linear alkanes Straight-chain alkanes are sometimes indicated by the prefix n- (for normal) where a non-linear isomer exists. Although this is not strictly necessary, the usage is still common in cases where there is an important difference in properties between the straight-chain and branched-chain isomers, e.g., n-hexane or 2- or 3-methylpentane. The members of the series (in terms of number of carbon atoms) are named as follows: methane, CH4 - one carbon and four hydrogen ethane, C2H6 - two carbon and six hydrogen propane, C3H8 - three carbon and 8 hydrogen butane, C4H10 - four carbon and 10 hydrogen pentane, C5H12 - five carbon and 12 hydrogen hexane, C6H14 - six carbon and 14 hydrogen These names were derived from methanol, ether, propionic acid and butyric acid, respectively. Alkanes with five or more carbon atoms are named by adding the suffix -ane to the appropriate numerical multiplier prefix[3] with elision of any terminal vowel (-a or -o) from the basic numerical term. Hence, pentane, C5H12; hexane, C6H14; heptane, C7H16; octane, C8H18; etc. The prefix is generally Greek, with the exceptions of nonane which has a Latin prefix, and undecane and tridecane which have mixed-language prefixes. For a more complete list, see List of alkanes. Branched alkanes Simple branched alkanes often have a common name using a prefix to distinguish them from linear alkanes, for example n-pentane, isopentane, and neopentane. IUPAC naming conventions can be used to produce a systematic name. The key steps in the naming of more complicated branched alkanes are as follows:[4] • Identify the longest continuous chain of carbon atoms • Name this longest root chain using standard naming rules • Name each side chain by changing the suffix of the name of the Ball-and-stick model of isopentane (common name) or 2-methylbutane (IUPAC systematic alkane from "-ane" to "-yl" name) • Number the root chain so that sum of the numbers assigned to each side group will be as low as possible • Number and name the side chains before the name of the root chain • If there are multiple side chains of the same type, use prefixes such as "di-" and "tri-" to indicate it as such, and number each one. • Add side chain names in alphabetical (disregarding "di-" etc. prefixes) order in front of the name of the root chain Alkane 89 Comparison of nomenclatures for three isomers of C5H12 Common name IUPAC name Structure n-pentane pentane isopentane neopentane 2-methylbutane 2,2-dimethylpropane Cyclic alkanes So-called cyclic alkanes are, in the technical sense, not alkanes, but cycloalkanes. They are hydrocarbons just like alkanes, but contain one or more rings. Simple cycloalkanes have a prefix "cyclo-" to distinguish them from alkanes. Cycloalkanes are named as per their acyclic counterparts with respect to the number of carbon atoms, e.g., cyclopentane (C5H10) is a cycloalkane with 5 carbon atoms just like pentane (C5H12), but they are joined up in a five-membered ring. In a similar manner, propane and cyclopropane, butane and cyclobutane, etc. Substituted cycloalkanes are named similar to substituted alkanes — the cycloalkane ring is stated, and the substituents are according to their position on the ring, with the numbering decided by Cahn-Ingold-Prelog rules.[3] Trivial names The trivial (non-systematic) name for alkanes is "paraffins." Together, alkanes are known as the paraffin series. Trivial names for compounds are usually historical artifacts. They were coined before the development of systematic names, and have been retained due to familiar usage in industry. Cycloalkanes are also called naphthenes. It is almost certain that the term paraffin stems from the petrochemical industry. Branched-chain alkanes are called isoparaffins. The use of the term "paraffin" is a general term and often does not distinguish between pure compounds and mixtures of isomers with the same chemical formula (i.e., like a chemical anagram), e.g., pentane and isopentane. Examples The following trivial names are retained in the IUPAC system: • isobutane for 2-methylpropane • isopentane for 2-methylbutane • neopentane for 2,2-dimethylpropane. Physical properties Table of alkanes Alkane 90 Alkane Methane Ethane Propane Butane Pentane Hexane Heptane Octane Nonane Decane Undecane Dodecane Icosane Triacontane Formula Boiling point [°C] Melting point [°C] Density [g·cm−3] (at 20 °C) CH4 C2H6 C3H8 C4H10 C5H12 C6H14 C7H16 C8H18 C9H20 C10H22 C11H24 C12H26 C20H42 C30H62 -162 -89 -42 0 36 69 98 126 151 174 196 216 343 450 525 575 625 -182 -183 -188 -138 -130 -95 -91 -57 -54 -30 -26 -10 37 66 82 91 100 gas gas gas gas 0.626 (liquid) 0.659 (liquid) 0.684 (liquid) 0.703 (liquid) 0.718 (liquid) 0.730 (liquid) 0.740 (liquid) 0.749 (liquid) solid solid solid solid solid Tetracontane C40H82 Pentacontane C50H102 Hexacontane C60H122 Boiling point Alkanes experience inter-molecular van der Waals forces. Stronger inter-molecular van der Waals forces give rise to greater boiling points of alkanes.[5] There are two determinants for the strength of the van der Waals forces: • the number of electrons surrounding the molecule, which increases with the alkane's molecular weight • the surface area of the molecule Melting (blue) and boiling (orange) points of the first 16 n-alkanes in °C. Under standard conditions, from CH4 to C4H10 alkanes are gaseous; from C5H12 to C17H36 they are liquids; and after C18H38 they are solids. As the boiling point of alkanes is primarily determined by weight, it should not be a surprise that the boiling point has almost a linear relationship with the size (molecular weight) of the molecule. As a rule of thumb, the boiling point rises 20–30 °C for each carbon added to the chain; this rule applies to other homologous series.[5] A straight-chain alkane will have a boiling point higher than a branched-chain alkane due to the greater surface area in contact, thus the greater van der Waals forces, between adjacent molecules. For example, compare isobutane (2-methylpropane) and n-butane (butane), which boil at −12 and 0 °C, and 2,2-dimethylbutane and 2,3-dimethylbutane which boil at 50 and 58 °C, respectively.[5] For the latter case, two molecules 2,3-dimethylbutane can "lock" into each other better than the cross-shaped 2,2-dimethylbutane, hence the greater van Alkane der Waals forces. On the other hand, cycloalkanes tend to have higher boiling points than their linear counterparts due to the locked conformations of the molecules, which give a plane of intermolecular contact. 91 Melting point The melting points of the alkanes follow a similar trend to boiling points for the same reason as outlined above. That is, (all other things being equal) the larger the molecule the higher the melting point. There is one significant difference between boiling points and melting points. Solids have more rigid and fixed structure than liquids. This rigid structure requires energy to break down. Thus the better put together solid structures will require more energy to break apart. For alkanes, this can be seen from the graph above (i.e., the blue line). The odd-numbered alkanes have a lower trend in melting points than even numbered alkanes. This is because even numbered alkanes pack well in the solid phase, forming a well-organized structure, which requires more energy to break apart. The odd-number alkanes pack less well and so the "looser" organized solid packing structure requires less energy to break apart.[6] The melting points of branched-chain alkanes can be either higher or lower than those of the corresponding straight-chain alkanes, again depending on the ability of the alkane in question to pack well in the solid phase: This is particularly true for isoalkanes (2-methyl isomers), which often have melting points higher than those of the linear analogues. Conductivity and solubility Alkanes do not conduct electricity, nor are they substantially polarized by an electric field. For this reason they do not form hydrogen bonds and are insoluble in polar solvents such as water. Since the hydrogen bonds between individual water molecules are aligned away from an alkane molecule, the coexistence of an alkane and water leads to an increase in molecular order (a reduction in entropy). As there is no significant bonding between water molecules and alkane molecules, the second law of thermodynamics suggests that this reduction in entropy should be minimized by minimizing the contact between alkane and water: Alkanes are said to be hydrophobic in that they repel water. Their solubility in nonpolar solvents is relatively good, a property that is called lipophilicity. Different alkanes are, for example, miscible in all proportions among themselves. The density of the alkanes usually increases with increasing number of carbon atoms, but remains less than that of water. Hence, alkanes form the upper layer in an alkane-water mixture. Molecular geometry The molecular structure of the alkanes directly affects their physical and chemical characteristics. It is derived from the electron configuration of carbon, which has four valence electrons. The carbon atoms in alkanes are always sp3 hybridized, that is to say that the valence electrons are said to be in four equivalent orbitals derived from the combination of the 2s orbital and the three 2p orbitals. These orbitals, which have identical energies, are arranged spatially in the form of a tetrahedron, the angle of cos−1(−⅓) ≈ 109.47° between them. sp3-hybridization in methane. Alkane 92 Bond lengths and bond angles An alkane molecule has only C – H and C – C single bonds. The former result from the overlap of a sp³-orbital of carbon with the 1s-orbital of a hydrogen; the latter by the overlap of two sp³-orbitals on different carbon atoms. The bond lengths amount to 1.09×10−10 m for a C – H bond and 1.54×10−10 m for a C – C bond. The spatial arrangement of the bonds is similar to that of the four sp³-orbitals—they are tetrahedrally arranged, with an angle of 109.47° between them. Structural formulae that represent the bonds as being at right angles to one another, while both common and useful, do not correspond with the reality. Conformation The structural formula and the bond angles are not usually sufficient to completely describe the geometry of a molecule. There is a further degree of freedom for each carbon – carbon bond: the torsion angle between the atoms or groups bound to the atoms at each end of the bond. The spatial arrangement described by the torsion angles of the molecule is known as its conformation. Ethane forms the simplest case for studying the conformation of alkanes, as there is only one C – C bond. If one looks down the axis of the C – C bond, one will see the so-called Newman projection. The hydrogen atoms on both the front and rear carbon atoms have an angle of 120° between them, resulting from the projection of the base of the tetrahedron onto a flat plane. However, the torsion angle between a given hydrogen atom attached to the front carbon and a given hydrogen atom attached to the rear carbon can vary freely between 0° and 360°. This is a consequence of the free rotation about a carbon – carbon single bond. Despite this apparent freedom, only two limiting conformations are important: eclipsed conformation and staggered conformation. The two conformations, also known as rotamers, differ in energy: The staggered conformation is 12.6 kJ/mol lower in energy (more stable) than the eclipsed conformation (the least stable). Ball-and-stick models of the two rotamers of ethane The tetrahedral structure of methane. Newman projections of the two conformations of ethane: eclipsed on the left, staggered on the right. This difference in energy between the two conformations, known as the torsion energy, is low compared to the thermal energy of an ethane molecule at ambient temperature. There is constant rotation about the C-C bond. The time taken for an ethane molecule to pass from one staggered conformation to the next, equivalent to the rotation of one CH3-group by 120° relative to the other, is of the order of 10−11 seconds. The case of higher alkanes is more complex but based on similar principles, with the antiperiplanar conformation always being the most favored around each carbon-carbon bond. For this reason, alkanes are usually shown in a zigzag arrangement in diagrams or in models. The actual structure will always differ somewhat from these idealized forms, as the differences in energy between the conformations are small compared to the thermal energy of the molecules: Alkane molecules have no fixed structural form, whatever the models may suggest. Alkane 93 Spectroscopic properties Virtually all organic compounds contain carbon – carbon and carbon – hydrogen bonds, and so show some of the features of alkanes in their spectra. Alkanes are notable for having no other groups, and therefore for the absence of other characteristic spectroscopic features. Infrared spectroscopy The carbon–hydrogen stretching mode gives a strong absorption between 2850 and 2960 cm−1, while the carbon–carbon stretching mode absorbs between 800 and 1300 cm−1. The carbon–hydrogen bending modes depend on the nature of the group: methyl groups show bands at 1450 cm−1 and 1375 cm−1, while methylene groups show bands at 1465 cm−1 and 1450 cm−1. Carbon chains with more than four carbon atoms show a weak absorption at around 725 cm−1. NMR spectroscopy The proton resonances of alkanes are usually found at δH = 0.5 – 1.5. The carbon-13 resonances depend on the number of hydrogen atoms attached to the carbon: δC = 8 – 30 (primary, methyl, -CH3), 15 – 55 (secondary, methylene, -CH2-), 20 – 60 (tertiary, methyne, C-H) and quaternary. The carbon-13 resonance of quaternary carbon atoms is characteristically weak, due to the lack of Nuclear Overhauser effect and the long relaxation time, and can be missed in weak samples, or samples that have not been run for a sufficiently long time. Mass spectrometry Alkanes have a high ionization energy, and the molecular ion is usually weak. The fragmentation pattern can be difficult to interpret, but, in the case of branched chain alkanes, the carbon chain is preferentially cleaved at tertiary or quaternary carbons due to the relative stability of the resulting free radicals. The fragment resulting from the loss of a single methyl group (M−15) is often absent, and other fragment are often spaced by intervals of fourteen mass units, corresponding to sequential loss of CH2-groups. Chemical properties In general, alkanes show an alkane activity, because their C bonds are relatively stable and cannot be easily broken. Unlike most other organic compounds, they possess no functional groups. They react only very poorly with ionic or other polar substances. The acid dissociation constant (pKa) values of all alkanes are above 60, hence they are practically inert to acids and bases (see: carbon acids). This inertness is the source of the term paraffins (with the meaning here of "lacking affinity"). In crude oil the alkane molecules have remained chemically unchanged for millions of years. However redox reactions of alkanes, in particular with oxygen and the halogens, are possible as the carbon atoms are in a strongly reduced condition; in the case of methane, the lowest possible oxidation state for carbon (−4) is reached. Reaction with oxygen (if an amount of the least is enough to meet the reaction stoichiometry) leads to combustion without any smoke; with halogens, substitution. In addition, alkanes have been shown to interact with, and bind to, certain transition metal complexes in (See: carbon-hydrogen bond activation). Free radicals, molecules with unpaired electrons, play a large role in most reactions of alkanes, such as cracking and reformation where long-chain alkanes are converted into shorter-chain alkanes and straight-chain alkanes into branched-chain isomers. In highly branched alkanes, the bond angle may differ significantly from the optimal value (109.5°) in order to allow the different groups sufficient space. This causes a tension in the molecule, known as steric hindrance, and can substantially increase the reactivity. Alkane 94 Reactions with oxygen (combustion reaction) All alkanes react with oxygen in a combustion reaction, although they become increasingly difficult to ignite as the number of carbon atoms increases. The general equation for complete combustion is: CnH2n+2 + (1.5n+0.5)O2 → (n+1)H2O + nCO2 In the absence of sufficient oxygen, carbon monoxide or even soot can be formed, as shown below: CnH(2n+2) + (n+0.5)O2 → (n+1)H2O + nCO CnH(2n+2) + (0.5n+0.5)O2 → (n+1)H2O + nC For example methane: 2CH4 + 3O2 → 2CO + 4H2O See the alkane heat of formation table for detailed data. The standard enthalpy change of combustion, ΔcHo, for alkanes increases by about 650 kJ/mol per CH2 group. Branched-chain alkanes have lower values of ΔcHo than straight-chain alkanes of the same number of carbon atoms, and so can be seen to be somewhat more stable. CH4 + 1.5O2 → CO + 2H2O Reactions with halogens Alkanes react with halogens in a so-called free radical halogenation reaction. The hydrogen atoms of the alkane are progressively replaced by halogen atoms. Free-radicals are the reactive species that participate in the reaction, which usually leads to a mixture of products. The reaction is highly exothermic, and can lead to an explosion. These reactions are an important industrial route to halogenated hydrocarbons. There are three steps: • Initiation the halogen radicals form by homolysis. Usually, energy in the form of heat or light is required. • Chain reaction or Propagation then takes place—the halogen radical abstracts a hydrogen from the alkane to give an alkyl radical. This reacts further. • Chain termination where step the radicals recombine. Experiments have shown that all halogenation produces a mixture of all possible isomers, indicating that all hydrogen atoms are susceptible to reaction. The mixture produced, however, is not a statistical mixture: Secondary and tertiary hydrogen atoms are preferentially replaced due to the greater stability of secondary and tertiary free-radicals. An example can be seen in the monobromination of propane:[5] [In the Figure below, the Statistical Distribution should be 25% and 75%] Alkane 95 Cracking Cracking breaks larger molecules into smaller ones. This can be done with a thermal or catalytic method. The thermal cracking process follows a homolytic mechanism with formation of free-radicals. The catalytic cracking process involves the presence of acid catalysts (usually solid acids such as silica-alumina and zeolites), which promote a heterolytic (asymmetric) breakage of bonds yielding pairs of ions of opposite charges, usually a carbocation and the very unstable hydride anion. Carbon-localized free-radicals and cations are both highly unstable and undergo processes of chain rearrangement, C-C scission in position beta (i.e., cracking) and intra- and intermolecular hydrogen transfer or hydride transfer. In both types of processes, the corresponding reactive intermediates (radicals, ions) are permanently regenerated, and thus they proceed by a self-propagating chain mechanism. The chain of reactions is eventually terminated by radical or ion recombination. Isomerization and reformation Dragan and his colleague were the first to report about isomerization in alkanes.[7] Isomerization and reformation are processes in which straight-chain alkanes are heated in the presence of a platinum catalyst. In isomerization, the alkanes become branched-chain isomers. In other words, it does not lose any carbons or hydrogens, keeping the same molecular weight.[7] In reformation, the alkanes become cycloalkanes or aromatic hydrocarbons, giving off hydrogen as a by-product. Both of these processes raise the octane number of the substance. Butane is the most common alkane that is put under the process of isomerization, as it makes many branched alkanes with high octane numbers.[7] Other reactions Alkanes will react with steam in the presence of a nickel catalyst to give hydrogen. Alkanes can be chlorosulfonated and nitrated, although both reactions require special conditions. The fermentation of alkanes to carboxylic acids is of some technical importance. In the Reed reaction, sulfur dioxide, chlorine and light convert hydrocarbons to sulfonyl chlorides. Nucleophilic Abstraction can be used to separate an alkane from a metal. Alkyl groups can be transferred from one compound to another by transmetalation reactions. Occurrence Occurrence of alkanes in the Universe Alkanes form a small portion of the atmospheres of the outer gas planets such as Jupiter (0.1% methane, 0.0002% ethane), Saturn (0.2% methane, 0.0005% ethane), Uranus (1.99% methane, 0.00025% ethane) and Neptune (1.5% methane, 1.5 ppm ethane). Titan (1.6% methane), a satellite of Saturn, was examined by the Huygens probe, which indicated that Titan's atmosphere periodically rains liquid methane onto the moon's surface.[8] Also on Titan, a methane-spewing volcano was spotted and this volcanism is believed to be a significant source of the methane in the atmosphere. There also appear to be Methane/Ethane lakes near the north polar regions of Titan, as discovered by Cassini's radar imaging. Methane and ethane have also been detected in the tail of the comet Hyakutake. Chemical analysis showed that the abundances of ethane and methane were roughly equal, which is thought to imply that its ices formed in interstellar Methane and ethane make up a tiny proportion of Jupiter's atmosphere Alkane 96 space, away from the Sun, which would have evaporated these volatile molecules.[9] Alkanes have also been detected in meteorites such as carbonaceous chondrites. Occurrence of alkanes on Earth Traces of methane gas (about 0.0002% or 1745 ppb) occur in the Earth's atmosphere, produced primarily by methanogenic microorganisms, such as Archaea in the gut of ruminants.[10] Extraction of oil, which contains many different The most important commercial sources for alkanes are natural gas and hydrocarbons including alkanes oil.[5] Natural gas contains primarily methane and ethane, with some propane and butane: oil is a mixture of liquid alkanes and other hydrocarbons. These hydrocarbons were formed when dead marine animals and plants (zooplankton and phytoplankton) died and sank to the bottom of ancient seas and were covered with sediments in an anoxic environment and converted over many millions of years at high temperatures and high pressure to their current form. Natural gas resulted thereby for example from the following reaction: C6H12O6 → 3CH4 + 3CO2 These hydrocarbon deposits, collected in porous rocks trapped beneath impermeable cap rocks, comprise commercial oil fields. They have formed over millions of years and once exhausted cannot be readily replaced. The depletion of these hydrocarbons reserves is the basis for what is known as the energy crisis. Methane is also present in what is called biogas, produced by animals and decaying matter, which is a possible renewable energy source. Alkanes have a low solubility in water, so the content in the oceans is negligible; however, at high pressures and low temperatures (such as at the bottom of the oceans), methane can co-crystallize with water to form a solid methane clathrate (methane hydrate). Although this cannot be commercially exploited at the present time, the amount of combustible energy of the known methane clathrate fields exceeds the energy content of all the natural gas and oil deposits put together. Methane extracted from methane clathrate is therefore a candidate for future fuels. Biological occurrence Although alkanes occur in nature in various way, they do not rank biologically among the essential materials. Cycloalkanes with 14 to 18 carbon atoms occur in musk, extracted from deer of the family Moschidae. All further information refers to (acyclic) alkanes. Bacteria and archaea Certain types of bacteria can metabolize alkanes: they prefer even-numbered carbon chains as they are easier to degrade than odd-numbered chains. On the other hand, certain archaea, the methanogens, produce large quantities of methane by the metabolism of carbon dioxide or other oxidized organic compounds. The energy is released by the oxidation of hydrogen: CO2 + 4H2 → CH4 + 2H2O Methanogens are also the producers of marsh gas in wetlands, and release about two billion tonnes of methane per year—the atmospheric Methanogenic archaea in the gut of this cow are responsible for some of the methane in Earth's atmosphere. Alkane content of this gas is produced nearly exclusively by them. The methane output of cattle and other herbivores, which can release up to 150 liters per day, and of termites, is also due to methanogens. They also produce this simplest of all alkanes in the intestines of humans. Methanogenic archaea are, hence, at the end of the carbon cycle, with carbon being released back into the atmosphere after having been fixed by photosynthesis. It is probable that our current deposits of natural gas were formed in a similar way. Fungi and plants Alkanes also play a role, if a minor role, in the biology of the three eukaryotic groups of organisms: fungi, plants and animals. Some specialized yeasts, e.g., Candida tropicale, Pichia sp., Rhodotorula sp., can use alkanes as a source of carbon and/or energy. The fungus Amorphotheca resinae prefers the longer-chain alkanes in aviation fuel, and can cause serious problems for aircraft in tropical regions.[11] In plants, the solid long-chain alkanes are found in the plant cuticle and epicuticular wax of many species, but are only rarely major constituents.[12] They protect the plant against water loss, prevent the leaching of important minerals by the rain, and protect against bacteria, fungi, and harmful insects. The carbon chains in plant alkanes are usually odd-numbered, between twenty-seven and thirty-three carbon atoms in length[12] and are made by the plants by decarboxylation of even-numbered fatty acids. The exact composition of the layer of wax is not only species-dependent, but changes also with the season and such environmental factors as lighting conditions, temperature or humidity.[12] Animals Alkanes are found in animal products, although they are less important than unsaturated hydrocarbons. One example is the shark liver oil, which is approximately 14% pristane (2,6,10,14-tetramethylpentadecane, C19H40). They are important as pheromones, chemical messenger materials, on which insects depend for communication. In some species, e.g. the support beetle Xylotrechus colonus, pentacosane (C25H52), 3-methylpentaicosane (C26H54) and 9-methylpentaicosane (C26H54) are transferred by body contact. With others like the tsetse fly Glossina morsitans morsitans, the pheromone contains the four alkanes 2-methylheptadecane (C18H38), 17,21-dimethylheptatriacontane (C39H80), 15,19-dimethylheptatriacontane (C39H80) and 15,19,23-trimethylheptatriacontane (C40H82), and acts by smell over longer distances. Waggle-dancing honeybees produce and release two alkanes, tricosane and pentacosane.[13] 97 Ecological relations One example, in which both plant and animal alkanes play a role, is the ecological relationship between the sand bee (Andrena nigroaenea) and the early spider orchid (Ophrys sphegodes); the latter is dependent for pollination on the former. Sand bees use pheromones in order to identify a mate; in the case of A. nigroaenea, the females emit a mixture of tricosane (C23H48), pentacosane (C25H52) and heptacosane (C27H56) in the ratio 3:3:1, and males are attracted by specifically this odor. The orchid takes advantage of this mating arrangement to get the male bee to collect and disseminate its pollen; parts of its flower not only resemble the appearance of sand bees, but also produce large quantities of the three alkanes in the same ratio as female sand bees. As a result numerous males are lured to the blooms and attempt to copulate with their imaginary partner: although this endeavor is not crowned with success for the bee, it allows the orchid to transfer its pollen, which will be dispersed after the departure of the frustrated male to different blooms. Early spider orchid (Ophrys sphegodes) Alkane 98 Production Petroleum refining As stated earlier, the most important source of alkanes is natural gas and crude oil.[5] Alkanes are separated in an oil refinery by fractional distillation and processed into many different products. Fischer-Tropsch The Fischer-Tropsch process is a method to synthesize liquid hydrocarbons, including alkanes, from carbon monoxide and hydrogen. This method is used to produce substitutes for petroleum distillates. An oil refinery at Martinez, California. Laboratory preparation There is usually little need for alkanes to be synthesized in the laboratory, since they are usually commercially available. Also, alkanes are generally non-reactive chemically or biologically, and do not undergo functional group interconversions cleanly. When alkanes are produced in the laboratory, it is often a side-product of a reaction. For example, the use of n-butyllithium as a strong base gives the conjugate acid, n-butane as a side-product: C4H9Li + H2O → C4H10 + LiOH However, at times it may be desirable to make a portion of a molecule into an alkane like functionality (alkyl group) using the above or similar methods. For example, an ethyl group is an alkyl group; when this is attached to a hydroxy group, it gives ethanol, which is not an alkane. To do so, the best-known methods are hydrogenation of alkenes: RCH=CH2 + H2 → RCH2CH3 (R = alkyl) Alkanes or alkyl groups can also be prepared directly from alkyl halides in the Corey-House-Posner-Whitesides reaction. The Barton-McCombie deoxygenation[14][15] removes hydroxyl groups from alcohols e.g. and the Clemmensen reduction[16][17][18][19] removes carbonyl groups from aldehydes and ketones to form alkanes or alkyl-substituted compounds e.g.: Alkane 99 Applications The applications of a certain alkane can be determined quite well according to the number of carbon atoms. The first four alkanes are used mainly for heating and cooking purposes, and in some countries for electricity generation. Methane and ethane are the main components of natural gas; they are normally stored as gases under pressure. It is, however, easier to transport them as liquids: This requires both compression and cooling of the gas. Propane and butane can be liquefied at fairly low pressures, and are well known as liquified petroleum gas (LPG). Propane, for example, is used in the propane gas burner and as a fuel for cars,[20] butane in disposable cigarette lighters. The two alkanes are used as propellants in aerosol sprays. From pentane to octane the alkanes are reasonably volatile liquids. They are used as fuels in internal combustion engines, as they vaporise easily on entry into the combustion chamber without forming droplets, which would impair the uniformity of the combustion. Branched-chain alkanes are preferred as they are much less prone to premature ignition, which causes knocking, than their straight-chain homologues. This propensity to premature ignition is measured by the octane rating of the fuel, where 2,2,4-trimethylpentane (isooctane) has an arbitrary value of 100, and heptane has a value of zero. Apart from their use as fuels, the middle alkanes are also good solvents for nonpolar substances. Alkanes from nonane to, for instance, hexadecane (an alkane with sixteen carbon atoms) are liquids of higher viscosity, less and less suitable for use in gasoline. They form instead the major part of diesel and aviation fuel. Diesel fuels are characterized by their cetane number, cetane being an old name for hexadecane. However, the higher melting points of these alkanes can cause problems at low temperatures and in polar regions, where the fuel becomes too thick to flow correctly. Alkanes from hexadecane upwards form the most important components of fuel oil and lubricating oil. In the latter function, they work at the same time as anti-corrosive agents, as their hydrophobic nature means that water cannot reach the metal surface. Many solid alkanes find use as paraffin wax, for example, in candles. This should not be confused however with true wax, which consists primarily of esters. Alkanes with a chain length of approximately 35 or more carbon atoms are found in bitumen, used, for example, in road surfacing. However, the higher alkanes have little value and are usually split into lower alkanes by cracking. Some synthetic polymers such as polyethylene and polypropylene are alkanes with chains containing hundreds of thousands of carbon atoms. These materials are used in innumerable applications, and billions of kilograms of these materials are made and used each year. Environmental transformations When released in the environment, alkanes don't undergo rapid biodegradation, because they have no functional groups (like hydroxyl or carbonyl) that are needed by most organisms in order to metabolize the compound. However, some bacteria can metabolize some alkanes (especially those linear and short), by oxidizing the terminal carbon atom. The product is an alcohol, that could be next oxidized to an aldehyde, and finally to a carboxylic acid. The resulting fatty acid could be metabolized through the fatty acid degradation pathway. Alkane 100 Hazards Methane is explosive when mixed with air (1 – 8% CH4). Other lower alkanes can also form explosive mixtures with air. The lighter liquid alkanes are highly flammable, although this risk decreases with the length of the carbon chain. Pentane, hexane, heptane, and octane are classed as dangerous for the environment and harmful. The straight-chain isomer of hexane is a neurotoxin. References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "alkanes" (http:/ / goldbook. iupac. org/ A00222. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.A00222. ISBN 0-9678550-9-8. . [2] IUPAC, Commission on Nomenclature of Organic Chemistry (1993). "R-2.2.1: Hydrocarbons" (http:/ / www. acdlabs. com/ iupac/ nomenclature/ 93/ r93_184. htm). A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations 1993). Blackwell Scientific. ISBN 0-632-03488-2. . Retrieved 12 February 2007. [3] William Reusch. "Nomenclature - Alkanes" (http:/ / www. cem. msu. edu/ ~reusch/ VirtualText/ nomen1. htm). Virtual Textbook of Organic Chemistry. . [4] William Reusch. "Examples of the IUPAC Rules in Practice" (http:/ / www. cem. msu. edu/ ~reusch/ VirtualText/ nomexmp1. htm). Virtual Textbook of Organic Chemistry. . [5] R. T. Morrison, R. N. Boyd (1992). Organic Chemistry (6th ed.). New Jersey: Prentice Hall. ISBN 0-13-643669-2. [6] Boese R, Weiss HC, Blaser D (1999). "The melting point alternation in the short-chain n-alkanes: Single-crystal X-ray analyses of propane at 30 K and of n-butane to n-nonane at 90 K". Angew Chemie Int Ed 38: 988–992. doi:10.1002/(SICI)1521-3773(19990401)38:73.3.CO;2-S. [7] Asinger, Friedrich. Paraffins; Chemistry and Technology. Oxford: Pergamon Press, 1967. Print. [8] Titan: Arizona in an Icebox? (http:/ / www. planetary. org/ news/ 2005/ huygens_science-results_0121. html), Emily Lakdawalla, 21 January 2004, verified 28 March 2005. [9] Mumma, M.J.; Disanti, M.A., dello Russo, N., Fomenkova, M., Magee-Sauer, K., Kaminski, C.D., and D.X. Xie (1996). "Detection of Abundant Ethane and Methane, Along with Carbon Monoxide and Water, in Comet C/1996 B2 Hyakutake: Evidence for Interstellar Origin". Science 272 (5266): 1310–4. Bibcode 1996Sci...272.1310M. doi:10.1126/science.272.5266.1310. PMID 8650540. [10] Janssen, P. H.; Kirs, M. (2008). "Structure of the Archaeal Community of the Rumen". Appl Environ Microbiol 74 (12): 3619–3625. doi:10.1128/AEM.02812-07. PMC 2446570. PMID 18424540. [11] Hendey, N. I. (1964). "Some observations on Cladosporium resinae as a fuel contaminant and its possible role in the corrosion of aluminium alloy fuel tanks". Transactions of the British Mycological Society 47 (7): 467–475. [12] EA Baker (1982) Chemistry and morphology of plant epicuticular waxes. pp139-165. In "The Plant Cuticle". edited by DF Cutler, KL Alvin and CE Price. Academic Press, London. ISBN 0-12-199920-3 [13] Thom, et al. (21 August 2007). "The Scent of the Waggle Dance". PLoS Biology 5 (9): e228. doi:10.1371/journal.pbio.0050228. PMC 1994260. PMID 17713987. [14] Barton, D. H. R.; McCombie, S. W. (1975). "A new method for the deoxygenation of secondary alcohols". J. Chem. Soc., Perkin Trans. 1 (16): 1574–1585. doi:10.1039/P19750001574. [15] Crich, David; Quintero, Leticia (1989). "Radical chemistry associated with the thiocarbonyl group". Chem. Rev. 89 (7): 1413–1432. doi:10.1021/cr00097a001. [16] Martin, E. L. Org. React. 1942, 1, 155. (Review) [17] Buchanan, J. G. St. C.; Woodgate, P. D. Quart. Rev. 1969, 23, 522, (Review). [18] Vedejs, E. Org. React. 1975, 22, 401, (Review). [19] Yamamura, S.; Nishiyama, S. Comp. Org. Syn. 1991, 8, 309-313,(Review). [20] Using propane as a fuel (http:/ / www. ferrellgas. com/ Resource_/ PageResource/ LA_Transit_Case_Study. pdf/ ) Further reading • Virtual Textbook of Organic Chemistry (http://www.cem.msu.edu/~reusch/VirtualText/intro1.htm) Amine 101 Amine Primary amine Secondary amine Tertiary amine Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group.[1] Important amines include amino acids, biogenic amines, trimethylamine, and aniline; see Category:Amines for a list of amines. Inorganic derivatives of ammonia are also called amines, such as chloramine (NClH2). Compounds with the nitrogen atom attached to a carbonyl of the structure R–CO–NR′R″ are called amides and have different chemical properties from amines. Classes of amines An aliphatic amine has no aromatic ring attached directly to the nitrogen atom.[2] Aromatic amines have the nitrogen atom connected to an aromatic ring as in the various anilines. The aromatic ring decreases the alkalinity of the amine, depending on its substituents. The presence of an amine group strongly increases the reactivity of the aromatic ring, due to an electron-donating effect. Amines are organized into four subcategories: • Primary amines - Primary amines arise when one of three hydrogen atoms in ammonia is replaced by an alkyl or aromatic. Important primary alkyl amines include methylamine, ethanolamine (2-aminoethanol), and the buffering agent tris, while primary aromatic amines include aniline. • Secondary amines - Secondary amines have two substituents (alkyl, aryl or both) bound to N together with one hydrogen. Important representatives include dimethylamine and methylethanolamine, while an example of an aromatic amine would be diphenylamine. • Tertiary amines - In tertiary amines, all three hydrogen atoms are replaced by organic substituents. Examples include trimethylamine, which has a distinctively fishy smell or triphenylamine. • Cyclic amines - Cyclic amines are either secondary or tertiary amines. Examples of cyclic amines include the 3-member ring aziridine and the six-membered ring piperidine. N-methylpiperidine and N-phenylpiperidine are examples of cyclic tertiary amines. It is also possible to have four organic substituents on the nitrogen. These species are not amines but are quaternary ammonium cations and have a charged nitrogen center. Quaternary ammonium salts exist with many kinds of anions. Amine 102 Naming conventions Amines are named in several ways. Typically, the compound is given the prefix "amino-" or the suffix: "-amine." The prefix "N-" shows substitution on the nitrogen atom. An organic compound with multiple amino groups is called a diamine, triamine, tetraamine and so forth. Systematic names for some common amines: Lower amines are named with the suffix -amine. Higher amines have the prefix amino as a functional group. methylamine 2-aminopentane (or sometimes: pent-2-yl-amine or pentan-2-amine) Physical properties Hydrogen bonding significantly influences the properties of primary and secondary amines.[3] Thus the boiling point of amines is higher than those of the corresponding phosphines, but generally lower than those of the corresponding alcohols. For example, methylamine and ethylamine are gases under standard conditions, whereas the corresponding methyl alcohol and ethyl alcohols are liquids. Gaseous amines possess a characteristic ammonia smell, liquid amines have a distinctive "fishy" smell. Also reflecting their ability to form hydrogen bonds, most aliphatic amines display some solubility in water. Solubility decreases with the increase in the number of carbon atoms. Aliphatic amines display significant solubility in organic solvents, especially polar organic solvents. Primary amines react with ketones such as acetone. The aromatic amines, such as aniline, have their lone pair electrons conjugated into the benzene ring, thus their tendency to engage in hydrogen bonding is diminished. Their boiling points are high and their solubility in water is low. Chirality  ⇌  Inversion of an amine. The pair of dots represents the lone electron pair on the nitrogen atom. Amines of the type NHRR′ and NRR′R″ are chiral: the nitrogen atom bears four substituents counting the lone pair. The energy barrier for the inversion of the stereocenter is relatively low, e.g., ~7 kcal/mol for a trialkylamine. The interconversion of the stereoisomers has been compared to the inversion of an open umbrella in to a strong wind. Because of this low barrier, amines such as NHRR′ cannot be resolved optically and NRR′R″ can only be resolved when the R, R′, and R″ groups are constrained in cyclic structures such as aziridines. Quaternary ammonium salts with four distinct groups on the nitrogen are capable of exhibiting optical activity. Amine 103 Properties as bases Like ammonia, amines are bases. Compared to alkali metal hydroxides, amines are weaker (see table for examples of conjugate acid Ka values). The basicity of amines depends on: 1. The electronic properties of the substituents (alkyl groups enhance the basicity, aryl groups diminish it). 2. Steric hindrance offered by the groups on nitrogen. 3. The degree of solvation of the protonated amine. The nitrogen atom features a lone electron pair that can bind H+ to form an ammonium ion R3NH+. The lone electron pair is represented in this article by a two dots above or next to the N. The water solubility of simple amines is largely due to hydrogen bonding between protons in the water molecules and these lone electron pairs. • Inductive effect of alkyl groups Ions of compound Ammonia NH3 Kb 1.8·10−5 M Propylamine CH3CH2CH2NH2 4.7·10−4 M 2-Propylamine (CH3)2CHNH2 3.4·10−4 M Methylamine CH3NH2 Dimethylamine (CH3)2NH Trimethylamine (CH3)3N 4.4·10−4 M 5.4·10−4 M 5.9·10−5 M +I effect of alkyl groups raises the energy of the lone pair of electrons, thus elevating the basicity. Thus the basicity of an amine may be expected to increase with the number of alkyl groups on the amine. However, there is no strict trend in this regard, as basicity is also governed by other factors mentioned above. Consider the Kb values of the methyl amines given above. The increase in Kb from methylamine to dimethylamine may be attributed to +I effect; however, there is a decrease from dimethylamine to trimethyl amine due to the predominance of steric hindrance offered by the three methyl groups to the approaching Brönsted acid. • Mesomeric effect of aromatic systems Ions of compound Ammonia NH3 Aniline C6H5NH2 Kb 1.8·10−5 M 3.8·10−10 M 4-Methylaniline 4-CH3C6H4NH2 1.2·10−9 M 2-Nitroaniline 3-Nitroaniline 4-Nitroaniline 1.5·10−15 M 2.8·10−13 M 9.5·10−14 M -M effect of aromatic ring delocalises the lone pair of electrons on nitrogen into the ring, resulting in decreased basicity. Substituents on the aromatic ring, and their positions relative to the amine group may also considerably alter basicity as seen above. The solvation of protonated amines changes upon their conversion to ammonium compounds. Typically salts of ammonium compounds exhibit the following order of solubility in water: primary ammonium (RNH3+) > secondary ammonium (R2NH2+) > tertiary ammonium (R3NH+). Quaternary ammonium salts usually exhibit the lowest solubility of the series. Amine In sterically hindered amines, as in the case of trimethylamine, the protonated form is not well-solvated. For this reason the parent amine is less basic than expected. In the case of aprotic polar solvents (like DMSO and DMF), wherein the extent of solvation is not as high as in protic polar solvents (like water and methanol), the basicity of amines is almost solely governed by the electronic factors within the molecule. 104 Synthesis Alkylation The most industrially significant amines are prepared from ammonia by alkylation with alcohols: ROH + NH3 → RNH2 + H2O These reactions require catalysts, specialized apparatus, and additional purification measures since the selectivity can be problematic. The same amines can be prepared by treatment of Haloalkanes with ammonia and amines: RX + 2 R′NH2 → RR′NH + [RR′NH2]X Such reactions, which are most useful for alkyl iodides and bromides, are rarely employed because the degree of alkylation is difficult to control.[4] Reductive routes Via the process of hydrogenation, nitriles are reduced to amines using hydrogen in the presence of a nickel catalyst. Reactions are sensitive acidic or alkaline conditions, which can cause hydrolysis of -CN group. LiAlH4 is more commonly employed for the reduction of nitriles on the laboratory scale. Similarly, LiAlH4 reduces amides to amines. Many amines are produced from aldehydes and ketones via reductive amination, which can either proceed catalytically or stoichiometrically. Aniline (C6H5NH2) and its derivatives are prepared by reduction of the nitroaromatics. In industry, hydrogen is the preferred reductant, whereas in the laboratory, tin and iron are often employed. Specialized methods Many laboratory methods exist for the preparation of amines, many of these methods being rather specialized. Reaction name Gabriel synthesis Staudinger reduction Schmidt reaction Aza-Baylis–Hillman reaction Hofmann degradation Substrate organohalide Azide carboxylic acid imine Synthesis of allylic amines reagent: potassium phthalimide This reaction also takes place with a reducing agent such as lithium aluminium hydride. Comment amide This reaction is valid for preparation of primary amines only. Gives good yields of primary amines uncontaminated with other amines. upon treatment with strong base Hofmann elimination Quaternary ammonium salt amides nitriles nitro compounds Amide reduction Nitrile reduction Reduction of nitro compounds Amine alkylation Delepine reaction can be accomplished with elemental zinc, tin or iron with an acid. haloalkane organohalide reagent hexamine Amine 105 aryl halide specific for aryl amines Buchwald–Hartwig reaction Menshutkin reaction hydroamination Hofmann–Löffler reaction tertiary amine alkenes and alkynes haloamine reaction product a quaternary ammonium cation Reactions Alkylation, acylation, and sulfonation Aside from their basicity, the dominant reactivity of amines is their nucleophilicity.[5] Most primary amines are good ligands for metal ions to give coordination complexes. Amines are alkylated by alkyl halides. Acyl chlorides and acid anhydrides react with primary and secondary amines to form amides (the "Schotten–Baumann reaction"). Similarly, with sulfonyl chlorides, one obtains sulfonamides. This transformation, known as the Hinsberg reaction, is a chemical test for the presence of amines. Because amines are basic, they neutralize acids to form the corresponding ammonium salts R3NH+. When formed from carboxylic acids and primary and secondary amines, these salts thermally dehydrate to form the corresponding amides. Amine 106 Diazotization Amines react with nitrous acid to give diazonium salts. The alkyl diazonium salts are of little synthetic importance because they are too unstable. The most important members are derivatives of aromatic amines such as aniline ("phenylamine") (A = aryl or naphthyl): Anilines and naphthylamines form more stable diazonium salts, which can be isolated in the crystalline form.[6] Diazonium salts undergo a variety of useful transformations involving replacement of the N2 group with anions. For example, cuprous cyanide gives the corresponding nitriles: AN2+ + Y− → AY + N2 Aryldiazonium couple with electron-rich aromatic compounds such as a phenol to form azo compounds. Such reactions are widely applied to the production of dyes.[7] ANH2 + HNO2 + HX → AN2+X− + 2 H2O Conversion to imines Imine formation is an important reaction. Primary amines react with ketones and aldehydes to form imines. In the case of formaldehyde (R′ = H), these products typically exist as cyclic trimers. RNH2 + R′2C=O → R′2C=NR + H2O Reduction of these imines gives secondary amines: R′2C=NR + H2 → R′2CH–NHR Similarly, secondary amines react with ketones and aldehydes to form enamines: R2NH + R′(R″CH2)C=O → R″CH=C(NR2)R′ + H2O Overview An overview of the reactions of amine is given below: Reaction name Amine alkylation Schotten–Baumann reaction Hinsberg reaction Amine-carbonyl condensation Organic oxidation Organic oxidation Zincke reaction Emde degradation Reaction product amines amides sulfonamides imines nitroso compounds diazonium salt Zincke aldehyde tertiary amine Reagent: peroxymonosulfuric acid Reagent: nitrous acid reagent pyridinium salts, with primary and secondary amines reduction of quaternary ammonium cations Comment degree of substitution increases Reagents: acyl chlorides, acid anhydrides Reagents: sulfonyl chlorides Hofmann–Martius rearrangement aryl substituted anilines Von Braun reaction Hofmann elimination Cope reaction carbylamine reaction Hoffmann's mustard oil test Organocyanamide Alkene Alkene Isonitrile Isothiocyanate By cleavage (tertiary amines only) with cyanogen bromide proceeds by β-elimination of less hindered carbon Similar to Hofmann elimination (primary amines only) CS2 and HgCl2 are used. Thiocyanate smells like mustard. Amine 107 Biological activity Amines are ubiquitous in biology. The breakdown of amino acids releases amines, famously in the case of decaying fish which smell of trimethylamine. Many neurotransmitters are amines, including epinephrine, norepinephrine, dopamine, serotonin, and histamine. Protonated amino groups (-NH3+) are the most common positively charged moieties in proteins, specifically in the amino acid lysine.[8] The anionic polymer DNA is typically bound to various amine-rich proteins.[9] Additionally, the terminal charged primary ammonium on lysine forms salt bridges with carboxylate groups of other amino acids in polypeptides, which is one of the primary influences on the three-dimensional structures of proteins.[10] Application of amines Dyes Primary aromatic amines are used as a starting material for the manufacture of azo dyes. It reacts with nitrous acid to form diazonium salt, which can undergo coupling reaction to form azo compound. As azo-compounds are highly coloured, they are widely used in dyeing industries, such as: • Methyl orange • Direct brown 138 • Sunset yellow FCF • Ponceau Drugs Many drugs are designed to mimic or to interfere with the action of natural amine neurotransmitters, exemplified by the amine drugs: • Chlorpheniramine is an antihistamine that helps to relieve allergic disorders due to cold, hay fever, itchy skin, insect bites and stings. • Chlorpromazine is a tranquillizer that sedates without inducing sleep. It is used to relieve anxiety, excitement, restlessness or even mental disorder. • Ephedrine and phenylephrine, as amine hydrochlorides, are used as decongestants. • Amphetamine, methamphetamine, and methcathinone are psychostimulant amines that are listed as controlled substances by the US DEA. • Amitriptyline, imipramine, lofepramine and clomipramine are tricyclic antidepressants and tertiary amines. • Nortriptyline, desipramine, and amoxapine are tricyclic antidepressants and secondary amines. (The tricyclics are grouped by the nature of the final amine group on the side chain.) Amine 108 Gas treatment Aqueous monoethanolamine (MEA), diglycolamine (DGA), diethanolamine (DEA), diisopropanolamine (DIPA) and methyldiethanolamine (MDEA) are widely used industrially for removing carbon dioxide (CO2) and hydrogen sulfide (H2S) from natural gas and refinery process streams. They may also be used to remove CO2 from combustion gases / flue gases and may have potential for abatement of greenhouse gases. Related processes are known as sweetening.[11] Safety Low molecular weight amines are toxic, and some are easily absorbed through the skin. Many higher molecular weight amines are, biologically, highly active. External links • Primary amine synthesis: synthetic protocols [12] from organic-reaction.com References [1] McMurry, John E. (1992), Organic Chemistry (3rd ed.), Belmont: Wadsworth, ISBN 0-534-16218-5 [2] http:/ / science. uvu. edu/ ochem/ index. php/ alphabetical/ a-b/ aliphatic-amine/ [3] Lide, D. R., ed. (2005). CRC Handbook of Chemistry and Physics (86th ed.). Boca Raton (FL): CRC Press. ISBN 0-8493-0486-5. [4] Karsten Eller, Erhard Henkes, Roland Rossbacher, Hartmut Höke "Amines, Aliphatic" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005. doi:10.1002/14356007.a02_001 [5] March, Jerry (1992), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (4th ed.), New York: Wiley, ISBN 0-471-60180-2 [6] A. N. Nesmajanow [sic] (1943), "β-Naphthylmercuric chloride" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv2p0432), Org. Synth., ; Coll. Vol. 2: 432 [7] Klaus Hunger, Peter Mischke, Wolfgang Rieper, Roderich Raue, Klaus Kunde, Aloys Engel "Azo Dyes” in Ullmann’s Encyclopedia of Industrial Chemistry, 2005, Wiley-VCH, Weinheim.doi:10.1002/14356007.a03_245. [8] Miguel A. Andrade, Sean I. O'Donoghue, Burkhard Rost, Adaptation of protein surfaces to subcellular location, Journal of Molecular Biology, Volume 276, Issue 2, 20 February 1998, Pages 517-525, ISSN 0022-2836 (http:/ / dx. doi. org/ 10. 1006/ jmbi. 1997. 1498) [9] Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6. [10] Dominant forces in protein folding, Ken A. Dill, Biochemistry 1990 29 (31), 7133-7155 (http:/ / dx. doi. org/ 10. 1021/ bi00483a001) [11] Georg Hammer, Torsten Lübcke, Roland Kettner, Mark R. Pillarella, Herta Recknagel, Axel Commichau, Hans-Joachim Neumann and Barbara Paczynska-Lahme "Natural Gas" in Ullmann's Encyclopedia of Industrial Chemistry, 2006, Wiley-VCH, Weinheim. doi:10.1002/14356007.a17_073.pub [12] http:/ / www. organic-reaction. com/ synthetic-protocols/ functionals-groups/ primary-amine/ Amide 109 Amide An amide is a compound with the functional group RnE(O)xNR'2 (R and R' refer to H or organic groups). Most common are "organic amides" (n = 1, E = C, x = 1), but many other important types of amides are known including Structures of three kinds of amides: an organic amide, a sulfonamide, and a phosphoramide. phosphor amides (n = 2, E = P, x = 1 and many related formulas) and sulfonamides (E = S, x= 2).[1] The term amide refers both to classes of compounds and to the functional group (RnE(O)xNR'2) within those compounds. Amide can also refer to the conjugate base of ammonia (the anion H2N–) or of an organic amine (an anion R2N–). For discussion of these "anionic amides," see Metal amides#Alkali metal amides. The remainder of this article is about the carbonyl-nitrogen sense of amide. Structure and bonding The simplest amides are derivatives of ammonia wherein one hydrogen atom has been replaced by an acyl group. The ensemble is generally represented as RC(O)NH2. Closely related and even more numerous are amides derived from primary amines (R'NH2) with the formula RC(O)NHR'. Amides are also commonly derived from secondary amines (R'RNH) with the formula RC(O)NR'R. Amide are usually regarded as derivatives of carboxylic acids in which the hydroxyl group has been replaced by an amine or ammonia. The lone pair of electrons on the nitrogen is delocalized into the carbonyl, thus forming a partial double bond between N and the carbonyl carbon. Consequently the nitrogen in amides is not pyramidal. It is estimated that acetamide is described by resonance structure A for 62% and by B for 28%[2] Amide 110 Nomenclature In the usual nomenclature, one adds the term "amide" to the stem of the parent acid's name. For instance, the amide derived from acetic acid is named acetamide (CH3CONH2). IUPAC recommends ethanamide, but this and related formal names are rarely encountered. When the amide is derived from a primary or secondary amine, the substitutents on nitrogen are indicated first in the name. Thus, the amide formed from dimethylamine and acetic acid is N,N-dimethylacetamide (CH3CONMe2, where Me = CH3). Usually even this name is simplified to dimethylacetamide. Cyclic amides are called lactams; they are necessarily secondary or tertiary amides. Functional groups consisting of -P(O)NR2 and -SO2NR2 are phosphonamides and sulfonamides, respectively.[3] Pronunciation Amides possess a conjugated system spread over the O, C and N atoms, consisting of molecular orbitals occupied by delocalized electrons. One of the π molecular orbitals in formamide is shown above. Some chemists make a pronunciation distinction between the two, saying /əˈmiːd/ for the carbonyl-nitrogen compound and i/ˈæmaɪd/ for the anion. Others substitute one of these with /ˈæmɪd/, while still others pronounce both /ˈæmɪd/, making them homonyms. Properties Basicity Compared to amines, amides are very weak bases. While the conjugate acid of an amine has a pKa of about 9.5, the conjugate acid of an amide has a pKa around -0.5. Therefore amides don't have as clearly noticeable acid-base properties in water. This relative lack of basicity is explained by the electron-withdrawing nature of the carbonyl group where the lone pair of electrons on the nitrogen is delocalized by resonance. On the other hand, amides are much stronger bases than carboxylic acids, esters, aldehydes, and ketones (conjugated acid pKa between -6 and -10). It is estimated in silico that acetamide is represented by resonance structure A for 62% and by B for 28%.[2] Resonance is largely prevented in the very strained quinuclidone. Because of the greater electronegativity of oxygen, the carbonyl (C=O) is a stronger dipole than the N-C dipole. The presence of a C=O dipole and, to a lesser extent a N-C dipole, allows amides to act as H-bond acceptors. In primary and secondary amides, the presence of N-H dipoles allows amides to function as H-bond donors as well. Thus amides can participate in hydrogen bonding with water and other protic solvents; the oxygen atom can accept hydrogen bonds from water and the N-H hydrogen atoms can donate H-bonds. As a result of interactions such as these, the water solubility of amides is greater than that of corresponding hydrocarbons. The proton of a primary or secondary amide does not dissociate readily under normal conditions; its pKa is usually well above 15. Conversely, under extremely acidic conditions, the carbonyl oxygen can become protonated with a pKa of roughly –1. Amide 111 Solubility The solubilities of amides and esters are roughly comparable. Typically amides are less soluble than comparable amines and carboxylic acids since these compounds can both donate and accept hydrogen bonds. Tertiary amides, with the important exception of N,N-dimethylformamide, exhibit low solubility in water. Characterization The presence of the functional group is generally easily established, at least in small molecules. They are the most common non-basic functional group. They can be distinguished from nitro and cyano groups by their IR spectra. Amides exhibit a moderately intense νCO band near 1650 cm−1. By 1H NMR spectroscopy, CONHR signals occur at low fields. In X-ray crystallography, the C(O)N center together with the three immediately adjacent atoms characteristically define a plane. Applications and occurrence Amides are pervasive in nature and technology as structural materials. The amide linkage is easily formed, confers structural rigidity, and resists hydrolysis. Nylons are polyamides as are the very resilient materials Aramid, Twaron, and Kevlar. Amide linkages in a biochemical context are called peptide linkages. Amide linkages constitute a defining molecular feature of proteins, the secondary structure of which is due in part to the hydrogen bonding abilities of amides. Low molecular weight amides, such as dimethylformamide (HC(O)N(CH3)2), are common solvents. Many drugs are amides, including penicillin and LSD. Moreover, plant N-alkylamides have a wide range of biological functionalities.[4] Amide synthesis Amides are commonly formed via reactions of a carboxylic acid with an amine. Many methods are known for driving the unfavorable equilibrium to the right: RCO2H + R'R"NH RC(O)NR'R" + H2O For the most part, these reactions involve "activating" the carboxylic acid and the best known method, the Schotten-Baumann reaction, which involves conversion of the acid to the acid chlorides: Reaction name Beckmann rearrangement Schmidt reaction nitrile hydrolysis Willgerodt-Kindler reaction Passerini reaction Ugi reaction cyclic ketone ketones nitrile Substrate reagent: hydroxylamine and acid reagent: hydrazoic acid reagent: water; acid catalyst sulfur and morpholine Details aryl alkyl ketones carboxylic acid, ketone or aldehyde isocyanide, carboxylic acid, ketone, primary amine [5][6] carboxylic acid, Grignard reagent with an aniline derivative ArNHR' Bodroux reaction Amide 112 aryl imino ether Chapman [7][8] rearrangement for N,N-diaryl amides. The reaction mechanism is based on a nucleophilic [9] aromatic substitution. Leuckart amide synthesis isocyanate [10] Reaction of arene with isocyanate catalysed by aluminium trichloride, formation of aromatic amide. Other methods The seemingly simple direct reaction between an alcohol and an amine to an amide was not tried until 2007 when a special ruthenium-based catalyst was reported to be effective in a so-called dehydrogenative acylation:[11] The generation of hydrogen gas compensates for unfavorable thermodynamics. The reaction is believed to proceed by one dehydrogenation of the alcohol to the aldehyde followed by formation of a hemiaminal and the after a second dehydrogenation to the amide. Elimination of water in the hemiaminal to the imine is not observed. Amide reactions Amides undergo many chemical reactions, usually through an attack on the carbonyl breaking the carbonyl double bond and forming a tetrahedral intermediate. Thiols, hydroxyls and amines are all known to serve as nucleophiles. Owing to their resonance stabilization, amides are less reactive under physiological conditions than esters. Enzymes, e.g. peptidases or artificial catalysts, are known to accelerate the hydrolysis reactions. They can be hydrolysed in hot alkali, as well as in strong acidic conditions. Acidic conditions yield the carboxylic acid and the ammonium ion while basic hydrolysis yield the carboxylate ion and ammonia. Amides are also versatile precursors to many other functional groups. Amide 113 Reaction name dehydration Hofmann rearrangement amide reduction nitrile Product Comment reagent: phosphorus pentoxide amine with one fewer carbon atoms reagents: bromine and sodium hydroxide amine reagent: lithium aluminium hydride POCl3, aromatic substrate, formamide Vilsmeier-Haack reaction imine References [1] http:/ / goldbook. iupac. org/ A00266. html [2] "Amide Resonance" Correlates with a Breadth of C-N Rotation Barriers Carl R. Kemnitz and Mark J. Loewen J. Am. Chem. Soc.; 2007; 129(9) pp 2521 - 2528; (Article) doi:10.1021/ja0663024 [3] Organic Chemistry IUPAC Gnomenclature. Rules C-821. Amides http:/ / www. acdlabs. com/ iupac/ nomenclature/ 79/ r79_540. htm [4] J. Boonen, A. Bronselaer, J. Nielandt, L. Veryser,G. De Tre, B. De Spiegeleer. "Alkamid database: Chemistry, occurrence and functionality of plant N-alkylamides" Journal of Ethnopharmacology 2012, volume 142, pages 563–590. doi:10.1016/j.jep.2012.05.038 [5] Bodroux F., Bull. Soc. Chim. France, 1905, 33, 831; [6] Bodroux reaction at the Institute of Chemistry, Skopje, Macedonia Link (http:/ / www. pmf. ukim. edu. mk/ PMF/ Chemistry/ reactions/ bodroux1. htm) [7] Schulenberg, J. W.; Archer, S. Org. React. 1965, 14. [8] A. W. Chapman, "CCLXIX. - Imino-aryl ethers. Part III. The molecular rearrangement of N-phenylbenziminophenyl ether", Journal of the Chemical Society, Transactions, 127:1992-1998, 1925. doi:10.1039/CT9252701992 [9] Advanced organic Chemistry, Reactions, mechanisms and structure 3ed. Jerry March ISBN 0-471-85472-7 [10] Ueber einige Reaktionen der aromatischen Cyanate R. Leuckart Berichte der deutschen chemischen Gesellschaft Volume 18 Issue 1, Pages 873 - 877 1885doi:10.1002/cber.188501801182 [11] Direct Synthesis of Amides from Alcohols and Amines with Liberation of H2 Chidambaram Gunanathan, Yehoshoa Ben-David, David Milstein Science 10 August 2007: Vol. 317. no. 5839, pp. 790 - 792 doi:10.1126/science.1145295 External links • Amide synthesis (coupling reaction) - Synthetic protocols (http://www.organic-reaction.com/ synthetic-protocols/coupling-reagents-in-amide-synthesis/) from organic-reaction.com • IUPAC Compendium of Chemical Terminology (http://www.rsc.org/Chemsoc/Chembytes/IUPACGoldbook. asp) Imine 114 Imine "Ketimine" redirects here. It should not be confused with "Ketamine" An imine (  /ɪˈmiːn/ or /ˈɪmɪn/) is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom (H) or an organic group. If this group is not a hydrogen atom, then the compound can sometimes be referred to as a Schiff base.[1] The carbon has two additional single bonds.[2][3][4] Nomenclature and classification It is related to ketones and aldehydes by replacement of the oxygen with an NR group. When R = H, the compound is a primary imine, when R is The general structure of an imine hydrocarbyl, the compound is a secondary imine. Imines exhibit diverse reactivity and are commonly encountered throughout chemistry.[4] When R3 is OH, the imine is called an oxime, and when R3 is NH2 the imine is called a hydrazone. Aldimines and ketimines A primary imine in which C is attached to both a hydrocarbyl and a H is called a primary aldimine; a secondary imine with such groups is called a secondary aldimine.[5] A primary imine in which C is attached to two hydrocarbyls is called a primary ketimine; an imine with such groups is called a secondary ketimine.[6] Primary aldimine Secondary aldimine Primary ketimine Secondary ketimine Synthesis of imines Imines are typically prepared by the condensation of primary amines and aldehydes and less commonly ketones. In terms of mechanism, such reactions proceed via the nucleophilic addition giving a hemiaminal -C(OH)(NHR)intermediate, followed by an elimination of water to yield the imine. (see alkylimino-de-oxo-bisubstitution for a detailed mechanism) The equilibrium in this reaction usually favors of the carbonyl compound and amine, so that azeotropic distillation or use of a dehydrating agent such as molecular sieves is required to push the reaction in favor of imine formation. Several other methods exist for the synthesis of imines. • Condensation of carbon acids with nitroso compounds. • The rearrangement of trityl N-haloamines in the Stieglitz rearrangement. • Dehydration of hemiaminals.[7] Imine • By reaction of alkenes with hydrazoic acid in the Schmidt reaction. • By reaction of a nitrile, hydrochloric acid and an arene in the Hoesch reaction. • Multicomponent synthesis of 3-thiazolines in the Asinger reaction. 115 Imine reactions The most important reactions of imines are their hydrolysis to the corresponding amine and carbonyl compound. Otherwise this functional group participates in many other reactions, many of which are analogous to the reactions of aldehydes and ketones. • • • • • An imine reacts with an amine to an aminal, see for example the synthesis of cucurbituril. An imine reacts with dienes in the Aza Diels-Alder reaction to a tetrahydropyridine. An imine can be oxidized with meta-chloroperoxybenzoic acid (mCPBA) to give an oxaziridine An aromatic imine reacts with an enol ether to a quinoline in the Povarov reaction. A tosylimine reacts with an α,β-unsaturated carbonyl compound to an allylic amine in the Aza-Baylis–Hillman reaction. • Imines are intermediates in the alkylation of amines with formic acid in the Eschweiler-Clarke reaction. • A rearrangement in carbohydrate chemistry involving an imine is the Amadori rearrangement. • A methylene transfer reaction of an imine by an unstabilised sulphonium ylide can give an aziridine system. • An imine is an intermediate in reductive amination. Acid-base reactions Somewhat like the parent amines, imines are mildly basic and reversibly protonate to give iminium salts. Iminium derivatives are particularly susceptible to reduction to the amines using transfer hydrogenation or by the stoichiometric action of sodium cyanoborohydride. Since imines derived from unsymmetrical ketones are prochiral, their reduction is a useful method for the synthesis of chiral amines. As ligands Imines are common ligands in coordination chemistry. The condensation of salicylaldehyde and acetylacetone give families of imine-containing chelating agents such as salen. Imine reductions An imine can be reduced to an amine via hydrogenation for example in a synthesis of m-tolylbenzylamine:[8] Other reducing agents are lithium aluminium hydride and sodium borohydride.[9] The first asymmetric imine reduction was reported in 1973 by Kagan using Ph(Me)C=NBn and PhSiH2 in a hydrosilylation with chiral ligand DIOP and rhodium catalyst (RhCl(CH2CH2)2)2.[10] Many systems have since been investigated.[11][12] Imine 116 Biological role Imines are common in nature. Vitamin B6 promotes the deamination of amino acids via the formation of imines, for example. References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "Schiff base" (http:/ / goldbook. iupac. org/ S05498. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.S05498. ISBN 0-9678550-9-8. . [2] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "imines" (http:/ / goldbook. iupac. org/ I02957. html. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.I02957.html. ISBN 0-9678550-9-8. . [3] March Jerry; (1985). Advanced Organic Chemistry reactions, mechanisms and structure (3rd ed.). New York: John Wiley & Sons, inc. ISBN 0-471-85472-7 [4] Fletcher, Dermer, Fox, Nomenclature of Organic Compounds (1974) doi:10.1021/ba-1974-0126.ch023 [5] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "aldimines" (http:/ / goldbook. iupac. org/ A00209. html. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.A00209.html. ISBN 0-9678550-9-8. . [6] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "ketimines" (http:/ / goldbook. iupac. org/ K03381. html. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.K03381.html. ISBN 0-9678550-9-8. . [7] W. J. Middleton and H. D. Carlson (1988), "Hexafluoroacetone imine" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv6p0664), Org. Synth., ; Coll. Vol. 6: 664. [8] C. F. H. Allen and James VanAllan (1955), "m-Tolylbenzylamine" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv3p0827), Org. Synth.: 827, ; Coll. Vol. 3 [9] For example: Ieva R. Politzer and A. I. Meyers (1988), "Aldehydes from 2-Benzyl-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine: 1-Phenylcyclopentanecarboxaldehyde" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv6p0905), Org. Synth., ; Coll. Vol. 6: 905 [10] Langlois, N (1973). "Synthese asymetrique d'amines par hydrosilylation d'imines catalysee par un complexe chiral du rhodium". Tet. Lett. 14 (49): 4865. doi:10.1016/S0040-4039(01)87358-5. [11] Kobayashi, Shū; Ishitani, Haruro (1999). "Catalytic Enantioselective Addition to Imines". Chem. Rev. 99 (5): 1069. doi:10.1021/cr980414z.. [12] J. Martens: Reduction of Imino Groups (C=N) in (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann) Houben-Weyl Stereoselective Synthesis, Workbench Edition E21 Volume 7, S. 4199-4238, Thieme Verlag Stuttgart, 1996, ISBN 3-13-106124-3. Schiff base 117 Schiff base A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen.[1] Schiff bases in a broad sense have the general formula R1R2C=NR3, where R is an organic side chain. In this definition, Schiff base is synonymous with azomethine. Some restrict the term to the secondary aldimines (azomethines where the carbon is connected to a hydrogen atom), thus with the general formula RCH=NR'.[2] The chain on the nitrogen makes the Schiff base a stable imine. A Schiff base derived from an aniline, where R3 is a phenyl or a substituted phenyl, can be called an anil.[3] General structure of an azomethine Synthesis Schiff bases can be synthesized from an aromatic amine and a carbonyl compound by nucleophilic addition forming a hemiaminal, followed by a dehydration to generate an imine. In a typical reaction, 4,4'-diaminodiphenyl ether reacts with o-vanillin:[4] General structure of a Schiff base (narrow definition) Biochemistry A mixture of 4,4'-diaminodiphenyl ether 1 (1.00 g, 5.00 mmol) and o-vanillin 2 (1.52 g, 10.00 mmol) in methanol (40.00 mL) is stirred at room temperature for one hour to give an orange precipitate and after filtration and washing with methanol to give the pure Schiff base 3 (2.27 g, 97.00%) There is a Schiff base intermediate in the fructose 1,6-bisphosphate aldolase catalyzed reaction during glycolysis and in the metabolism of amino acids. References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "Schiff base" (http:/ / goldbook. iupac. org/ S05498. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.S05498. ISBN 0-9678550-9-8. . [2] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "azomethines" (http:/ / goldbook. iupac. org/ A00564. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.A00564. ISBN 0-9678550-9-8. . [3] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "anils" (http:/ / goldbook. iupac. org/ A00357. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.A00357. ISBN 0-9678550-9-8. . [4] Jarrahpour, A. A.; M. Zarei (February 24, 2004). "Synthesis of 2-({[4-(4-{[(E)-1-(2-hydroxy-3-methoxyphenyl)methylidene amino}phenoxy)phenyl imino}methyl)- 6 -methoxy phenol" (http:/ / www. mdpi. net/ molbank/ molbank2004/ m0352. htm). Molbank M352. ISSN 1422-8599. . Retrieved February 22, 2010. See Also • Retinal (example of a Schiff base linkage in nature) Aldehyde 118 Aldehyde An aldehyde (  /ˈældɪhaɪd/) is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center (a carbon double bonded to oxygen) bonded to hydrogen and an R group,[1] which is any generic alkyl or side chain. The group without R is called the aldehyde group or formyl group. Aldehydes differ from ketones in that the carbonyl is placed at the end of a carbon skeleton rather than between two carbon atoms. Aldehydes are common in organic chemistry. Many fragrances are aldehydes. Structure and bonding Aldehydes feature an sp2-hybridized, planar carbon center that is connected by a double bond to oxygen and a single bond to hydrogen. The C-H bond is not acidic. Because of resonance stabilization of the conjugate base, an α-hydrogen in an aldehyde (not shown in the picture above) is far more acidic, with a pKa near 17, than a C-H bond in a typical alkane (pKa about 50).[2] This acidification is attributed to (i) the electron-withdrawing quality of the formyl center and (ii) the fact that the conjugate base, an enolate anion, delocalizes its negative charge. Related to (i), the aldehyde group is somewhat polar. An aldehyde. Aldehydes (except those without an alpha carbon, or without protons on the alpha carbon, such as formaldehyde and benzaldehyde) can exist in either the keto or the enol tautomer. Keto-enol tautomerism is catalyzed by either acid or base. Usually the enol is the minority tautomer, but it is more reactive. Formaldehyde, the simplest aldehyde Nomenclature IUPAC names for aldehydes The common names for aldehydes do not strictly follow official guidelines, such as those recommended by IUPAC but these rules are useful. IUPAC prescribes the following nomenclature for aldehydes:[3][4][5] 1. Acyclic aliphatic aldehydes are named as derivatives of the longest carbon chain containing the aldehyde group. Thus, HCHO is named as a derivative of methane, and CH3CH2CH2CHO is named as a derivative of butane. The name is formed by changing the suffix -e of the parent alkane to -al, so that HCHO is named methanal, and CH3CH2CH2CHO is named butanal. 2. In other cases, such as when a -CHO group is attached to a ring, the suffix -carbaldehyde may be used. Thus, C6H11CHO is known as cyclohexanecarbaldehyde. If the presence of another functional group demands the use of a suffix, the aldehyde group is named with the prefix formyl-. This prefix is preferred to methanoyl-. 3. If the compound is a natural product or a carboxylic acid, the prefix oxo- may be used to indicate which carbon atom is part of the aldehyde group; for example, CHOCH2COOH is named 3-oxopropanoic acid. 4. If replacing the aldehyde group with a carboxyl group (-COOH) would yield a carboxylic acid with a trivial name, the aldehyde may be named by replacing the suffix -ic acid or -oic acid in this trivial name by -aldehyde. Aldehyde 119 Etymology The word aldehyde was coined by Justus von Liebig as a contraction of the Latin alcohol dehydrogenatus (dehydrogenated alcohol).[6] In the past, aldehydes were sometimes named after the corresponding alcohols, for example, vinous aldehyde for acetaldehyde. (Vinous is from Latin vinum = wine (the traditional source of ethanol), cognate with vinyl.) The term formyl group is derived from the Latin and/or Italian word formica = ant. This word can be recognized in the simplest aldehyde, formaldehyde (methanal), and in the simplest carboxylic acid, formic acid (methanoic acid, an acid, but also an aldehyde). Formic acid Physical properties and characterization Aldehydes have properties that are diverse and that depend on the remainder of the molecule. Smaller aldehydes are more soluble in water, formaldehyde and acetaldehyde completely so. The volatile aldehydes have pungent odors. Aldehydes degrade in air via the process of autoxidation. The two aldehydes of greatest importance in industry, formaldehyde and acetaldehyde, have complicated behavior because of their tendency to oligomerize or polymerize. They also tend to hydrate, forming the geminal diol. The oligomers/polymers and the hydrates exist in equilibrium with the parent aldehyde. Aldehydes are readily identified by spectroscopic methods. Using IR spectroscopy, they display a strong νCO band near 1700 cm−1. In their 1H NMR spectra, the formyl hydrogen center absorbs near δ9, which is a distinctive part of the spectrum. This signal shows the characteristic coupling to any protons on the alpha carbon. Applications and occurrence Important aldehydes and related compounds. The aldehyde group (or formyl group) is colored red. From the left: (1) formaldehyde and (2) its trimer 1,3,5-trioxane, (3) acetaldehyde and (4) its enol vinyl alcohol, (5) glucose (pyranose form as α-D-glucopyranose), (6) the flavorant cinnamaldehyde, (7) the visual pigment retinal, and (8) the vitamin pyridoxal. Naturally occurring aldehydes Traces of many aldehydes are found in essential oils and often contribute to their favorable odors, e.g. cinnamaldehyde, cilantro, and vanillin. Possibly because of the high reactivity of the formyl group, aldehydes are not common in several of the natural building blocks: amino acids, nucleic acids, lipids. Most sugars, however, are derivatives of aldehydes. These "aldoses" exist as hemiacetals, a sort of masked form of the parent aldehyde. For example, in aqueous solution only a tiny fraction of glucose exists as the aldehyde. Aldehyde 120 Synthesis There are several methods for preparing aldehydes,[7] but the dominant technology is hydroformylation.[8] Illustrative is the generation of butyraldehyde by hydroformylation of propene: H2 + CO + CH3CH=CH2 → CH3CH2CH2CHO Oxidative routes Aldehydes are commonly generated by alcohol oxidation. In industry, formaldehyde is produced on a large scale by oxidation of methanol.[9] Oxygen is the reagent of choice, being "green" and cheap. In the laboratory, more specialized oxidizing agents are used, but chromium(VI) reagents are popular. Oxidation can be achieved by heating the alcohol with an acidified solution of potassium dichromate. In this case, excess dichromate will further oxidize the aldehyde to a carboxylic acid, so either the aldehyde is distilled out as it forms (if volatile) or milder reagents such as PCC are used.[10] [O] + CH3(CH2)9OH → CH3(CH2)8CHO + H2O Oxidation of primary alcohols to form aldehydes and can be achieved under milder, chromium-free conditions by employing methods or reagents such as IBX acid, Dess-Martin periodinane, Swern oxidation, TEMPO, or the Oppenauer oxidation. Another oxidation route significant in industry is the Wacker process, whereby ethylene is oxidized to acetaldehyde in the presence of copper and palladium catalysts (acetaldehyde is also produced on a large scale by the hydration of acetylene). Specialty methods Reaction name Ozonolysis Organic reduction Substrate alkene ester Comment ozonolysis of non-fully-substituted alkenes yield aldehydes upon reductive work-up. Reduction of an ester with diisobutylaluminium hydride (DIBAL-H) or sodium aluminium hydride or using lithium tri-t-butoxyaluminium hydride (LiAlH(OtBu)3). reagent methoxymethylenetriphenylphosphine in a modified Wittig reaction. various reactions for example the Vilsmeier-Haack reaction Rosenmund reaction Wittig reaction Formylation reactions acid chloride ketone nucleophilic arenes Nitro compound pyridines Nef reaction Zincke reaction Zincke aldehydes form in a variation reagents tin(II) chloride and hydrochloric acid. oxazine hydrolysis is a base-catalyzed thermal decomposition of acylsulfonylhydrazides Stephen aldehyde synthesis nitriles Meyers synthesis McFadyen-Stevens reaction oxazine hydrazide Aldehyde 121 Common reactions Aldehydes are highly reactive and participate in many reactions.[7]" From the industrial perspective, important reactions are condensations, e.g. to prepare plasticizers and polyols, and reduction to produce alcohols, especially "oxo-alcohols." From the biological perspective, the key reactions involve addition of nucleophiles to the formyl carbon in the formation of imines (oxidative deamination) and hemiacetals (structures of aldose sugars).[7] Reduction The formyl group can be readily reduced to a primary alcohol (-CH2OH). Typically this conversion is accomplished by catalytic hydrogenation either directly or by transfer hydrogenation. Stoichiometric reductions are also popular, as can be effected with sodium borohydride. Oxidation The formyl group readily oxidizes to the corresponding carboxylic acid (-COOH). The preferred oxidant in industry is oxygen or air. In the laboratory, popular oxidizing agents include potassium permanganate, nitric acid, chromium(VI) oxide, and chromic acid. The combination of manganese dioxide, cyanide, acetic acid and methanol will convert the aldehyde to a methyl ester.[11] Another oxidation reaction is the basis of the silver mirror test. In this test, an aldehyde is treated with Tollens' reagent, which is prepared by adding a drop of sodium hydroxide solution into silver nitrate solution to give a precipitate of silver(I) oxide, and then adding just enough dilute ammonia solution to redissolve the precipitate in aqueous ammonia to produce [Ag(NH3)2]+ complex. This reagent will convert aldehydes to carboxylic acids without attacking carbon-carbon double-bonds. The name silver mirror test arises because this reaction will produce a precipitate of silver whose presence can be used to test for the presence of an aldehyde. A further oxidation reaction involves Fehling's reagent as a test. The Cu2+ complex ions are reduced to a red brick coloured Cu2O precipitate. If the aldehyde cannot form an enolate (e.g., benzaldehyde), addition of strong base induces the Cannizzaro reaction. This reaction results in disproportionation, producing a mixture of alcohol and carboxylic acid. Nucleophilic addition reactions Nucleophiles add readily to the carbonyl group. In the product, the carbonyl carbon becomes sp3 hybridized, being bonded to the nucleophile, and the oxygen center becomes protonated: RCHO + Nu- → RCH(Nu)ORCH(Nu)O- + H+ → RCH(Nu)OH In many cases, a water molecule is removed after the addition takes place; in this case, the reaction is classed as an addition-elimination or addition-condensation reaction. There are many variations of nucleophilic addition reactions. Oxygen nucleophiles In the acetalisation reaction, under acidic or basic conditions, an alcohol adds to the carbonyl group and a proton is transferred to form a hemiacetal. Under acidic conditions, the hemiacetal and the alcohol can further react to form an acetal and water. Simple hemiacetals are usually unstable, although cyclic ones such as glucose can be stable. Acetals are stable, but revert to the aldehyde in the presence of acid. Aldehydes can react with water to form hydrates, R-C(H)(OH)(OH). These diols are stable when strong electron withdrawing groups are present, as in chloral hydrate. The mechanism of formation is identical to hemiacetal formation. Aldehyde Nitrogen nucleophiles In alkylimino-de-oxo-bisubstitution, a primary or secondary amine adds to the carbonyl group and a proton is transferred from the nitrogen to the oxygen atom to create a carbinolamine. In the case of a primary amine, a water molecule can be eliminated from the carbinolamine to yield an imine. This reaction is catalyzed by acid. Hydroxylamine (NH2OH) can also add to the carbonyl group. After the elimination of water, this will result in an oxime. An ammonia derivative of the form H2NNR2 such as hydrazine (H2NNH2) or 2,4-dinitrophenylhydrazine can also be the nucleophile and after the elimination of water, resulting in the formation of a hydrazone, which are usually orange crystalline solids. This reaction forms the basis of a test for aldehydes and ketones.[12] Carbon nucleophiles The cyano group in HCN can add to the carbonyl group to form cyanohydrins, R-C(H)(OH)(CN). In this reaction the CN− ion is the nucleophile which attacks the partially positive carbon atom of the carbonyl group. The mechanism involves a pair of electrons from the carbonyl group double bond transferring to the oxygen atom, leaving it single bonded to carbon and giving the oxygen atom a negative charge. This intermediate ion rapidly reacts with H+, such as from the HCN molecule, to form the alcohol group of the cyanohydrin. In the Grignard reaction, a Grignard reagent adds to the group, eventually yielding an alcohol with a substituted group from the Grignard reagent. Related reactions are the Barbier reaction and the Nozaki-Hiyama-Kishi reaction. In organostannane addition tin replaces magnesium. In the aldol reaction, the metal enolates of ketones, esters, amides, and carboxylic acids will add to aldehydes to form β-hydroxycarbonyl compounds (aldols). Acid or base-catalyzed dehydration will then lead to α,β-unsaturated carbonyl compounds. The combination of these two steps is known as the aldol condensation. The Prins reaction occurs when a nucleophilic alkene or alkyne reacts with an aldehyde as electrophile. The product of the Prins reaction varies with reaction conditions and substrates employed. Bisulphite reaction Aldehydes characteristically form "addition compounds" with sodium bisulphite: This reaction is used as a test for aldehydes.[12] RCHO + HSO3- → RCH(OH)(SO3)- 122 More complex reactions Reaction name Wolff-Kishner reduction Product alkane Comment If an aldehyde is converted to a simple hydrazone (RCH=NHNH2) and this is heated with a base such as KOH, the terminal carbon is fully reduced to a methyl group. The Wolff-Kishner reaction may be performed as a one-pot reaction, giving the overall conversion RCH=O → RCH3. with reducing agents such as magnesium reagent an ylide diorganochromium reagent phosphine-dibromomethylene reagent reagent dimethyl (diazomethyl)phosphonate reagent a sulfonium ylide Pinacol coupling reaction Wittig reaction Takai reaction Corey-Fuchs reactions Ohira–Bestmann reaction Johnson-Corey-Chaykovsky reaction Oxo Diels Alder reaction diol alkene alkene alkyne alkyne epoxide pyran Aldehydes can, typically in the presence of suitable catalysts, serve as partners in cycloaddition reactions. The aldehyde serves as the dienophile component, giving a pyran or related compound. In hydroacylation an aldehyde is added over an unsaturated bond to form a ketone. Hydroacylation ketone Aldehyde 123 alkane catalysed by transition metals decarbonylation Dialdehydes A dialdehyde is an organic chemical compound with two aldehyde groups. The nomenclature of dialdehydes have the ending -dial or sometimes -dialdehyde. Short aliphatic dialdehydes are sometimes named after the diacid from which they can de derived. An example is butanedial, which is also called succinaldehyde (from succinic acid). Examples of aldehydes • • • • • • • • • Formaldehyde (methanal) Acetaldehyde (ethanal) Propionaldehyde (propanal) Butyraldehyde (butanal) Benzaldehyde Cinnamaldehyde Tolualdehyde Furfural Retinaldehyde Dialdehydes • • • • • Glyoxal Malondialdehyde Succindialdehyde Glutaraldehyde Phthalaldehyde Uses Of all aldehydes, formaldehyde is produced on the largest scale, about 6,000,000 tons/y. It is mainly used in the production of resins when combined with urea, melamine, and phenol (e.g., Bakelite). It is a precursor to methylene diphenyl diisocyanate ("MDI"), a precursor to polyurethanes.[9] The second main aldehyde is butyraldehyde, of which about 2,500,000 tons/y are prepared by hydroformylation. It is the principal precursor to 2-ethylhexanol, which is used as a plasticizer.[13] Acetaldehyde once was a dominating product, but production levels have declined to less than 1M tons/y because it mainly served as a precursor to acetic acid, which is now prepared by carbonylation of methanol. Many other aldehydes find commercial applications, often as precursors to alcohols, the so-called oxo alcohols, which are used in detergents. Some aldehydes are produced only on a small scale (less than 1000 tons/y) and are famously used as ingredients in perfumes and flavors. These include cinnamaldehyde and its derivatives, citral, and lilial. Aldehyde 124 References [1] IUPAC Gold Book aldehydes (http:/ / goldbook. iupac. org/ A00208. html) [2] Chemistry of Enols and Enolates - Acidity of alpha-hydrogens (http:/ / pharmaxchange. info/ press/ 2011/ 02/ chemistry-of-enolates-and-enols-acidity-of-alpha-hydrogens/ ) [3] Short Summary of IUPAC Nomenclature of Organic Compounds (http:/ / www. uwc. edu/ dept/ chemistry/ helpful_files/ nomenclature. pdf), web page, University of Wisconsin Colleges, accessed on line August 4, 2007. [4] §R-5.6.1, Aldehydes, thioaldehydes, and their analogues, A Guide to IUPAC Nomenclature of Organic Compounds: recommendations 1993 (http:/ / www. acdlabs. com/ iupac/ nomenclature/ 93/ r93_449. htm), IUPAC, Commission on Nomenclature of Organic Chemistry, Blackwell Scientific, 1993. [5] §R-5.7.1, Carboxylic acids, A Guide to IUPAC Nomenclature of Organic Compounds: recommendations 1993 (http:/ / www. acdlabs. com/ iupac/ nomenclature/ 93/ r93_480. htm), IUPAC, Commission on Nomenclature of Organic Chemistry, Blackwell Scientific, 1993. [6] Crosland, Maurice P. (2004), Historical Studies in the Language of Chemistry (http:/ / books. google. com/ books?id=kwQQaltqByAC& pg=PA297& dq=alcohol+ dehydrogenatus#v=onepage& q=alcohol dehydrogenatus& f=false), Courier Dover Publications, [7] Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (http:/ / books. google. com/ books?id=JDR-nZpojeEC& printsec=frontcover) (6th ed.), New York: Wiley-Interscience, ISBN 0-471-72091-7, [8] W." Bertleff, M. Roeper, X. Sava, “Carbonylation” in Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH: Weinheim, 2003. doi: 10.1002/14356007.a05_217.pub2 [9] G. Reuss, W. Disteldorf, A. O. Gamer, A. Hilt, "Formaldehyde" in Ullmann's Encyclopedia of Industrial Chemistry 2005 Wiley-VCH, Weinheim. doi:10.1002/14356007.a11 619 [10] R. W. Ratcliffe (1988), "Oxidation with the Chromium Trioxide-Pyridine Complex Prepared in situ: 1-Decanal" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv6p0373), Org. Synth., ; Coll. Vol. 6: 373 [11] New methods for the oxidation of aldehydes to carboxylic acids and esters Elias J. Corey, Norman W. Gilman, and B. E. Ganem J. Am. Chem. Soc. 1968; 90(20) pp 5616 - 5617; doi:10.1021/ja01022a059. [12] "The Systematic Identification of Organic Compounds" R.L. Shriner, C.K.F. Hermann, T.C. Morrill, D.Y. Curtin, and R.C. Fuson John Wiley & Sons, 1997 0-471-59748-1. [13] C. Kohlpaintner, M. Schulte, J. Falbe, P. Lappe, J. Weber, "Aldehydes, Aliphatic" in Ullmann's Encyclopedia of Industrial Chemistry 2008 Wiley-VCH, Weinheim. doi:10.1002/14356007.a01_321.pub2. External links • Aldehyde synthesis - Synthetic protocols (http://www.organic-reaction.com/synthetic-protocols/ functionals-groups/aldehyde/) from organic-reaction.com Racemic mixture 125 Racemic mixture In chemistry, a racemic mixture, or racemate (  /reɪˈsimeɪt/), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid. Nomenclature A racemic mixture is denoted by the prefix (±)- or dl- (for sugars the prefix dl- may be used), indicating an equal (1:1) mixture of dextro and levo isomers. Also the prefix rac- (or racem-) or the symbols RS and SR (all in italic letters) are used. If the ratio is not 1:1 (or is not known), the prefix (+)/(−), d/l- or d/l- (with a slash) is used instead. The usage of d and l is strongly discouraged by IUPAC. [1][2] Properties A racemate is optically inactive, meaning that there is no net rotation of plane-polarized light. Although the two enantiomers rotate plane-polarized light in opposite directions, the rotations cancel because they are present in equal amounts. In contrast to the two pure enantiomers, which have identical physical properties except for the direction of rotation of plane-polarized light, a racemate sometimes has different properties from either of the pure enantiomers. Different melting points are most common, but different solubilities and boiling points are also possible. Pharmaceuticals may be available as a racemate or as the pure enantiomer, which might have different potencies. Crystallization There are four ways in which a racemate can crystallize, three of which H. W. B. Roozeboom had distinguished by 1899: • Conglomerate (sometimes racemic mixture or racemic conglomerate) A mechanical mixture of enantiomerically pure crystals of one enantiomer and its opposite. Molecules in the crystal structure have a greater affinity for the same enantiomer than for the opposite enantiomer. The melting point of the racemic conglomerate is always lower than that of the pure enantiomer. Addition of a small amount of one enantiomer to the conglomerate increases the melting point. • Racemic compound (sometimes true racemate) Molecules have a greater affinity for the opposite enantiomer than for the same enantiomer; the substance forms a single crystalline phase in which the two enantiomers are present in an ordered 1:1 ratio in the elementary cell. Adding a small amount of one enantiomer to the racemic compound decreases the melting point. But the pure enantiomer can have a higher or lower melting point than the compound. • Pseudoracemate (sometimes racemic solid solution) In contrast to the racemic compound or conglomerate, there is no big difference in affinity between the same and opposite enantiomers. Overall, both enantiomers occur in equal proportions in the crystal, but they coexist in an unordered manner in the crystal lattice. Addition of a small amount of one enantiomer changes the melting point just little bit or not at all. • Quasiracemate A quasiracemate is a mixture of two similar but distinct compounds, one of which is left-handed and the other right-handed. Although chemically different, they are sterically similar (isosteric) and are still able to form a Racemic mixture racemic crystalline phase. One of the first such racemates studied, by Pasteur in 1853, forms from a 1:2 mixture of the bis ammonium salt of (+)-tartaric acid and the bis ammonium salt of (−)-malic acid in water. Re-investigated in 2008,[3] the crystals formed are dumbbell-shape with the central part consisting of ammonium (+)-bitartrate, whereas the outer parts are a quasiracemic mixture of ammonium (+)-bitartrate and ammonium (−)-bimalate. 126 Resolution The separation of a racemate into its components, the pure enantiomers, is called a chiral resolution. There are various methods, including crystallization, chromatography, and the use of enzymes. The first successful resolution of a racemate was performed by Louis Pasteur, who manually separated the crystals of a conglomerate. Synthesis Without a chiral influence (for example a chiral catalyst, solvent or starting material), a chemical reaction that makes a chiral product will always yield a racemate. That can make the synthesis of a racemate cheaper and easier than making the pure enantiomer, because it does not require special conditions. This fact also leads to the question of how biological homochirality evolved on what is presumed to be a racemic primordial earth. The reagents of, and the reactions that produce, racemic mixtures are said to be "not stereospecific" or "not stereoselective," for their indecision in a particular stereoisomerism. Racemic pharmaceuticals Some drug molecules are chiral, and the enantiomers have different effects on biological entities. They can be sold as one enantiomer or as a racemic mixture. Examples include thalidomide, ibuprofen, and salbutamol. Adderall is a mixture of several different amphetamine enantiomers. A single amphetamine dose combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and D/L-amphetamine aspartate monohydrate. The prescription analgesic tramadol is also a racemate. In some cases (e.g., ibuprofen and thalidomide), the enantiomers interconvert or racemize in vivo. This means that preparing a pure enantiomer for medication is largely pointless. However, sometimes samples containing pure enantiomers may be made and sold at a higher cost in cases where the use requires specifically one isomer (e.g., for a stereospecific reagent); compare omeprazole and esomeprazole. While often only one enantiomer of the drug may be active, in cases like salbutamol[4] and thalidomide, the other enantiomer may be harmful. The (R) enantiomer of thalidomide is effective against morning sickness, while the (S) enantiomer is teratogenic, causing birth defects. Since the drug racemizes, the drug cannot be considered safe for use by women of child-bearing age,[5] and its use is tightly controlled when used for treating other illness.[6] Methamphetamine is available by prescription under the brand name Desoxyn. The active component of Desoxyn is dextromethamphetamine hydrochloride. This is the right-hand isomer of methamphetamine. The left-handed isomer of methamphetamine, levomethamphetamine, is an OTC drug that is less centrally-acting and more peripherally-acting.11 Racemic mixture 127 Wallach's rule Wallach's rule (first proposed by Otto Wallach) states that racemic crystals tend to be denser than their chiral counterparts.[7] This rule has been substantiated by crystallographic database analysis [8] References [1] G.P. Moss:  Basic terminology of stereochemistry (http:/ / iupac. org/ publications/ pac/ 68/ 12/ 2193/ pdf/ ) ( Recommendations 1996); Pure Appl. Chem., 1996, Vol. 68, No. 12, p. 2205-2216; doi:10.1351/pac199668122193 [2] Nomenclature of Carbohydrates (http:/ / www. chem. qmul. ac. uk/ iupac/ 2carb/ 03n04. html#04) (Recommendations 1996), 2-Carb-4. Configurational symbols and prefixes [3] Rediscovering Pasteur's Quasiracemates Kraig A. Wheeler, Rebecca C. Grove, Raymond E. Davis, and W. Scott Kassel Angew. Chem. Int. Ed. 2008, 47, 78 –81 doi:10.1002/anie.200704007 [4] (R)-Albuterol for Asthma: Pro, Bill T. Ameredes and William J. Calhoun (http:/ / ajrccm. atsjournals. org/ cgi/ content/ full/ 174/ 9/ 965) [5] "Use of thalidomide in leprosy" (http:/ / www. who. int/ lep/ research/ thalidomide/ en/ index. html). WHO:leprosy elimination. WHO. . Retrieved 22 April 2010. [6] Sheryl Gay Stolberg (17 July 1998). "Thalidomide Approved to Treat Leprosy, With Other Uses Seen" (http:/ / www. nytimes. com/ 1998/ 07/ 17/ us/ thalidomide-approved-to-treat-leprosy-with-other-uses-seen. html). New York Times. . Retrieved 8 January 2012. [7] (Wallach, O. (1895). Liebigs Ann. Chem. 286, 90-143.) [8] Carolyn Pratt Brock, W. Bernd Schweizer, and Jack D. Dunitz (1991). "On the validity of Wallach's rule: on the density and stability of racemic crystals compared with their chiral counterparts" (http:/ / pubs. acs. org/ doi/ abs/ 10. 1021/ ja00026a015). J. Am. Chem. Soc. 113 (26): 9811. doi:10.1021/ja00026a015. . Aldimine In organic chemistry, an aldimine is an imine that is an analog of an aldehyde.[1] As such, aldimines have the general formula R–CH=N–R'. Aldimines are similar to ketimines, which are analogs of ketones. An important subset of aldimines are the Schiff bases, in which the substituent on the nitrogen atom (R') is an alkyl or aryl group (i.e. not a hydrogen atom).[2] Primary aldimine Secondary aldimine Aldehyde Nomenclature Aldimine 128 Nomenclature CH3–CH2–CH2–CH=NH 1 2 3 obsolete butanimine butylideneazane butylideneamine butyraldehyde imine CH3–CH=N–CH3 N-methylethanimine ethylidene(methyl)azane N-methylethylideneamine acetaldehyde N-methylimine Aldimines may be named in three different manners:[3] 1. by replacing the final -e of the parent hydride, R–CH3, with the suffix "-imine"; 2. as alkylidene derivatives of azane; 3. (rare) as alkylidene derivatives of "amine". An obsolete nomenclature treats aldimines as derivatives of a parent aldehyde. References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "aldimines" (http:/ / goldbook. iupac. org/ A00209. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.{{{file}}}. ISBN 0-9678550-9-8. . [2] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "Schiff bases (Schiff's bases)" (http:/ / goldbook. iupac. org/ S05498. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.{{{file}}}. ISBN 0-9678550-9-8. . [3] Panico, R.; Powell, W. H.; Richer, J. C., eds. (1993). "Recommendation R-5.4.3" (http:/ / www. acdlabs. com/ iupac/ nomenclature/ ). A Guide to IUPAC Nomenclature of Organic Compounds. IUPAC/Blackwell Science. pp. 89–90. ISBN 0-632-03488-2. . Acid anhydride An acid anhydride is an organic compound that has two acyl groups bound to the same oxygen atom.[1] Most commonly, the acyl groups are derived from the same carboxylic acid, the formula of the anhydride being (RC(O))2O. Symmetrical acid anhydrides of this type are named by replacing the word acid in the name of the parent carboxylic acid by the word anhydride.[2] Thus, (CH3CO)2O is called acetic anhydride. Mixed (or unsymmetrical) acid anhydrides, such as acetic formic anhydride (see below), are known. Generic example of an acid anhydride. Important acid anhydrides Acetic anhydride is a major industrial chemical widely used for preparing acetate esters, e.g. cellulose acetate. Maleic anhydride is the precursor to various resins by copolymerization with styrene. Maleic anhydride is a dienophile in the Diels-Alder reaction.[3] Anhydrides not derived from carboxylic acids only Anhydrides derived from other organic acids One or both acyl groups of an acid anhydride may also be derived from another type of organic acid, such as sulfonic acid or a phosphonic acid. Acid anhydride 129 Anhydrides that include an inorganic acid One of the acyl groups of an acid anhydride can be derived from an inorganic acid such as phosphoric acid. The mixed anhydride 1,3-bisphosphoglycerate, which is an intermediate in the formation of ATP via glycolysis[4], is the mixed anhydride between 3-phosphoglyceric acid and phosphoric acid. Preparation Acid anhydrides are prepared in industry by diverse means. Acetic anhydride is mainly produced by the carbonylation of methyl acetate.[5] Maleic anhydride is produced by the oxidation of benzene or butane. Laboratory routes emphasize the dehydration of the corresponding acids. The conditions vary from acid to acid, but phosphorus pentoxide is a common dehydrating agent: Acid chlorides are also effective precursors:[6] CH3C(O)Cl + HCO2Na → HCO2COCH3 + NaCl Mixed anhydrides containing the acetyl group are prepared from ketene: RCO2H + H2C=C=O → RCO2C(O)CH3 2 CH3COOH + P4O10 → CH3C(O)OC(O)CH3 + "(HO)2P4O9" Reactions Acid anhydrides are a source of reactive acyl groups, and their reactions and uses resemble those of acyl halides. In reactions with protic substrates, the reactions afford equal amounts of the acylated product and the carboxylic acid: RC(O)OC(O)R + HY → RC(O)Y + RCO2H for HY = HOR (alcohols), HNR'2 (ammonia, primary, secondary amines), aromatic ring (see Friedel-Crafts acylation). Acid anhydrides tend to be less electrophilic than acyl chlorides, and only one acyl group is transferred per molecule of acid anhydride, which leads to a lower atom efficiency. The low cost, however, of acetic anhydride makes it a common choice for acetylation reactions. Sulfur analogues Sulfur can replace oxygen, either in the carbonyl group or in the bridge. In the former case, the name of the acyl group is enclosed in parentheses to avoid ambiguity in the name,[2] e.g., (thioacetic) anhydride (CH3C(S)OC(S)CH3). When two acyl groups are attached to the same sulfur atom, the resulting compound is called a thioanhydride,[2] e.g., acetic thioanhydride ((CH3C(O))2S). Dianhydrides Dianhydrides are molecules containing two acid anhydride functions. They are mainly used to synthesize polyimides and sometimes polyesters and polyamides. Examples of dianhydrides: pyromellitic dianhydride (PMDA), 3,3’, 4,4’ - oxydiphtalic dianhydride (ODPA), 3,3’, 4,4’-benzophenone tetracarboxylic dianhydride (BTDA), 4,4’-diphtalic (hexafluoroisopropylidene) anhydride (6FDA), benzoquinonetetracarboxylic dianhydride, ethylenetetracarboxylic dianhydride. Acid anhydride 130 Polyanhydrides Polyanhydrides are a class of polymers characterized by anhydride bonds that connect repeat units of the polymer backbone chain. References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "acid anhydrides" (http:/ / goldbook. iupac. org/ A00072. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.{{{file}}}. ISBN 0-9678550-9-8. . [2] Panico, R.; Powell, W. H.; Richer, J. C., eds. (1993). "Recommendation R-5.7.7" (http:/ / www. acdlabs. com/ iupac/ nomenclature/ ). A Guide to IUPAC Nomenclature of Organic Compounds. IUPAC/Blackwell Science. pp. 123–25. ISBN 0-632-03488-2. . [3] Heimo Held, Alfred Rengstl, Dieter Mayer "Acetic Anhydride and Mixed Fatty Acid Anhydrides" Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a01_065 [4] Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6. [5] Zoeller, J. R.; Agreda, V. H.; Cook, S. L.; Lafferty, N. L.; Polichnowski, S. W.; Pond, D. M. "Eastman Chemical Company Acetic Anhydride Process" Catalysis Today (1992), volume 13, pp.73-91. doi:10.1016/0920-5861(92)80188-S [6] Lewis I. Krimen (1988), "Acetic Formic Anhydride" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=CV6P0008), Org. Synth., ; Coll. Vol. 6: 8 http://www.chemguide.co.uk/organicprops/anhydrides/background.html Carboxylic acid Carboxylic acids (  /ˌkɑrbɒkˈsɪlɪk/) are organic acids characterized by the presence of at least one carboxyl group.[1] The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group. A carboxyl group (or carboxy) is a functional group consisting of a carbonyl (RR'C=O) and a hydroxyl (R-O-H), which has the formula -C(=O)OH, usually written as -COOH or -CO2H.[2] Carboxylic acids are Brønsted-Lowry acids because they are proton (H+) donors. They are the most common type of organic acid. Among the simplest examples are formic acid H-COOH, which occurs in ants, and acetic acid CH3-COOH, which gives vinegar its sour taste. Acids with two or more carboxyl groups are called dicarboxylic, tricarboxylic, etc. The simplest dicarboxylic example is oxalic acid (COOH)2, which is just two connected carboxyls. Mellitic acid is an example of a hexacarboxylic acid. Other important natural examples are citric acid (in lemons) and tartaric acid (in tamarinds). Salts and esters of carboxylic acids are called carboxylates. When a carboxyl group is deprotonated, its conjugate base, a carboxylate anion is formed. Carboxylate ions are resonance stabilized and this increased stability makes carboxylic acids more acidic than alcohols. Carboxylic acids can be seen as reduced or alkylated forms of the Lewis acid carbon dioxide; under some circumstances they can be decarboxylated to yield carbon dioxide. Structure of a carboxylic acid Carboxylate ion Physical properties Carboxylic acid 131 The 3D structure of the carboxyl group Solubility Carboxylic acids are polar. Because they are both hydrogen-bond acceptors (the carbonyl) and hydrogen-bond donors (the hydroxyl), they also participate in hydrogen bonding. Together the hydroxyl and carbonyl group forms the functional group carboxyl. Carboxylic acids usually exist as dimeric pairs in nonpolar media due to their tendency to “self-associate.” Smaller carboxylic acids (1 to 5 carbons) are Carboxylic acid dimers soluble in water, whereas higher carboxylic acids are less soluble due to the increasing hydrophobic nature of the alkyl chain. These longer chain acids tend to be rather soluble in less-polar solvents such as ethers and alcohols.[3] Boiling points Carboxylic acids tend to have higher boiling points than water, not only because of their increased surface area, but because of their tendency to form stabilised dimers. Carboxylic acids tend to evaporate or boil as these dimers. For boiling to occur, either the dimer bonds must be broken, or the entire dimer arrangement must be vaporised, both of which increase enthalpy of vaporisation requirements significantly. Acidity Carboxylic acids are typically weak acids, meaning that they only partially dissociate into H+ cations and RCOO– anions in neutral aqueous solution. For example, at room temperature, only 0.4% of all acetic acid molecules are dissociated. Electronegative substituents give stronger acids. Carboxylic acid Formic acid (HCO2H) Acetic acid (CH3COOH) Chloroacetic acid (CH2ClCO2H) [4] pKa 3.75 4.76 2.86 Dichloroacetic acid (CHCl2CO2H) 1.29 Trichloroacetic acid (CCl3CO2H) Trifluoroacetic acid (CF3CO2H) Oxalic acid (HO2CCO2H) Benzoic acid (C6H5CO2H) 0.65 0.5 1.27 4.2 Deprotonation of carboxylic acids gives carboxylate anions, which is resonance stabilized because the negative charge is delocalized between the two oxygen atoms increasing its stability. Each of the carbon-oxygen bonds in Carboxylic acid carboxylate anion has partial double-bond character. 132 Odor Carboxylic acids often have strong odors, especially the volatile derivatives. Most common are acetic acid (vinegar) and butanoic acid (rancid butter). On the other hand, esters of carboxylic acids tend to have pleasant odors and many are used in perfumes. Characterization Carboxylic acids are most readily identified as such by infrared spectroscopy. They exhibit a sharp band associated with vibration of the C-O vibration bond (νC=O) between 1680 and 1725 cm−1. A characteristic νO-H band appears as a broad peak in the 2500 to 3000 cm−1 region.[3] By 1H NMR spectrometry, the hydroxyl hydrogen appears in the 10–13 ppm region, although it is often either broadened or not observed owing to exchange with traces of water. Occurrence and applications Many carboxylic acids are produced industrially on a large scale. They are also pervasive in nature. Esters of fatty acids are the main components of lipids and polyamides of aminocarboxylic acids are the main components of proteins. Carboxylic acids are used in the production of polymers, pharmaceuticals, solvents, and food additives. Industrially important carboxylic acids include acetic acid (component of vinegar, precursor to solvents and coatings), acrylic and methacrylic acids (precursors to polymers, adhesives), adipic acid (polymers), citric acid (beverages), ethylenediaminetetraacetic acid (chelating agent), fatty acids (coatings), maleic acid (polymers), propionic acid (food preservative), terephthalic acid (polymers). Synthesis Industrial routes Industrial routes to carboxylic acids generally differ from those used on smaller scale because they require specialized equipment. • Oxidation of aldehydes with air using cobalt and manganese catalysts. The required aldehydes are readily obtained from alkenes by hydroformylation. • Oxidation of hydrocarbons using air. For simple alkanes, the method is nonselective but so inexpensive to be useful. Allylic and benzylic compounds undergo more selective oxidations. Alkyl groups on a benzene ring oxidized to the carboxylic acid, regardless of its chain length. Benzoic acid from toluene and terephthalic acid from para-xylene, and phthalic acid from ortho-xylene are illustrative large-scale conversions. Acrylic acid is generated from propene.[5] • Base-catalyzed dehydrogenation of alcohols. • Carbonylation is versatile method when coupled to the addition of water. This method is effective for alkenes that generate secondary and tertiary carbocations, e.g. isobutylene to pivalic acid. In the Koch reaction, the addition of water and carbon monoxide to alkenes is catalyzed by strong acids. Acetic acid and formic acid are produced by the carbonylation of methanol, conducted with iodide and alkoxide promoters, respectively and often with high pressures of carbon monoxide, usually involving additional hydrolytic steps. Hydrocarboxylations involve the simultaneous addition of water and CO. Such reactions are sometimes called "Reppe chemistry": HCCH + CO + H2O → CH2=CHCO2H • Some long chain carboxylic acids are obtained by the hydrolysis of triglycerides obtained from plant or animal oils. These methods are related to soap making. Carboxylic acid • fermentation of ethanol is used in the production of vinegar. 133 Laboratory methods Preparative methods for small scale reactions for research or for production of fine chemicals often employ expensive consumable reagents. • oxidation of primary alcohols or aldehydes with strong oxidants such as potassium dichromate, Jones reagent, potassium permanganate, or sodium chlorite. The method is amenable to laboratory conditions compared to the industrial use of air, which is “greener” since it yields less inorganic side products such as chromium or manganese oxides. • Oxidative cleavage of olefins by ozonolysis, potassium permanganate, or potassium dichromate. • Carboxylic acids can also be obtained by the hydrolysis of nitriles, esters, or amides, generally with acid- or base-catalysis. • Carbonation of a Grignard and organolithium reagents: RLi + CO2 RCO2Li RCO2Li + HCl RCO2H + LiCl • Halogenation followed by hydrolysis of methyl ketones in the haloform reaction • The Kolbe-Schmitt reaction provides a route to salicylic acid, precursor to aspirin. Less-common reactions Many reactions afford carboxylic acids but are used only in specific cases or are mainly of academic interest: • Disproportionation of an aldehyde in the Cannizzaro reaction • Rearrangement of diketones in the benzilic acid rearrangement involving the generation of benzoic acids are the von Richter reaction from nitrobenzenes and the Kolbe-Schmitt reaction from phenols. Reactions The most widely practiced reactions convert carboxylic acids into esters, amides, carboxylate salts, acid chlorides, and alcohols. Carboxylic acids react with bases to form carboxylate salts, in which the hydrogen of the hydroxyl (-OH) group is replaced with a metal cation. Thus, acetic acid found in vinegar reacts with sodium bicarbonate (baking soda) to form sodium acetate, carbon dioxide, and water: CH3COOH + NaHCO3 → CH3COO−Na+ + CO2 + H2O Carboxylic acids also react with alcohols to give esters. This process is heavily used in the production of polyesters. Similarly carboxylic acids are converted into amides, but this conversion typically does not occur by direct reaction of the carboxylic acid and the amine. Instead esters are typical precursors to amides. The conversion of amino acids into peptides is a major biochemical process that requires ATP. The hydroxyl group on carboxylic acids may be replaced with a chlorine atom using thionyl chloride to give acyl chlorides. In nature, carboxylic acids are converted to thioesters. Carboxylic acid can be reduced to the alcohol by hydrogenation or using stoichiometric hydride reducing agents such as lithium aluminium hydride. N,N-dimethylchloromethylenammonium chloride is a highly chemoselective agent for carboxylic acid reduction. It selectively activate the carboxylic acid and is known to tolerate active functionalities such as ketone as well as the moderate ester, olefin, nitrile and halide moeties.[6] Carboxylic acid 134 Specialized reactions • As with all carbonyl compounds, the protons on the α-carbon are labile due to keto-enol tautomerization. Thus the α-carbon is easily halogenated in the Hell-Volhard-Zelinsky halogenation. • The Schmidt reaction converts carboxylic acids to amines. • Carboxylic acids are decarboxylated in the Hunsdiecker reaction. • The Dakin-West reaction converts an amino acid to the corresponding amino ketone. • In the Barbier-Wieland degradation, the alpha-methylene group in an aliphatic carboxylic acid is removed in a sequence of reaction steps, effectively a chain-shortening.[7][8] The inverse procedure is the Arndt-Eistert synthesis, where an acid is converted into acyl halide and reacts with diazomethane to give the highest homolog. • Many acids undergo oxidative decarboxylation. Enzymes that catalyze these reactions are known as carboxylases (EC 6.4.1) and decarboxylases (EC 4.1.1). • Carboxylic acids are reduced to aldehydes via the ester and DIBAL, via the acid chloride in the Rosenmund reduction and via the thioester in the Fukuyama reduction. • In ketonic decarboxylation carboxylic acids are converted to ketones. Nomenclature and examples Carboxylic acids are commonly named as indicated in the table below. Although rarely used, IUPAC-recommended names also exist. For example, butyric acid (C3H7CO2H) is, according to IUPAC guidelines, also known as butanoic acid.[9] The carboxylate anion R-COO– is usually named with the suffix -ate, so acetic acid, for example, becomes acetate ion. In IUPAC nomenclature, carboxylic acids have an -oic acid suffix (e.g., octadecanoic acid). In common nomenclature, the suffix is usually -ic acid (e.g., stearic acid). Straight-chained, saturated carboxylic acids Carbon atoms Common name 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Palmitic acid Margaric acid Formic acid Acetic acid Propionic acid Butyric acid Valeric acid Caproic acid Enanthic acid Caprylic acid Pelargonic acid Capric acid Undecylic acid Lauric acid Tridecylic acid Myristic acid IUPAC name Methanoic acid Ethanoic acid Propanoic acid Butanoic acid Pentanoic acid Hexanoic acid Heptanoic acid Octanoic acid Nonanoic acid Decanoic acid Undecanoic acid Dodecanoic acid Tridecanoic acid Tetradecanoic acid Chemical formula HCOOH CH3COOH CH3CH2COOH CH3(CH2)2COOH CH3(CH2)3COOH CH3(CH2)4COOH CH3(CH2)5COOH CH3(CH2)6COOH CH3(CH2)7COOH CH3(CH2)8COOH CH3(CH2)9COOH CH3(CH2)10COOH Coconut oil and hand wash soaps. CH3(CH2)11COOH CH3(CH2)12COOH Nutmeg Coconuts and breast milk Pelargonium Common location or use Insect stings Vinegar Preservative for stored grains Rancid butter Valerian Goat fat Pentadecanoic acid CH3(CH2)13COOH Hexadecanoic acid CH3(CH2)14COOH Palm oil Heptadecanoic acid CH3(CH2)15COOH Carboxylic acid 135 18 20 Stearic acid Arachidic acid Octadecanoic acid Icosanoic acid CH3(CH2)16COOH Chocolate, waxes, soaps, and oils CH3(CH2)18COOH Peanut oil Other carboxylic acids Compound class unsaturated monocarboxylic acids Fatty acids Members acrylic acid (2-propenoic acid) – CH2=CHCOOH, used in polymer synthesis medium to long-chain saturated and unsaturated monocarboxylic acids, with even number of carbons examples docosahexaenoic acid and eicosapentaenoic acid (nutritional supplements) the building blocks of proteins acids of biochemical significance that contain a ketone group e.g. acetoacetic acid and pyruvic acid Amino acids Keto acids Aromatic carboxylic acids benzoic acid, the sodium salt of benzoic acid is used as a food preservative, salicylic acid – a beta hydroxy type found in many skin care products Dicarboxylic acids containing two carboxyl groups examples adipic acid the monomer used to produce nylon and aldaric acid – a family of sugar acids containing three carboxyl groups example citric acid – found in citrus fruits and isocitric acid containing a hydroxy group example glyceric acid, glycolic acid and lactic acid (2-hydroxypropanoic acid) – found in sour milk tartaric acid – found in wine Tricarboxylic acids Alpha hydroxy acids Carboxyl radical The radical ·COOH (CAS# 2564-86-5) has only a separate fleeting existence.[10] The acid dissociation constant of ·COOH has been measured using electron paramagnetic resonance spectroscopy.[11] The carboxyl group tends to dimerise to form oxalic acid. References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "carboxylic acids" (http:/ / goldbook. iupac. org/ C00852. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.C00852. ISBN 0-9678550-9-8. . [2] March, Jerry (1992), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (4th ed.), New York: Wiley, ISBN 0-471-60180-2 [3] R.T. Morrison, R.N. Boyd. Organic Chemistry, 6th Ed. (1992) ISBN 0-13-643669-2. [4] Haynes, William M., ed. (2011). CRC Handbook of Chemistry and Physics (92nd ed.). CRC Press. pp. 5–94 to 5–98. ISBN 1439855110. [5] Wilhelm Riemenschneider “Carboxylic Acids, Aliphatic” in Ullmann's Encyclopedia of Industrial Chemistry, 2002, Wiley-VCH, Weinheim. doi: 10.1002/14356007.a05_235. [6] Tamotsu Fujisawa and Toshio Sato, Organic Syntheses, Coll. Vol. 8, p.498 (1993); Vol. 66, p.121 (1988) [7] Organic Syntheses, Coll. Vol. 3, p.234 (1955); Vol. 24, p.38 (1944) Link (http:/ / www. orgsynth. org/ orgsyn/ pdfs/ CV3P0234. pdf) [8] Organic Syntheses, Coll. Vol. 3, p.237 (1955); Vol. 24, p.41 (1944) Link (http:/ / www. orgsynth. org/ orgsyn/ pdfs/ CV3P0237. pdf). [9] Recommendations 1979 (http:/ / www. acdlabs. com/ iupac/ nomenclature/ 79/ r79_24. htm). Organic Chemistry IUPAC Nomenclature. Rules C-4 Carboxylic Acids and Their Derivatives. [10] Milligan, D. E.; Jacox, M. E. (1971). "Infrared Spectrum and Structure of Intermediates in Reaction of OH with CO". Journal of Chemical Physics 54 (3): 927–942. Bibcode 1971JChPh..54..927M. doi:10.1063/1.1675022. [11] The value is pKa = -0.2 ± 0.1.Jeevarajan, A. S.; Carmichael, I.; Fessenden, R. W. (1990). "ESR Measurement of the pKa of Carboxyl Radical and Ab Initio Calculation of the C-13 Hyperfine Constant". Journal of Physical Chemistry 94 (4): 1372–1376. doi:10.1021/j100367a033. Carboxylic acid 136 External links • Carboxylic acids synthesis – Collection of links pertaining to synthesis of Carboxylic acid (http://www.uduko. com/topic_detail/details/40) • Carboxylic acids pH and titration – freeware for calculations, data analysis, simulation, and distribution diagram generation (http://www2.iq.usp.br/docente/gutz/Curtipot_.html) Carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. The term carbonyl can also refer to carbon monoxide as a ligand in an inorganic or organometallic complex (a metal carbonyl, e.g. nickel carbonyl). The remainder of this article concerns itself with the organic chemistry definition of carbonyl, where carbon and oxygen share a double bond. Carbonyl group Carbonyl compounds A carbonyl group characterizes the following types of compounds: Compound Structure Aldehyde Ketone Carboxylic acid Ester Amide General formula RCHO RCOR' RCOOH RCOOR' RCONR'R'' Compound Structure Enone Acyl halide Acid anhydride Imide General formula RC(O)C(R')CR''R''' RCOX (RCO)2O RC(O)N(R')C(O)R''' Note that the most specific labels are usually employed. For example, R(CO)O(CO)R' structures are known as acid anhydride rather than the more generic ester, even though the ester motif is present. Other organic carbonyls are urea and the carbamates, the derivatives of acyl chlorides chloroformates and phosgene, carbonate esters, thioesters, lactones, lactams, hydroxamates, and isocyanates. Examples of inorganic carbonyl compounds are carbon dioxide and carbonyl sulfide. Carbon dioxide A special group of carbonyl compounds are 1,3-dicarbonyl compounds that have acidic protons in the central methylene unit. Examples are Meldrum's acid, diethyl malonate and acetylacetone. Carbonyl 137 Reactivity Oxygen is more electronegative than carbon, and thus draws electron density away from carbon to increase the bond's polarity. Therefore, the carbonyl carbon becomes electrophilic, and thus more reactive with nucleophiles. Also, the electronegative oxygen can react with an electrophile; for example a proton in an acidic solution or other Lewis Acid forming a oxocarbenium ion. The alpha hydrogens of a carbonyl compound are much more acidic Carbonyl group (~103 times more acidic) than a typical C-H bond. For example, the pKa values of acetaldehyde and acetone are 16.7 and 19, respectively.[1] This is because a carbonyl is in tautomeric resonance with an enol. The deprotonation of the enol with a strong base produces an enolate, which is a powerful nucleophile and can alkylate electrophiles such as other carbonyls. Amides are the most stable of the carbonyl couplings due to their high resonance stabilization between the nitrogen-carbon and carbon-oxygen bonds. Carbonyl groups can be reduced by reaction with hydride reagents such as NaBH4 and LiAlH4, or catalytically by hydrogen and a catalyst such as copper chromite, Raney nickel, rhenium, ruthenium or even rhodium. Ketones give secondary alcohols; aldehydes, esters and carboxylic acids give primary alcohols. Carbonyls would be alkylated by nucleophilic attack by organometallic reagents such as organolithium reagents and Grignard reagents. Carbonyls also may be alkylated by enolates as in aldol reactions. Carbonyls are also the prototypical groups with vinylogous reactivity, e.g. the Michael reaction where an unsaturated carbon in conjugation with the carbonyl is alkylated instead of the carbonyl itself. Other important reactions include: • • • • • • • • • • • • • • • • Wittig Reaction a phosphonium ylid is used to create an alkene Wolff-Kishner reduction into a hydrazone and further into a saturated alkane Clemmensen reduction into a saturated alkane Mozingo reduction into a saturated alkane Conversion into thioacetals Hydration to hemiacetals and hemiketals, and then to acetals and ketals Reaction with ammonia and primary amines to form imines Reaction with hydroxylamines to form oximes Reaction with cyanide anion to form cyanohydrins Oxidation with oxaziridines to acyloins Reaction with Tebbe's reagent and phosphonium ylides to alkenes. Perkin reaction, an aldol reaction variant Aldol condensation, a reaction between an enolate and a carbonyl Cannizzaro reaction, a disproportionation of aldehydes into alcohols and acids Tishchenko reaction, another disproportionation of aldehydes that gives a dimeric ester Nucleophilic abstraction is used to produce carbon dioxide Carbonyl 138 α,β-Unsaturated carbonyl compounds α,β-Unsaturated carbonyl compounds are an important class of carbonyl compounds with the general structure −(O=C)−Cα=Cβ−. In these compounds the carbonyl group is conjugated with an alkene (hence the adjective unsaturated), from which they derive special properties. Unlike the case for simple carbonyls, α,β-unsaturated carbonyl compounds are often attacked by nucleophiles at the β carbon. This pattern of reactivity is called vinylogous. Examples of unsaturated carbonyls are acrolein (propenal), mesityl oxide, acrylic acid, and maleic acid. Unsaturated carbonyls can be prepared in the laboratory in an aldol reaction and in the Perkin reaction. Acrolein, an α,β-unsaturated carbonyl compound. The carbonyl group draws electrons away from the alkene, and the alkene group is, therefore, deactivated towards an electrophile, such as bromine or hydrochloric acid. As a general rule with unsymmetric electrophiles, hydrogen attaches itself at the α-position in an electrophilic addition. On the other hand, these compounds are activated towards nucleophiles in nucleophilic conjugate addition. Since α,β-unsaturated compounds are electrophiles, many α,β-unsaturated carbonyl compounds are toxic, mutagenic and carcinogenic. DNA can attack the β carbon and thus be alkylated. However, the endogenous scavenger compound glutathione naturally protects from toxic electrophiles in the body. Spectroscopy • Infrared spectroscopy: the C=O double bond absorbs infrared light at wavenumbers between approximately 1600–1900 cm−1. The exact location of the absorption is well understood with respect to the geometry of the molecule. This absorption is known as the "carbonyl stretch" when displayed on an infrared absorption spectrum.[2] • Nuclear magnetic resonance: the C=O double-bond exhibits different resonances depending on surrounding atoms, generally a downfield shift. The 13C NMR of a carbonyl carbon is in the range of 160-220 ppm. References [1] Ouellette, R.J. and Rawn, J.D. “Organic Chemistry” 1st Ed. Prentice-Hall, Inc., 1996: New Jersey. ISBN 0-02-390171-3. [2] Mayo D.W., Miller F.A and Hannah R.W “Course Notes On The Interpretation of Infrared and Raman Spectra” 1st Ed. John Wiley & Sons Inc, 2004: New Jersey. ISBN 0-471-24823-1. Further reading • L.G. Wade, Jr. Organic Chemistry, 5th ed. Prentice Hall, 2002. ISBN 0-13-033832-X • The Frostburg State University Chemistry Department. Organic Chemistry Help (http://www.chemhelper.com/ ) (2000). • Advanced Chemistry Development, Inc. IUPAC Nomenclature of Organic Chemistry (http://www.acdlabs. com/iupac/nomenclature) (1997). • William Reusch. tara VirtualText of Organic Chemistry (http://www.cem.msu.edu/~reusch/VirtualText/ intro1.htm) (2004). • Purdue Chemistry Department (http://chemed.chem.purdue.edu/genchem/topicreview/bp/2organic/ carbonyl.html) (retrieved Sep 2006). Includes water solubility data. • William Reusch. (2004) Aldehydes and Ketones (http://www.cem.msu.edu/~reusch/VirtualText/aldket1. htm) Retrieved 23 May 2005. • ILPI. (2005) The MSDS Hyperglossary- Anhydride (http://www.ilpi.com/msds/ref/anhydride.html). Cyanide 139 Cyanide A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom.[1] Cyanides most commonly refer to salts of the anion CN−, which is isoelectronic with carbon monoxide and with molecular nitrogen.[2][3] Most cyanides are highly toxic.[4] Nomenclature and etymology In IUPAC nomenclature, organic compounds that have a –C≡N functional group are called nitriles. Thus, nitriles are organic compounds.[5][6] An example of a nitrile is CH3CN, acetonitrile, also known as methyl cyanide. Nitriles usually do not release cyanide ions. A functional group with a hydroxyl and cyanide bonded to the same carbon is called cyanohydrin. Unlike nitriles, cyanohydridins do release hydrogen cyanide. In inorganic chemistry, salts containing the C≡N− ion are referred to as cyanides. Occurrence and reactions Cyanides are produced by certain bacteria, fungi, and algae and are found in a number of plants. Cyanides are found, although in small amounts, in certain seeds and fruit stones, e.g., those of apple, mango, peach, and bitter almonds.[7] In plants, cyanides are usually bound to sugar molecules in the form of cyanogenic glycosides and defend the plant against herbivores. Cassava roots (also called manioc), an important potato-like food grown in tropical countries (and the base from which tapioca is made), also contain cyanogenic glycosides.[8][9] The cyanide ion, CN−. From the top: 1. Valence-bond structure 2. Space-filling model 3. Electrostatic potential surface 4. "Carbon lone pair" HOMO/LUMO Interstellar medium The cyanide radical CN· has been identified in interstellar space.[10] The cyanide radical (called cyanogen) is used to measure the temperature of interstellar gas clouds.[11] Pyrolysis and combustion product Hydrogen cyanide is produced by the combustion or pyrolysis of certain materials under oxygen-deficient conditions. For example, it can be detected in the exhaust of internal combustion engines and tobacco smoke. Certain plastics, especially those derived from acrylonitrile, release hydrogen cyanide when heated or burnt.[12] Coordination chemistry The cyanide anion is a ligand for many transition metals.[13] The high affinities of metals for this anion can be attributed to its negative charge, compactness, and ability to engage in π-bonding. Well-known complexes include: • hexacyanides [M(CN)6]3− (M = Ti, V, Cr, Mn, Fe, Co), which are octahedral in shape; • the tetracyanides, [M(CN)4]2− (M = Ni, Pd, Pt), which are square planar in their geometry; • the dicyanides [M(CN)2]− (M = Cu, Ag, Au), which are linear in geometry. Cyanide The dye Prussian blue was first accidentally made around 1706, by heating substances containing iron and carbon and nitrogen. Prussian blue consists of an iron-containing compound called "ferrocyanide" ({Fe(CN)6]4-) meaning "blue substance with iron", from Latin ferrum = "iron" and Greek kyanos = "(dark) blue".[14] Prussian blue is the deep-blue pigment used in the making of blueprints. The enzymes called hydrogenases contain cyanide ligands attached to iron in their active sites. The biosynthesis of cyanide in the [NiFe]-hydrogenases proceeds from carbamoylphosphate, which converts to cysteinyl thiocyanate, the CN− donor.[15] 140 Organic derivatives Because of the cyanide anion's high nucleophilicity, cyano groups are readily introduced into organic molecules by displacement of a halide group (e.g., the chloride on methyl chloride). In general, organic cyanides are called nitriles. Thus, CH3CN can be called methyl cyanide but more commonly is referred to as acetonitrile. In organic synthesis, cyanide is a C-1 synthon; i.e., it can be used to lengthen a carbon chain by one, while retaining the ability to be functionalized. RX + CN− → RCN + X− (nucleophilic substitution) followed by 1. RCN + 2 H2O → RCOOH + NH3 (hydrolysis under reflux with mineral acid catalyst), or 2. 2 RCN + LiAlH4 + (second step) 4 H2O → 2 RCH2NH2 + LiAl(OH)4 (under reflux in dry ether, followed by addition of H2O) Manufacture The principal process used to manufacture cyanides is the Andrussow process in which gaseous hydrogen cyanide is produced from methane and ammonia in the presence of oxygen and a platinum catalyst.[16][17] 2 CH4 + 2 NH3 + 3 O2 → 2 HCN + 6 H2O Gaseous hydrogen cyanide may be dissolved in aqueous sodium hydroxide solution to produce sodium cyanide. Toxicity Many cyanides are highly toxic. The cyanide anion is an inhibitor of the enzyme cytochrome c oxidase (also known as aa3) in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It attaches to the iron within this protein. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted, meaning that the cell can no longer aerobically produce ATP for energy.[18] Tissues that depend highly on aerobic respiration, such as the central nervous system and the heart, are particularly affected. This is an example of histotoxic hypoxia.[19] The most hazardous compound is hydrogen cyanide, which is a gas at ambient temperatures and pressure and can therefore be inhaled. For this reason, an air respirator supplied by an external oxygen source must be worn when working with hydrogen cyanide. Hydrogen cyanide is produced when a solution containing a labile cyanide is made acidic, because HCN is a weak acid. Alkaline solutions are safer to use because they do not evolve hydrogen cyanide gas. Hydrogen cyanide may be produced in the combustion of polyurethanes; for this reason, polyurethanes are not recommended for use in domestic and aircraft furniture. Oral ingestion of a small quantity of solid cyanide or a cyanide solution as little as 200 mg, or to airborne cyanide of 270 ppm is sufficient to cause death within minutes.[19] Organic nitriles do not readily release cyanide ions, and so have low toxicities. By contrast, compounds such as trimethylsilyl cyanide (CH3)3SiCN readily release HCN or the cyanide ion upon contact with water. Cyanide 141 Antidote Hydroxocobalamin reacts with cyanide to form cyanocobalamin, which can be safely eliminated by the kidneys. This method has the advantage of avoiding the formation of methemoglobin (see below). This antidote kit is sold under the brand name Cyanokit and was approved by the FDA in 2006.[20] An older cyanide antidote kit included administration of three substances: amyl nitrite pearls (administered by inhalation), sodium nitrite, and sodium thiosulfate (administered by infusion). The goal of the antidote was to generate a large pool of ferric iron (Fe3+) to compete with cyanide cytochrome a3 (so that cyanide will bind to the antidote rather that the enzyme). The nitrites oxidize hemoglobin to methemoglobin, which competes with cytochrome oxidase for the cyanide ion. Cyanmethemoglobin is formed and the cytochrome oxidase enzyme is restored. The major mechanism to remove the cyanide from the body is by enzymatic conversion to thiocyanate by the mitochondrial enzyme rhodanese. Thiocyanate is a relatively non-toxic molecule and is excreted by the kidneys. To accelerate this detoxification, sodium thiosulfate is administered to provide a sulfur donor for rhodanese, needed in order to produce thiocyanate. Sensitivity Minimum risk levels (MRLs) may not protect for delayed health effects or health effects acquired following repeated sublethal exposure, such as hypersensitivity, asthma, or bronchitis. MRLs may be revised after sufficient data accumulates (Toxicological Profile for Cyanide, U.S. Department of Health and Human Services, 2006). Applications Mining Cyanide is mainly produced for the mining of gold and silver: It helps dissolve these metals and their ores. In the cyanide process, finely ground high-grade ore is mixed with the cyanide (concentration of about two kilogram NaCN per tonne); low-grade ores are stacked into heaps and sprayed with a cyanide solution (concentration of about one kilogram NaCN per ton). The precious metals are complexed by the cyanide anions to form soluble derivatives, e.g., [Au(CN)2]− and [Ag(CN)2]−.[21] 4 Au + 8 NaCN + O2 + 2 H2O → 4 Na[Au(CN)2] + 4 NaOH Silver is less "noble" than gold and often occurs as the sulfide, in which case redox is not invoked (no O2 is required). Instead, a displacement reaction occurs: Ag2S + 4 NaCN + H2O → 2 Na[Ag(CN)2] + NaSH + NaOH The "pregnant liquor" containing these ions is separated from the solids, which are discarded to a tailing pond or spent heap, the recoverable gold having been removed. The metal is recovered from the "pregnant solution" by reduction with zinc dust or by adsorption onto activated carbon. This process can result in environmental and health problems. Aqueous cyanide is hydrolyzed rapidly, especially in sunlight. It can mobilize some heavy metals such as mercury if present. Gold can also be associated with arsenopyrite (FeAsS), which is similar to iron pyrite (fool's gold), wherein half of the sulfur atoms are replaced by arsenic. Gold-containing arsenopyrite ores are similarly reactive toward inorganic cyanide. Cyanide is also used in electroplating, where it stabilizes metal ions in the electrolyte solution prior to their deposition. Cyanide 142 Industrial organic chemistry Some nitriles are produced on a large scale, e.g., adiponitrile is a precursor to nylon. Such compounds are often generated by combining hydrogen cyanide and alkenes, i.e., hydrocyanation: RCH=CH2 + HCN → RCH(CN)CH3. Metal catalysts are required for such reactions. Medical uses The cyanide compound sodium nitroprusside is used mainly in clinical chemistry to measure urine ketone bodies mainly as a follow-up to diabetic patients. On occasion, it is used in emergency medical situations to produce a rapid decrease in blood pressure in humans; it is also used as a vasodilator in vascular research. The cobalt in artificial vitamin B12 contains a cyanide ligand as an artifact of the purification process; this must be removed by the body before the vitamin molecule can be activated for biochemical use. During World War I, a copper cyanide compound was briefly used by Japanese physicians for the treatment of tuberculosis and leprosy.[22] Fishing Cyanides are illegally used to capture live fish near coral reefs for the aquarium and seafood markets. The practice is controversial, dangerous, and damaging but is driven by the lucrative exotic fish market. Pest control Cyanide is used for pest control in New Zealand particularly for possums, an introduced marsupial that threatens the conservation of native species and spreads tuberculosis amongst cattle. Possums can become bait shy but the use of pellets containing the cyanide reduces bait shyness. Cyanide has been known to kill native birds, including the endangered kiwi.[23] Cyanide is also effective for controlling the Dama Wallaby, another introduced marsupial pest in New Zealand.[24] A licence is required to store, handle and use cyanide in New Zealand. Niche uses Potassium ferrocyanide is used to achieve a blue color on cast bronze sculptures during the final finishing stage of the sculpture. On its own, it will produce a very dark shade of blue and is often mixed with other chemicals to achieve the desired tint and hue. It is applied using a torch and paint brush while wearing the standard safety equipment used for any patina application: rubber gloves, safety glasses, and a respirator. The actual amount of cyanide in the mixture varies according to the recipes used by each foundry. Cyanide is also used in jewelry-making and certain kinds of photography such as sepia toning. Cyanides are used as insecticides for fumigating ships. Cyanide salts are used for killing ants, and have in some places been used as rat poison (the less toxic poison arsenic is more common). Although usually thought to be toxic, cyanide and cyanohydrins have been demonstrated to increase germination in various plant species.[25][26] Human poisoning Deliberate cyanide poisoning of humans has occurred many times throughout history.[27] For notable cyanide deaths, see Cyanide poisoning: Historical cases. Most significantly, hydrogen cyanide released from pellets of Zyklon-B was used extensively in the systematic mass murders of the Holocaust, especially in extermination camps. Poisoning by hydrogen cyanide gas within a gas chamber (as a salt of hydrocyanic acid is dropped into a strong acid, usually sulfuric acid) is one method of executing a condemned prisoner as the condemned prisoner eventually breathes the lethal fumes. Cyanide Food additive Due to the high stability of their complexation with iron, ferrocyanides (Sodium ferrocyanide E535, Potassium ferrocyanide E536, and Calcium ferrocyanide E538[28]) do not decompose to lethal levels in the human body and are used in the food industry as, e.g., an anticaking agent in table salt.[29] 143 Chemical tests for cyanide Prussian blue Iron(II) sulfate is added to a solution suspected of containing cyanide, such as the filtrate from the sodium fusion test. The resulting mixture is acidified with mineral acid. The formation of Prussian blue is a positive result for cyanide. para-Benzoquinone in DMSO A solution of para-benzoquinone in DMSO reacts with inorganic cyanide to form a cyanophenol, which is fluorescent. Illumination with a UV light gives a green/blue glow if the test is positive.[30] Copper and an aromatic amine As used by fumigators to detect hydrogen cyanide, copper(II) salt and an aromatic amine such as benzidine is added to the sample; as an alternative to benzidine an alternative amine di-(4,4-bis-dimethylaminophenyl) methane can be used. A positive test gives a blue color. Copper(I) cyanide is poorly soluble. By sequestering the copper(I) the copper(II) is rendered a stronger oxidant. The copper, in a cyanide facilitated oxidation, converts the amine into a colored compound. The Nernst equation explains this process. Another good example of such chemistry is the way in which the saturated calomel reference electrode (SCE) works. The copper, in a cyanide-facilitated oxidation, converts the amine into a colored compound. Pyridine-barbituric acid colorimetry A sample containing inorganic cyanide is purged with air from a boiling acid solution into a basic absorber solution. The cyanide salt absorbed in the basic solution is buffered at pH 4.5 and then reacted with chlorine to form cyanogen chloride. The cyanogen chloride formed couples pyridine with barbituric acid to form a strongly colored red dye that is proportional to the cyanide concentration. This colorimetric method following distillation is the basis for most regulatory methods (for instance EPA 335.4) used to analyze cyanide in water, wastewater, and contaminated soils. Distillation followed by colorimetric methods, however, have been found to be prone to interferences from thiocyanate, nitrate, thiosulfate, sulfite, and sulfide that can result in both positive and negative bias. It has been recommended by the USEPA (MUR March 12, 2007) that samples containing these compounds be analyzed by Gas-Diffusion Flow Injection Analysis — Amperometry. Gas diffusion flow injection analysis — amperometry Instead of distilling, the sample is injected into an acidic stream where the HCN formed is passed under a hydrophobic gas diffusion membrane that selectively allows only HCN to pass through. The HCN that passes through the membrane is absorbed into a basic carrier solution that transports the CN to an amperometric detector that accurately measures cyanide concentration with high sensitivity. Sample pretreatment determined by acid reagents, ligands, or preliminary UV irradiation allow cyanide speciation of free cyanide, available cyanide, and total cyanide respectively. The relative simplicity of these flow injection analysis methods limit the interference experienced by the high heat of distillation and also prove to be cost effective since time consuming distillations are not required. Cyanide 144 References [1] [2] [3] [4] IUPAC Gold Book cyanides (http:/ / goldbook. iupac. org/ C01486. html) Greenwood, N. N.; & Earnshaw, A. (1997). Chemistry of the Elements (2nd Edn.), Oxford:Butterworth-Heinemann. ISBN 0-7506-3365-4. G. L. Miessler and D. A. Tarr "Inorganic Chemistry" 3rd Ed, Pearson/Prentice Hall publisher, ISBN 0-13-035471-6. "Environmental and Health Effects of Cyanide" (http:/ / www. cyanidecode. org/ cyanide_environmental. php). International Cyanide Management Institute. 2006. . Retrieved 4 August 2009. [5] IUPAC Gold Book nitriles (http:/ / goldbook. iupac. org/ N04151. html) [6] NCBI-MeSH Nitriles (http:/ / www. ncbi. nlm. nih. gov/ mesh/ 68009570) [7] "ToxFAQs for Cyanide" (http:/ / www. atsdr. cdc. gov/ tfacts8. html). Agency for Toxic Substances and Disease Registry. July 2006. . Retrieved 2008-06-28. [8] Vetter, J. (2000). "Plant cyanogenic glycosides". Toxicon 38 (1): 11–36. doi:10.1016/S0041-0101(99)00128-2. PMID 10669009. [9] Jones, D. A. (1998). "Why are so many food plants cyanogenic?". Phytochemistry 47 (2): 155–162. doi:10.1016/S0031-9422(97)00425-1. PMID 9431670. [10] Pieniazek, Piotr A.; Bradforth, Stephen E.; Krylov, Anna I. (2005-12-07). "Spectroscopy of the Cyano Radical in an Aqueous Environment" (http:/ / www-bcf. usc. edu/ ~krylov/ pubs/ pdf/ jpca-110-4854. pdf) (PDF). The journal of physical chemistry. A (Los Angeles, California 90089-0482: Department of Chemistry, University of Southern California) 110 (14): 4854–65. doi:10.1021/jp0545952. PMID 16599455. . [11] Roth, K. C.; Meyer, D. M.; Hawkins, I. (1993). "Interstellar Cyanogen and the Temperature of the Cosmic Microwave Background Radiation" (http:/ / articles. adsabs. harvard. edu/ cgi-bin/ nph-iarticle_query?1993ApJ. . . 413L. . 67R& amp;data_type=PDF_HIGH& amp;whole_paper=YES& amp;type=PRINTER& amp;filetype=. pdf) (pdf). The Astrophysical Journal 413 (2): L67–L71. Bibcode 1993ApJ...413L..67R. doi:10.1086/186961. . [12] Anon (27 January 2004). "Facts about cyanide:Where cyanide is found and how it is used" (http:/ / www. bt. cdc. gov/ Agent/ cyanide/ basics/ facts. asp). CDC Emergency preparedness and response. Centers for Disease Control and Prevention. . Retrieved 13 April 2010. [13] Sharpe, A. G. The Chemistry of Cyano Complexes of the Transition Metals; Academic Press: London, 1976 [14] Senning, Alexander (2006). Elsevier's Dictionary of Chemoetymology. Elsevier. ISBN 0-444-52239-5. [15] Reissmann, Stefanie; Elisabeth Hochleitner, Haofan Wang, Athanasios Paschos, Friedrich Lottspeich, Richard S. Glass and August Böck (2003). "Taming of a Poison: Biosynthesis of the NiFe-Hydrogenase Cyanide Ligands" (http:/ / www. sciencemag. org/ cgi/ content/ abstract/ 299/ 5609/ 1067). Science 299 (5609): 1067–1070. Bibcode 2003Sci...299.1067R. doi:10.1126/science.1080972. PMID 12586941. . Retrieved 2008-06-28. [16] Leonid Andrussow (1927). "Über die schnell verlaufenden katalytischen Prozesse in strömenden Gasen und die Ammoniak-Oxydation (V)". Berichte der deutschen chemischen Gesellschaft 60 (8): 2005–2018. doi:10.1002/cber.19270600857. [17] L. Andrussow (1935). "Über die katalytische Oxydation von Ammoniak-Methan-Gemischen zu Blausäure (The catalytic oxidation of ammonia-methane-mixtures to hydrogen cyanide)". Angewandte Chemie 48 (37): 593–595. doi:10.1002/ange.19350483702. [18] Nelson, David L.; Cox, Michael M. (2000). Lehniger Principles of Biochemistry (3rd ed.). New York: Worth Publishers. pp. 668,670-71,676. ISBN 1-57259-153-6. [19] Biller, José (2007). Interface of neurology and internal medicine (http:/ / books. google. com/ books?id=SRIvmTVcYBwC) (illustrated ed.). Lippincott Williams & Wilkins. p. 939. ISBN 0-7817-7906-5. ., Chapter 163, page 939 (http:/ / books. google. com/ books?id=SRIvmTVcYBwC& pg=PA939) [20] "Cyanide Toxicity Treatment & Management" (http:/ / emedicine. medscape. com/ article/ 814287-treatment). Emedicine.medscape.com. . Retrieved 2012-11-07. [21] Andreas Rubo, Raf Kellens, Jay Reddy, Norbert Steier, Wolfgang Hasenpusch "Alkali Metal Cyanides" in Ullmann's Encyclopedia of Industrial Chemistry 2006 Wiley-VCH, Weinheim, Germany.ISBN 10.1002/14356007.i01 i01 [22] Takano, R. (August 1916). "THE TREATMENT OF LEPROSY WITH CYANOCUPROL" (http:/ / www. jem. org/ cgi/ content/ abstract/ 24/ 2/ 207). The Journal of Experimental Medicine 24 (2): 207–211. doi:10.1084/jem.24.2.207. PMC 2125457. PMID 19868035. . Retrieved 2008-06-28. [23] Green, Wren (July 2004). "The use of 1080 for pest control" (http:/ / www. doc. govt. nz/ upload/ documents/ conservation/ threats-and-impacts/ animal-pests/ use-of-1080-04. pdf). New Zealand Department of Conservation. . Retrieved 8 June 2011. [24] Shapiro, Lee; et. al. (21 March 2011). "Effectiveness of cyanide pellets for control of dama wallabies (Macropus eugenii)" (http:/ / www. nzes. org. nz/ nzje/ new_issues/ NZJEcol35_3_1_IP_Shapiro. pdf). New Zealand Journal of Ecology 35 (3). . [25] Taylorson, R.; Hendricks, SB (1973). "Promotion of Seed Germination by Cyanide". Plant Physiol. 52 (1): 23–27. doi:10.1104/pp.52.1.23. PMC 366431. PMID 16658492. [26] Mullick, P.; Chatterji, U. N. (1967). "Effect of sodium cyanide on germination of two leguminous seeds". Plant Systematics and Evolution 114: 88–91. doi:10.1007/BF01373937. [27] Bernan (2008). Medical Management of Chemical Casualties Handbook (http:/ / books. google. com/ books?id=oiw2ZzsBvsoC) (4 ed.). Government Printing Off. p. 41. ISBN 0-16-081320-4. ., Extract p. 41 (http:/ / books. google. com/ books?id=oiw2ZzsBvsoC& pg=PA41) [28] Bender, David A.; Bender, Arnold Eric (1997). Benders' dictionary of nutrition and food technology (http:/ / books. google. com/ books?id=IrYfDEl7XPYC) (7 ed.). Woodhead Publishing. p. 459. ISBN 1-85573-475-3. ., Extract of page 459 (http:/ / books. google. com/ books?id=IrYfDEl7XPYC& pg=PA459) Cyanide [29] Schulz, Horst D.; Hadeler, Astrid; Deutsche Forschungsgemeinschaft (2003). Geochemical processes in soil and groundwater: measurement—modelling—upscaling (http:/ / books. google. com/ books?id=Fo1PjKW9GpUC). Wiley-VCH. p. 67. ISBN 3-527-27766-8. ., Extract of page 67 (http:/ / books. google. com/ books?id=Fo1PjKW9GpUC& pg=PA67) [30] Ganjeloo, A; Isom, GE; Morgan, RL; Way, JL (1980). "Fluorometric determination of cyanide in biological fluids with p-benzoquinone*1". Toxicology and Applied Pharmacology 55 (1): 103–7. doi:10.1016/0041-008X(80)90225-2. PMID 7423496. 145 External links • ATSDR medical management guidelines for cyanide poisoning (US) (http://www.atsdr.cdc.gov/mmg/mmg. asp?id=1073&tid=19) • HSE recommendations for first aid treatment of cyanide poisoning (UK) (http://www.hse.gov.uk/pubns/ firindex.htm) • Hydrogen cyanide and cyanides (http://www.inchem.org/documents/cicads/cicads/cicad61.htm) (CICAD 61) • IPCS/CEC Evaluation of antidotes for poisoning by cyanides (http://www.inchem.org/documents/antidote/ antidote/ant02.htm#SubSectionNumber:1.13.1) • National Pollutant Inventory – Cyanide compounds fact sheet (http://www.npi.gov.au/database/ substance-info/profiles/29.html) • Eating apple seeds is safe despite the small amount of cyanide (http://www.snopes.com/food/warnings/ apples.asp#add) • Toxicological Profile for Cyanide, U.S. Department of Health and Human Services, July 2006 (http://www. atsdr.cdc.gov/toxprofiles/tp8.pdf) Safety data (French): • Institut national de recherche et de sécurité (1997). " Cyanure d'hydrogène et solutions aqueuses (http://www. inrs.fr/inrs-pub/inrs01.nsf/inrs01_ftox_view/860430FE710FCFD7C1256CE8004F67CB/$File/ft4.pdf)". Fiche toxicologique n° 4, Paris:INRS, 5pp. (PDF file, in French) • Institut national de recherche et de sécurité (1997). " Cyanure de sodium. Cyanure de potassium (http://www. inrs.fr/inrs-pub/inrs01.nsf/inrs01_ftox_view/48145297F4EF18BBC1256CE8005A9FC2/$File/ft111.pdf)". Fiche toxicologique n° 111, Paris:INRS, 6pp. (PDF file, in French) Alkoxide 146 Alkoxide An alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They can be written as RO−, where R is the organic substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands. Alkoxides, although generally not stable in protic solvents such as water, occur widely as intermediates in various reactions, including the Williamson ether synthesis. Transition metal alkoxides are widely used for coatings and as catalysts.[1][2] Enolates are unsaturated alkoxide derived by deprotonation of a C-H bond adjacent to a ketone or aldehyde. The nucleophilic center for simple alkoxides is located on the oxygen, whereas the nucleophilic site on enolates is delocalized onto both carbon and oxygen sites. Phenoxides are closely related to alkoxides, except the organic substitutent is a derivative of benzene. Phenol is more acidic than a typical alcohol, thus phenoxides are correspondingly less basic and less nucleophilic. They are however often easier to handle and yield derivatives that are more crystalline than the alkoxides. The structure of a typical alkoxide group. Preparation From reducing metals Alkoxides can be produced by several routes starting from an alcohol. Highly reducing metals react directly with alcohols to give the corresponding metal alkoxide. The alcohol serves as an acid, and hydrogen is produced as a by-product. A classic case is sodium methoxide produced by the addition of sodium metal to methanol: 2CH3OH + 2Na → 2CH3ONa + H2 Other alkali metals can be used in place of sodium, and most alcohols can be used in place of methanol. From electrophilic chlorides The tetrachloride of titanium reacts with alcohols to give the corresponding tetraalkoxides, concomitant with the evolution of hydrogen chloride: TiCl4 + 4 (CH3)2CHOH → Ti(OCH(CH3)2)4 + 4 HCl The reaction can be accelerated by the addition of a base, such as a tertiary amine. Many other metal and main group halides can be used instead of titanium, for example SiCl4, ZrCl4, and PCl3. Alkoxide 147 By metathesis reactions Many alkoxides are prepared by salt-forming reactions from a metal chloride and sodium alkoxide: n NaOR + MCln → M(OR)n + n NaCl Such reactions are favored by the lattice energy of the NaCl, and purification of the product alkoxide is simplified by the fact that NaCl is insoluble in common organic solvents. By electrochemical processes Many alkoxides can be prepared by anodic dissolution of the corresponding metals in water-free alcohols in the presence of electroconductive additive. The metals may be Co, Ga, Ge, Hf, Fe, Ni, Nb, Mo, La, Re, Sc, Si, Ti, Ta, W, Y, Zr, etc. The conductive additive may be lithium chloride, quaternary ammonium halogenide, or other. Some examples of metal alkoxides obtained by this technique: Ti(OC3H7-iso)4, Nb2(OCH3)10, Ta2(OCH3)10, [MoO(OCH3)4]2, Re2O3(OCH3)6, Re4O6(OCH3)12, and Re4O6(OC3H7-iso)10. Properties Hydrolysis and transesterification Metal alkoxides hydrolyse with water according to the following equation [3]: 2 LnMOR + H2O → [LnM]2O + 2 ROH where R is an organic substituent and L is an unspecified ligand (often an alkoxide) A well-studied case is the irreversible hydrolysis of titanium ethoxide: 1/n [Ti(OCH2CH3)4]n + 2 H2O → TiO2 + 4 HOCH2CH3 By controlling the stoichiometry and steric properties of the alkoxide, such reactions can be arrested leading to metal-oxy-alkoxides, which usually are oligonuclear complexes. Other alcohols can be employed in place of water. In this way one alkoxide can be converted to another, and the process is properly referred to as alcoholysis (unfortunately, there is an issue of terminology confusion with transesterification, a different process - see below). The position of the equilibrium can be controlled by the acidity of the alcohol; for example phenols typically react with alkoxides to release alcohols, giving the corresponding phenoxide. More simply, the alcoholysis can be controlled by selectively evaporating the more volatile component. In this way, ethoxides can be converted to butoxides, since ethanol (b.p. 78 °C) is more volatile than butanol (b.p. 118 °C). In the transesterification process, metal alkoxides react with esters to bring about an exchange of alkyl groups between metal alkoxide and ester. With the metal alkoxide complex in focus, the result is the same as for alcoholysis, namely the replacement of alkoxide ligands, but at the same time the alkyl groups of the ester are changed, which can also be the primary goal of the reaction. Sodium methoxide, for example, is commonly used for this purpose, a reaction that is relevant to the production of "bio-diesel." Alkoxide 148 Formation of oxo-alkoxides Many metal alkoxide compounds also feature oxo-ligands. Oxo-ligands typically arise via the hydrolysis, often accidentally, and via ether elimination: 2 LnMOR → [LnM]2O + R2O Additionally, low valent metal alkoxides are susceptible to oxidation by air . Formation of polynuclear and heterometallic derivatives Characteristically, transition metal alkoxides are polynuclear, that is they contain more than one metal. Alkoxides are sterically undemanding and highly basic ligands that tend to bridge metals. Upon the isomorphic substitution of metal atoms close in properties crystalline complexes of variable composition are formed. The metal ratio in such compounds can vary over a broad range. For instance, the substitution of molybdenum and tungsten for rhenium in the complexes Re4O6-y(OCH3)12+y allowed one to obtain complexes Re4-xMoxO6-y(OCH3)12+y in the range of (x = 0 to 2.82) and Re4-xWxO6-y(OCH3)12+y in the range of (x = 0 to 2]. Thermal stability Many metal alkoxides thermally decompose in the range ~100–300 °C. Depending on process conditions, this thermolysis can afford nanosized powders of oxide or metallic phases. This approach is a basis of processes of fabrication of functional materials intended for aircraft, space, electronic fields, and chemical industry: individual oxides, their solid solutions, complex oxides, powders of metals and alloys active towards sintering. Decomposition of mixtures of mono- and heterometallic alkoxide derivatives has also been examined. This method represents a prospective approach possessing an advantage of capability of obtaining functional materials with increased phase and chemical homogeneity and controllable grain size (including the preparation of nanosized materials) at relatively low temperature (less than 500−900 °C) as compared with the conventional techniques. Illustrative alkoxides • titanium isopropoxide, used as a catalyst in organic synthesis and a precursor to TiO2. • aluminium isopropoxide, used as a reagent in organic synthesis. • tetraethylorthosilicate, used as a precursor to SiO2. • Potassium tert-butoxide, used as a base for organic elimination reactions. • Rhenium oxomethoxide Re4O6(OCH3)12, a tetranuclear rhenium derivative.[4] References [1] Bradley, D. C.; Mehrotra, R.; Rothwell, I.; Singh, A. "Alkoxo and Aryloxo Derivatives of Metals" Academic Press, San Diego, 2001. ISBN 0-12-124140-8. [2] Turova, N.Y.; Turevskaya, E.P.; Kessler, V.G.; Yanovskaya, M.I. "The Chemistry of Metal Alkoxides" Kluwer AP, Dordrecht, 2002. ISBN 0-7923-7521-1. The structure of tetranuclear rhenium oxomethoxide (hydrogen atoms omitted for the sake of simplicity) [3] "Single and mixed phase TiO2 powders by excess hydrolysis of titanium isopropoxide" (http:/ / www. scribd. com/ doc/ 91767773/ Single-and-Mixed-Phase-TiO2-Powders-by-hydrolysis-of-Ti-isopropoxide). Advances in Applied Ceramics 111 (3). 2012. . [4] P.A. Shcheglov, D.V. Drobot. Rhenium Alkoxides (Review). Russian Chemical Bulletin. 2005. V. 54, No. 10. P. 2247-2258. doi: 10.1007/s11172-006-0106-5 Alkoxide 149 Further reading • N.Ya. Turova. Metal oxoalkoxides. Synthesis, properties and structures (Review). Russian Chemical Reviews. 2004. V. 73, No. 11. P. 1041-1064. doi:10.1070/RC2004v073n11ABEH000855 Acyl halide An acyl halide (also known as an acid halide) is a chemical compound derived from an oxoacid[1] by replacing a hydroxyl group with a halide group.[2] If the acid is a carboxylic acid, the compound contains a –COX functional group, which consists of a carbonyl group singly bonded to a halogen atom. The general formula for such an acyl halide can be written RCOX, where R may be, for example, an alkyl group, CO is the carbonyl group, and X represents the halide, such as chloride. Acyl chlorides are the most commonly encountered acyl halides, but acetyl iodide is the one produced (transiently) on the largest scale. Billions of kilograms are generated annually in the production of acetic acid.[3] The hydroxyl group of a sulfonic acid may also be replaced by a halogen to produce the corresponding sulfonyl halide. In practical terms this is almost always chloride to give the sulfonyl chloride. Acyl Halide Preparation A common laboratory method for the synthesis of acyl halides entails reaction of carboxylic acids with reagents such as thionyl chloride or phosphorus pentachloride for acyl chlorides, phosphorus pentabromide for acyl bromides and cyanuric fluoride for acyl fluorides. Aromatic acyl chlorides can be prepared by chloroformylation, a specific type of Friedel-Crafts acylation using formaldehyde as the reagent. Acetyl chloride is an acyl halide. Reactions Acyl halides are rather reactive compounds often synthesized to be used as intermediates in the synthesis of other organic compounds. For example, an acyl halide can react with: • water, to form a carboxylic acid. This hydrolysis is the most heavily exploited reaction for acyl halides as it occurs in the industrial synthesis of acetic acid. • an alcohol to form an ester • an amine to form an amide Acyl halide • an aromatic compound, using a Lewis acid catalyst such as AlCl3, to form an aromatic ketone. See Friedel-Crafts acylation. In the above reactions, HX (hydrogen halide or hydrohalic acid) is also formed. For example, if the acyl halide is an acyl chloride, HCl (hydrogen chloride or hydrochloric acid) is also formed. 150 Multiple functional groups A molecule can have more than one acyl halide functional group. For example, "adipoyl dichloride", usually simply called adipoyl chloride, has two acyl chloride functional groups; see the structure at right. It is the dichloride (i.e., double chloride) of the 6-carbon dicarboxylic acid adipic acid. An important use of adipoyl chloride is polymerization with an organic di-amino compound to form a polyamide called nylon or polymerization with certain other organic compounds to form polyesters. Adipoyl chloride Phosgene (carbonyl dichloride, Cl–CO–Cl) is a very toxic gas that is the dichloride of carbonic acid (HO–CO–OH). Both chloride radicals in phosgene can undergo reactions analogous to the preceding reactions of acyl halides. Phosgene is used a reactant in the production of polycarbonate polymers, among other industrial applications. General hazards Volatile acyl halides are lachrymatory because they can react with water at the surface of the eye producing hydrohalic and organic acids irritating to the eye. Similar problems can result if one inhales acyl halide vapors. In general, acyl halides (even non-volatile compounds such as tosyl chloride) are irritants to the eyes, skin and mucous membranes. References [1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "acyl groups" (http:/ / goldbook. iupac. org/ A00123. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.A00123. ISBN 0-9678550-9-8. . [2] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "acyl halides" (http:/ / goldbook. iupac. org/ A00124. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.A00124. ISBN 0-9678550-9-8. . [3] Hosea Cheung, Robin S. Tanke, G. Paul Torrence “Acetic Acid” in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a01_045 Acetyl chloride 151 Acetyl chloride Acetyl chloride[1] Identifiers CAS number ChemSpider UNII ChEBI RTECS number Jmol-3D images 75-36-5 6127 [3] [2]   [4]       QD15RNO45K CHEBI:37580 AO6390000 Image 1 Properties [6] [5] Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water CH COCl 3 78.49 g/mol colorless liquid 1.104 g/ml, liquid -112 °C, 161 K, -170 °F 52 °C, 325 K, 126 °F Reacts Structure Dipole moment 2.45 D Hazards Acetyl chloride 152 EU classification R-phrases S-phrases Autoignition temperature Explosive limits Flammable (F) Corrosive (C) R11 R14 R34 (S1/2) S9 S16 S26 S45 390 °C 7.3–19% Related compounds Related acyl chlorides Related compounds Propionyl chloride Butyryl chloride Acetic acid Acetic anhydride Acetyl bromide   (verify) [7]  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Acetyl chloride, CH3COCl, also known as ethanoyl chloride or acyl chloride, is an acid chloride derived from acetic acid. It belongs to the class of organic compounds called acyl halides. It is a colorless liquid. Acetyl chloride does not exist in nature, because contact with water would hydrolyze it into acetic acid and hydrogen chloride. In fact, if handled in open air it gives off white smoke owing to the hydrolysis from the moisture in the air. The "smoke" is actually small droplets of hydrochloric acid formed by hydrolysis. Synthesis The usual method involves the reaction of acetic acid with standard inorganic chlorodehydrating agents, such as by using PCl3, PCl5, SO2Cl2, or SOCl2. However, this usually gives acetyl chloride which is contaminated by phosphorus or sulfur impurities, which may interfere with the organic reactions.[8] It is produced by the reaction of hydrogen chloride with acetic anhydride:[9] (CH3CO)2O + HCl → CH3COCl + CH3CO2H HCl impurities can be removed by distilling the crude product from dimethylaniline or by degassing the mixture by a stream of argon. It may also be synthesized from the catalytic carbonylation of methyl chloride.[10] Acetyl chloride 153 Heating dichloroacetic chloride with acetic acid also gives acetyl chloride in 70% yield.[8] Uses It is a chemical for acetylation in the synthesis or derivatization of organic compounds. Examples of acetylation reactions include acylation processes such as esterification (see below) and the Friedel-Crafts reaction. CH3COCl + HO-CH2-CH3 → CH3-COO-CH2-CH3 + H-Cl Frequently such acylations are carried out in the presence of a base such as pyridine, triethylamine, or DMAP, which act as catalysts to help promote the reaction and as bases neutralize the resulting HCl. Such reactions will often proceed via ketene. Can containing a bottle of acetyl chloride Acetylation is the introduction of an acetyl group via acylation using a reactant such as acetyl chloride or acetic anhydride. An acetyl group is an acyl group having the formula -C(=O)-CH3 For further information on the types of chemical reactions compounds such as acetyl chloride can undergo, see acyl halide. References [1] [2] [3] [4] [5] [6] [7] Merck Index, 11th Edition, 79. http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=75-36-5 http:/ / www. chemspider. com/ 6127 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=QD15RNO45K https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=37580 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=ClC%28%3DO%29C http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=446282072& page2=%3AAcetyl+ chloride [8] Leo A. Paquette (2005). "Acetyl chloride". Handbook of Reagents for Organic Synthesis, Activating Agents and Protective Groups. John Wiley & Sons. p. 16. ISBN 978-0-471-97927-2. [9] Hosea Cheung, Robin S. Tanke, G. Paul Torrence “Acetic Acid” in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a01_045 [10] US 4352761 (http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=US4352761) External links • International Chemical Safety Card 0210 (http://www.inchem.org/documents/icsc/icsc/eics0210.htm) Haloalkane 154 Haloalkane The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of chemical compounds derived from alkanes containing one or more halogens. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely used commercially and, consequently, are known under many chemical and commercial names. They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals. Subsequent to the widespread use in commerce, many halocarbons have also been shown to be serious pollutants and toxins. For example, the chlorofluorocarbons have been shown to lead to ozone depletion. Methyl bromide is a controversial fumigant. Only haloalkanes which contain chlorine, bromine, and iodine are a threat to the ozone layer, but fluorinated volatile haloalkanes in theory may have activity as greenhouse gases. Methyl iodide, a naturally occurring substance, however, does not have ozone-depleting properties and the United States Environmental Protection Agency has designated the compound a non-ozone layer depleter. For more information, see Halomethane. Haloalkanes have been known for centuries. Ethyl chloride was produced synthetically in the 15th century. The systematic synthesis of such compounds developed in the 19th century in step with the development of organic chemistry and the understanding of the structure of alkanes. Methods were developed for the selective formation of C-halogen bonds. Especially versatile methods included the addition of halogens to alkenes, hydrohalogenation of alkenes, and the conversion of alcohols to alkyl halides. These methods are so reliable and so easily implemented that haloalkanes became cheaply available for use in industrial chemistry because the halide could be further replaced by other functional groups. While most haloalkanes are human-produced, non-artificial-source haloalkanes do occur on Earth, mostly through enzyme-mediated synthesis by bacteria, fungi, and especially sea macroalgae (seaweeds). More than 1600 halogenated organics have been identified, with bromoalkanes being the most common haloalkanes. Brominated organics in biology range from biologically produced methyl bromide to non-alkane aromatics and unsaturates (indoles, terpenes, acetogenins, and phenols).[1] [2] Halogenated alkanes in land plants are more rare, but do occur, as for example the fluoroacetate produced as a toxin by at least 40 species of known plants. Specific dehalogenase enzymes in bacteria which remove halogens from haloalkanes, are also known. Tetrafluoroethane (a haloalkane) is a colorless liquid that boils well below room temperature (as seen here) and can be extracted from common canned air canisters by simply inverting them during use. Haloalkane 155 Classes of haloalkanes From the structural perspective, haloalkanes can be classified according to the connectivity of the carbon atom to which the halogen is attached. In primary (1°) haloalkanes, the carbon that carries the halogen atom is only attached to one other alkyl group. An example is chloroethane (CH3CH2Cl). In secondary (2°) haloalkanes, the carbon that carries the halogen atom has two C–C bonds. In tertiary (3°) haloalkanes, the carbon that carries the halogen atom has three C–C bonds. Haloalkanes can also be classified according to the type of halogen. Haloalkanes containing carbon bonded to fluorine, chlorine, bromine, and iodine results in organofluorine, organochlorine, organobromine and organoiodine compounds, respectively. Compounds containing more than one kind of halogen are also possible. Several classes of widely used haloalkanes are classified in this way chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs). These abbreviations are particularly common in discussions of the environmental impact of haloalkanes. Properties Haloalkanes generally resemble the parent alkanes in being colorless, relatively odorless, and hydrophobic. Their boiling points are higher than the corresponding alkanes and scale with the atomic weight and number of halides. This is due to the increased strength of the intermolecular forces—from London dispersion to dipole-dipole interaction because of the increased polarity. Thus carbon tetraiodide (CI4) is a solid whereas carbon tetrafluoride (CF4) is a gas. As they contain fewer C–H bonds, halocarbons are less flammable than alkanes, and some are used in fire extinguishers. Haloalkanes are better solvents than the corresponding alkanes because of their increased polarity. Haloalkanes containing halogens other than fluorine are more reactive than the parent alkanes—it is this reactivity that is the basis of most controversies. Many are alkylating agents, with primary haloalkanes and those containing heavier halogens being the most active (fluoroalkanes do not act as alkylating agents under normal conditions). The ozone-depleting abilities of the CFCs arises from the photolability of the C–Cl bond. Occurrence Haloalkanes are of wide interest because they are widespread and have diverse beneficial and detrimental impacts. The oceans are estimated to release 1-2 million tons of bromomethane annually.[3] A large number of pharmaceuticals contain halogens, especially fluorine. An estimated one fifth of pharmaceuticals contain fluorine, including several of the top drugs.[4] Examples include 5-fluorouracil, fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole. The beneficial effects arise because the C-F bond is relatively unreactive. Fluorine-substituted ethers are volatile anesthetics, including the commercial products methoxyflurane, enflurane, isoflurane, sevoflurane and desflurane. Fluorocarbon anesthetics reduce the hazard of flammability with diethyl ether and cyclopropane. Perfluorinated alkanes are used as blood substitutes. Chlorinated or fluorinated alkenes undergo polymerization. Important halogenated polymers include polyvinyl chloride (PVC), and polytetrafluoroethene (PTFE, or Teflon). The production of these materials releases substantial amounts of wastes. Nomenclature Teflon structure Haloalkane 156 IUPAC The formal naming of haloalkanes should follow IUPAC nomenclature, which put the halogen as a prefix to the alkane. For example, ethane with bromine becomes bromoethane, methane with four chlorine groups becomes tetrachloromethane. However, many of these compounds have already an established trivial name, which is endorsed by the IUPAC nomenclature, for example chloroform (trichloromethane) and methylene chloride (dichloromethane). For unambiguity, this article follows the systematic naming scheme throughout. Production Haloalkanes can be produced from virtually all organic precursors. From the perspective of industry, the most important ones are alkanes and alkenes. From alkanes Alkanes react with halogens by free radical halogenation. In this reaction a hydrogen atom is removed from the alkane, then replaced by a halogen atom by reaction with a diatomic halogen molecule. The reactive intermediate in this reaction is a free radical and the reaction is called a radical chain reaction. Free radical halogenation typically produces a mixture of compounds mono- or multihalogenated at various positions. It is possible to predict the results of a halogenation reaction based on bond dissociation energies and the relative stabilities of the radical intermediates. Another factor to consider is the probability of reaction at each carbon atom, from a statistical point of view. Due to the different dipole moments of the product mixture, it may be possible to separate them by distillation. From alkenes and alkynes In hydrohalogenation, an alkene reacts with a dry hydrogen halide (HX) like hydrogen chloride (HCl) or hydrogen bromide (HBr) to form a mono-haloalkane. The double bond of the alkene is replaced by two new bonds, one with the halogen and one with the hydrogen atom of the hydrohalic acid. Markovnikov's rule states that in this reaction, the halogen is more likely to become attached to the more substituted carbon. This is a electrophilic addition reaction. Water must be absent otherwise there will be a side product of a halohydrin. The reaction is necessarily to be carried out in a dry inert solvent such as CCl4 or directly in the gaseous phase. The reaction of alkynes are similar, with the product being a geminal dihalide; once again, Markovnikov's rule is followed. Alkenes also react with halogens (X2) to form haloalkanes with two neighboring halogen atoms in a halogen addition reaction. Alkynes react similarly, forming the tetrahalo compounds. This is sometimes known as "decolorizing" the halogen, since the reagent X2 is colored and the product is usually colorless and odorless. From alcohols Tertiary alkanol reacts with hydrochloric acid directly to produce tertiary chloroalkane, but if primary or secondary alkanol is used, an activator such as zinc chloride is needed. This reaction is exploited in the Lucas test. The most popular conversion is effected by reacting the alcohol with thionyl chloride (SOCl2) in the "Darzen's Process," which is one of the most convenient laboratory methods because the byproducts are gaseous. Both phosphorus pentachloride (PCl5) and phosphorus trichloride (PCl3) also convert the hydroxyl group to the chloride. Alcohols may likewise be converted to bromoalkanes using hydrobromic acid or phosphorus tribromide (PBr3). A catalytic amount of PBr3 may be used for the transformation using phosphorus and bromine; PBr3 is formed in situ. Iodoalkanes may similarly be prepared using red phosphorus and iodine (equivalent to phosphorus triiodide). The Appel reaction is also useful for preparing alkyl halides. The reagent is tetrahalomethane and triphenylphosphine; the co-products are haloform and triphenylphosphine oxide. Haloalkane 157 From carboxylic acids Two methods for the synthesis of alkyl halides from carboxylic acids are the Hunsdiecker reaction and the Kochi reaction. Biosynthesis Many chloro and bromolkanes are formed naturally. The principal pathways involve the enzymes chloroperoxidase and bromoperoxidase. Reactions Haloalkanes are reactive towards nucleophiles. They are polar molecules: the carbon to which the halogen is attached is slightly electropositive where the halogen is slightly electronegative. This results in an electron deficient (electrophilic) carbon which, inevitably, attracts nucleophiles. Substitution Substitution reactions involve the replacement of the halogen with another molecule—thus leaving saturated hydrocarbons, as well as the halogenated product. Alkyl halides behave as the R+ synthon, and readily react with nucleophiles. Hydrolysis, a reaction in which water breaks a bond, is a good example of the nucleophilic nature of halogenoalkanes. The polar bond attracts a hydroxide ion, OH– (NaOH(aq) being a common source of this ion). This OH– is a nucleophile with a clearly negative charge, as it has excess electrons it donates them to the carbon, which results in a covalent bond between the two. Thus C–X is broken by heterolytic fission resulting in a halide ion, X–. As can be seen, the OH is now attached to the alkyl group, creating an alcohol. (Hydrolysis of bromoethane, for example, yields ethanol). Reaction with ammonia give primary amines. Alkyl chlorides and bromides are readily substituted by iodide in the Finkelstein reaction. The alkyl iodides produced easily undergo further reaction. Sodium iodide is used thus as a catalyst. Alkyl halides react with ionic nucleophiles (e.g. cyanide, thiocyanate, azide); the halogen is replaced by the respective group. This is of great synthetic utility: alkyl chlorides are often inexpensively available. For example, after undergoing substitution reactions, alkyl cyanides may be hydrolyzed to carboxylic acids, or reduced to primary amines using lithium aluminium hydride. Alkyl azides may be reduced to primary alkyl amines by the Staudinger reduction or lithium aluminium hydride. Amines may also be prepared from alkyl halides in amine alkylation, the Gabriel synthesis and Delepine reaction, by undergoing nucleophilic substitution with potassium phthalimide or hexamine respectively, followed by hydrolysis. In the presence of a base, alkyl halides alkylate alcohols, amines, and thiols to obtain ethers, N-substituted amines, and thioethers respectively. They are substituted by Grignard reagents to give magnesium salts and an extended alkyl compound. Mechanism Where the rate-determining step of a nucleophilic substitution reaction is unimolecular, it is known as an SN1 reaction. In this case, the slowest (thus rate-determining step) is the heterolysis of a carbon-halogen bond to give a carbocation and the halide anion. The nucleophile (electron donor) attacks the carbocation to give the product. SN1 reactions are associated with the racemization of the compound, as the trigonal planar carbocation may be attacked from either face. They are favored mechanism for tertiary alkyl halides, due to the stabilization of the positive charge on the carbocation by three electron-donating alkyl groups. They are also preferred where the substituents are sterically bulky, hindering the SN2 mechanism. Haloalkane 158 Elimination Rather than creating a molecule with the halogen substituted with something else, one can completely eliminate both the halogen and a nearby hydrogen, thus forming an alkene by dehydrohalogenation. For example, with bromoethane and sodium hydroxide (NaOH) in ethanol, the hydroxide ion HO- abstracts a hydrogen atom. Bromide ion is then lost, resulting in ethylene), H2O and NaBr. Thus, haloalkanes can be converted to alkenes. Similarly, dihaloalkanes can be converted to alkynes. In related reactions, 1,2-dibromocompounds are debrominated by zinc dust to give alkenes and geminal dihalides can react with strong bases to give carbenes. Other Alkyl halides undergo free-radical reactions with elemental magnesium to give alkylmagnesium compounds: Grignard reagents. Alkyl halides also react with lithium metal to give organolithium compounds. Both Grignard reagents and organolithium compounds behave as the R- synthon. Alkali metals such as sodium and lithium are able to cause alkyl halides to couple in the Wurtz reaction, giving symmetrical alkanes. Alkyl halides, especially iodides, also undergo oxidative addition reactions to give organometallic compounds. Applications Haloalkanes are widely used as synthon equivalents to alkyl cation (R+) in organic synthesis. They can also participate in a wide variety of other organic reactions. Short chain haloalkanes such as dichloromethane, trichloromethane (chloroform) and tetrachloromethane are commonly used as hydrophobic solvents in chemistry. They were formerly very common in industry, however, their use has been greatly curtailed due to their toxicity and negative environmental effects. Chlorofluorocarbons were used almost universally as refrigerants and propellants due to their relatively low toxicity and high heat of vaporization. Starting in the 1980s, as their contribution to ozone depletion became known, their use was increasingly restricted, and they have now largely been replaced by HFCs. References [1] Butler, Alison; Catter-Facklin, Jayen M. (2004). "The role of vanadium bromoperoxidase in the biosynthesis of halogenated marine natural products". Natural Product Reports 21 (1): 180–188. doi:10.1039/b302337k. PMID 15039842. [2] PMID 19363038 Review of vanadium-dependent bromoperoxidases in nature [3] Gordon W. Gribble (1998). "Naturally Occurring Organohalogen Compounds". Acc. Chem. Res. 31 (3): 141–152. doi:10.1021/ar9701777. [4] Ann M. Thayer “Fabulous Fluorine” Chemical and Engineering News, June 5, 2006, Volume 84, pp. 15-24. http:/ / pubs. acs. org/ cen/ coverstory/ 84/ 8423cover1. html Hemiaminal 159 Hemiaminal A hemiaminal is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: -C(OH)(NR2)-. R can be hydrogen or an alkyl group. Hemiaminals are intermediates in imine formation from an amine and a carbonyl by alkylimino-de-oxo-bisubstitution. An example is of an hemiaminal is that obtained from reaction of secondary amine carbazole and formaldehyde [1][2] Generic hemiaminal Those generated from primary amines are unstable to the extent that they have never been isolated and very rarely been observed directly. In a 2007 study a hemiaminal substructure trapped in the cavity of a host-guest complex was studied with a chemical half-life of 30 minutes. Because both amine and carbonyl group are isolated in a cavity, hemiaminal formation is favored due to a high forward reaction rate comparable to a intramolecular reaction and also due to restricted access of external base (another amine) to the same cavity which would favor elimination of water to the imine.[3] Hemiaminal formation is a key step in an asymmetric total synthesis of saxitoxin [4]: In this reaction step the alkene group is first oxidized to an intermediate acyloin by action of osmium(III) chloride, oxone (sacrificial catalyst) and sodium carbonate (base). Hemiaminal 160 References [1] Carbazol-9-yl-methanol Milata Viktora, Kada Rudolfa, Lokaj J¨¢nb Molbank 2004, M354 open access publication (http:/ / www. mdpi. net/ molbank/ molbank2004/ m0354. htm) [2] Reaction in methanol in reflux with potassium carbonate. Acid catalysis turns the hemiaminal to the aminal N,N´-biscarbazol-9-yl-methane. [3] Stabilization of Labile Carbonyl Addition Intermediates by a Synthetic Receptor Tetsuo Iwasawa, Richard J. Hooley, Julius Rebek Jr. Science 317, 493 (2007) doi:10.1126/science.1143272 [4] (+)-Saxitoxin: A First and Second Generation Stereoselective Synthesis James J. Fleming, Matthew D. McReynolds, and J. Du Bois J. Am. Chem. Soc., 129 (32), 9964 -9975, 2007. doi:10.1021/ja071501o Carboximidate Carboximidates (or less specifically imidates) are organic compounds which can be thought of as esters formed between a carboximidic acid (R-C(=NR')OH) and an alcohol. They have the general formula R-C(=NR')OR". Carboximidates are also known as imino ethers, since they can be thought of as imines (>C=N-) with an oxygen atom connected to the carbon atom. Use Benzyl trichloroethanimidate Carboximidates find use in organic synthesis as building blocks and intermediates for example in the Mumm rearrangement and the Overman rearrangement. An example of an imidate is benzyl trichloroethanimidate, which is used to protect an alcohol as a benzyl ether with release of trichloroacetamide. Imidate/amidate anions Amidate anions, which are the equivalent resonance structure of imidate anions, can be though of as the corresponding amide enolates, with the formula R-N=C(O-)R. Imidate/amidate anions find use as ligands. Imidate/amidate resonance structure Enol 161 Enol Enol Enolate Enediol Reductone Enols (also known as alkenols) are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates. A reductone is a compound that has an enediol structure with an adjacent carbonyl-group. The C=C double bond with adjacent alcohol gives enols and enediols their chemical characteristics, by which they present keto-enol tautomerism. In keto-enol tautomerism, enols interconvert with ketones or aldehydes. The words enol and alkenol are portmanteaus of the words "alkene" (or just -ene, the suffix given to C=C double bonded alkenes) and "alcohol" (which represents the enol's hydroxyl group). Keto-enol tautomerism Enols interconvert with carbonyl compounds that have an α-hydrogen, like ketones and aldehydes. The compound is deprotonated on one side and protonated on another side, whereas a single bond and a double bond are exchanged. This is called keto-enol tautomerism. Keto-enol tautomers Right the enol form The enol form is usually unstable, does not survive long, and changes into the keto (ketone). This is because oxygen is more electronegative than carbon and thus forms stronger bonds. Enol 162 Tautomerism in multi-carbonyl compounds In 1,3-dicarbonyl and 1,3,5-tricarbonyl compounds, however, the (mono-)enol form predominates. This is due to intramolecular hydrogen bonding and possibly to an easy internal proton transfer. [1] Hydrogen bond between carbonyls Thus, at equilibrium, over 99% of propanedial (OHCCH2CHO) molecules exist as the mono-enol. The percentage is lower for 1,3-aldehyde ketones and diketones (acetylacetone, for example, 80% enol form). Propanedial, a 1,3-dicarbonyl Enolates When keto-enol tautomerism occurs the keto or enol is deprotonated and an anion, which is called the enolate, is formed as intermediate. Enolates can exist in quantitative amounts in strictly Brønsted acid free conditions, since they are generally very basic. In enolates the anionic charge is delocalized over the oxygen and the carbon .[2] Enolates are somewhat stabilized by this delocalization of the charge over three atoms.[3] In older descriptions of bonding, particularly valence bond theory this was explained by a phenomenon known as resonance. Keto-enol-tautomerism Interconversion between keto form and enolate; deprotonation of the α-C-atom. Enolate anion, described is terms of resonance. Left the carbanion. Interconversion between enolate and enol; protonation of the enolate. Movement of electron pairs in deprotonation of ascorbic acid (vitamin C), converting an enediol (left) into an enolate (right) Enol 163 Enolates in MO-theory Later theories of chemical bonding, particularly the theory of Molecular Orbitals do away with the twin resonant structures, where electrons are assumed to be attached either to one or to two atoms only. Instead a three-center four-electron bond explanation is employed. Selective deprotonation in enolate forming In ketones with α-hydrogens on both sides of the carbonyl carbon, selectivity of deprotonation may be achieved to generate two different enolate structures. At low temperatures (-78°C, i.e. dry ice bath), in aprotic solvents, and with bulky non-equilibrating bases (e.g. LDA) the Enolate π molecular orbitals "kinetic" proton may be removed. The "kinetic" proton is the one which is sterically most accessible. Under thermodynamic conditions (higher temperatures, weak base, and protic solvent) equilibrium is established between the ketone and the two possible enolates, the enolate favoured is termed the "thermodynamic" enolate and is favoured because of its lower energy level than the other possible enolate. Thus, by choosing the optimal conditions to generate an enolate, one can increase the yield of the desired product while minimizing formation of undesired products. Enediols Enediols are alkenes with a hydroxyl group on both sides of the C=C double bond. Enediols are reaction intermediates in the Lobry-de Bruyn-van Ekenstein transformation. Ketol-enediol tautomerism. In the middle the enediol. Left and right two acyloin isomers. Enol 164 Reductones Enediols with a carbonyl group adjacent to the enediol group are called reductones. The enediol structure is stabilized by the resonance resulting from the tautomerism with the adjacent carbonyl. Therefore, the chemical equilibrium produces mainly the enediol form rather than the keto form. Reductones are strong reducing agents, thus efficacious antioxidants, and fairly strong acids.[4] Examples of reductones are tartronaldehyde, reductic acid and ascorbic acid. Examples of reductones Tartronaldehyde Reductic acid Ascorbic acid (Vitamin C) External links • Enols and enolates in biological reactions [5] References [1] W. Caminati, J.-U. Grabow (2006). "The C2v Structure of Enolic Acetylacetone". Journal of the American Chemical Society 128 (3): 854–857. doi:10.1021/ja055333g. PMID 16417375. [2] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "enolates" (http:/ / goldbook. iupac. org/ E02123. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.E02123. ISBN 0-9678550-9-8. . [3] Chemistry of Enolates and Enols - Acidity of alpha-hydrogens (http:/ / pharmaxchange. info/ press/ 2011/ 02/ chemistry-of-enolates-and-enols-acidity-of-alpha-hydrogens/ ) [4] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "reductones" (http:/ / goldbook. iupac. org/ R05224. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.R05224. ISBN 0-9678550-9-8. . [5] http:/ / chemwiki. ucdavis. edu/ Organic_Chemistry/ Organic_Chemistry_With_a_Biological_Emphasis/ Chapter_13%3a_Reactions_with_stabilized_carbanion_intermediates_I/ Section_13. 1%3a_Tautomers Hydroxylamine 165 Hydroxylamine Hydroxylamine Identifiers CAS number PubChem ChemSpider UNII EC number KEGG MeSH ChEBI ChEMBL RTECS number Gmelin Reference 3DMet Jmol-3D images 7803-49-8 787 766 [2] [3]   [4]   [1]   2FP81O2L9Z 232-259-2 C00192 [5]   [6] Hydroxylamine CHEBI:15429 [7]   [9]   [8] CHEMBL1191361 NC2975000 478 B01184 [10] [11] Image 1 [12] Image 2 Properties Molecular formula Molar mass Appearance Density Melting point Boiling point H NO 3 33.03 g mol−1 Vivid white, opaque crystals 1.21 g cm-3 (at 20 °C) 33 °C, 306 K, 91 °F 58 °C, 331 K, 136 °F (decomposes) [13] Hydroxylamine 166 -0.758 13.7 0.3 Structure log P Acidity (pKa) Basicity (pKb) Coordination geometry Molecular shape Dipole moment Trigonal at N Tetrahedral at N 0.67553 D Thermochemistry Std enthalpy of formation ΔfHo298 Standard molar o entropy S 298 Specific heat capacity, C -39.9 kJ mol-1 236.18 J K mol -1 -1 46.47 J K mol -1 -1 Hazards MSDS EU Index EU classification E R-phrases S-phrases NFPA 704 Flash point Autoignition temperature LD50 129 °C 265 °C Xn Xi N ICSC 0661 [14] 612-122-00-7 R2, R21/22, R37/38, R40, R41, R43, R48/22, R50 (S2), S26, S36/37/39, S61 408 mg/kg (oral, mouse); 59–70 mg/kg (intraperitoneal mouse, rat); 29 mg/kg (subcutaneous, [15] rat) Related compounds Related hydroxylammonium salts Related compounds Hydroxylammonium chloride Hydroxylammonium nitrate Hydroxylammonium sulfate Ammonia Hydrazine   (verify) [16]  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Hydroxylamine is an inorganic compound with the formula NH2OH. The pure material is a white, unstable crystalline, hygroscopic compound.[17] However, hydroxylamine is almost always provided and used as an aqueous solution. It is used to prepare oximes, an important functional group. It is also an intermediate in biological nitrification. The oxidation of NH3 is mediated by the enzyme hydroxylamine oxidoreductase (HAO). Hydroxylamine 167 Production NH2OH can be produced via several routes. The main route is via Raschig synthesis: aqueous ammonium nitrite is reduced by HSO4− and SO2 at 0°C to yield a hydroxylamido-N,N-disulfate anion: NH4NO2 + 2 SO2 + NH3 + H2O → 2 NH4+ + N(OH)(OSO2)22− This anion is then hydrolyzed to give (NH3OH)2SO4: N(OH)(OSO2)22− + H2O → NH(OH)(OSO2)− + HSO4− 2 NH(OH)(OSO2)− + 2 H2O → (NH3OH)2SO4 + SO Solid NH2OH can be collected by treatment with liquid ammonia. Ammonium sulfate, (NH4)2SO4, a side-product insoluble in liquid ammonia, is removed by filtration; the liquid ammonia is evaporated to give the desired product.[17] The net reaction is: 2NO + 4SO2 + 6H2O + 6NH3 → 4SO + 6NH (NH3OH)Cl + NaOBu → NH2OH + NaCl + BuOH[17] Hydroxylamine can also be produced by the reduction of nitrous acid or potassium nitrite with bisulfite: HNO2 + 2 HSO3− → N(OH)(OSO2)22− + H2O → NH(OH)(OSO2)− + HSO4− NH(OH)(OSO2)− + H3O+ (100°C/1 h) → NH3(OH)+ + HSO4− + 2NH2OH Hydroxylammonium salts can then be converted to hydroxylamine by neutralization: Reactions Hydroxylamine reacts with electrophiles, such as alkylating agents, which can attach to either the oxygen or the nitrogen: R-X + NH2OH → R-ONH2 + HX R-X + NH2OH → R-NHOH + HX The reaction of NH2OH with an aldehyde or ketone produces an oxime. R2C=O + NH2OH∙HCl , NaOH → R2C=NOH + NaCl + H2O This reaction is useful in the purification of ketones and aldehydes: if hydroxylamine is added to an aldehyde or ketone in solution, an oxime forms which generally precipitates from solution; heating the precipitate with an inorganic acid then restores the original aldehyde or ketone.[18] Oximes, e.g., dimethylglyoxime, are also employed as ligands. NH2OH reacts with chlorosulfonic acid to give hydroxylamine-O-sulfonic acid, a useful reagent for the synthesis of caprolactam. HOSO2Cl + NH2OH → NH2OSO2OH + HCl The hydroxylamine-O-sulfonic acid, which should be stored at 0 °C to prevent decomposition, can be checked by iodometric titration. Hydroxylamine (NH2OH), or hydroxylamines (R-NHOH) can be reduced to amines.[19] NH2OH (Zn/HCl) → NH3 R-NHOH (Zn/HCl) → R-NH2 Hydroxylamine explodes with heat: 4 NH2OH + O2 → 2 N2 + 6 H2O Hydroxylamine 168 Uses Hydroxylamine and its salts are commonly used as reducing agents in myriad organic and inorganic reactions. They can also act as antioxidants for fatty acids. Some non-chemical uses include removal of hair from animal hides and photography developing solutions.[13] The nitrate salt, hydroxylammonium nitrate, is being researched as a rocket propellant, both in water solution as a monopropellant and in its solid form as a solid propellant. This has also been used in the past by biologists to introduce random mutations by switching base pairs from G to A, or from C to T. This is to probe functional areas of genes to elucidate what happens if their functions are broken. Nowadays other mutagens are used. Hydroxylamine can also be used to highly selectively cleave asparaginyl-glycine peptide bonds in peptides and proteins. It also bonds to and permanently disables (poisons) heme-containing enzymes. It is used as an irreversible inhibitor of the oxygen-evolving complex of photosynthesis on account of its similar structure to water. In the semiconductor industry, hydroxylamine is often a component in the "resist stripper" which removes photoresist after lithography. Safety Hydroxylamine may explode on heating. The nature of the explosive hazard is not well understood. At least two factories dealing in hydroxylamine have been destroyed since 1999 with loss of life.[20] It is known, however, that ferrous and ferric iron salts accelerate the decomposition of 50% NH2OH solutions.[21] Hydroxylamine and its derivatives are more safely handled in the form of salts. It is an irritant to the respiratory tract, skin, eyes, and other mucous membranes. It may be absorbed through the skin, is harmful if swallowed, and is a possible mutagen.[22] Functional group Substituted derivatives of hydroxylamine are known. If the hydroxyl hydrogen is substituted, this is called an O-hydroxylamine, if one of the amine hydrogens is substituted, this is called an N-hydroxylamine. Similarly to ordinary amines, one can distinguish primary, secondary and tertiary hydroxylamines, the latter two referring to compounds where two or three hydrogens are substituted, respectively. Examples of compounds containing a hydroxylamine functional group are N-tert-butyl-hydroxylamine or the glycosidic bond in calicheamicin. N,O-Dimethylhydroxylamine is a coupling agent, used to synthesize Weinreb amides. References [1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=7803-49-8 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=787 [3] http:/ / www. chemspider. com/ 766 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=2FP81O2L9Z [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=232-259-2 [6] http:/ / www. kegg. jp/ entry/ C00192 [7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Hydroxylamine [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=15429 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1191361 [10] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B01184. html [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=NO [12] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=ON [13] Lide, David R., ed. (2006). CRC Handbook of Chemistry and Physics (87th ed.). Boca Raton, FL: CRC Press. ISBN 0-8493-0487-3. [14] http:/ / www. inchem. org/ documents/ icsc/ icsc/ eics0661. htm [15] Martel, B.; Cassidy, K. (2004). Chemical Risk Analysis: A Practical Handbook. Butterworth–Heinemann. pp. 362. ISBN 1-903996-65-1. [16] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=461773624& page2=%3AHydroxylamine Hydroxylamine [17] Greenwood and Earnshaw. Chemistry of the Elements. 2nd Edition. Reed Educational and Professional Publishing Ltd. pp. 431-432. 1997. [18] Ralph Lloyd Shriner, Reynold C. Fuson, and Daniel Y. Curtin, The Systematic Identification of Organic Compounds: A Laboratory Manual, 5th ed. (New York, New York: Wiley, 1964), chapter 6. [19] Smith, Michael and Jerry March. March's advanced organic chemistry : reactions, mechanisms, and structure. New York. Wiley. p. 1554. 2001. [20] Japan Science and Technology Agency Failure Knowledge Database (http:/ / shippai. jst. go. jp/ en/ Detail?fn=0& id=CC1000050& ). [21] Cisneros, L.O., Rogers, W.J., Mannan, M.S., Li, X and Koseki, H. “ Effect of Iron Ion in the Thermal Decomposition of 50 mass% Hydroxylamnie/Water Solutions” J. Chem. Eng Data 48(5), (2003) 1164-1169. [22] MSDS (http:/ / www. sigmaaldrich. com/ cgi-bin/ hsrun/ Suite7/ Suite/ HAHTpage/ Suite. HsSigmaAdvancedSearch. formAction) Sigma-Aldrich 169 Further reading • Hydroxylamine (http://www.mrw.interscience.wiley.com/eros/articles/rh057/sect0-fs.html) • Walters, Michael A. and Andrew B. Hoem. "Hydroxylamine." e-Encyclopedia of Reagents for Organic Synthesis. 2001. • Schupf Computational Chemistry Lab (http://www.colby.edu/chemistry/webmo/hydroxylamine.html) • M. W. Rathke A. A. Millard "Boranes in Functionalization of Olefins to Amines: 3-Pinanamine" Organic Syntheses, Coll. Vol. 6, p. 943; Vol. 58, p. 32. (preparation of hydroxylamine-O-sulfonic acid). External links • Calorimetric studies of hydroxylamine decomposition (http://psc.tamu.edu/research/ reactive-chemical-research) • Chemical company BASF info (http://www.basf.de/en/produkte/chemikalien/anorganika/hydroxyl/ hydroxyl_fb/hafb_sucess.htm?id=FcjY57aR-bsf2_l) • MSDS (http://www.basf.de/en/produkte/chemikalien/anorganika/hydroxyl/hydroxyl_fb/pinfo. htm?id=FcjY57aR-bsf2_l) • Deadly detonation of hydroxylamine at Concept Sciences facility (http://www.wsws.org/articles/1999/ feb1999/penn-f24.shtml) Oxime 170 Oxime An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds. Amidoximes are oximes of hemiaminals with general structure RC(=NOH)(NRR'). Oximes are usually generated by the reaction of hydroxylamine and aldehydes or ketones. The term oxime dates back to the 19th century, a portmanteau of the words oxygen and imide.[1] Structure and properties Oximes exist as two geometric stereoisomers: a syn isomer and an anti isomer. Aldoximes, except for aromatic aldoximes which exist only as anti isomers, and ketoximes can be separated almost completely and obtained as a syn isomer and an anti isomer. Oximes have three characteristic bands in the infrared spectrum, at wavenumbers 3600 (O-H), 1665 (C=N) and 945 (N-O).[2] In aqueous solution, aliphatic oximes are 102- to 103-fold more resistant to hydrolysis than analogous hydrazones.[3] Preparation Oximes can be synthesized by condensation of an aldehyde or a ketone with hydroxylamine. The condensation of aldehydes with hydroxylamine gives aldoxime, and ketoxime is produced from ketones and hydroxylamine. Generally, oximes exist as colorless crystals and are poorly soluble in water. Therefore, oximes can be used for the identification of ketone or aldehyde. Oximes can also be obtained from reaction of nitrites such as isoamyl nitrite with compounds containing an acidic hydrogen atom. Examples are the reaction of ethyl acetoacetate and sodium nitrite in acetic acid,[4][5] the reaction of methyl ethyl ketone with ethyl nitrite in hydrochloric acid.[6] and a similar reaction with propiophenone,[7] the reaction of phenacyl chloride,[8] the reaction of malononitrile with sodium nitrite in acetic acid[9] A conceptually related reaction is the Japp-Klingemann reaction. Oxime 171 Reactions The hydrolysis of oximes proceeds easily by heating in the presence of various inorganic acids, and the oximes decompose into the corresponding ketones or aldehydes, and hydroxylamines. The reduction of oximes by sodium amalgam, hydrogenation, or reaction with hydride reagents produces amines. The reduction of aldoximes gives both primary amines and secondary amines. Generally oximes can be changed to the corresponding amide derivatives by treatment with various acids. This reaction is called Beckmann rearrangement. In this reaction, a hydroxyl group is exchanged with the group that is in the anti position of the hydroxyl group. The amide derivatives that are obtained by Beckmann rearrangement can be transformed into a carboxylic acid by means of hydrolysis (base or acid catalyzed).And an amine by hoffman degradation of the amide in the presence of alkali hypoclorites at 80 degrees Celsius, the degradation is itself prone to side reactions namely, the formation of biurets or, cyanate polymers, To avoid this side reaction strict temperature control is necessary, the reaction must be conducted at sufficient temperature to isomerise the cyanate to the isocyante. also, good solvation is also crucial to be successful. Beckmann rearrangement is used for the industrial synthesis of caprolactam (see applications below). The Ponzio reaction (1906) [10] concerning the conversion of m-nitrobenzaldoxime to m-nitrophenyldinitromethane with dinitrogen tetroxide, was the result of research into TNT-like high explosives:[11] In the Neber rearrangement certain oximes are converted to the corresponding alpha-amino ketones. Certain amidoximes react with benzenesulfonyl chloride to substituted ureas in the Tiemann rearrangement [12][13] Oxime 172 Uses In their largest application, an oxime is an intermediate in the industrial production of caprolactam, a precursor to Nylon 6. About half of the world's supply of cyclohexanone, more than a billion kilograms annually, is converted to the oxime. In the presence of sulfuric acid catalyst, the oxime undergoes the Beckmann rearrangement to give the cyclic amide caprolactam: Other applications • Dimethylglyoxime (dmgH2) is a reagent for the analysis of nickel and a popular ligand in its own right. Typically a metal reacts with two equivalents of dmgH2 concomitant with ionization of one proton. • Oxime compounds are used as antidotes for nerve agents. A nerve agent inactivates acetylcholinesterase molecules by phosphorylation of the molecule. Oxime compounds can reactivate acetylcholinesterate by attaching to the phosphorus atom and forming an oxime-phosphonate which then splits away from the acetylcholinesterase molecule. The most effective oxime nerve-agent antidotes are pralidoxime (also known as 2-PAM), obidoxime, methoxime, HI-6, Hlo-7, and TMB-4.[14] The effectiveness of the oxime treatment depends on the particular nerve agent used.[15] • Perillartine, the oxime of perillaldehyde is used as an artificial sweetener in Japan, as it is 2000 times sweeter than sucrose. • Salicylaldoxime is a chelator. • Glyoxime, produced via the condensation of glyoxal with hydroxylamine,[16] forms highly energetic copper, lead and silver salts (copper, lead and silver glyoximate respectively).[17] However these compounds are too unstable to be of any commercial value. • Diaminoglyoxime, a glyoxime derivative, is a key synthetic precursor, used to prepare various compounds, containing the highly reactive furazan ring. • Methyl Ethyl Ketoxime is a skin-preventing additive in many oil-based paints. • Some amidoximes like polyacrylamidoxime can be used to capture trace amounts of uranium from sea water[18][19] Figure. Structure of Ni(dmgH)2. References [1] The name "oxime" is derived from "oximide" (i.e., oxy- + amide). According to the German organic chemist Victor Meyer (1848-1897) -who, with Alois Janny, synthesized the first oximes -- an "oximide" was an organic compound containing the group (=N-OH) attached to a carbon atom. The existence of oximides was questioned at the time (ca. 1882). (See page 1164 of: Victor Meyer und Alois Janny (1882a) "Ueber stickstoffhaltige Acetonderivate" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k90694n/ f1165. langEN) (On nitrogenous derivatives of acetone), Berichte der Deutschen chemischen Gesellschaft, 15: 1164-1167.) However, in 1882, Meyer and Janny succeeded in synthesizing methylglyoxime (CH3C(=NOH)CH(=NOH)), which they named "Acetoximsäure" (acetoximic acid) (Meyer & Janny, 1882a, p. 1166). Subsequently, they synthesized 2-propanone, oxime ((CH3)2C=NOH), which they named "Acetoxim" (acetoxime), in analogy with Acetoximsäure. From Victor Meyer and Alois Janny (1882b) "Ueber die Einwirkung von Hydroxylamin auf Aceton" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k90694n/ f1323. image. langEN) (On the effect of hydroxylamine on acetone), Berichte der Deutschen chemischen Gesellschaft, 15: 1324-1326, page 1324: "Die Substanz, welche wir, wegen ihrer nahen Beziehungen zur Acetoximsäure, und da sie keine Oxime sauren Eigenschaften besitzt, vorläufig Acetoxim nennen wollen, …" (The substance, which we -- on account of its close relations to acetoximic acid, and since it possesses no acid properties -- will, for the present, name "acetoxime," … ) [2] W. Reusch. "Infrared Spectroscopy" (http:/ / www. cem. msu. edu/ ~reusch/ VirtTxtJml/ Spectrpy/ InfraRed/ infrared. htm). Virtual Textbook of Organic Chemistry. Michigan State University. . [3] Kalia, J.; Raines, R. T. (2008). "Hydrolytic stability of hydrazones and oximes". Angew. Chem. Int. Ed. 47 (39): 7523-7526. PMC 2743602. PMID 18712739. [4] Hans Fischer (1943), "2,4-Dimethyl-3,5-dicarbethoxypyrrole" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv2p0202), Org. Synth., ; Coll. Vol. 2: 202 [5] Hans Fischer (1955), "Kryptopyrrole" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv3p0513), Org. Synth., ; Coll. Vol. 3: 513 [6] W. L. Semon and V. R. Damerell (1943), "Dimethoxyglyoxime" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv2p0204), Org. Synth., ; Coll. Vol. 2: 204 [7] Walter H. Hartung and Frank Crossley (1943), "Isonitrosopropiophenone" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv2p0363), Org. Synth., ; Coll. Vol. 2: 363 [8] Nathan Levin and Walter H. Hartung (1955), "ω-chloroisonitrosoacetophenone" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv3p0191), Org. Synth., ; Coll. Vol. 3: 191 [9] J. P. Ferris, R. A. Sanchez, and R. W. Mancuso (1973), "p-toluenesulfonate" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv5p0032), Org. Synth., ; Coll. Vol. 5: 32 [10] Giacomo Ponzio (1906). "Einwirkung von Stickstofftetroxyd auf Benzaldoxim". J. Prakt. Chem. 73: 494. doi:10.1002/prac.19060730133. [11] Louis F. Fieser and William von E. Doering (1946). "Aromatic-Aliphatic Nitro Compounds. III. The Ponzio Reaction; 2,4,6-Trinitrobenzyl Nitrate". J. Am. Chem. Soc. 68 (11): 2252. doi:10.1021/ja01215a040. [12] Ferdinand Tiemann (1891). "Ueber die Einwirkung von Benzolsulfonsäurechlorid auf Amidoxime". Chemische Berichte 24 (2): 4162–4167. doi:10.1002/cber.189102402316. [13] Robert Plapinger, Omer Owens (1956). "Notes - The Reaction of Phosphorus-Containing Enzyme Inhibitors with Some Hydroxylamine Derivatives". J. Org. Chem. 21 (10): 1186. doi:10.1021/jo01116a610. [14] Aaron Rowe (2007-11-27). New Nerve Gas Antidotes (http:/ / blog. wired. com/ wiredscience/ 2007/ 11/ building-a-bett. html). Wired (magazine). [15] Kassa, J. (2002). "Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents". Journal of Toxicology — Clinical Toxicology 40 (6): 803. doi:10.1081/CLT-120015840. [16] Michelman, J; Michelman, J. S. (1965). "Furazan". Journal of Organic Chemistry 30 (6): 1854–1859. doi:10.1021/jo01017a034. [17] Urben, Peter (1999). Bretherick's Handobook of Reactive Chemical Hazards. 1 (5 ed.). Butterworth-Heinemann. p. 799. [18] Rao, Linfeng. "Recent International R&D Activities in the Extraction of Uranium from Seawater" (http:/ / escholarship. org/ uc/ item/ 12h981cf). Lawrence Berkeley National Laboratory. . Retrieved 21 September 2012. [19] Kanno, M. "Present status of study on extraction of uranium from sea water" (http:/ / www. tandfonline. com/ doi/ abs/ 10. 1080/ 18811248. 1984. 9731004). Journal of Nuclear Science and Technology. . Retrieved 21 September 2012. 173 Nitrile 174 Nitrile A nitrile is any organic compound that has a -C≡N functional group.[1] The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, including methyl cyanoacrylate, used in super glue, and nitrile butadiene rubber, a nitrile-containing polymer used in latex-free laboratory and medical gloves. Organic compounds containing multiple nitrile groups are known as cyanocarbons. The structure of a nitrile, the functional group is highlighted blue. Inorganic compounds containing the -C≡N group are not called nitriles, but cyanides instead.[2] Though both nitriles and cyanides can be derived from cyanide salts, most nitriles are not nearly as toxic. History The first compound of the homolog row of nitriles, the nitrile of formic acid, hydrogen cyanide was first synthesized by C.W. Scheele in 1782.[3][4] In 1811 J. L. Gay-Lussac was able to prepare the very toxic and volatile pure acid.[5] The nitrile of benzoic acids was first prepared by Friedrich Wöhler and Justus von Liebig, but due to minimal yield of the synthesis neither physical nor chemical properties were determined nor a structure suggested. Théophile-Jules Pelouze synthesized propionitrile in 1834 suggesting it to be an ether of propionic alcohol and hydrocyanic acid.[6] The synthesis of benzonitrile by Hermann Fehling in 1844, by heating ammonium benzoate, was the first method yielding enough of the substance for chemical research. He determined the structure by comparing it to the already known synthesis of hydrogen cyanide by heating ammonium formate to his results. He coined the name "nitrile" for the newfound substance, which became the name for this group of compounds.[7] Synthesis Industrially, the main methods for producing nitriles are ammoxidation and hydrocyanation. Both routes are green in the sense that they do not generate stoichiometric amounts of salts. Ammoxidation In ammonoxidation, a hydrocarbon is partially oxidized in the presence of ammonia. This conversion is practiced on a large scale for acrylonitrile:[8] CH3CH=CH2 + 3/2 O2 + NH3 → NCCH=CH2 + 3 H2O A side product of this process is acetonitrile. Most derivatives of benzonitrile as well as Isobutyronitrile are prepared by ammoxidation. Hydrocyanation An example of hydrocyanation is the production of adiponitrile from 1,3-butadiene: CH2=CH-CH=CH2 + 2 HCN → NC(CH2)4CN From organic halides and cyanide salts Often for more specialty applications, nitriles can be prepared by a wide variety of other methods. For example, alkyl halides undergo nucleophilic aliphatic substitution with alkali metal cyanides in the Kolbe nitrile synthesis. Aryl nitriles are prepared in the Rosenmund-von Braun synthesis. Nitrile 175 Cyanohydrins The cyanohydrins are a special class of nitriles that result from the addition of metal cyanides to aldehydes in the cyanohydrin reaction. Because of the polarity of the organic carbonyl, this reaction requires no catalyst, unlike the hydrocyanation of alkenes. Dehydration of amides and oximes Nitriles can be prepared by the Dehydration of primary amides. Many reagents are available, the combination of ethyl dichlorophosphate and DBU just one of them in this conversion of benzamide to benzonitrile:[9] Two intermediates in this reaction are amide tautomer A and its phosphate adduct B. In a related dehydration, secondary amides give nitriles by the von Braun amide degradation. In this case, one C-N bond is cleaved. The dehydration of aldoximes (RCH=NOH) also affords nitriles. Typical reagents for this transformation arewith triethylamine/sulfur dioxide, zeolites, or sulfuryl chloride. Exploiting this approach is the One-pot synthesis of nitriles from aldehyde with hydroxylamine in the presence of sodium sulfate.[10] • from aryl carboxylic acids (Letts nitrile synthesis) Nitrile 176 Sandmeyer reaction Aromatic nitriles are often prepared in the laboratory from the aniline via diazonium compounds. This is the Sandmeyer reaction. It requires transition metal cyanides.[11] ArN2+ + CuCN → ArCN + N2 + Cu+ Other methods • A commercial source for the cyanide group is diethylaluminum cyanide Et2AlCN which can be prepared from triethylaluminium and HCN.[12] It has been used in nucleophilic addition to ketones.[13] For an example of its use see: Kuwajima Taxol total synthesis • cyanide ions facilitate the coupling of dibromides. Reaction of α,α'-dibromo adipic acid with sodium cyanide in ethanol yields the cyano cyclobutane:[14] In the so-called Franchimont Reaction (A. P. N. Franchimont, 1872) an α-bromocarboxylic acid is dimerized after hydrolysis of the cyanogroup and decarboxylation [15] • Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines (RC(CCl3)=NH) in the Houben-Fischer synthesis [16][17] Reactions Nitrile groups in organic compounds can undergo various reactions when subject to certain reactants or conditions. A nitrile group can be hydrolyzed, reduced, or ejected from a molecule as a cyanide ion. Hydrolysis The hydrolysis of nitriles RCN proceeds in the distinct steps under acid or base treatment to achieve carboxamides RC(=O)NH2 and then carboxylic acids RCOOH. The hydrolysis of nitriles is generally considered to be one of the best methods for the preparation of carboxylic acids. However, these base or acid catalyzed reactions have certain limitations and/or disadvantages for preparation of amides. The general restriction is that the final neutralization of either base or acid leads to an extensive salt formation with inconvenient product contamination and pollution effects. Particular limitations are as follows: • The base catalyzed reactions. The kinetic studies allowed the estimate of relative rates for the hydration at each step of the reaction and, as a typical example, the second-order rate constants for hydroxide-ion catalyzed hydrolysis of acetonitrile and acetamide are 1.6×10−6 and 7.4×10−5M−1s−1, respectively. Comparison of these two values indicates that the second step of the hydrolysis for the base-catalyzed reaction is faster than the first one, and the reaction should proceed to the final hydration product (the carboxylate salt) rather than stopping at the amide stage. This implies that amides prepared in the conventional metal-free base-catalyzed reaction should be contaminated with carboxylic acids and they can be isolated in only moderate yields. • The acid catalyzed reactions. Application of strong acidic solutions requires a careful control of the temperature and of the ratio of reagents in order to avoid the formation of polymers, which is promoted by the exothermic character of the hydrolysis.[18] Nitrile 177 Reduction In organic reduction the nitrile is reduced by reacting it with hydrogen with a nickel catalyst; an amine is formed in this reaction (see nitrile reduction). Reduction to the amine followed by hydrolysis to the aldehyde takes place in the Stephen aldehyde synthesis Alkylation Alkyl nitriles are sufficiently acidic to form the carbanion, which alkylate a wide variety of electrophiles. Key to the exceptional nucleophilicity is the small steric demand of the CN unit combined with its inductive stabilization. These features make nitriles ideal for creating new carbon-carbon bonds in sterically demanding environments for use in syntheses of medicinal chemistry. Recent developments have shown that the nature of the metal counter-ion causes different coordination to either the nitrile nitrogen or the adjacent nucleophilic carbon, often with profound differences in reactivity and stereochemistry.[19] Nucleophiles A nitrile is an electrophile at the carbon atom in a nucleophilic addition reactions: • with an organozinc compound in the Blaise reaction • and with alcohols in the Pinner reaction. • likewise, the reaction of the amine sarcosine with cyanamide yields creatine [20] • Nitriles react in Friedel-Crafts acylation in the Houben-Hoesch reaction to ketones Miscellaneous methods and compounds • In reductive decyanation the nitrile group is replaced by a proton.[21] An effective decyanation is by a dissolving metal reduction with HMPA and potassium metal in tert-butanol. α-Amino-nitriles can be decyanated with lithium aluminium hydride. • Nitriles self-react in presence of base in the Thorpe reaction in a nucleophilic addition • In organometallic chemistry nitriles are known to add to alkynes in carbocyanation:[22] Nitrile 178 Nitrile derivatives Organic cyanamides Cyanamides are N-cyano compounds with general structure R1R2N-CN and related to the inorganic parent cyanamide. For an example see: von Braun reaction. Nitrile oxides Nitrile oxides have the general structure R-CNO. Occurrence and applications Nitriles occur naturally in a diverse set of plant and animal sources. Over 120 naturally occurring nitriles have been isolated from terrestrial and marine sources. Nitriles are commonly encountered in fruit pits, especially almonds, and during cooking of Brassica crops (such as cabbage, brussel sprouts, and cauliflower), which release nitriles being released through hydrolysis. Mandelonitrile, a cyanohydrin produced by ingesting almonds or some fruit pits, releases hydrogen cyanide and is responsible for the toxicity of cyanogenic glycosides.[23] Over 30 nitrile-containing pharmaceuticals are currently marketed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. The nitrile group is quite robust and, in most cases, is not readily metabolized but passes through the body unchanged. The types of pharmaceuticals containing nitriles is diverse, from Vildagliptin an antidiabetic drug to Anastrazole which is the gold standard in treating breast cancer. In many instances the nitrile mimics functionality present in substrates for enzymes, whereas in other cases the nitrile increases water solubility or decreases susceptibility to oxidative metabolism in the liver.[24]The nitrile functional group is found in several drugs. Structure of periciazine, an antipsychotic studied in the treatment of opiate dependence. Structure of citalopram, an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class. Structure of cyamemazine, an antipsychotic drug. Structure of fadrozole, an aromatase inhibitor for the treatment of breast cancer. Structure of letrozole, an oral non-steroidal aromatase inhibitor for the treatment of certain breast cancers. Nitrile 179 References [1] IUPAC Gold Book nitriles (http:/ / goldbook. iupac. org/ N04151. html) [2] NCBI-MeSH Nitriles (http:/ / www. ncbi. nlm. nih. gov/ mesh/ 68009570) [3] See: Carl W. Scheele (1782) "Försök, beträffande det färgande ämnet uti Berlinerblå" (http:/ / books. google. com/ books?id=mHVJAAAAcAAJ& pg=PA264#v=onepage& q& f=false) (Experiment concerning the colored substance in Berlin blue), Kungliga Svenska Vetenskapsakademiens handlingar (Royal Swedish Academy of Science's Proceedings), 3: 264-275 (in Swedish). • Reprinted in Latin as: "De materia tingente caerulei berolinensis" (http:/ / books. google. com/ books?id=BLo5AAAAcAAJ& pg=PA148#v=onepage& q& f=false) in: Carl Wilhelm Scheele with Ernst Benjamin Gottlieb Hebenstreit (ed.) and Gottfried Heinrich Schäfer (trans.), Opuscula Chemica et Physica (Leipzig ("Lipsiae"), (Germany): Johann Godfried Müller, 1789), vol. 2, pages 148-174. [4] David T. Mowry (1948). "The Preparation of Nitriles" (http:/ / pubs. acs. org/ cgi-bin/ abstract. cgi/ chreay/ 1942/ 42/ i02/ f-pdf/ f_cr60132a001. pdf) (– Scholar search (http:/ / scholar. google. co. uk/ scholar?hl=en& lr=& q=intitle:The+ Preparation+ of+ Nitriles& as_publication=[[Chemical+ Reviews]]& as_ylo=1948& as_yhi=1948& btnG=Search)). Chemical Reviews 42 (2): 189–283. doi:10.1021/cr60132a001. . [5] Gay-Lussac produced pure, liquified hydrogen cyanide in: Gay-Lussac (1811) "Note sur l'acide prussique" (http:/ / books. google. com/ books?id=uJs5AAAAcAAJ& pg=PA128#v=onepage& q& f=false) (Note on prussic acid), Annales de chimie, 44: 128 - 133. [6] J. Pelouze (1834). "Notiz über einen neuen Cyanäther [Note on a new cyano-ether]" (http:/ / books. google. com/ books?id=P0s9AAAAcAAJ& pg=PA249#v=onepage& q& f=false). Annalen der Pharmacie 10 (3): 249. doi:10.1002/jlac.18340100302. . [7] Hermann Fehling (1844). "Ueber die Zersetzung des benzoësauren Ammoniaks durch die Wärme (On the decomposition of ammonium benzoate by heat)" (http:/ / books. google. com/ books?id=2U09AAAAcAAJ& pg=PA91#v=onepage& q& f=false). Annalen der Chemie und Pharmacie 49 (1): 91–97. doi:10.1002/jlac.18440490106. . On page 96, Fehling writes: "Da Laurent den von ihm entdeckten Körper schon Nitrobenzoyl genannt hat, auch schon ein Azobenzoyl existirt, so könnte man den aus benzoësaurem Ammoniak entstehenden Körper vielleicht Benzonitril nennen." (Since Laurent named the substance that was discovered by him "nitrobenzoyl" -- also an "azobenzoyl" already exists -- so one could name the substance that originates from ammonium benzoate perhaps "benzonitril".) [8] Peter Pollak, Gérard Romeder, Ferdinand Hagedorn, Heinz-Peter Gelbke "Nitriles" Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a17_363 [9] Chun-Wei Kuo, Jia-Liang Zhu, Jen-Dar Wu, Cheng-Ming Chu, Ching-Fa Yao and Kak-Shan Shia (2007). "A convenient new procedure for converting primary amides into nitriles". Chem. Commun. 2007 (3): 301–303. doi:10.1039/b614061k. PMID 17299646. [10] Sharwan K, Dewan, Ravinder Singh, and Anil Kumar (2006). "One pot synthesis of nitriles from aldehydes and hydroxylamine hydrochloride using sodium sulfate (anhyd) and sodium bicarbonate in dry media under microwave irradiation" (http:/ / www. arkat-usa. org/ ark/ journal/ 2006/ I02_General/ 1646/ 05-1646D as published mainmanuscript. pdf) (open access). Arkivoc: (ii) 41–44. . [11] o-Tolunitrile and p-Tolunitrile" H. T. Clarke and R. R. Read Org. Synth. 1941, Coll. Vol. 1, 514. [12] W. Nagata and M. Yoshioka (1988), "Diethylaluminum cyanide" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv6p0436), Org. Synth., ; Coll. Vol. 6: 436 [13] W. Nagata, M. Yoshioka, and M. Murakami (1988), "Preparation of cyano compounds using alkylaluminum intermediates: 1-cyano-6-methoxy-3,4-dihydronaphthalene" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv6p0307), Org. Synth., ; Coll. Vol. 6: 307 [14] Reynold C. Fuson, Oscar R. Kreimeier, and Gilbert L. Nimmo (1930). "Ring Closures In The Cyclobutane Series. Ii. Cyclization Of Α,Α′-Dibromo-Adipic Esters". J. Am. Chem. Soc. 52 (10): 4074–4076. doi:10.1021/ja01373a046. [15] Franchimont Reaction (http:/ / www. drugfuture. com/ OrganicNameReactions/ ONR143. htm) [16] J. Houben, Walter Fischer (1930) "Über eine neue Methode zur Darstellung cyclischer Nitrile durch katalytischen Abbau (I. Mitteil.)," Berichte der deutschen chemischen Gesellschaft (A and B Series) 63 (9): 2464 - 2472. doi:10.1002/cber.19300630920 [17] http:/ / www. drugfuture. com/ OrganicNameReactions/ ONR197. htm Merck & Co., Inc., Whitehouse Station [18] V. Yu. Kukushkin, A. J. L. Pombeiro, Metal-mediated and metal-catalyzed hydrolysis of nitriles (a review), Inorg. Chim. Acta, 358 (2005) 1–21 [19] Tetrahedron Volume 61, Issue 4, 24 January 2005, Pages 747-789 doi: 10.1016/j.tet.2004.11.012 (http:/ / dx. doi. org/ 10. 1016/ j. tet. 2004. 11. 012) [20] Smith, Andri L.; Tan, Paula (2006). "Creatine Synthesis: An Undergraduate Organic Chemistry Laboratory Experiment" (http:/ / jchemed. chem. wisc. edu/ Journal/ Issues/ 2006/ Nov/ abs1654. html). J. Chem. Educ. 83: 1654. Bibcode 2006JChEd..83.1654S. doi:10.1021/ed083p1654. . [21] The reductive decyanation reaction: chemical methods and synthetic applications Jean-Marc Mattalia, Caroline Marchi-Delapierre, Hassan Hazimeh, and Michel Chanon Arkivoc (AL-1755FR) pp 90-118 2006 Article (http:/ / www. arkat-usa. org/ ark/ journal/ 2006/ I04_Lattes/ 1755/ AL-1755FR as published mainmanuscript. asp) [22] Yoshiaki Nakao, Akira Yada, Shiro Ebata, and Tamejiro Hiyama (2007). "A Dramatic Effect of Lewis-Acid Catalysts on Nickel-Catalyzed Carbocyanation of Alkynes" (Communication). J. Am. Chem. Soc. 129 (9): 2428–2429. doi:10.1021/ja067364x. PMID 17295484. [23] Natural Product Reports Issue 5, 1999 Nitrile-containing natural products (http:/ / pubs. rsc. org/ en/ Content/ ArticleLanding/ 1999/ NP/ a804370a) • Nitrile [24] Fleming, Fraser F.; Yao, Lihua; Ravikumar, P. C.; Funk, Lee; Shook, Brian C. (November 2010). "Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore". J Med Chem 53 (22): 7902–17. doi:10.1021/jm100762r. PMC 2988972. PMID 20804202. 180 External links: • Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "nitrile" (http://goldbook.iupac.org/N04151.html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.N04151. ISBN 0-9678550-9-8. • Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "cyanide" (http://goldbook.iupac.org/C01486.html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.C01486. ISBN 0-9678550-9-8. Hydrogen cyanide 181 Hydrogen cyanide Hydrogen cyanide Identifiers CAS number PubChem ChemSpider UNII EC number UN number KEGG MeSH ChEBI RTECS number 3DMet Jmol-3D images 74-90-8 768 748 [2] [3]   [4]   [1]   2WTB3V159F 200-821-6 1051 C01326 [6]   [5] Hydrogen+Cyanide CHEBI:18407 MW6825000 B00275 Image 1 Properties [9] [10] [8]   [7] Molecular formula Molar mass Appearance Odor Density Melting point Boiling point Solubility in water Solubility in ethanol k H a CHN 27.03 g mol−1 Very pale, blue, transparent liquid Oil of bitter almond 0.687 g mL−1 -14--12 °C, 259-261 K, 7-10 °F 25-26 °C, 298.5-299.5 K, 78-79 °F Miscible Miscible 75 μmol Pa−1 kg−1 9.21 4.79 D Acidity (pK ) Basicity (pK ) b [11] Refractive index (n ) 1.2675 [12] Hydrogen cyanide 182 Viscosity 201 μPa s Structure Molecular shape Dipole moment Linear 2.98 D Thermochemistry Std enthalpy of formation ΔfHo298 Std enthalpy of combustion ΔcHo298 Standard molar entropy So298 Specific heat capacity, C -4.999 MJ kg−1 [13] 642 kJ mol−1 113.01 J K−1 mol−1 71.00 kJ K Hazards −1 mol −1 (at 27 °C) EU Index EU classification 006-006-00-X F+ R-phrases S-phrases NFPA 704 Flash point Autoignition temperature −17.8 °C 538 °C Related compounds Related alkanenitriles • • • • • • • • • • •   (verify) [14] T+ N R12, R26/27/28, R50/53 (S1/2), S16, S36/37, S38, S45, S53, S59, S61 Hydrogen isocyanide Isocyanic acid Thiocyanic acid Cyanogen iodide Cyanogen bromide Cyanogen chloride Cyanogen fluoride Acetonitrile Aminoacetonitrile Glycolonitrile Cyanogen  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Hydrogen cyanide (with the alternate archaic name of prussic acid) is an inorganic compound[15] with chemical formula HCN. It is a colorless, extremely poisonous liquid that boils slightly above room temperature at 26 °C (79 °F). Hydrogen cyanide is a linear molecule, with a triple bond between carbon and nitrogen. A minor tautomer of HCN is HNC, hydrogen isocyanide. Hydrogen cyanide is weakly acidic with a pKa of 9.2. It partially ionizes in water solution to give the cyanide anion, CN–. A solution of hydrogen cyanide in water is called hydrocyanic acid. The salts of hydrogen cyanide are known as cyanides. Hydrogen cyanide HCN has a faint, bitter, almond-like odor that some people are unable to detect owing to a genetic trait.[16] The volatile compound has been used as inhalation rodenticide and human poison. Cyanide ions interfere with iron-containing respiratory enzymes. HCN is produced on an industrial scale and is a highly valuable precursor to many chemical compounds ranging from polymers to pharmaceuticals. 183 History of discovery Hydrogen cyanide was first isolated from a blue pigment (Prussian blue) which had been known from 1704 but whose structure was unknown. It is now known to be a coordination polymer with a complex structure and an empirical formula of hydrated ferric ferrocyanide. In 1752, the French chemist Pierre Macquer made the important step of showing that Prussian blue could be converted to iron oxide plus a volatile component and that these could be used to reconstitute it.[17] The new component was what we now know as hydrogen cyanide. Following Macquer's lead, it was first prepared from Prussian blue by the Swedish chemist Carl Wilhelm Scheele in 1782,[18] and was eventually given the German name Blausäure (lit. "Blue acid") because of its acidic nature in water and its derivation from Prussian blue. In English it became known popularly as Prussic acid. The red colored ferricyanide ion, one component of Prussian blue In 1787 the French chemist Claude Louis Berthollet showed that Prussic acid did not contain oxygen,[19] an important contribution to acid theory, which had hitherto postulated that acids must contain oxygen[20] (hence the name of oxygen itself, which is derived from Greek elements that mean "acid-former" and are likewise calqued into German as Sauerstoff). In 1811 Joseph Louis Gay-Lussac prepared pure, liquified hydrogen cyanide.[21] In 1815 Gay-Lussac deduced Prussic acid's chemical formula.[22] The radical cyanide in hydrogen cyanide was given its name from cyan, not only an English word for a shade of blue but the Greek word for blue, again owing to its derivation from Prussian blue. Production and synthesis Hydrogen cyanide forms in at least limited amounts from many combinations of hydrogen, carbon, and ammonia. Hydrogen cyanide is currently produced in great quantities by several processes, as well as being a recovered waste product from the manufacture of acrylonitrile.[15] In the year 2000, 732,552 tons were produced in the US.[23] The most important process is the Andrussow oxidation invented by Leonid Andrussow at IG Farben in which methane and ammonia react in the presence of oxygen at about 1200 °C over a platinum catalyst:[24] 2 CH4 + 2 NH3 + 3 O2 → 2 HCN + 6 H2O The energy needed for the reaction is provided by the partial oxidation of methane and ammonia. Of lesser importance is the Degussa process (BMA process) in which no oxygen is added and the energy must be transferred indirectly through the reactor wall:[25] CH4 + NH3 → HCN + 3H2 This reaction is akin to steam reforming, the reaction of methane and water to give carbon monoxide and hydrogen. In the Shawinigan Process, hydrocarbons, e.g. propane, are reacted with ammonia: Hydrogen cyanide C3H8 + 3 NH3 → 3 HCN + 7 H2 When heated strongly, formamide decomposes to hydrogen cyanide and water vapor: CH(O)NH2 → HCN + H2O In the laboratory, small amounts of HCN are produced by the addition of acids to cyanide salts of alkali metals: H+ + NaCN → HCN + Na+ This reaction is sometimes the basis of accidental poisonings because the acid converts a nonvolatile cyanide salt into the gaseous HCN. 184 Historical methods of production The demand for cyanides for mining operations in the 1890s was met by George Thomas Beilby, who patented a method to produce hydrogen cyanide by passing ammonia over glowing coal in 1892. This method was used until Hamilton Castner in 1894 developed a synthesis starting from coal, ammonia, and sodium yielding sodium cyanide, which reacts with acid to form gaseous HCN. Applications HCN is the precursor to sodium cyanide and potassium cyanide, which are used mainly in gold and silver mining and for the electroplating of those metals. Via the intermediacy of cyanohydrins, a variety of useful organic compounds are prepared from HCN including the monomer methyl methacrylate, from acetone, the amino acid methionine, via the Strecker synthesis, and the chelating agents EDTA and NTA. Via the hydrocyanation process, HCN is added to butadiene to give adiponitrile, a precursor to Nylon 66.[15] Occurrence HCN is obtainable from fruits that have a pit, such as cherries, apricots, apples, and bitter almonds, from which almond oil and flavoring are made. Many of these pits contain small amounts of cyanohydrins such as mandelonitrile and amygdalin, which slowly release hydrogen cyanide.[26][27] One hundred grams of crushed apple seeds can yield about 70 mg of HCN.[28] Some millipedes release hydrogen cyanide as a defense mechanism,[29] as do certain insects, such as some burnet moths. Hydrogen cyanide is contained in the exhaust of vehicles, in tobacco and wood smoke, and in smoke from burning nitrogen-containing plastics. So-called "bitter" roots of the cassava plant may contain up to 1 gram of HCN per kilogram.[30][31] HCN and the origin of life Hydrogen cyanide has been discussed as a precursor to amino acids and nucleic acids. For example, HCN is proposed to have played a part in the origin of life.[32] Although the relationship of these chemical reactions to the origin of life theory remains speculative, studies in this area have led to discoveries of new pathways to organic compounds derived from the condensation of HCN.[33] HCN in space HCN has been detected in the interstellar medium.[34] Since then, extensive studies have probed formation and destruction pathways of HCN in various environments and examined its use as a tracer for a variety of astronomical species and processes. HCN can be observed from ground-based telescopes through a number of atmospheric windows.[35] The J=1→0, J=3→2, J= 4→3, and J=10→9 pure rotational transitions have all been observed.[34][36][37] HCN is formed in interstellar clouds through one of two major pathways:[38] via a neutral-neutral reaction (CH2 + N → HCN + H) and via dissociative recombination (HCNH+ + e- → HCN + H). The dissociative recombination Hydrogen cyanide pathway is dominant by 30%; however, the HCNH+ must be in its linear form. Dissociative recombination with its structural isomer, H2NC+, exclusively produces hydrogen isocyanide (HNC). HCN is destroyed in interstellar clouds through a number of mechanisms depending on the location in the cloud.[38] In photon-dominated regions (PDRs), photodissociation dominates, producing CN (HCN + ν → CN + H). At further depths, photodissociation by cosmic rays dominate, producing CN (HCN + cr → CN + H). In the dark core, two competing mechanisms destroy it, forming HCN+ and HCNH+ (HCN + H+ → HCN+ + H; HCN + HCO+ → HCNH+ + CO). The reaction with HCO+ dominates by a factor of ~3.5. HCN has been used to analyze a variety of species and processes in the interstellar medium. It has been suggested as a tracer for dense molecular gas[39][40] and as a tracer of stellar inflow in high-mass star-forming regions.[41] Further, the HNC/HCN ratio has been shown to be an excellent method for distinguishing between PDRs and X-ray-dominated regions (XDRs).[42] 185 Hydrogen cyanide as a poison and chemical weapon A hydrogen cyanide concentration of 300 mg/m3 in air will kill a human within about 10 minutes.[43] A hydrogen cyanide concentration of 3500 ppm (about 3200 mg/m3) will kill a human in about 1 minute.[43] The toxicity is caused by the cyanide ion, which halts cellular respiration by inhibiting an enzyme in mitochondria called cytochrome c oxidase. Hydrogen cyanide absorbed into a carrier for use as a pesticide (under IG Farben's brand name Cyclone B, or in German Zyklon B, with the B standing for Blausäure)[44] was employed by Nazi Germany in the mid-20th century in extermination camps. The same product is currently made in the Czech Republic under the trademark "Uragan D2." Hydrogen cyanide is also the agent used in gas chambers employed in judicial execution in some U.S. states, where it is produced during the execution by the action of sulfuric acid on an egg-sized mass of potassium cyanide. Hydrogen cyanide is commonly listed amongst chemical warfare agents known as blood agents.[45] As a substance listed under Schedule 3 of the Chemical Weapons Convention as a potential weapon which has large-scale industrial uses, manufacturing plants in signatory countries which produce more than 30 tonnes per year must be declared to, and can be inspected by, the Organisation for the Prohibition of Chemical Weapons. Under the name prussic acid, HCN has been used as a killing agent in whaling harpoons.[46] Hydrogen cyanide gas in air is explosive at concentrations over 5.6%.[47] This is far above its toxicity level. 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Synthetic Nitrogen Products: A Practical Guide to the Products and Processes (http:/ / books. google. com/ books?id=TvMnWtQKnlAC& pg=PA348). Springer. p. 348. ISBN 978-0-306-48225-0. . Retrieved 2012-06-03. [14] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=476999282& page2=%3AHydrogen+ cyanide [15] Gail, E.; Gos, S.; Kulzer, R.; Lorösch, J.; Rubo, A.; Sauer, M. (2005), "Cyano Compounds, Inorganic", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a08_159.pub2 [16] "Cyanide, inability to smell" (http:/ / www. ncbi. nlm. nih. gov/ omim/ 304300). Online Mendelian Inheritance in Man. . Retrieved 2010-03-31. Hydrogen cyanide [17] Pierre-Joseph Macquer (presented: 1752 ; published: 1756) "Éxamen chymique de bleu de Prusse" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k35505/ f242) (Chemical examination of Prussian blue), Mémoires de l'Académie royale des Sciences , pages 60-77. [18] See: Carl W. Scheele (1782) "Försök, beträffande det färgande ämnet uti Berlinerblå" (http:/ / books. google. com/ books?id=mHVJAAAAcAAJ& pg=PA264#v=onepage& q& f=false) (Experiment concerning the coloring substance in Berlin blue), Kungliga Svenska Vetenskapsakademiens handlingar (Royal Swedish Academy of Science's Proceedings), 3: 264-275 (in Swedish). • Reprinted in Latin as: "De materia tingente caerulei berolinensis" (http:/ / books. google. com/ books?id=BLo5AAAAcAAJ& pg=PA148#v=onepage& q& f=false) in: Carl Wilhelm Scheele with Ernst Benjamin Gottlieb Hebenstreit (ed.) and Gottfried Heinrich Schäfer (trans.), Opuscula Chemica et Physica (Leipzig ("Lipsiae"), (Germany): Johann Godfried Müller, 1789), vol. 2, pages 148-174. [19] See: • Berthollet (presented: 1787 ; published: 1789) "Mémoire sur l'acide prussique" (http:/ / books. google. com/ books?id=fC5EAAAAcAAJ& pg=PA148#v=onepage& q& f=false) (Memoir on prussic acid), Mémoires de l'Académie Royale des Sciences, pages 148-161. Reprinted in: Berthollet (1789) "Extrait d'un mémoire sur l'acide prussique" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k110315k/ f40. image. langEN) (Extract of a memoir on prussic acid), Annales de chimie 1: 30-39. [20] Newbold, B. T. (1999-11-01). "Claude Louis Berthollet: A Great Chemist in the French Tradition" (http:/ / www. allbusiness. com/ north-america/ canada/ 370855-1. html). Canadian Chemical News. . Retrieved 2010-03-31. [21] Gay-Lussac (1811) "Note sur l'acide prussique" (http:/ / books. google. com/ books?id=uJs5AAAAcAAJ& pg=PA128#v=onepage& q& f=false) (Note on prussic acid), Annales de chimie, 44: 128 - 133. [22] Gay-Lussac (1815) "Recherche sur l'acide prussique" (http:/ / books. google. com/ books?id=m9s3AAAAMAAJ& pg=PA136#v=onepage& q& f=false) (Research on prussic acid) Annales de Chimie 95: 136-231. [23] The Innovation Group (http:/ / www. the-innovation-group. com/ ChemProfiles/ Hydrogen Cyanide. htm). The Innovation Group. Retrieved on 2012-06-02. [24] Andrussow, L. (1935). "The catalytic oxydation of ammonia-methane-mixtures to hydrogen cyanide". Angewandte Chemie 48 (37): 593–595. doi:10.1002/ange.19350483702. [25] Endter, F. (1958). "Die technische Synthese von Cyanwasserstoff aus Methan und Ammoniak ohne Zusatz von Sauerstoff". Chemie Ingenieur Technik 30 (5): 305–310. doi:10.1002/cite.330300506. [26] Vetter, J. (2000). "Plant cyanogenic glycosides". Toxicon 38 (1): 11–36. doi:10.1016/S0041-0101(99)00128-2. PMID 10669009. [27] Jones, D. A. (1998). "Why are so many food plants cyanogenic?". Phytochemistry 47 (2): 155–162. doi:10.1016/S0031-9422(97)00425-1. PMID 9431670. [28] "Are Apple Cores Poisonous? The Naked Scientists September 2010" (http:/ / www. thenakedscientists. com/ HTML/ content/ latest-questions/ question/ 2737/ ). . Retrieved 6 September 2012. [29] Blum, M. S.; Woodring, J. P. (1962). "Secretion of Benzaldehyde and Hydrogen Cyanide by the Millipede Pachydesmus crassicutis (Wood)". Science 138 (3539): 512–513. Bibcode 1962Sci...138..512B. doi:10.1126/science.138.3539.512. PMID 17753947. [30] Aregheore, E. M.; Agunbiade, O. O. (1991). "The toxic effects of cassava (manihot esculenta grantz) diets on humans: a review". Veterinary and Human Toxicology 33 (3): 274–275. PMID 1650055. [31] White, W. L. B.; Arias-Garzon, D. I.; McMahon, J. M.; Sayre, R. T. (1998). "Cyanogenesis in Cassava, The Role of Hydroxynitrile Lyase in Root Cyanide Production". Plant Physiology 116 (4): 1219–1225. doi:10.1104/pp.116.4.1219. PMC 35028. PMID 9536038. [32] Matthews, C. N. (2004). "The HCN World: Establishing Protein - Nucleic Acid Life via Hydrogen Cyanide Polymers". Origins: Genesis, Evolution and Diversity of Life. Cellular Origin and Life in Extreme Habitats and Astrobiology. 6. pp. 121–135. doi:10.1007/1-4020-2522-X_8. ISBN 978-1-4020-2522-8. [33] Al-Azmi, A.; Elassar, A.-Z. A.; Booth, B. L. (2003). "The Chemistry of Diaminomaleonitrile and its Utility in Heterocyclic Synthesis". Tetrahedron 59 (16): 2749–2763. doi:10.1016/S0040-4020(03)00153-4. [34] Snyder, L. E.; Buhl, D. (1971). "Observations of Radio Emission from Interstellar Hydrogen Cyanide" (http:/ / articles. adsabs. harvard. edu/ cgi-bin/ nph-iarticle_query?1971ApJ. . . 163L. . 47S& amp;data_type=PDF_HIGH& amp;whole_paper=YES& amp;type=PRINTER& amp;filetype=. pdf) (pdf). Astrophysical Journal 163: L47–L52. Bibcode 1971ApJ...163L..47S. doi:10.1086/180664. . [35] Treffers, R.; Larson, H. P.; Fink, U.; Gautier, T. N. (1978). "Upper limits to trace constituents in Jupiter's atmosphere from an analysis of its 5-μm spectrum". Icarus 34 (2): 331–343. Bibcode 1978Icar...34..331T. doi:10.1016/0019-1035(78)90171-9. [36] Bieging, J. H.; Shaked, S.; Gensheimer, P. D. (2000). "Submillimeter‐ and Millimeter‐Wavelength Observations of SiO and HCN in Circumstellar Envelopes of AGB Stars" (http:/ / iopscience. iop. org/ 0004-637X/ 543/ 2/ 897/ pdf/ 0004-637X_543_2_897. pdf) (pdf). Astrophysical Journal 543 (2): 897–921. Bibcode 2000ApJ...543..897B. doi:10.1086/317129. . [37] Schilke, P.; Menten, K. M. (2003). "Detection of a Second, Strong Sub-millimeter HCN Laser Line toward Carbon Stars" (http:/ / iopscience. iop. org/ 0004-637X/ 583/ 1/ 446/ pdf/ 0004-637X_583_1_446. pdf) (pdf). Astrophysical Journal 583 (1): 446–450. Bibcode 2003ApJ...583..446S. doi:10.1086/345099. . [38] Boger, G. I.; Sternberg, A. (2005). "CN and HCN in Dense Interstellar Clouds" (http:/ / iopscience. iop. org/ 0004-637X/ 632/ 1/ 302/ pdf/ 0004-637X_632_1_302. pdf) (pdf). Astrophysical Journal 632 (1): 302–315. arXiv:astro-ph/0506535. Bibcode 2005ApJ...632..302B. doi:10.1086/432864. . • • 186 Hydrogen cyanide [39] Gao, Y.; Solomon, P. M. (2004). "The Star Formation Rate and Dense Molecular Gas in Galaxies" (http:/ / iopscience. iop. org/ 0004-637X/ 606/ 1/ 271/ pdf/ 0004-637X_606_1_271. pdf) (pdf). Astrophysical Journal 606 (1): 271–290. arXiv:astro-ph/0310339. Bibcode 2004ApJ...606..271G. doi:10.1086/382999. . [40] Gao, Y.; Solomon, P. M. (2004). "HCN Survey of Normal Spiral, Infrared‐luminous, and Ultraluminous Galaxies" (http:/ / iopscience. iop. org/ 0067-0049/ 152/ 1/ 63/ pdf/ 0067-0049_152_1_63. pdf) (pdf). Astrophysical Journal Supplements 152: 63–80. arXiv:astro-ph/0310341. Bibcode 2004ApJS..152...63G. doi:10.1086/383003. . [41] Wu, J.; Evans, N. J. (2003). "Indications of Inflow Motions in Regions Forming Massive Stars" (http:/ / iopscience. iop. org/ 1538-4357/ 592/ 2/ L79/ pdf/ 1538-4357_592_2_L79. pdf) (pdf). Astrophysical Journal 592 (2): L79–L82. arXiv:astro-ph/0306543. Bibcode 2003ApJ...592L..79W. doi:10.1086/377679. . [42] Loenen, A. F. (2007). Proceedings IAU Symposium 202. [43] Environmental and Health Effects (http:/ / www. cyanidecode. org/ cyanide_environmental. php). Cyanidecode.org. Retrieved on 2012-06-02. [44] Dwork, D.; van Pelt, R. J. (1996). Auschwitz, 1270 to the present. Norton. p. 443. ISBN 0-393-03933-1. [45] "Hydrogen Cyanide" (http:/ / www. opcw. org/ about-chemical-weapons/ types-of-chemical-agent/ blood-agents/ hydrogen-cyanide/ ). Organisation for the Prohibition of Chemical Weapons. . Retrieved 2009-01-14. [46] Poison Hand Darted Harpoons and Lances (http:/ / www. whalecraft. net/ Poison_Irons. html). [47] "Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs) – 74908" (http:/ / www. cdc. gov/ Niosh/ idlh/ 74908. html). NIOSH. . 187 External links • Institut national de recherche et de sécurité (1997). " Cyanure d'hydrogène et solutions aqueuses (http://www. inrs.fr/inrs-pub/inrs01.nsf/inrs01_ftox_view/860430FE710FCFD7C1256CE8004F67CB/$File/ft4.pdf)". Fiche toxicologique n° 4, Paris:INRS, 5pp. (PDF file, in French) • International Chemical Safety Card 0492 (http://www.inchem.org/documents/icsc/icsc/eics0492.htm) • Hydrogen cyanide and cyanides (http://www.inchem.org/documents/cicads/cicads/cicad61.htm) (CICAD 61) • National Pollutant Inventory: Cyanide compounds fact sheet (http://www.npi.gov.au/database/substance-info/ profiles/29.html) • NIOSH Pocket Guide to Chemical Hazards (http://www.cdc.gov/niosh/npg/npgd0333.html) • Department of health review (http://www.hpa.org.uk/infections/topics_az/deliberate_release/chemicals/ cyanide.pdf#search=""dicobalt edetate"") • OSHA: HCN Health Guidelines (http://www.osha.gov/SLTC/healthguidelines/hydrogencyanide/recognition. html) Ethyl chloroformate 188 Ethyl chloroformate Ethyl chloroformate[1] Identifiers CAS number PubChem ChemSpider Jmol-3D images 541-41-3 10928 10465 [3] [4]   [2]   Image 1 Properties [5] Molecular formula Molar mass Appearance Density Boiling point Solubility in water C3H5ClO2 108.52 g/mol Clear liquid 1.1403 g/cm 3 95 °C, 368 K, 203 °F Decomposes Hazards Main hazards Flash point   (verify) [6] Corrosive Flammable 61 °F  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Ethyl chloroformate is the ethyl ester of chloroformic acid. It is a reagent used in organic synthesis for the introduction of the ethyl carbamate protecting group[7] and for the formation of carboxylic anhydrides. Ethyl chloroformate 189 References [1] [2] [3] [4] [5] [6] [7] Merck Index, 11th Edition, 3742. http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=541-41-3 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=10928 http:/ / www. chemspider. com/ 10465 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=ClC%28%3DO%29OCC http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=396487307& page2=%3AEthyl+ chloroformate Protective Groups in Organic Synthesis, Third Edition, Theodora W. Greene and Peter G. M. Wuts, pages 504-506, ISBN 0-471-16019-9 Dithiocarbamate A dithiocarbamate is a functional group in organic chemistry. It is the analog of a carbamate in which both oxygen atoms are replaced by sulfur atoms. Sodium diethyldithiocarbamate is a common ligand in inorganic chemistry. Most primary and secondary amines react with carbon disulfide and sodium hydroxide to form dithiocarbamates. They are used as ligands for chelating metals. Dithiocarbamates readily react with many metal salts such as copper, ferrous, ferric, cobaltous, and nickel salts and are mostly found as octahedral complexes. Chemical structure of dithiocarbamates Isothiocyanate Isothiocyanate is the chemical group –N=C=S, formed by substituting the oxygen in the isocyanate group with a sulfur. Many natural isothiocyanates from plants are produced by enzymatic conversion of metabolites called glucosinolates. These natural isothiocyanates, such as allyl isothiocyanate, are also known as mustard oils. An artificial isothiocyanate, phenyl isothiocyanate, is used for amino acid sequencing in the Edman degradation. General structure of an isothiocyanate Isothiocyanate 190 Synthesis and reactions The general method for the formation of isothiocyanates proceeds through the reaction between a primary amine (e.g. aniline) and carbon disulfide in aqueous ammonia. This results in precipitation of the ammonium dithiocarbamate salt, which is then treated with lead nitrate to yield the corresponding isothiocyanate.[1] Another method relies on a tosyl chloride mediated decomposition of dithiocarbamate salts that are generated in the first step above.[2] Isothiocyanates may also be accessed via the thermally-induced fragmentation reactions of 1,4,2-oxathiazoles.[3] This synthetic methodology has been applied to a polymer-supported synthesis of isothiocyanates.[4] Isothiocyanates are weak electrophiles. Akin to the reactions of carbon dioxide, nucleophiles attack at carbon. Reflecting their electrophilic character, isothiocyanates are susceptible to hydrolysis. Biological activity Isothiocyanates occur widely in nature and are of interest in food science and medicine. Vegetable foods with characteristic flavors due to isothiocyanates include wasabi, horseradish, mustard, radish, Brussels sprouts, watercress, nasturtiums, and capers. These species generate isothiocyanates in different proportions, and so have different, but recognisably related, flavors. These species are members of the order Brassicales, which is characterised by the production of glucosinolates, and of the enzyme myrosinase, which acts on glucosinolates to release isothiocyanates. • • • • Sinigrin is the precursor to allyl isothiocyanate Glucotropaeolin is the precursor to benzyl isothiocyanate Gluconasturtiin is the precursor to phenethyl isothiocyanate Glucoraphanin is the precursor to sulforaphane Isothiocyanate 191 Medical applications Phenethyl isothiocyanate (PEITC) and sulforaphane inhibit carcinogenesis and tumorigenesis in certain circumstances. Their mechanism of action is proposed to involve inhibition of of cytochrome P450 enzymes, which oxidize compounds such as benzo[a]pyrene and other polycyclic aromatic hydrocarbons (PAHs) into more polar epoxy-diols, which can then cause mutation and induce cancer development.[5] Phenethyl isothiocyanate (PEITC) has been shown to induce apoptosis in certain cancer cell lines, and, in some cases, is even able to induce apoptosis in cells that are resistant to some currently used chemotherapeutic drugs, for example, in drug-resistant leukemia cells that produce the powerful apoptosis inhibitor protein Bcl-2.[6] Furthermore, isothiocyanates have been the basis of a drug in development that replaces the sulfur bonds with selenium, with far stronger potency against melanoma.[7] Certain isothiocyanates have also been shown to bind to the mutated p53 proteins found in many types of tumors, causing an increase in the rate of cell death.[8][9] The results on the genotoxic effects of the isothiocyanates and glucosinolate precursors are conflicting.[10] Some authors report weak genotoxicity for allyl isothiocyanate and phenethyl isothiocyanate. Induction of point mutations in Salmonella TA98 and TA100, repairable DNA damage in E.coli K-12 cells, and clastogenic effects in mammalian cells by extracts from cruciferous vegetables have also been observed. The goitrogenic effect of Brassicaceae vegetables, interfering with iodine uptake, is also a concern at elevated doses. The average intake of such sulfur-containing compounds through supplementation should not exceed normal levels of consumption. References [1] Dains FB; Brewster RQ; Olander CP (1926), "Phenyl Isothiocyanate" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=CV1P0447), Org. Synth. 6: 72, ; Coll. Vol. 1: 447 [2] Wong, R; Dolman, SJ (2007). "Isothiocyanates from tosyl chloride mediated decomposition of in situ generated dithiocarbamic acid salts". The Journal of Organic Chemistry 72 (10): 3969–3971. doi:10.1021/jo070246n. PMID 17444687. [3] O’Reilly, RJ; Radom, L (2009). "Ab initio investigation of the fragmentation of 5,5-diamino-substituted 1,4,2-oxathiazoles". Organic Letters 11 (6): 1325–1328. doi:10.1021/ol900109b. PMID 19245242. [4] Burkett, BA; Kane-Barber, JM; O’Reilly, RJ; Shi, L (2007). "Polymer-supported thiobenzophenone : a self-indicating traceless 'catch and release' linker for the synthesis of isothiocyanates". Tetrahedron Letters 48 (31): 5355–5358. doi:10.1016/j.tetlet.2007.06.025. [5] Zhang, Y; Kensler, TW; Cho, CG; Posner, GH; Talalay, P (1994). "Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates". Proceedings of the National Academy of Sciences of the United States of America 91 (8): 3147–3150. Bibcode 1994PNAS...91.3147Z. doi:10.1073/pnas.91.8.3147. PMC 43532. PMID 8159717. [6] Tsimberidou AM, Keating MJ (2009 Jul 1). "Treatment of fludarabine-refractory chronic lymphocytic leukemia". Cancer 115 (13): 2824–36. doi:10.1002/cncr.24329. PMID 19402170. [7] Madhunapantula SV, Robertson GP (2011 Mar 23). "Therapeutic Implications of Targeting AKT Signaling in Melanoma". Enzyme Res 2011: 327923. doi:10.4061/2011/327923. PMC 3065045. PMID 21461351. Lay summary (http:/ / www. physorg. com/ news155132202. html). [8] Wang X, Di Pasqua AJ, Govind S, McCracken E, Hong C, Mi L, Mao Y, Wu JY, Tomita Y, Woodrick JC, Fine RL, Chung FL (2011 Jan 11). "Selective depletion of mutant p53 by cancer chemopreventive isothiocyanates and their structure-activity relationships". J Med Chem. doi:10.1021/jm101199t. PMID 21241062. (primary source) [9] Wall, Tim (March 10, 2011). "How brocolli fights cancer" (http:/ / news. discovery. com/ human/ how-broccoli-fights-cancer-110310. html). Discovery News. . [10] Higdon JV, Delage B, Williams DE, Dashwood RH (2007 Mar). "Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis". Pharmacol Res 55 (3): 224-36. doi:10.1016/j.phrs.2007.01.009. PMC 2737735. PMID 17317210. Glucosinolate 192 Glucosinolate The glucosinolates are a class of organic compounds that contain sulfur and nitrogen and are derived from glucose and an amino acid. They occur as secondary metabolites of almost all plants of the order Brassicales (including the family Brassicaceae, Capparidaceae and Caricaceae), but also in the genus Drypetes (family Euphorbiaceae).[1] Chemistry Glucosinolate structure; side group R varies Glucosinolates are water-soluble anions and belong to the glucosides. Every glucosinolate contains a central carbon atom, which is bound via a sulfur atom to the thioglucose group (making a sulfated aldoxime) and via a nitrogen atom to a sulfate group. In addition, the central carbon is bound to a side group; different glucosinolates have different side groups, and it is variation in the side group that is responsible for the variation in the biological activities of these plant compounds. Biochemistry Natural diversity from a few amino acids About 120 different glucosinolates are known to occur naturally in plants. They are synthesized from certain amino acids: So-called aliphatic glucosinolates derived from mainly methionine, but also alanine, leucine, isoleucine, or valine. (Most glucosinolates are actually derived from chain-elongated homologues of these amino acids, e.g. glucoraphanin is derived from dihomomethionine, which is methionine chain-elongated twice). Aromatic glucosinolates include indolic glucosinolates, such as glucobrassicin, derived from tryptophan and others from phenylalanine, its chain-elongated homologue homophenylalanine, and sinalbin derived from tyrosine. Enzymatic activation The plants contain the enzyme myrosinase, which, in the presence of water, cleaves off the glucose group from a glucosinolate. The remaining molecule then quickly converts to an isothiocyanate, a nitrile, or a thiocyanate; these are the active substances that serve as defense for the plant. Glucosinolates are also called mustard oil glycosides. The standard product of the reaction is the isothiocyanate (mustard oil); the other two products mainly occur in the presence of specialised plant proteins that alter the outcome of the reaction.[2] To prevent damage to the plant itself, the myrosinase and glucosinolates are stored in separate compartments of the cell and come together only or mainly under conditions of physical injury. Glucosinolate 193 Biological effects Bitter, toxic – and healthy? The use of glucosinolate-containing crops as primary food source for animals has negative effects. Some crops such as canola contain very low amounts of glucosinolates. The glucosinolate sinigrin, among others, was shown to be responsible for the bitterness of cooked cauliflower and Brussels sprouts.[3] On the other hand, plants producing large amounts of glucosinolates also are of interest because substances derived from them can serve as natural pesticides and are under investigation for mitigating cancer, with sulforaphane from broccoli being the best known example. Consumers of higher levels of Brassica vegetables, particularly broccoli, Brussels sprouts and cabbage, may benefit from a lower risk of cancer at a variety of organ sites, although this information is neither scientifically conclusive nor approved by any national regulatory authority as of 2011. Effects on humans and other mammals Glucosinolates are well known for their toxic effects (mainly as goitrogens) in both humans and animals at high doses. In fact, they were even shown to alter animal behavior. [4] In contrast, at subtoxic doses, their hydrolytic and metabolic products act as chemoprotective agents against chemically-induced carcinogens by blocking the initiation of tumors in a variety of rodent tissues, such as the liver, colon, mammary gland, pancreas, etc. They exhibit their effect by inducing Phase I and Phase II enzymes, inhibiting the enzyme activation, modifying the steroid hormone metabolism and protecting against oxidative damages.[5] In particular, the chemopreventive effects of the glucosinolates present in cruciferous vegetables are related to their activity as Histone deacetylase inhibitors.[6] Relations to insect specialists A characteristic, specialised insect fauna is found on glucosinolate-containing plants, including familiar butterflies such as Large White, Small White, and Orange Tip, but also certain aphids, moths, saw flies, flea beetles, etc. The biochemical basis of these specialisations are being unraveled. The whites and orange tips all possess the so-called nitrile specifier protein, which diverts glucosinolate hydrolysis toward nitriles rather than reactive isothiocyanates.[7] In contrast, the diamondback moth (Plutella xylostella) possesses a completely different protein, glucosinolate sulfatase, which desulfates glucosinolates, thereby making them unfit for degradation to toxic products by myrosinase.[8] Other kinds of insects (specialised sawflies and aphids) sequester glucosinolates.[9] In specialised aphids, but not in sawflies, a distinct animal-myrosinase is found in muscle tissue, leading to degradation of sequestered glucosinolates upon aphid tissue destruction.[10] This diverse panel of biochemical solutions to the same plant chemical plays a key role in current attempts to understand the evolution of plant-insect relationships.[11] References [1] James E. Rodman, Kenneth G. Karol, Robert A. Price and Kenneth J. Sytsma (1996). "Molecules, Morphology, and Dahlgren's Expanded Order Capparales". Systematic Botany 21 (3): 289. JSTOR 2419660. [2] Burow, M; Bergner, A; Gershenzon, J; Wittstock, U (2007). "Glucosinolate hydrolysis in Lepidium sativum--identification of the thiocyanate-forming protein.". Plant molecular biology 63 (1): 49–61. doi:10.1007/s11103-006-9071-5. PMID 17139450. [3] Van Doorn, Hans E; Van Der Kruk, Gert C; Van Holst, Gerrit-Jan; Raaijmakers-Ruijs, Natasja C M E; Postma, Erik; Groeneweg, Bas; Jongen, Wim H F (1998). "The glucosinolates sinigrin and progoitrin are important determinants for taste preference and bitterness of Brussels sprouts". Journal of the Science of Food and Agriculture 78: 30. doi:10.1002/(SICI)1097-0010(199809)78:13.0.CO;2-N. [4] Samuni-Blank, M; Izhaki, I; Dearing, MD; Gerchman, Y; Trabelcy, B; Lotan, A; Karasov, WH; Arad, Z (2012). Intraspecific directed deterrence by the mustard oil bomb in a desert plant. Current Biology. 22:1-3. [5] Srinibas Das, Amrish Kumar Tyagi and Harjit Kaur (2000). "Cancer modulation by glucosinolates: A review" (http:/ / www. ias. ac. in/ currsci/ dec252000/ 1665. pdf). Current Science 79 (12): 1665. . [6] Hayes, JD; Kelleher, MO; Eggleston, IM (2008). "The cancer chemopreventive actions of phytochemicals derived from glucosinolates.". European journal of nutrition 47 Suppl 2: 73–88. doi:10.1007/s00394-008-2009-8. PMID 18458837. Glucosinolate [7] Wittstock, U; Agerbirk, N; Stauber, EJ; Olsen, CE; Hippler, M; Mitchell-Olds, T; Gershenzon, J; Vogel, H (2004). "Successful herbivore attack due to metabolic diversion of a plant chemical defense". Proceedings of the National Academy of Sciences of the United States of America 101 (14): 4859–64. Bibcode 2004PNAS..101.4859W. doi:10.1073/pnas.0308007101. PMC 387339. PMID 15051878. [8] Ratzka, A. (2002). "Disarming the mustard oil bomb". Proceedings of the National Academy of Sciences 99 (17): 11223. Bibcode 2002PNAS...9911223R. doi:10.1073/pnas.172112899. [9] Müller, C; Agerbirk, N; Olsen, CE; Boevé, JL; Schaffner, U; Brakefield, PM (2001). "Sequestration of host plant glucosinolates in the defensive hemolymph of the sawfly Athalia rosae". Journal of chemical ecology 27 (12): 2505–16. doi:10.1023/A:1013631616141. PMID 11789955. [10] Bridges, M.; Jones, A. M. E.; Bones, A. M.; Hodgson, C.; Cole, R.; Bartlet, E.; Wallsgrove, R.; Karapapa, V. K. et al. (2002). "Spatial organization of the glucosinolate-myrosinase system in brassica specialist aphids is similar to that of the host plant". Proceedings of the Royal Society B: Biological Sciences 269 (1487): 187. doi:10.1098/rspb.2001.1861. [11] Wheat, C. W.; Vogel, H.; Wittstock, U.; Braby, M. F.; Underwood, D.; Mitchell-Olds, T. (2007). "The genetic basis of a plant insect coevolutionary key innovation". Proceedings of the National Academy of Sciences 104 (51): 20427. Bibcode 2007PNAS..10420427W. doi:10.1073/pnas.0706229104. PMC 2154447. PMID 18077380. 194 External links • Glucosinolate metabolism pathways (http://biocyc.org/META/new-image?object=GLUCOSINOLATE-SYN) from MetaCyc Thiourea 195 Thiourea Thiourea Identifiers CAS number PubChem ChemSpider UNII UN number KEGG ChEBI ChEMBL RTECS number Jmol-3D images 62-56-6 [1]   2723790 2005981 [2] [3]   [4]   GYV9AM2QAG 2811 C14415 [5]   [6] CHEBI:36946   [7]   CHEMBL260876 YU2800000 Image 1 Properties [8] Molecular formula Molar mass Appearance Density Melting point Solubility in water CH4N2S 76.12 g/mol white solid 1.405 g/ml 182 °C, 455 K, 360 °F 14.2 g/100ml (25°C) Hazards MSDS EU Index EU classification External MSDS 612-082-00-0 [9] Carc. Cat. 3 Repr. Cat. 3 Harmful (Xn) Dangerous for the environment (N) R22, R40, R51/53, R63 (S2), S36/37, S61 R-phrases S-phrases NFPA 704 Related compounds Thiourea 196 Related compounds   (verify) [10] Urea  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Thiourea is an organosulfur compound with the formula SC(NH2)2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad class of compounds with the general structure (R1R2N)(R3R4N)C=S. Thioureas are related to thioamides, e.g. RC(S)NR2, where R is methyl, ethyl, etc. Structure and bonding Thiourea is a planar molecule. The C=S bond distance is 160 ± 01 Å for thiourea (as well as many of its derivatives). The material has the unusual property of changing to ammonium thiocyanate upon heating above 130 °C. Upon cooling, the ammonium salt converts back to thiourea. General chemical structure of a thiourea Thiourea occurs in two tautomeric forms. In aqueous solution, the thione shown on the left below predominates: Production The global annual production of thiourea is around 10,000 tons.[11] About 40% is produced in Germany, another 40% in China, and 20% in Japan. Thiourea is produced from ammonium thiocyanate, but more commonly it is produced by the reaction of hydrogen sulfide with calcium cyanamide in the presence of carbon dioxide.[11] Synthesis of substituted thioureas Many derivatives of thiourea derivatives are useful in organocatalysis. N,N-unsubstituted thioureas can be generally prepared by treating the corresponding cyanamide with "LiAlHSH" in the presence of 1 N HCl in anhydrous diethyl ether. The "LiAlHSH" is prepared by treating lithium aluminium hydride with elemental sulfur.[12] Alternatively, N,N' disubstituted thioureas can be prepared by coupling two amines with thiophosgene:[13] Amines also condense with thiocyanates to give thioureas:[14] R2NH + R'NCS → (R2N)(R'(H)N)CS R2NH + R'2NH + CSCl2 + 2 pyridine → (R2N)(R'2N)CS + 2 [Hpyridine]Cl Thiourea 197 Applications The main application of thiourea is in textile processing.[11] Organic synthesis Thiourea reduces peroxides to the corresponding diols.[15] The intermediate of the reaction is an unstable epidioxide which can only be identified at −100 °C. Epidioxide is similar to epoxide except with two oxygen atoms. This intermediate reduces to diol by thiourea. Thiourea is also used in the reductive workup of ozonolysis to give carbonyl compounds.[16] Dimethyl sulfide is also an effective reagent for this reaction, but it is highly volatile (b.p. 37 °C) and has an obnoxious odor whereas thiourea is odorless and conveniently non-volatile (reflecting its polarity). Source of sulfide Thiourea is commonly employed as a source of sulfide, e.g. for converting alkyl halides to thiols. Such reactions proceed via the intermediacy of isothiuronium salts. The reaction capitalizes on the high nucleophilicity of the sulfur center and easy hydrolysis of the intermediate isothiouronium salt: CS(NH2)2 + RX → RSC(NH2)2+XRSC(NH2)2+X- + 2 NaOH → RSNa + OC(NH2)2 + NaX RSNa + HCl → RSH + NaCl In this example, ethane-1,2-dithiol is prepared from 1,2-dibromoethane:[17] C2H4Br2 + 2 SC(NH2)2 → [ C2H4(SC(NH2)2)2]Br2 [ C2H4(SC(NH2)2)2]Br2 + 2 KOH → C2H4(SH)2 + 2 OC(NH2)2 + 2 KBr Like thioamides, thiourea can serve as a source of sulfide upon reaction with soft metal ions. For example, mercury sulfide forms when mercuric salts in aqueous solution are treated with thiourea: Hg2+ + 2 SC(NH2)2 + H2O → HgS + OC(NH2)2 + 2 H+ Thiourea Precursor to heterocycles Thioureas are used a building blocks to pyrimidine derivatives. Thus thioureas condense with β-dicarbonyl compounds.[18] The amino group on the thiourea initially condenses with a carbonyl, followed by cyclization and tautomerization. Desulfurization delivers the pyrimidine. 198 Similarly, aminothiazoles can be synthesized by the reaction of alpha-halo ketones and thiourea.[19] The pharmaceuticals thiobarbituric acid and sulfathiazole is prepared using thiourea. Silver polishing According to the label on the consumer product, the liquid silver cleaning product TarnX contains thiourea, a detergent, and sulfamic acid. A lixiviant for gold and silver leaching can be created by selectively oxidizing thiourea, bypassing the steps of cyanide use and smelting.[20] Organocatalysis Substituted thioureas are useful catalysts for organic synthesis. The phenomenon is called thiourea organocatalysis.[21] Other uses Other industrial uses of thiourea include production of flame retardant resins, and vulcanization accelerators. Thiourea is used as an auxiliary agent in diazo paper, light-sensitive photocopy paper and almost all other types of copy paper. It is also used to tone silver-gelatin photographic prints. Thiourea 199 Safety The LD50 for thiourea is 125 mg/kg for rats (oral).[22] A goitrogenic effect (enlargement of the thyroid gland) has been reported for chronic exposure, reflecting the ability of thiourea to interfere with iodide uptake.[11] References [1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=62-56-6 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=2723790 [3] http:/ / www. chemspider. com/ 2005981 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=GYV9AM2QAG [5] http:/ / www. kegg. jp/ entry/ C14415 [6] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=36946 [7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL260876 [8] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28%3DS%29%28N%29N [9] http:/ / msds. chem. ox. ac. uk/ TH/ thiourea. html [10] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=477863582& page2=%3AThiourea [11] Bernd Mertschenk, Ferdinand Beck, Wolfgang Bauer "Thiourea and Thiourea Derivatives" in Ullmann's Encyclopedia of Industrial Chemistry 2002 by Wiley-VCH Verlag GmbH & Co. KGaA. All rights reserved. doi:10.1002/14356007.a26_803 [12] Koketsu, Mamoru; Kobayashi, Chikashi; Ishihara, Hideharu (2003). "Synthesis ofN-arylS-alkylthiocarbamates". Heteroatom Chemistry 14 (4): 374. doi:10.1002/hc.10163. [13] Yi-Bo Huang, Wen-Bin Yi, and Chun Cai "Thiourea Based Fluorous Organocatalyst" Top Curr Chem 2012, vol. 308, p. 191–212. doi:10.1007/128_2011_248 [14] Miyabe, H.; Takemoto, Y. "Discovery and application of asymmetric reaction by multifunctional thioureas" Bull Chem Soc Jpn 2008, vol. 81, p785ff. [15] C. Kaneko, A. Sugimoro, and S. Tanaka (1974). "A facile one-step synthesis of cis-2-cyclopentene and cis-2-cyclohexene-1,4-diols from the corresponding cyclodienes". Synthesis 1974 (12): 876. doi:10.1055/s-1974-23462. [16] Gupta, D., Soman, G., and Dev, S. (1982). "Thiourea, a convenient reagent for the reductive cleavage of olefin ozonolysis products". Tetrahedron 38 (20): 3013. doi:10.1016/0040-4020(82)80187-7. [17] Speziale, A. J. (1963), "Ethanedithiol" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv4p0401), Org. Synth., ; Coll. Vol. 4: 401 [18] Foster, H. M., and Snyder, H. R. (1963), "4-Methyl-6-hydroxypyrimidine" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv4p0638), Org. Synth., ; Coll. Vol. 4: 638 [19] Dodson, R. M., and King, L. C. (1945). "The reaction of ketones with halogens and thiourea". J. Am. Chem. Soc. 67 (12): 2242. doi:10.1021/ja01228a059. PMID 21005695. [20] Anthony Esposito. "Peñoles, UAM unveil pilot thiourea Au-Ag leaching plant - Mexico". (http:/ / www. bnamericas. com/ story. jsp?idioma=I& sector=7& noticia=399641) Business News Americas (July 13, 2007). [21] Peter R. Schreiner, "Metal-free organocatalysis through explicit hydrogen bonding interactions" Chem. Soc. Rev., 2003, vol. 32, 289-296. [22] http:/ / gis. dep. wv. gov/ tri/ cheminfo/ msds1385. txt Further reading • The Chemistry of double-bonded functional groups edited by S. Patai. pp 1355–1496. John Wiley & Sons. New York, NY, 1977. ISBN 0-471-92493-8. External links • INCHEM assessment of thiourea (http://www.inchem.org/documents/cicads/cicads/cicad49.htm) • International Chemical Safety Card 0680 (http://www.inchem.org/documents/icsc/icsc/eics0680.htm) Urea 200 Urea Urea Identifiers CAS number PubChem ChemSpider UNII DrugBank KEGG ChEBI ChEMBL RTECS number ATC code Jmol-3D images 57-13-6 1176 1143 [2] [3]   [4]   [1]   8W8T17847W DB03904 D00023 [5]   [6] CHEBI:16199 CHEMBL985 YR6250000 B05 BC02 Image 1 Properties [9] [7] [8]     ,D02 AE01 [10] [11] Molecular formula Molar mass Appearance Density Melting point CH N O 4 2 60.06 g mol−1 White solid 1.32 g/cm3 133–135 °C Urea 201 Solubility in water 107.9 g/100 ml (20 °C) 167 g/100ml (40 °C) 251 g/100 ml (60 °C) 400 g/100 ml (80 °C) 50g/L ethanol, 500g/L glycerol pKBH+ = 0.18 Structure Dipole moment 4.56 D Hazards MSDS EU Index Flash point LD50 JT Baker [14] [13] [12] Solubility Basicity (pKb) Not listed Non-flammable 8500 mg/kg (oral, rat) Related compounds Related ureas Related compounds Thiourea Hydroxycarbamide Carbamide peroxide Urea phosphate   (verify) [15]  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Urea or carbamide is an organic compound with the chemical formula CO(NH2)2. The molecule has two —NH2 groups joined by a carbonyl (C=O) functional group. Urea serves an important role in the metabolism of nitrogen-containing compounds by animals and is the main nitrogen-containing substance in the urine of mammals. It is a colorless, odorless solid, although the ammonia that it gives off in the presence of water, including water vapor in the air, has a strong odor. It is highly soluble in water and practically non-toxic (LD50 is 15 g/kg for rat). Dissolved in water, it is neither acidic nor alkaline. The body uses it in many processes, the most notable one being nitrogen excretion. Urea is widely used in fertilizers as a convenient source of nitrogen. Urea is also an important raw material for the chemical industry. The synthesis of this organic compound by Friedrich Wöhler in 1828 from an inorganic precursor was an important milestone in the development of organic chemistry, as it showed for the first time that a molecule found in living organisms could be synthesized in the lab without biological starting materials (thus contradicting a theory widely prevalent at one time, called vitalism). Urea 202 Related chemicals The terms urea and carbamide are also used for a class of chemical compounds sharing the same functional group RR'N—CO—NRR', namely a carbonyl group attached to two organic amine residues. Examples include carbamide peroxide, allantoin, and hydantoin. Ureas are closely related to biurets and related in structure to amides, carbamates, carbodiimides, and thiocarbamides. History Urea was first discovered in urine in 1727 by the Dutch scientist Herman Boerhaave, though this discovery is often attributed to the French chemist Hilaire Rouelle.[16] In 1828, the German chemist Friedrich Wöhler obtained urea by treating silver isocyanate with ammonium chloride.[17][18][19] AgNCO + NH4Cl → (NH2)2CO + AgCl This was the first time an organic compound was artificially synthesized from inorganic starting materials, without the involvement of living organisms. The results of this experiment implicitly discredited vitalism: the theory that the chemicals of living organisms are fundamentally different from inanimate matter. This insight was important for the development of organic chemistry. His discovery prompted Wöhler to write triumphantly to Berzelius: "I must tell you that I can make urea without the use of kidneys, either man or dog. Ammonium cyanate is urea." For this discovery, Wöhler is considered by many the father of organic chemistry. Physiology Urea is synthesized in the body of many organisms as part of the urea cycle, either from the oxidation of amino acids or from ammonia. In this cycle, amino groups donated by ammonia and L-aspartate are converted to urea, while L-ornithine, citrulline, L-argininosuccinate, and L-arginine act as intermediates. Urea production occurs in the liver and is regulated by N-acetylglutamate. Urea is found dissolved in blood (in the reference range of 2.5 to 6.7 mmol/liter) and is excreted by the kidney as a component of urine. In addition, a small amount of urea is excreted (along with sodium chloride and water) in sweat. Amino acids from ingested food that are not used for the synthesis of proteins and other biological substances are oxidized by the body, yielding urea and carbon dioxide, as an alternative source of energy.[20] The oxidation pathway starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle. Ammonia (NH3) is another common byproduct of the metabolism of nitrogenous compounds. Ammonia is smaller, more volatile and more mobile than urea. If allowed to accumulate, ammonia would raise the pH in cells to toxic levels. Therefore many organisms convert ammonia to urea, even though this synthesis has a net energy cost. Being practically neutral and highly soluble in water, urea is a safe vehicle for the body to transport and excrete excess nitrogen. In water, the amine groups undergo slow displacement by water molecules, producing ammonia and carbonate anion. For this reason, old, stale urine has a stronger odor than fresh urine. In humans The handling of urea by the kidneys is a vital part of human metabolism. Besides its role as carrier of waste nitrogen, urea also plays a role in the countercurrent exchange system of the nephrons, that allows for re-absorption of water and critical ions from the excreted urine. Urea is reabsorbed in the inner medullary collecting ducts of the nephrons,[21] thus raising the osmolarity in the medullary interstitium surrounding the thin ascending limb of the loop of Henle, which in turn causes water to be reabsorbed. By action of the urea transporter 2, some of this reabsorbed urea will eventually flow back into the thin ascending limb of the tubule, through the collecting ducts, Urea and into the excreted urine. This mechanism, which is controlled by the antidiuretic hormone, allows the body to create hyperosmotic urine, that has a higher concentration of dissolved substances than the blood plasma. This mechanism is important to prevent the loss of water, to maintain blood pressure, and to maintain a suitable concentration of sodium ions in the blood plasmas. The equivalent nitrogen content (in gram) of urea (in mmol) can be estimated by the conversion factor 0.028 g/mmol.[22] Furthermore, Dry sweat stain on a white cotton T-shirt, with 1 gram of nitrogen is roughly equivalent to 6.25 grams of protein, and yellow color indicating the presence of urea 1 gram of protein is roughly equivalent to 5 grams of muscle tissue. In situations such as muscle wasting, 1 mmol of excessive urea in the urine (as measured by urine volume in litres multiplied by urea concentration in mmol/l) roughly corresponds to a muscle loss of 0.67 gram. 203 In other species In aquatic organisms the most common form of nitrogen waste is ammonia, whereas land-dwelling organisms convert the toxic ammonia to either urea or uric acid. Urea is found in the urine of mammals and amphibians, as well as some fish. Birds and saurian reptiles have a different form of nitrogen metabolism, that requires less water and leads to nitrogen excretion in the form of uric acid. It is noteworthy that tadpoles excrete ammonia but shift to urea production during metamorphosis. Despite the generalization above, the urea pathway has been documented not only in mammals and amphibians but in many other organisms as well, including birds, invertebrates, insects, plants, yeast, fungi, and even microorganisms. Uses Agriculture More than 90% of world production of urea is destined for use as a nitrogen-release fertilizer. Urea has the highest nitrogen content of all solid nitrogenous fertilizers in common use. Therefore, it has the lowest transportation costs per unit of nitrogen nutrient. The standard crop-nutrient rating of urea is 46-0-0.[23] Many soil bacteria possess the enzyme urease, which catalyzes the conversion of the urea molecule to two ammonia molecules and one carbon dioxide molecule, thus urea fertilizers are very rapidly transformed to the ammonium form in soils. Among soil bacteria known to carry urease, some ammonia-oxidizing bacteria (AOB), such as species of Nitrosomonas, are also able to assimilate the carbon dioxide released by the reaction to make biomass via the Calvin Cycle, and harvest energy by oxidizing ammonia (the other product of urease) to nitrite, a process termed nitrification.[24] Nitrite-oxidizing bacteria, especially Nitrobacter, oxidize nitrite to nitrate, which is extremely mobile in soils and is a major cause of water pollution from agriculture. Ammonia and nitrate are readily absorbed by plants, and are the dominant sources of nitrogen for plant growth. Urea is also used in many multi-component solid fertilizer formulations. Urea is highly soluble in water and is, therefore, also very suitable for use in fertilizer solutions (in combination with ammonium nitrate: UAN), e.g., in 'foliar feed' fertilizers. For fertilizer use, granules are preferred over prills because of their narrower particle size distribution, which is an advantage for mechanical application. The most common impurity of synthetic urea is biuret, which impairs plant growth. Urea is usually spread at rates of between 40 and 300 kg/ha but rates vary. Smaller applications incur lower losses due to leaching. During summer, urea is often spread just before or during rain to minimize losses from volatilization Urea (process wherein nitrogen is lost to the atmosphere as ammonia gas). Urea is not compatible with other fertilizers. Because of the high nitrogen concentration in urea, it is very important to achieve an even spread. The application equipment must be correctly calibrated and properly used. Drilling must not occur on contact with or close to seed, due to the risk of germination damage. Urea dissolves in water for application as a spray or through irrigation systems. In grain and cotton crops, urea is often applied at the time of the last cultivation before planting. In high rainfall areas and on sandy soils (where nitrogen can be lost through leaching) and where good in-season rainfall is expected, urea can be side- or top-dressed during the growing season. Top-dressing is also popular on pasture and forage crops. In cultivating sugarcane, urea is side-dressed after planting, and applied to each ratoon crop. In irrigated crops, urea can be applied dry to the soil, or dissolved and applied through the irrigation water. Urea will dissolve in its own weight in water, but it becomes increasingly difficult to dissolve as the concentration increases. Dissolving urea in water is endothermic, causing the temperature of the solution to fall when urea dissolves. As a practical guide, when preparing urea solutions for fertigation (injection into irrigation lines), dissolve no more than 30 kg urea per 100 L water. In foliar sprays, urea concentrations of 0.5% – 2.0% are often used in horticultural crops. Low-biuret grades of urea are often indicated. Urea absorbs moisture from the atmosphere and therefore is typically stored either in closed/sealed bags on pallets or, if stored in bulk, under cover with a tarpaulin. As with most solid fertilizers, storage in a cool, dry, well-ventilated area is recommended. 204 Chemical industry Urea is a raw material for the manufacture of many important chemical compounds, such as • Various plastics, especially the urea-formaldehyde resins. • Various adhesives, such as urea-formaldehyde or the urea-melamine-formaldehyde used in marine plywood. • Potassium cyanate, another industrial feedstock. Explosive Urea can be used to make urea nitrate, a high explosive that is used industrially and as part of some improvised explosive devices. Automobile systems Urea is used in SNCR and SCR reactions to reduce the NOx pollutants in exhaust gases from combustion from diesel, dual fuel, and lean-burn natural gas engines. The BlueTec system, for example, injects water-based urea solution into the exhaust system. The ammonia produced by the hydrolysis of the urea reacts with the nitrogen oxide emissions and is converted into nitrogen and water within the catalytic converter. Other commercial uses • A stabilizer in nitrocellulose explosives • A component of animal feed, providing a relatively cheap source of nitrogen to promote growth • A non-corroding alternative to rock salt for road de-icing, and the resurfacing of snowboarding halfpipes and terrain parks • A flavor-enhancing additive for cigarettes • A main ingredient in hair removers such as Nair and Veet • A browning agent in factory-produced pretzels • An ingredient in some skin cream,[25] moisturizers, hair conditioners Urea • A reactant in some ready-to-use cold compresses for first-aid use, due to the endothermic reaction it creates when mixed with water • A cloud seeding agent, along with other salts • A flame-proofing agent, commonly used in dry chemical fire extinguisher charges such as the urea-potassium bicarbonate mixture • An ingredient in many tooth whitening products • An ingredient in dish soap • Along with ammonium phosphate, as a yeast nutrient, for fermentation of sugars into ethanol • A nutrient used by plankton in ocean nourishment experiments for geoengineering purposes • As an additive to extend the working temperature and open time of hide glue • As a solubility-enhancing and moisture-retaining additive to dye baths for textile dyeing or printing 205 Laboratory uses Urea in concentrations up to 10 M is a powerful protein denaturant as it disrupts the noncovalent bonds in the proteins. This property can be exploited to increase the solubility of some proteins. A mixture of urea and choline chloride is used as a deep eutectic solvent, a type of ionic liquid. Urea can in principle serve as a hydrogen source for subsequent power generation in fuel cells. Urea present in urine/wastewater can be used directly (though bacteria normally quickly degrade urea.) Producing hydrogen by electrolysis of urea solution occurs at a lower voltage (0.37V) and thus consumes less energy than the electrolysis of water (1.2V).[26] Urea in concentrations up to 8 M can be used to make fixed brain tissue transparent to visible light while still preserving florescent signals from labeled cells. This allows for much deeper imaging of neuronal processes then previously obtainable using conventional one photon or two photon confocal microscopes.[27] Medical use Urea-containing creams are used as topical dermatological products to promote rehydration of the skin. Urea 40% is indicated for psoriasis, xerosis, onychomycosis, ichthyosis, eczema, keratosis, keratoderma, corns, and calluses. If covered by an occlusive dressing, 40% urea preparations may also be used for nonsurgical debridement of nails. Urea 40% "dissolves the intercellular matrix"[28] of the nail plate. Only diseased or dystrophic nails are removed, as there is no effect on healthy portions of the nail. This drug is also used as an earwax removal aid. Urea can also be used as a Diuretic. Certain types of instant cold packs (or ice packs) contain water and separated urea crystals. Rupturing the internal water bag starts an endothermic reaction and allows the pack to be used to reduce swelling. Like saline, urea injection is used to perform abortions. Urea is the main component of an alternative medicinal treatment referred to as urine therapy. The blood urea nitrogen (BUN) test is a measure of the amount of nitrogen in the blood that comes from urea. It is used as a marker of renal function. Urea labeled with carbon-14 or carbon-13 is used in the urea breath test, which is used to detect the presence of the bacteria Helicobacter pylori (H. pylori) in the stomach and duodenum of humans, associated with peptic ulcers. The test detects the characteristic enzyme urease, produced by H. pylori, by a reaction that produces ammonia from urea. This increases the pH (reduces acidity) of the stomach environment around the bacteria. Similar bacteria species to H. pylori can be identified by the same test in animals such as apes, dogs, and cats (including big cats). Urea 206 Analysis Urea is readily quantified by a number of different methods, such as the diacetyl monoxime colorimetric method, and the Berthelot reaction (after initial conversion of urea to ammonia via urease). These methods are amenable to high throughput instrumentation, such as automated flow injection analyzers[29] and 96-well micro-plate spectrophotometers.[30] Production Urea is produced on a scale of some 100,000,000 tons per year worldwide.[31] Industrial methods For use in industry, urea is produced from synthetic ammonia and carbon dioxide. Large quantities of carbon dioxide are produced during the manufacture of ammonia from coal or from hydrocarbons such as natural gas and petroleum-derived raw materials. Such point sources of CO2 facilitate direct synthesis of urea. The basic process, developed in 1922, is also called the Bosch-Meiser urea process after its discoverers. The various urea processes are characterized by the conditions under which urea formation takes place and the way in which unconverted reactants are further processed. The process consists of two main equilibrium reactions, with incomplete conversion of the reactants. The first is an exothermic reaction of liquid ammonia with dry ice to form ammonium carbamate (H2N-COONH4):[32] 2 NH3 + CO2 ↔ H2N-COONH4 The second is an endothermic decomposition of ammonium carbamate into urea and water: Both reactions combined are exothermic.[31] Unconverted reactants can be used for the manufacture of other products, for example ammonium nitrate or sulfate, or they can be recycled for complete conversion to urea in a total-recycle process. Urea can be produced as prills, granules, pellets, crystals, and solutions. Solid urea is marketed as prills or granules. The advantage of prills is that, in general, they can be produced more cheaply than granules. Properties such as impact strength, crushing strength, and free-flowing behaviour are, in particular, important in product handling, storage, and bulk transportation. Typical impurities in the production are biuret and isocyanic acid: 2 NH2CONH2 → H2NCONHCONH2 + NH3 NH2CONH2 → HNCO + NH3 The biuret content is a serious concern because it is often toxic to the very plants that are to be fertilized. Urea is classified on the basis of its biuret content. H2N-COONH4 ↔ (NH2)2CO + H2O Laboratory preparation Ureas in the more general sense can be accessed in the laboratory by reaction of phosgene with primary or secondary amines, proceeding through an isocyanate intermediate. Non-symmetric ureas can be accessed by reaction of primary or secondary amines with an isocyanate. Also, urea is produced when phosgene reacts with ammonia: COCl2 + 4 NH3 → (NH2)2CO + 2 NH4Cl Urea 207 Historical process Urea was first noticed by Hermann Boerhaave in the early 18th century from evaporates of urine. In 1773, Hilaire Rouelle obtained crystals containing urea from dog's urine by evaporating it and treating it with alcohol in successive filtrations. This method was aided by Carl Wilhelm Scheele's discovery that urine treated by concentrated nitric acid precipitated crystals. Antoine François, comte de Fourcroy and Louis Nicolas Vauquelin discovered in 1799 that the nitrated crystals were identical to Rouelle's substance and invented the term "urea." Berzelius made further improvements to its purification and finally William Prout, in 1817, succeeded in obtaining and determining the chemical composition of the pure substance. In the evolved procedure, urea was precipitated as urea nitrate by adding strong nitric acid to urine. To purify the resulting crystals, they were dissolved in boiling water with charcoal and filtered. After cooling, pure crystals of urea nitrate form. To reconstitute the urea from the nitrate, the crystals are dissolved in warm water, and barium carbonate added. The water is then evaporated and anhydrous alcohol added to extract the urea. This solution is drained off and allowed to evaporate resulting in pure urea. Chemical properties Molecular and crystal structure The urea molecule is planar in the crystal structure, but the geometry around the nitrogens is pyramidal in the gas-phase minimum-energy structure.[33] In solid urea, the oxygen center is engaged in two N-H-O hydrogen bonds. The resulting dense and energetically favourable hydrogen-bond network is probably established at the cost of efficient molecular packing: The structure is quite open, the ribbons forming tunnels with square cross-section. The carbon in urea is described as sp2 hybridized, the C-N bonds have significant double bond character, and the carbonyl oxygen is basic compared to, say, formaldehyde. Urea's high aqueous solubility reflects its ability to engage in extensive hydrogen bonding with water. By virtue of its tendency to form a porous frameworks, urea has the ability to trap many organic compounds. In these so-called clathrates, the organic "guest" molecules are held in channels formed by interpenetrating helices composed of hydrogen-bonded urea molecules. This behaviour can be used to separate mixtures, e.g. in the production of aviation fuel and lubricating oils, and in the separation of paraffins. As the helices are interconnected, all helices in a crystal must have the same molecular handedness. This is determined when the crystal is nucleated and can thus be forced by seeding. The resulting crystals have been used to separate racemic mixtures. Reactions Urea reacts with alcohols to form urethanes. Urea reacts with malonic esters to make barbituric acids. Safety Urea can be irritating to skin, eyes, and the respiratory tract. Repeated or prolonged contact with urea in fertilizer form on the skin may cause dermatitis. High concentrations in the blood can be damaging. Ingestion of low concentrations of urea, such as are found in typical human urine, are not dangerous with additional water ingestion within a reasonable time-frame. Many animals (e.g., dogs) have a much more concentrated urine and it contains a higher urea amount than normal human urine; this can prove dangerous as a source of liquids for consumption in a life-threatening situation (such as in a desert). Urea can cause algal blooms to produce toxins, and its presence in the runoff from fertilized land may play a role in the increase of toxic blooms.[34] Urea The substance decomposes on heating above melting point, producing toxic gases, and reacts violently with strong oxidants, nitrites, inorganic chlorides, chlorites and perchlorates, causing fire and explosion. 208 References [1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=57-13-6 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1176 [3] http:/ / www. chemspider. com/ 1143 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=8W8T17847W [5] http:/ / www. drugbank. ca/ drugs/ DB03904 [6] http:/ / www. kegg. jp/ entry/ D00023 [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=16199 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL985 [9] http:/ / www. whocc. no/ atc_ddd_index/ ?code=B05BC02 [10] http:/ / www. whocc. no/ atc_ddd_index/ ?code=D02AE01 [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28%3DO%29%28N%29N [12] http:/ / toxnet. nlm. nih. gov/ cgi-bin/ sis/ search/ f?. / temp/ ~ZAvqWP:1:sol [13] Williams, R. (2001-10-24). "pKa Data" (http:/ / research. chem. psu. edu/ brpgroup/ pKa_compilation. pdf). . Retrieved 2009-11-27. [14] http:/ / hazard. com/ msds/ mf/ baker/ baker/ files/ u4725. htm [15] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=443307328& page2=%3AUrea [16] Kurzer, Frederick; Sanderson, Phyllis M. (1956). "Urea in the History of Organic Chemistry" (http:/ / dx. doi. org/ 10. 1021/ ed033p452). Journal of Chemical Education (American Chemical Society) 33 (9): 452–459. doi:10.1021/ed033p452. . Retrieved 2011-10-11. [17] Friedrich Wöhler (1828) "Ueber künstliche Bildung des Harnstoffs" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k15097k/ f261. image) (On the artificial formation of urea), Annalen der Physik und Chemie, 88 (2) : 253-256. Available in English at: Chem Team (http:/ / www. chemteam. info/ Chem-History/ Wohler-article. html). [18] Nicolaou, Kyriacos Costa; Tamsyn Montagnon (2008). Molecules That Changed The World. Wiley-VCH. p. 11. ISBN 978-3-527-30983-2. [19] Gibb, Bruce C. (2009). "Teetering towards chaos and complexity" (http:/ / www. nature. com/ nchem/ journal/ v1/ n1/ full/ nchem. 148. html). Nature Chemistry (Nature Publishing Group) 1 (1): 17–18. doi:10.1038/nchem.148. PMID 21378787. . Retrieved 2011-06-29. [20] Sakami W, Harrington H (1963). "Amino acid metabolism". Annual Review of Biochemistry 32 (1): 355–98. doi:10.1146/annurev.bi.32.070163.002035. PMID 14144484. [21] Walter F. Boron. Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 837 [22] Section 1.9.2 (page 76) in: Jacki Bishop; Thomas, Briony (2007). Manual of Dietetic Practice. Wiley-Blackwell. ISBN 1-4051-3525-5. [23] ICIS, http:/ / www. icis. com/ v2/ chemicals/ 9076559/ urea/ uses. html [24] Marsh, K. L., G. K. Sims, and R. L. Mulvaney. 2005. Availability of urea to autotrophic ammonia-oxidizing bacteria as related to the fate of 14C- and 15N-labeled urea added to soil. Biol. Fert. Soil. 42:137-145. [25] www.dooyoo.co.uk (2009-06-19). "Lacura Multi Intensive Serum - Review - Excellent value for money - Lacura Multi Intensive Serum "Aqua complete"" (http:/ / www. dooyoo. co. uk/ skin-care/ lacura-multi-intensive-serum/ 1264192/ ). Dooyoo.co.uk. . Retrieved 2010-12-28. [26] Researchers develop urea fuel cell. (http:/ / www. ohio. edu/ outlook/ 08-09/ November/ 194. cfm) [27] http:/ / www. nature. com/ neuro/ journal/ vaop/ ncurrent/ full/ nn. 2928. html [28] "UriSec 40 How it Works" (http:/ / www. odanlab. com/ urisec/ winter/ ). Odan Laboratories. January 2009. . Retrieved February 15, 2011. [29] Baumgartner, M., M. Flöck, P. Winter, W. Lu, and W. Baumgartner. 2005. Evaluation of flow injection analysis for determination of urea in sheep's and cow's milk. Acta Veterinaria Hungarica. 50 (3): 263-271. [30] Greenan, N. S., R.L. Mulvaney, and G.K. Sims. 1995. A microscale method for colorimetric determination of urea in soil extracts. Communications in Soil Science and Plant Analysis. 26:2519-2529. [31] Jozef H. Meessen and Harro Petersen “Urea” in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a27_333 [32] "Inorganic Chemicals » AMMONIUM CARBAMATE" (http:/ / www. hillakomem. com/ tag/ ammonium-carbamate). Hillakomem.com. 2008-10-02. . Retrieved 2010-12-28. [33] Godfrey, Peter; Brown, Ronald and Hunter, Andrew (1997). "The shape of urea". Journal of Molecular Structure 413-414: 405–414. doi:10.1016/S0022-2860(97)00176-2. [34] newscientist.com (http:/ / www. newscientist. com/ channel/ life/ mg19426085. 900-us-set-to-track-toxic-algal-blooms. html) – US set to track toxic algal blooms Urea 209 External links • MSDS sheet on urea (http://www.sciencelab.com/xMSDS-Urea-9927317) • Use of urea in hand dyeing (http://www.pburch.net/dyeing/FAQ/urea.shtml) Allyl isothiocyanate Allyl isothiocyanate Identifiers CAS number PubChem ChemSpider UNII KEGG ChEMBL Jmol-3D images 57-06-7 5971 [2] [3]   [4]   [1]   21105854 BN34FX42G3 D02818 [5]   CHEMBL233248 Image 1 [7] [6]   Properties Molecular formula Molar mass Density Melting point Boiling point C H NS 4 5 99.15 g mol−1 1.013–1.020 g/cm3 −102 °C, unknown operator: u'\u2212' K, unknown operator: u'\u2212' °F 148-154 °C, 421-427 K, 298-309 °F  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)   (verify) [8] Infobox references Allyl isothiocyanate (AITC) is the organosulfur compound with the formula CH2CHCH2NCS. This colorless oil is responsible for the pungent taste of mustard, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC is mediated through the TRPA1 and TRPV1 ion channels.[9][10][11] It is slightly soluble in water, but well soluble in most organic solvents.[12] Allyl isothiocyanate 210 Biosynthesis and biological functions Allyl isothiocyanate comes from the seeds of black mustard (Brassica nigra) or brown Indian mustard (Brassica juncea). When these mustard seeds are broken, the enzyme myrosinase is released and acts on a glucosinolate known as sinigrin to give allyl isothiocyanate. Allyl isothiocyanate serves the plant as a defense against herbivores; since it is harmful to the plant itself, it is stored in the harmless form of the glucosinolate, separate from the myrosinase enzyme. When an animal chews the plant, the allyl isothiocyanate is released, repelling the animal. Commercial and other applications Allyl isothiocyanate is produced commercially by the reaction of allyl chloride and potassium thiocyanate:[12] CH2=CHCH2Cl + KSCN → CH2=CHCH2NCS + KCl. The product obtained in this fashion is sometimes known as synthetic mustard oil. Allyl isothiocyanate can also be liberated by dry distillation of the seeds. The product obtained in this fashion is known as volatile oil of mustard and is usually around 92% pure. It is used principally as a flavoring agent in foods. Synthetic allyl isothiocyanate is used as an insecticide, bacteriocide[13], and nematocide, and is used in certain cases for crop protection.[12] Hydrolysis of allyl isothiocyanate gives allyl amine.[14] Safety Allyl isothiocyanate is fairly toxic with LD50 of 151 mg/kg and is a dangerous lachrymator.[12] References [1] [2] [3] [4] [5] [6] [7] [8] [9] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=57-06-7 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5971 http:/ / www. chemspider. com/ 21105854 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=BN34FX42G3 http:/ / www. kegg. jp/ entry/ D02818 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL233248 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%3DCCN%3DC%3DS http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=413309467& page2=%3AAllyl+ isothiocyanate Everaerts, W.; Gees, M.; Alpizar, Y. A.; Farre, R.; Leten, C.; Apetrei, A.; Dewachter, I.; van Leuven, F. et al. (2011). "The Capsaicin Receptor TRPV1 is a Crucial Mediator of the Noxious Effects of Mustard Oil". Current Biology 21 (4): 316–321. doi:10.1016/j.cub.2011.01.031. PMID 21315593. [10] Brône, B.; Peeters, P. J.; Marrannes, R.; Mercken, M.; Nuydens, R.; Meert, T.; Gijsen, H. J. (2008). "Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor". Toxicology and Applied Pharmacology 231 (2): 150–156. doi:10.1016/j.taap.2008.04.00. PMID 18501939. [11] Ryckmans, T.; Aubdool, A. A.; Bodkin, J. V.; Cox, P.; Brain, S. D.; Dupont, T.; Fairman, E.; Hashizume, Y.; Ishii, N. et al. (2011). "Design and Pharmacological Evaluation of PF-4840154, a Non-Electrophilic Reference Agonist of the TrpA1 Channel". Bioorganic and Medicinal Chemistry Letters 21 (16): 4857–4859. doi:10.1016/j.bmcl.2011.06.035. PMID 21741838. [12] Romanowski, F.; Klenk, H. (2005), "Thiocyanates and Isothiocyanates, Organic", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a26_749 [13] Shin, I. S.; Masuda, H.; Naohide, K. (2004). "Bactericidal Activity of Wasabi (Wasabia japonica) against Helicobacter pylori". International Journal of Food Microbiology 94 (3): 255–261. doi:10.1016/S0168-1605(03)00297-6. PMID 15246236. [14] Leffler, M. T. (1938), "Allylamine" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=CV2P0024), Org. Synth. 18: 5, ; Coll. Vol. 2: 24 Methyl isothiocyanate 211 Methyl isothiocyanate Methyl isothiocyanate Identifiers CAS number PubChem ChemSpider KEGG ChEMBL Jmol-3D images 556-61-6 11167 10694 [2] [3]     [5]   [1]   C18587 [4] CHEMBL396000 Image 1 Properties [6] Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water C2H3NS 73.12 g mol −1 colourless solid 1.07 g cm –3 31 °C, 304 K, 88 °F 117 °C, 390 K, 243 °F 8.2g/L Hazards MSDS NFPA 704 ACC# 07204 [7] Structure Dipole moment 3.528 D Related compounds Related compounds Methyl isocyanate Methyl thiocyanate   (verify) [8]  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Methyl isothiocyanate is the organosulfur compound with the formula CH3N=C=S. This low melting colorless solid is a powerful lachrymator. As a precursor to a variety of valuable bioactive compounds, it is the most important organic isothiocyanate in industry.[9] Methyl isothiocyanate 212 Synthesis It is prepared industrially by two routes. Annual production in 1993 was estimated to be 4M kg. The main method involves the thermal rearrangement of methyl thiocyanate:[9] CH3S-C≡N → CH3N=C=S It is also prepared via with the reaction of methylamine with carbon disulfide followed by oxidation of the resulting dithiocarbamate with hydrogen peroxide. A related method is useful to prepare this compound in the laboratory.[10] MITC forms naturally upon the enzymatic degradation of glucocapparin, a modified sugar found in capers. Reactions A characteristic reaction is with amines to give methyl thioureas: CH3NCS + R2NH → R2NC(S)NHCH3 Other nucleophiles add similarly. Applications Solutions of MITC is used in agriculture as a soil fumigant, mainly for protection against fungi and nematodes. MITC is a building block for the synthesis of 1,3,4-thiadiazoles, which are heterocyclic compounds used as herbicides. Commercial products include "Spike", "Ustilan," and "Erbotan." Well known pharmaceuticals prepared using MITC include Zantac and Tagamet. Safety MITC is a dangerous lachrymator as well as being poisonous. References [1] [2] [3] [4] [5] [6] [7] [8] [9] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=556-61-6 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=11167 http:/ / www. chemspider. com/ 10694 http:/ / www. kegg. jp/ entry/ C18587 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL396000 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=S%3DC%3DNC https:/ / fscimage. fishersci. com/ msds/ 07204. htm http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=415837766& page2=%3AMethyl+ isothiocyanate Romanowski, F.; Klenk, H. (2005), "Thiocyanates and Isothiocyanates, Organic", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a26_749 [10] Moore, M. L.; Crossley, F. S. (1941), "Methyl Isothiocyanate" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=CV3P0599), Org. Synth. 21: 81, ; Coll. Vol. 3: 599 Ethyl carbamate 213 Ethyl carbamate Ethyl carbamate Identifiers CAS number PubChem ChemSpider UNII EC number UN number DrugBank KEGG MeSH ChEBI ChEMBL RTECS number 3DMet Jmol-3D images 51-79-6 5641 5439 [2] [3]   [4]   [1]   3IN71E75Z5 200-123-1 2811 DB04827 C01537 [6]   [5] [7] Urethane [8] [9]   [10]   CHEBI:17967 CHEMBL462547 FA8400000 B00312 [11] [12] Image 1 [13] Image 2 Properties Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water log P Vapor pressure Acidity (pK ) a C H NO 3 7 2 89.09 g mol−1 White crystals 1.056 g cm-3 46-50 °C, 319-323 K, 115-122 °F 182-185 °C, 455-458 K, 360-365 °F 0.480 g cm-3 at 15 °C -0.190(4) 1.3 kPa at 78 °C 13.58 0.5206015862 D Hazards Dipole moment Ethyl carbamate 214 EU Index EU classification T R-phrases S-phrases Main hazards NFPA 704 Flash point   (verify) [14] 607-149-00-6 R45 S45, S53 Harmful if swallowed May cause cancer 92 °C  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Ethyl carbamate (also called urethane) is a chemical compound with the molecular formula C3H7NO2 first prepared in the nineteenth century. Structurally, it is an ester of carbamic acid. Despite its common name, it is not a component of polyurethanes. Synthesis Ethyl carbamate is a white crystalline substance produced by the action of ammonia on ethyl chloroformate or by heating urea nitrate and ethyl alcohol:[15] Uses Ethyl carbamate has been produced commercially in the United States for many years. It has been used as an antineoplastic agent and for other medicinal purposes but this ended after it was discovered to be carcinogenic in 1943. However, Japanese usage in medical injections continued and from 1950 to 1975 an estimated 100 million 2 ml ampules of 7 to 15% solutions of ethyl carbamate were injected into patients as a co-solvent in water for dissolving water-insoluble analgesics used for post-operation pain. These doses were estimated by Nomura (Cancer Research, 35, 2895–2899, October 1975) to be at levels that are carcinogenic in mice. This practice was stopped in 1975. "This regrettable medical situation appears to have involved the largest number (millions) of humans exposed to the largest doses of a pure carcinogen that is on record" (Japanese Journal of Cancer Research, 82, 1323–1324, December 1991). The author, U.S. cancer researcher James A. Miller, called for studies to determine the effects on Japanese cancer rates to be performed but apparently none were ever done. Prior to World War II, ethyl carbamate saw relatively heavy use in the treatment of multiple myeloma before it was found to be toxic, carcinogenic and largely ineffective.[16] By US FDA regulations, ethyl carbamate has been withdrawn from pharmaceutical use. However, small quantities of ethyl carbamate are also used in laboratories as an anesthetic for animals.[17] Ethyl carbamate was upgraded to a Group 2A carcinogen by IARC in 2007. Ethyl carbamate Formerly, crosslinking agents for permanent press textile treatments were synthesized from ethyl carbamate.[18] 215 Occurrence in beverages and food The discovery of the widespread presence of ethyl carbamate in alcoholic beverages first occurred during the mid-1980s. To raise public awareness of this issue, the U.S. Center for Science in the Public Interest published, in 1987, Tainted Booze: The Consumer's Guide to Urethane in Alcoholic Beverages. Studies have shown that most, if not all, yeast-fermented alcoholic beverages contain traces of ethyl carbamate (15 ppb to 12 ppm).[19] Other foods and beverages prepared by means of fermentation also contain ethyl carbamate. For example, bread has been found to contain 2 ppb;[20] as much as 20 ppb has been found in some samples of soy sauce.[21] Amounts of both ethyl carbamate and methyl carbamate have also been found in wines, sake, beer, brandy, whiskey and other fermented alcoholic beverages. It has been shown that ethyl carbamate forms from the reaction of alcohol (ethanol) with urea: This reaction occurs much faster at higher temperatures, and therefore higher concentrations of ethyl carbamate are found in beverages that are heated during processing, such as brandy, whiskey, and other distilled beverages. Additionally, heating after bottling either during shipping or in preparation will cause ethyl carbamate levels to rise further. The urea in wines results from the metabolism of arginine or citrulline by yeast or other organisms. The urea waste product is initially metabolised inside the yeast cell until it builds up to a certain level. At that point, it is excreted externally where it is able to react with the alcohol to create ethyl carbamate. In 1988, wine and other alcoholic beverage manufacturers in the United States agreed to control the level of ethyl carbamate in wine to less than 15 ppb, and in stronger alcoholic drinks to less than 125 ppb.[19] Although the urea cannot be eliminated, it can be minimized by controlling the fertilization of grape vines, minimizing their heat exposure, using self-cloning yeast[22] and other actions.[23] Furthermore, some strains of yeast have been developed to help reduce ethyl carbamate during commercial production of alcoholic beverages.[24] Another important mechanism for ethyl carbamate formation in alcoholic beverages is the reaction from cyanide as precursor, which causes comparably high levels in spirits derived from cyanogenic plants (i.e. predominantly stone-fruit spirits and cachaca).[25] Ethyl carbamate 216 Hazards Ethyl carbamate is not acutely toxic to humans, as shown by its use as a medicine. Acute toxicity studies show that the lowest fatal dose in rats, mice, and rabbits equals 1.2 grams/kg or more. When ethyl carbamate was used medicinally, about 50 percent of the patients exhibited nausea and vomiting, and long time use led to gastroenteric hemorrhages.[26] The compound has almost no odor and a cooling, saline, bitter taste.[27] Studies with rats, mice, and hamsters has shown that ethyl carbamate will cause cancer when it is administered orally, injected, or applied to the skin, but no adequate studies of cancer in humans caused by ethyl carbamate has been reported due to the ethical considerations of such studies.[28] However, in 2007, the International Agency for Research on Cancer raised ethyl carbamate to a Group 2A carcinogen that is "probably carcinogenic to humans," one level below fully carcinogenic to humans. IARC has stated that ethyl carbamate can be “reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals.”[29] In 2006, the Liquor Control Board of Ontario in Canada rejected imported cases of sherry due to excessive levels of ethyl carbamate. Alcoholic beverages, particularly certain stone-fruit spirits and whiskies, tend to contain much higher concentrations of urethane. Heating (e.g., cooking) the beverage increases the ethyl carbamate content, and some concern exists over shipping wines to overseas markets in containers that tend to overheat. In addition, urethane has a tendency to accumulate in the human body from a number of daily dietary sources, e.g., alcohols, bread and other fermented grain products, soy sauce, orange juice and commonly consumed foods. Hence, exposure risk to human health is increasingly evaluated on the total ethyl carbamate intake from the daily diet (WHO refers to this as "margin of exposure" or MOE), of which alcoholic beverages often provide the most significant portion. Studies in Korea (2000) and Hong Kong (2009) outline the extent of the accumulative exposure to ethyl carbamate in daily life. Fermented foods such as soy sauce, kimchi, soybean paste, breads, rolls, buns, crackers and bean curd, along with wine, sake and plum wine, were found to be the foods with the highest ethyl carbamate levels in traditional Asian diets. In 2005, the JECFA (Joint FAO/WHO Expert Committee On Food Additives) risk assessment evaluation of ethyl carbamate concluded that the MOE intake of ethyl carbamate from daily food and alcoholic beverages combined is of concern and mitigation measures to reduce ethyl carbamate in some alcoholic beverages should continue. There is little doubt that ethyl carbamate in alcoholic beverages is very important to health authorities, while the cumulative daily exposure in the typical diet is also an issue of rising concern that merits closer observation. The Korean study concluded, "It would be desirable to closely monitor ethyl carbamate levels in Korean foods and find ways to reduce the daily intake." The IARC evaluation has led to the following US regulatory actions: • NESHAP: Listed as a Hazardous Air Pollutant (HAP) • Comprehensive Environmental Response, Compensation, and Liability Act: Reportable Quantity (RQ) = 100 lb • Emergency Planning and Community Right-To-Know Act, EPA’s Toxics Release Inventory: A listed substance subject to RCRA reporting requirements • RCRA Listed Hazardous Waste: substance - U238 Related compounds Other carbamates include methyl carbamate (urethylane, m. p. 52-54 °C),[30] butyl carbamate,[31] and phenyl carbamate (m. p. 149-152 °C),[32] which can also be prepared from the corresponding chloroformate and ammonia. These esters are white, crystalline solids at room temperature. Except for the phenyl carbamate, they sublime at moderate temperatures; methyl carbamate sublimes at room temperatures. The first two and ethyl carbamate are very soluble in water, benzene, and ether.[27][30][31] These other carbamates (methyl, butyl, and phenyl) are only used in small quantities for research purposes. Ethyl carbamate 217 References [1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-79-6 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5641 [3] http:/ / www. chemspider. com/ 5439 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=3IN71E75Z5 [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=200-123-1 [6] http:/ / www. drugbank. ca/ drugs/ DB04827 [7] http:/ / www. kegg. jp/ entry/ C01537 [8] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Urethane [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17967 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL462547 [11] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B00312. html [12] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CCOC%28N%29%3DO [13] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28OCC%29N [14] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=414047867& page2=%3AEthyl+ carbamate [15] The Merck Index, 11th Edition, 9789 [16] Holland, JR; Hosley, H; Scharlau, C; Carbone, PP; Frei E, 3rd; Brindley, CO; Hall, TC; Shnider, BI et al. (1966). "A controlled trial of urethane treatment in multiple myeloma". Blood 27 (3): 328–42. PMID 5933438. [17] Virginia Commonwealth University, The Chemical/Biological Safety Section (CBSS) of the Office of Environmental Health and Safety, Working with Urethane (http:/ / www. vcu. edu/ oehs/ chemical/ biosafe/ urethane. pdf), 2006. Accessed May 13, 2006 [18] NTP National Toxicology Program, NIEHS, National Institutes of Health, Eleventh Report on Carcinogens, Urethane (http:/ / ntp. niehs. nih. gov/ ntp/ roc/ eleventh/ profiles/ s184uret. pdf), 2005. Accessed May 13, 2006 [19] Segal, M Too Many Drinks Spiked with Urethane (http:/ / www. cfsan. fda. gov/ ~frf/ fc0488ur. html), US Food and Drug Administration, September 1988 [20] Haddon W F, M I Mancini, M Mclaren, A Effio, L A Harden, R I Egre, & J L Bradford (1994). Cereal Chemistry 71 (2): 207–215. [21] Matsudo T, T Aoki, K Abe, N Fukuta, T Higuchi, M Sasaki & K Uchida (1993). "Determination of ethyl carbamate in soy sauce and its possible precursor". J Agric Food Chem 41 (3): 352–356. doi:10.1021/jf00027a003. [22] American Journal of Enology and Viticulture 57 (2): 113–124. 2006. [23] Butzke, C E & L F Bisson, Ethyl Carbamate Preventative Action Manual (http:/ / www. cfsan. fda. gov/ ~frf/ ecaction. html), Depart. of Viticulture & Enology, U. of CA, Davis, CA, for US FDA, 1997 accessed May 13, 2006 [24] http:/ / www. ec. gc. ca/ subsnouvelles-newsubs/ default. asp?lang=En& n=AECC21AD-1 [25] Lachenmeier DW, Lima MC, Nóbrega IC, Pereira JA, Kerr-Corrêa F, Kanteres F, Rehm J. (2010). "Cancer risk assessment of ethyl carbamate in alcoholic beverages from Brazil with special consideration to the spirits cachaça and tiquira". BMC Cancer 10: 266. doi:10.1186/1471-2407-10-266. PMC 2892455. PMID 20529350. [26] Office of Toxic Substances, “Chemical Hazard Information Profile Urethane, CAS No. 51-79-6 , U.S. EPA, Washington, D.C., 12 pages, 26 references, 1979, accessed May 13, 2006 at http:/ / toxnet. nlm. nih. gov [27] National Library of Medicine, Hazardous Data Bank, Ethyl Carbamate 2006a, accessed May 13, 2006 at http:/ / toxnet. nlm. nih. gov/ [28] IARC, 1974 [29] NTP 2005 [30] National Library of Medicine, Hazardous Data Bank, Methyl Carbamate 2006b, accessed May 13, 2006 at http:/ / toxnet. nlm. nih. gov [31] National Library of Medicine, Hazardous Data Bank, Butyl Carbamate 2006c, accessed May 13, 2006 at http:/ / toxnet. nlm. nih. gov [32] Dean, JA (editor), Lange’s Handbook of Chemistry, 13th Ed., 1985, p. 7-586, #p191. External links • NLM Hazardous Substances Databank – Ethyl carbamate (http://toxnet.nlm.nih.gov/cgi-bin/sis/search/ r?dbs+hsdb:@term+@rn+@rel+51-79-6) • Urethane (http://chem.sis.nlm.nih.gov/chemidplus/direct.jsp?regno=51-79-6) in the ChemIDplus database Carbamate 218 Carbamate Carbamates are organic compounds derived from carbamic acid (NH2COOH). A carbamate group, carbamate ester (e.g., ethyl carbamate), and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes. Synthesis Carbamic acids are derived from amines: R2NH + CO2 → R2NCO2H Chemical structure of carbamates Carbamic acid is about as acidic as acetic acid. Ionization of a proton gives the carbamate anion, the conjugate base of carbamic acid: R2NCO2H → R2NCO2- + H+ Carbamates also arise via hydrolysis of chloroformamides: R2NC(O)Cl + H2O → R2NCO2H + HCl Carbamates may be formed from the Curtius Rearrangement, where isocyanates formed are reacted with an alcohol. RNCO + R'OH → RNHCO2R' Applications and occurrence Although most of this article concerns organic carbamates, the inorganic salt ammonium carbamate is produced on a large scale as an intermediate in the production of the commodity chemical urea from ammonia and carbon dioxide. Carbamates in biochemistry N-terminal amino groups of valine residues in the α- and β-chains of deoxyhemoglobin exist as carbamates. They help to stabilise the protein, when it becomes deoxyhemoglobin and increases the likelihood of the release of remaining oxygen molecules bound to the protein. The influence of these carbamates on the affinity of hemoglobin for O2 is called the Bohr effect. The ε-amino groups of the lysine residues in urease and phosphotriesterase also feature carbamate. The carbamate derived from aminoimidazole is an intermediate in the biosynthesis of inosine. Carbamoyl phosphate is generated from carboxyphosphate rather than CO2.[1] CO2 capture by ribulose 1,5-bisphosphate carboxylase Perhaps the most important carbamate is the one involved in the capture of CO2 by plants since this process is relevant to global warming. The enzyme Ribulose 1,5-bisphosphate carboxylase/oxygenase fixes a molecule of carbon dioxide as a carbamate at the start of the Calvin cycle). At the active site of the enzyme, a Mg2+ ion is bound to glutamate and aspartate residues as well as a lysine carbamate. The carbamate is formed when an uncharged lysine side-chain near the ion reacts with a carbon dioxide molecule from the air (not the substrate carbon dioxide molecule), which then renders it charged, and, therefore, able to bind the Mg2+ ion. Carbamate 219 Commercial carbamate compounds Carbamate insecticides The so-called carbamate insecticides feature the carbamate ester functional group. Included in this group are aldicarb, carbofuran (Furadan), carbaryl (Sevin), ethienocarb, fenobucarb, oxamyl and methomyl. These insecticides kill insects by reversibly inactivating the enzyme acetylcholinesterase. The organophosphate pesticides also inhibit this enzyme, although irreversibly, and cause a more severe form of cholinergic poisoning.[2] Fenoxycarb has a carbamate group but acts as a juvenile hormone mimic, rather than inactivating acetylcholinesterase.[3] The carbamate insecticide Carbaryl. The insect repellent icaridin is a substituted carbamate. Polyurethanes Polyurethanes contain multiple carbamate groups as part of their structure. The "urethane" in the name "polyurethane" refers to these carbamate groups; ethyl carbamate (common name "urethane") is neither a component of polyurethanes, nor is used in their manufacture. Polyurethane polymers have a wide range of properties and are commercially available as foams, elastomers, and solids. Typically, polyurethane polymers are made by combining diisocyanates, e.g. toluene diisocyanate, and diols, where the carbamate groups are formed by reaction of the alcohols with the isocyanates: RN=C=O + R'OH → RNHC(O)OR' Preservatives and cosmetics Iodopropynyl butylcarbamate is a wood and paint preservative and used in cosmetics.[4] In human medicine Urethane or ethyl carbamate was once produced commercially in the United States as an antineoplastic agent and for other medicinal purposes. It was found to be toxic and largely ineffective.[5] It is occasionally used as a veterinary medicine. In addition, some carbamates are used in human pharmacotherapy, for example, the cholinesterase inhibitors neostigmine and rivastigmine, whose chemical structure is based on the natural alkaloid physostigmine. Other examples are meprobamate and its derivatives like carisoprodol, felbamate, and tybamate, a class of anxiolytic and muscle relaxant drugs widely used in the 60s before the rise of benzodiazepines, and still used nowadays in some cases. The protease inhibitor darunavir for HIV treatment also contains a carbamate functional group. Carbamate 220 Sulfur analogues There are two oxygen atoms in a carbamate (1), ROC(=O)NR2, and either or both of them can be conceptually replaced by sulfur. Analogues of carbamates with only one of the oxygens replaced by sulfur are called thiocarbamates (2 and 3). Carbamates with both oxygens replaced by sulfur are called dithiocarbamates (4), RSC(=S)NR2. There are two different structurally isomeric types of thiocarbamate: • O-thiocarbamates (2), ROC(=S)NR2, where the carbonyl group (C=O) is replaced with a thiocarbonyl group (C=S) • S-thiocarbamates (3), RSC(=O)NR2, where the R–O– group is replaced with an R–S– group O-thiocarbamates can isomerise to S-thiocarbamates, for example in the Newman-Kwart rearrangement. References [1] Bartoschek, S.; Vorholt, J. A.; Thauer, R. K.; Geierstanger, B. H. and Griesinger, C., "N-Carboxymethanofuran (carbamate) formation from methanofuran and CO2 in methanogenic archaea : Thermodynamics and kinetics of the spontaneous reaction", Eur. J. Biochem., 2001, 267, 3130-3138. doi:10.1046/j.1432-1327.2000.01331.x [2] Robert L. Metcalf “Insect Control” in Ullmann’s Encyclopedia of Industrial Chemistry” Wiley-VCH, Weinheim, 2002. doi:10.1002/14356007.a14_263 [3] Cornell University site on Fenoxycarb (http:/ / pmep. cce. cornell. edu/ profiles/ extoxnet/ dienochlor-glyphosate/ fenoxycarb-ext. html) [4] Badreshia, S (2002). "Iodopropynyl butylcarbamate". American Journal of Contact Dermatitis 13 (2): 77–79. doi:10.1053/ajcd.2002.30728. ISSN 1046199X. [5] Holland JR, Hosley H, Scharlau C, Carbone PP, Frei E 3rd, Brindley CO, Hall TC, Shnider BI, Gold GL, Lasagna L, Owens AH Jr, Miller SP (1 March 1966). "A controlled trial of urethane treatment in multiple myeloma" (http:/ / bloodjournal. hematologylibrary. org/ cgi/ content/ abstract/ 27/ 3/ 328) (free fulltext). Blood 27 (3): 328–42. ISSN 0006-4971. PMID 5933438. . Sodium diethyldithiocarbamate 221 Sodium diethyldithiocarbamate Sodium diethyldithiocarbamate Identifiers CAS number PubChem ChemSpider UNII ChEMBL Jmol-3D images 148-18-5 533728 8642 [1]   [2]   [4]   [5]   [3] A5304YEB5E CHEMBL107217 Image 1 Properties [6] Molecular formula Molar mass Appearance Density Melting point Solubility in water Solubility C5H10NS2Na 171.259 g/mol (anhydrous) White, slightly brown, or slightly pink crystalline solid 1.1 g/cm3 95 °C, 368 K, 203 °F Soluble soluble in alcohol, acetone insoluble in ether, benzene Hazards Main hazards   (verify) Harmful [7]  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Sodium diethyldithiocarbamate is the organosulfur compound with the formula NaS2CN(C2H5)2. Sodium diethyldithiocarbamate 222 Preparation This salt is obtained by treating carbon disulfide with diethylamine in the presence of sodium hydroxide: CS2 + HN(C2H5)2 + NaOH → NaS2CN(C2H5)2 + H2O Other dithiocarbamates can be prepared similarly from secondary amines and carbon disulfide. They are used as chelating agents for transition metal ions and as precursors to herbicides and vulcanization reagents. Oxidation to thiuram disulfide Oxidation of sodium diethyldithiocarbamate gives the disulfide, also called a thiuram disulfide (Et = ethyl): 2 NaS2CNEt2 + I2 → Et2NC(S)S-SC(S)NEt2 + 2 NaI This disulfide is marketed as an anti-alcoholism drug under the labels Antabuse and Disulfiram. Chlorination of the above-mentioned thiuram disulfide affords the thiocarbamoyl chloride.[8] Ligand bonding The diethyldithiocarbamate ion chelates to many "softer" metals via the two sulfur atoms. Other more complicated bonding modes are known including binding as unidentate ligand and a bridging ligand using one or both sulfur atoms.[9] Spin trapping of nitric oxide radicals Complexes of Dithiocarbamates with iron provide one of the very few methods to study the formation of nitric oxide (NO) radicals in biological materials. Although the lifetime of NO in tissues is too short to allow detection of this radical itself, NO readily binds to iron-dithiocarbamate complexes. The resulting mono-nitrosyl-iron complex (MNIC) is stable, and may be detected with Electron Paramagnetic Resonance (EPR) spectroscopy.[10][11][12] In cancer The effect of diethyldithiocarbamate of chelating zinc inhibits metalloproteinases, which in turn prevents the degradation of extracellular matrix, which is an initial step in cancer metastasis and angiogenesis. [13] Antioxidant Diethyldithiocarbamate inhibits superoxide dismutase, which can both have antioxidant and oxidant effects on cells, depending on the time of administration.[13] References [1] [2] [3] [4] [5] [6] [7] [8] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=148-18-5 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=533728 http:/ / www. chemspider. com/ 8642 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=A5304YEB5E https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL107217 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=%5BNa%2B%5D. %5BS-%5DC%28%3DS%29N%28CC%29CC http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=442092403& page2=%3ASodium+ diethyldithiocarbamate Goshorn, R. H.; Levis, Jr., W. W. ;Jaul, E.; Ritter, E. J. (1963), "Diethylthiocarbamyl Chloride" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv4p0307), Org. Synth., ; Coll. Vol. 4: 307 [9] Cotton, F. Albert; Wilkinson, Geoffrey; Murillo, Carlos A.; Bochmann, Manfred (1999), Advanced Inorganic Chemistry (6th ed.), New York: Wiley-Interscience, ISBN 0-471-19957-5 [10] Henry Y.; Guissani A.; Ducastel B. (eds); "Nitric oxide research from chemistry to biology: EPR spectroscopy of nitrosylated compounds." Landes, Austin 1997. [11] Vanin A.F.; Huisman A.; van Faassen E.E.; "Iron dithiocarbamates as spin trap for nitric oxide: Pitfalls and successes." Methods in Enzymology vol 359 (2002) 27 - 42. Sodium diethyldithiocarbamate [12] van Faassen E.E.; Vanin A.F. (eds); "Radicals for life: The various forms of nitric oxide." Elsevier, Amsterdam 2007. [13] diethyldithiocarbamate (http:/ / www. cancer. gov/ Templates/ drugdictionary. aspx?CdrID=40247) National Cancer Institute - Drug Dictionary 223 Further reading • Cvek B, Dvorak Z (2007). "Targeting of nuclear factor-kappaB and proteasome by dithiocarbamate complexes with metals" (http://www.bentham-direct.org/pages/content.php?CPD/2007/00000013/00000030/0010B. SGM). Curr. Pharm. Des. 13 (30): 3155–67. doi:10.2174/138161207782110390. PMID 17979756. Thiocarbamate Thiocarbamates are a family of organosulfur compounds. There are two isomeric forms of thiocarbamate esters: O-thiocarbamates, ROC(=S)NR2, and S-thiocarbamates, RSC(=O)NR2. O-thiocarbamates can isomerise to S-thiocarbamates, for example in the Newman-Kwart rearrangement. Synthesis Thiocarbamates can be synthesised by hydrolysis of thiocyanates:[1] RSCN + H2O → RSC(=O)NH2 General structural formulae of O-organyl (1) and S-organyl (2) thiocarbamates Where R is aryl, this method is known as the Riemschneider thiocarbamate synthesis. References [1] March, 6th edn., p. 1269 Pyridoxal phosphate 224 Pyridoxal phosphate Pyridoxal phosphate Identifiers CAS number PubChem MeSH ChEMBL ATC code Jmol-3D images 54-47-7 1051 [2] [3] [1]   Pyridoxal+Phosphate CHEMBL82202 A11 HA06 Image 1 Properties [6] [5] [4]   Molecular formula Molar mass Density Melting point Acidity (pK ) a C8H10NO6P 247.142 g/mol 1.638±0.06 g/cm3 139-142°C 1.56 Hazards [9] [8] [7] Flash point   (verify) [11] 296.0±32.9 °C [10]  (what is:  / ?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Pyridoxal-phosphate (PLP, pyridoxal-5'-phosphate, P5P) is a prosthetic group of some enzymes. It is the active form of vitamin B6, which comprises three natural organic compounds, pyridoxal, pyridoxamine and pyridoxine. Pyridoxal phosphate 225 Role as a coenzyme PLP acts as a coenzyme in all transamination reactions, and in some decarboxylation and deamination reactions of amino acids. The aldehyde group of PLP forms a Schiff-base linkage (internal aldimine) with the ε-amino group of a specific lysine group of the aminotransferase enzyme. The α-amino group of the amino acid substrate displaces the ε-amino group of the active-site lysine residue. The resulting external aldimine becomes deprotonated to become a quinoid intermediate, which in turn accepts a proton at a different position to become a ketimine. The resulting ketimine is hydrolysed so that the amino group remains on the complex.[12] In addition, PLP is used by aminotransferases (or transaminases) that act upon unusual sugars such as perosamine and desosamine.[13] In these reactions, the PLP reacts with glutamate, which transfers its alpha-amino group to PLP to make pyridoxamine phosphate (PMP). PMP then transfers its nitrogen to the sugar, making an amino sugar. PLP is also involved in various beta-elimination reactions such as the reactions carried out by serine dehydratase and GDP-4-keto-6-deoxymannose-3-dehydratase (ColD).[13] It is also active in the condensation reaction in heme synthesis. PLP plays a role in the conversion of dopa into dopamine, allows the conversion of the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter GABA, and allows SAM to be decarboxylated to form propylamine, which is a precursor to polyamines. Non-classical examples of PLP PLP is also found on glycogen phosphorylase in the liver, where it is used to break down glycogen in glycogenolysis when glucagon or epinephrine signals it to do so. However, this enzyme does not exploit the reactive aldehyde group, but instead utilizes the phosphate group on PLP to perform its reaction. Although the vast majority of PLP-dependent enzymes form an internal aldimine with PLP via an active site lysine residue; some PLP-dependent enzymes do not have this lysine residue, but instead have an active site histidine. In such a case, the histidine cannot form the internal aldimine, and, therefore, the cofactor never becomes covalently tethered to the enzyme. GDP-4-keto-6-deoxymannose-3-dehydratase (ColD) is an example of such an enzyme.[14] Catalytic Mechanism The pyridoxal-5′-phosphate-dependent enzymes (PLP enzymes) catalyze a myriad of biochemical reactions. Although the scope of PLP-catalyzed reactions initially appears to be immensely diverse, there is a simple unifying principle: In the resting state, the cofactor (PLP) is covalently bonded to the amino group of an active site lysine, forming an internal aldimine. Once the amino substrate interacts with the active site, a new Schiff base is generated, commonly referred to as the external aldimine. Only after this step, the mechanistic pathway for each PLP-catalyzed reaction diverges. Density functional methods have been applied to investigate the transimination reaction, and the results have shown that the reaction involves three sequential steps: (i) formation of a tetrahedral intermediate with the active site lysine and the amino substrate bonded to the PLP cofactor; (ii) nondirect proton transfer between the amino substrate and the lysine residue; and (iii) formation of the external aldimine after the dissociation of the lysine residue. The overall reaction is exothermic (−12.0 kcal/mol), and the rate-limiting step is the second one with 12.6 kcal/mol for the activation energy[15] Pyridoxal phosphate 226 Biological Synthesis It is synthesized from pyridoxal by the enzyme pyridoxal kinase, requiring one ATP. It is metabolized in the liver. References [1] [2] [3] [4] [5] [6] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=54-47-7 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1051 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Pyridoxal+ Phosphate https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL82202 http:/ / www. whocc. no/ atc_ddd_index/ ?code=A11HA06 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CC1%3DNC%3DC%28C%28%3DC1O%29%3Cbr%3EC%3DO%29COP%28%3DO%29%28O%29O [7] Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2011 ACD/Labs) [8] Kozlov E.I., L. M. S. Stability of water-soluble vitamins and coenzymes. Hydrolysis of pyridoxal-5-phosphate in acidic, neutral, and weakly alkaline solutions. Pharmaceutical Chemistry Journal 1978, 11, 1543. [9] Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2011 ACD/Labs) [10] Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2011 ACD/Labs) [11] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=393759663& page2=%3APyridoxal+ phosphate [12] Toney, M. D. "Reaction specificity in pyridoxal enzymes." Archives of biochemistry and biophysics (2005) 433: 279-287. [13] Samuel, G. and Reeves, P. "Biosynthesis of O-antigens: genes and pathways involved in nucleotide sugar precusor synthesis and O-antigen assembly." Carbohydrate research (2003) 338:2503-2519. [14] Cook P. D., Thoden J.B. and Holden H. M. "The structure of GDP-4-keto-6-deoxymannose-3-dehydratase: a unique coenzyme B6-dependent enzyme." Protein Science (2006) 15:2093-2106. [15] N. M. F. S. A. Cerqueira, P. A. Fernandes, M. J. Ramos (2011). "Computational Mechanistic Studies Addressed to the Transimination Reaction Present in All Pyridoxal 5′-Phosphate-Requiring Enzymes". Journal of Chemical Theory and Computation 7 (5): 1356–1368. doi:10.1021/ct1002219. External links • A11 HA06 (http://www.whocc.no/atc_ddd_index/?code=A11HA06) Article Sources and Contributors 227 Article Sources and Contributors Nucleophilic addition  Source: http://en.wikipedia.org/w/index.php?oldid=522480006  Contributors: 124Nick, Apcpca, Aushulz, Bensaccount, Brane.Blokar, Ceyockey, Cmrufo, DA3N, Dolanclass, ELApro, Edgar181, Gaius Cornelius, Giftlite, Gladissk, Hoo man, Itub, Keenan Pepper, Mailer diablo, Maneesh, Michael Hardy, Moink, Onco p53, PV=nRT, Physchim62, R'n'B, Sadeep kumar, Secalinum, Su-no-G, Tincup, User A1, V8rik, Walkerma, 39 anonymous edits Tetrahedral carbonyl addition compound  Source: http://en.wikipedia.org/w/index.php?oldid=500843397  Contributors: Beetstra, Chem-awb, Itub, JarlaxleArtemis, Mairi, Molybdenumblue, Nikolaivica, Physchim62, Rjwilmsi, Sadads, Shoy, WereSpielChequers, 7 anonymous edits Nucleophilic substitution  Source: http://en.wikipedia.org/w/index.php?oldid=502111323  Contributors: Allens, Amigadave, Apcpca, Aushulz, BRG, Benjah-bmm27, Bizdorph, Bomac, Borgx, Cambiassobaby, Capaccio, Chasingsol, Chem-awb, Chesnok, ChrisGualtieri, Christian75, Dougher, Elvim, Esprit15d, Fawcett5, Hede2000, Hmains, Jag123, JenOrgoChem, Jimfbleak, Jü, Karlwick, Keenan Pepper, LoyalSoldier, Marcipangris, Michał Sobkowski, Minestrone Soup, Moxon414, Nimlot, Oblemboy, Peter, Pwdent, Qmwne235, Rifleman 82, Skinny McGee, Sxoa, T.vanschaik, Tarquin, The Anome, V8rik, Walkerma, Wolfch, 39 anonymous edits Nucleophilic acyl substitution  Source: http://en.wikipedia.org/w/index.php?oldid=509545957  Contributors: Apcpca, Bender235, Choij, Christian75, Ckalnmals, DMacks, Fikus, Ian Pitchford, Itub, Keenan Pepper, Odyssomay, Pwdent, Razorflame, Rifleman 82, Smokefoot, Spellmaster, Su-no-G, Thisismikesother, V8rik, 5 anonymous edits Addition reaction  Source: http://en.wikipedia.org/w/index.php?oldid=523073063  Contributors: Apcpca, Bender235, Bracodbk, Brane.Blokar, CNMIN, Cburnett, Ceyockey, Chris the speller, ChrisGualtieri, Dcirovic, Denisarona, Dysprosia, EPO, Edgar181, Falcon Kirtaran, Gaius Cornelius, Helix84, Icairns, IvanLanin, JAn Dudík, Keenan Pepper, Marcipangris, Neodop, Ojigiri, Okedem, Physchim62, Russot1, Secalinum, Snuffles72, Spinal83, Stepa, Timo Honkasalo, V8rik, Vuong Ngan Ha, Waggers, Wikipelli, Xinyu, ~K, 27 anonymous edits Condensation reaction  Source: http://en.wikipedia.org/w/index.php?oldid=512633487  Contributors: Ahoerstemeier, Alexandrov, Amozafari, Apcpca, Astanhope, Attys, Avenged Eightfold, Bart133, Bensaccount, Blader4life, Borb, Camembert, Cdc, Chem538grp5w09, Christian75, DMacks, Deor, Deville, Dirac1933, Dirac66, Docboat, Drphilharmonic, Dustinl4m3, Dwmyers, ELApro, Edgar181, Fibonachi, Fotinakis, Freestyle-69, Gentgeen, Glenn, Gogo Dodo, H Padleckas, Icairns, Isopropyl, Itub, Jingxin, Keenan Pepper, LouisBB, Lukenjack1, Magnus Manske, Marcpatt14, Miquonranger03, Mmxx, Mr Stephen, Myrryam, Nathaniel, Nono64, Ostione, Oxymoron83, PS., Person unknown, Recycled.jack, Rifleman 82, Ronhjones, SJP, Sagaciousuk, SkyBoxx, Spoladore, Stone, SuperSpeller22, Targuman, Tarquin, ThomasWinwood, Thurt, Ugen64, UserDoe, V8rik, Walkerma, WikHead, Xiong Chiamiov, Zedla, 98 anonymous edits Substitution reaction  Source: http://en.wikipedia.org/w/index.php?oldid=525338530  Contributors: Andres, Apcpca, Bender235, Bomac, Cacycle, Chanchis2, ChemGardener, ChrisG, DMacks, Dirac1933, Edgar181, Gaius Cornelius, Glassneko, Hugo-cs, J. Finkelstein, KJ 419, Keenan Pepper, Kendrewmak, Malachirality, Owen, Pedrora, Physchim62, R'n'B, SudhirP, Tide rolls, V8rik, VanessaLylithe, Wingchi, Xanchester, 32 anonymous edits Elimination reaction  Source: http://en.wikipedia.org/w/index.php?oldid=525279698  Contributors: Arcadian, Brandon5485, Briansal, Bubbachuck, Ceyockey, ChrisGualtieri, CommonsDelinker, D3, DMacks, Edgar181, Elvim, Esprit15d, Gladissk, GraemeL, Hadal, Icairns, Itub, Jfx319, Jupiterccnetcom, Karlwick, Keenan Pepper, LOL, Lamro, Lovecz, MER-C, Marcipangris, Michael Hardy, Mikearmet, Naddy, Nonagonal Spider, Ovy, Park4223, Pedrora, Person unknown, Polychrome, RedWolf, Rifleman 82, Robodoc.at, Russot1, Sam Hocevar, Shadowjams, Shuffdog, Sushant gupta, Thecurran91, Tobraider, V8rik, 93 anonymous edits Leaving group  Source: http://en.wikipedia.org/w/index.php?oldid=521193668  Contributors: Bensaccount, Bomac, Cseizert, DMacks, Drbreznjev, GregorB, J. Finkelstein, Joseph Solis in Australia, Kurgus, Kwertii, LoneSeeker, Menchi, Modster, Morven, Omegakent, PV=nRT, Puppy8800, Rifleman 82, Sidar, THEN WHO WAS PHONE?, Tim Q. Wells, V8rik, 48 anonymous edits Reductive amination  Source: http://en.wikipedia.org/w/index.php?oldid=520645948  Contributors: Apcpca, Choij, DMacks, Drphilharmonic, Giftlite, LilHelpa, MarSch, Mephisto spa, Physchim62, Puppy8800, Rich Farmbrough, Rifleman 82, Rjwilmsi, Sam Hocevar, Smokefoot, Srychnov, V8rik, Walkerma, Wickey-nl, ~K, 24 anonymous edits Aldol condensation  Source: http://en.wikipedia.org/w/index.php?oldid=523899809  Contributors: Aagrober, Alai, Anurag145, Apcpca, Benjah-bmm27, Bensaccount, Borgx, Calabe1992, Chphe, DA3N, DMacks, Dcirovic, Demong, Drphilharmonic, Edgar181, FrozenPurpleCube, Gaius Cornelius, Galaxiaad, Ganímedes, Itub, Jordi picart, Keenan Pepper, Kendrewmak, M stone, Mel Etitis, Meta, Quale, Rifleman 82, Rjwilmsi, Rsrikanth05, Shalom Yechiel, Stone, V8rik, Vismit Parihar, Wilbiddle42, ZeroOne, ~K, 43 anonymous edits SN1 reaction  Source: http://en.wikipedia.org/w/index.php?oldid=525992770  Contributors: ! Biswas Amitava !, 99of9, AirMonk, Alextelford, Arcadian, Astrochemist, Belovedfreak, Bender235, Beninakepi, Benjah-bmm27, Borgx, Bryan Derksen, CDN99, Cadmium, Calvero JP, ChemGardener, CommonsDelinker, Csw3190, CyberSkull, Diberri, Elvim, Flipperinu, Hoo man, Ibjhb, Itub, J. Finkelstein, Jim1138, Jupiterccnetcom, Karlwick, Keenan Pepper, Kehenr01, Khaister, LinkinPark, Marek69, Mark PEA, Menchi, Mgyannick, Michel Awkal, Minimac, Mortense, Morven, Mr Bound, Naraht, Nathaniel, Nomoreamoron, Nono64, Petergans, Puppy8800, Remember the dot, Rich Farmbrough, Richard001, Rifleman 82, Robbie.flick, SVI, Shootbamboo, Taoster, Tarquin, The Anome, Travisbrady, V8rik, Walkerma, Whkoh, Whoop whoop pull up, Wik, Zeldaoot, 63 anonymous edits SN2 reaction  Source: http://en.wikipedia.org/w/index.php?oldid=524740983  Contributors: Ahoerstemeier, Amigadave, Arcadian, Arthena, Astrochemist, Basement12, Benjah-bmm27, Bensaccount, CDN99, Cadmium, Captain panda, ChemistHans, Chris the speller, Closedmouth, CyberSkull, DMacks, Dashboardy, Diberri, Drpickem, Edgar181, Elvim, Ewen, Felix Wan, Fluxions1643, Francisco Quiumento, Fredrik, Freywa, Hamsterlopithecus, Heron, Iodineisacockblock, Iridescent, Itub, J. Finkelstein, JForget, Jupiterccnetcom, Jynto, Karlwick, Keenan Pepper, MITBeaverRocks, Mailer diablo, Mgyannick, Michel Awkal, Mishh, Olin, Polimerek, Puppy8800, Remember the dot, Rifleman 82, Rjwilmsi, RotAnal, SHL-at-Sv, SVI, Shriram, Silly shrimp, Slicky, Stone, Suffusion of Yellow, Taoster, Travisbrady, Uncle Milty, V8rik, Vaibhav kant tiwari, ViolentRage, Walkerma, Whkoh, Wickey-nl, Wik, Zeldaoot, 84 anonymous edits Alkylimino-de-oxo-bisubstitution  Source: http://en.wikipedia.org/w/index.php?oldid=514328476  Contributors: Coppertwig, Element16, Ghiles, Nono64, Rifleman 82, V8rik, WVhybrid, 2 anonymous edits Schotten–Baumann reaction  Source: http://en.wikipedia.org/w/index.php?oldid=497584945  Contributors: Benjah-bmm27, Chem-awb, ChemNerd, Choij, Christian75, D6, Itub, MightyWarrior, Physchim62, Shoy, Sikkema, Stone, V8rik, 3 anonymous edits Mannich reaction  Source: http://en.wikipedia.org/w/index.php?oldid=524623021  Contributors: Apcpca, Borgx, Caknuck, Chem-awb, Choij, Christian75, Elwology, Francisco Quiumento, Gaius Cornelius, Georgesgoossens, Giftlite, Imran inderlok, Jacspaper, Japanese Searobin, Jü, Kurgus, Nuklear, Olkol, OrganicReactions, Ph0987, Rat102312, Seb35, SeventyThree, Simon12, Stone, Tanevala, That Guy, From That Show!, Tolien, TommyCP, V8rik, Walkerma, ~K, 36 anonymous edits Edman degradation  Source: http://en.wikipedia.org/w/index.php?oldid=520652473  Contributors: A3camero, Aa77zz, Alchymical Kettle, Arakin, Benj613, CRGreathouse, CheekyMonkey, Chem-awb, Choij, Christian75, Christopherlin, Danny-w, David Josephy, JOK, Jeppelbaum, Kadamczy, Kkmurray, M stone, Michał Sobkowski, Mushin, Norsci, Pdcook, Rifleman 82, Sasata, TimVickers, Twooars, Uppland, V8rik, Victor D, ~K, 33 anonymous edits Carbocation  Source: http://en.wikipedia.org/w/index.php?oldid=523793913  Contributors: ABCD, Anthony Appleyard, Ashi Starshade, Benjah-bmm27, Bernard Marx, BryanHolland, Cjfuller, Coppertwig, Dcirovic, Deflective, Diberri, Eagle-0, Edgar181, 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Original uploader was V8rik at en.wikipedia Image:NucleophilicAdditionGeneral.svg  Source: http://en.wikipedia.org/w/index.php?title=File:NucleophilicAdditionGeneral.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: V8rik (talk). Original uploader was V8rik at en.wikipedia Image:ReactionStyreneTolueneWithSodium.svg  Source: http://en.wikipedia.org/w/index.php?title=File:ReactionStyreneTolueneWithSodium.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: V8rik (talk). Original uploader was V8rik at en.wikipedia File:Claisen's 1887 reaction.png  Source: http://en.wikipedia.org/w/index.php?title=File:Claisen's_1887_reaction.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Burgi-Dunitz trajectory.png  Source: http://en.wikipedia.org/w/index.php?title=File:Burgi-Dunitz_trajectory.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Tetrodotoxin.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Tetrodotoxin.svg  License: Public Domain  Contributors: Ayacop, Benjah-bmm27, Yikrazuul File:N-brosylmitomycin A.png  Source: http://en.wikipedia.org/w/index.php?title=File:N-brosylmitomycin_A.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Tetrahedral intermediate cationic.png  Source: http://en.wikipedia.org/w/index.php?title=File:Tetrahedral_intermediate_cationic.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Carbinol tet intermediate.png  Source: http://en.wikipedia.org/w/index.php?title=File:Carbinol_tet_intermediate.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:HydrationKs.png  Source: http://en.wikipedia.org/w/index.php?title=File:HydrationKs.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Cyclic hemiacetals.png  Source: http://en.wikipedia.org/w/index.php?title=File:Cyclic_hemiacetals.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Acetal formation.png  Source: http://en.wikipedia.org/w/index.php?title=File:Acetal_formation.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Dioxolane protection.png  Source: http://en.wikipedia.org/w/index.php?title=File:Dioxolane_protection.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Weinreb.png  Source: http://en.wikipedia.org/w/index.php?title=File:Weinreb.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica File:Oxyanion hole.png  Source: http://en.wikipedia.org/w/index.php?title=File:Oxyanion_hole.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Nikolaivica Image:Sn2 Sn1 Graph.png  Source: http://en.wikipedia.org/w/index.php?title=File:Sn2_Sn1_Graph.png  License: GNU Free Documentation License  Contributors: SudhirP (talk) (Uploads) File:1-phenylethylchloride methanolysis.svg  Source: http://en.wikipedia.org/w/index.php?title=File:1-phenylethylchloride_methanolysis.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Dissolution File:SN1 reaction mechanism.png  Source: http://en.wikipedia.org/w/index.php?title=File:SN1_reaction_mechanism.png  License: Public Domain  Contributors: Calvero. File:SN2 reaction mechanism.png  Source: http://en.wikipedia.org/w/index.php?title=File:SN2_reaction_mechanism.png  License: Public Domain  Contributors: Calvero. File:General Scheme for Acid Catalyzed Nucleophilic Acyl Substitution.png  Source: http://en.wikipedia.org/w/index.php?title=File:General_Scheme_for_Acid_Catalyzed_Nucleophilic_Acyl_Substitution.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:General Scheme for Base Catalyzed Nucleophilc Acyl Substitution.png  Source: http://en.wikipedia.org/w/index.php?title=File:General_Scheme_for_Base_Catalyzed_Nucleophilc_Acyl_Substitution.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Nucleophilic Acyl Substitution with a Labeled Oxygen.png  Source: http://en.wikipedia.org/w/index.php?title=File:Nucleophilic_Acyl_Substitution_with_a_Labeled_Oxygen.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Reactivity of Carboxylic Acid Derivatives Towards Nucleophiles.png  Source: 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http://en.wikipedia.org/w/index.php?title=File:Ethyl_acetate.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Ethoxide.png  Source: http://en.wikipedia.org/w/index.php?title=File:Ethoxide.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Acetamide.png  Source: http://en.wikipedia.org/w/index.php?title=File:Acetamide.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Amide anion.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amide_anion.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Resonance Forms of an Amide.png  Source: http://en.wikipedia.org/w/index.php?title=File:Resonance_Forms_of_an_Amide.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Reaction of Benzoyl Chloride and Acetic Acid to Give a Mixed Anhydride.png  Source: http://en.wikipedia.org/w/index.php?title=File:Reaction_of_Benzoyl_Chloride_and_Acetic_Acid_to_Give_a_Mixed_Anhydride.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Reaction of Benzoyl Chloride With an Excess of Methylmagnesium Bromide.png  Source: http://en.wikipedia.org/w/index.php?title=File:Reaction_of_Benzoyl_Chloride_With_an_Excess_of_Methylmagnesium_Bromide.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:A Generic Weinreb Amide.png  Source: http://en.wikipedia.org/w/index.php?title=File:A_Generic_Weinreb_Amide.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Nucleophilic Acyl Substitution on an Anhydride Catalyzed by DMAP.png  Source: http://en.wikipedia.org/w/index.php?title=File:Nucleophilic_Acyl_Substitution_on_an_Anhydride_Catalyzed_by_DMAP.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Fischer Esterification-Hydrolysis Equilibrium.png  Source: http://en.wikipedia.org/w/index.php?title=File:Fischer_Esterification-Hydrolysis_Equilibrium.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:General Mechanism of the Claisen Condensation.png  Source: http://en.wikipedia.org/w/index.php?title=File:General_Mechanism_of_the_Claisen_Condensation.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Formylation of Benzene using Phenyllithium and DMF.png  Source: http://en.wikipedia.org/w/index.php?title=File:Formylation_of_Benzene_using_Phenyllithium_and_DMF.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals File:Mechanism of the Reaction of a Carboxylic Acid and Thionyl Chloride.png  Source: http://en.wikipedia.org/w/index.php?title=File:Mechanism_of_the_Reaction_of_a_Carboxylic_Acid_and_Thionyl_Chloride.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Ckalnmals Image:Chlorine and etene addition.png  Source: http://en.wikipedia.org/w/index.php?title=File:Chlorine_and_etene_addition.png  License: GNU Free Documentation License  Contributors: Karelj, Polimerek, Rhadamante, Werckmeister Image Sources, Licenses and Contributors File:Addition reactions general overview.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Addition_reactions_general_overview.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Dissolution Image:AminoacidCondensation.svg  Source: http://en.wikipedia.org/w/index.php?title=File:AminoacidCondensation.svg  License: Public Domain  Contributors: V8rik at en.wikipedia Image:Dieckmann Condensation Scheme.png  Source: http://en.wikipedia.org/w/index.php?title=File:Dieckmann_Condensation_Scheme.png  License: Public Domain  Contributors: Hystrix, ~K Image:SubstitutionReaction.svg  Source: http://en.wikipedia.org/w/index.php?title=File:SubstitutionReaction.svg  License: 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Image:2-amino-pentane.png  Source: http://en.wikipedia.org/w/index.php?title=File:2-amino-pentane.png  License: Public Domain  Contributors: User Magnus Manske on en.wikipedia Image:Amine R-N.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Amine_R-N.svg  License: Creative Commons Zero  Contributors: Incnis Mrsi Image:Amine N-R.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Amine_N-R.svg  License: Creative Commons Zero  Contributors: Incnis Mrsi Image:Amide formation from amine.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Amide_formation_from_amine.gif  License: Public Domain  Contributors: User:H Padleckas Image:Amine plus Carboxylic Acid.PNG  Source: http://en.wikipedia.org/w/index.php?title=File:Amine_plus_Carboxylic_Acid.PNG  License: Public Domain  Contributors: H Padleckas File:AmideTypes.png  Source: http://en.wikipedia.org/w/index.php?title=File:AmideTypes.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Smokefoot Image:AmideResonance.png  Source: http://en.wikipedia.org/w/index.php?title=File:AmideResonance.png  License: GNU Free Documentation License  Contributors: Original uploader was V8rik at en.wikipedia Image:Formamide-MO-3D-balls.png  Source: http://en.wikipedia.org/w/index.php?title=File:Formamide-MO-3D-balls.png  License: Public Domain  Contributors: Benjah-bmm27, Karelj Image:Speakerlink.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Speakerlink.svg  License: Creative Commons Attribution 3.0  Contributors: Woodstone. 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