Acyl carbon, substitution

The difference in behavior between aldehydes/ketones and carboxylic acic derivatives is a consequence of structure. Carboxylic acid derivatives have ai acyl carbon bonded to a group -Y that can leave as a stable anion. As soon a the tetrahedral intermediate is formed, the leaving group is expelled to general- a new carbonyl compound. Aldehydes and ketones have no such leaving grouj however, and therefore don t undergo substitution. 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

Nucleophilic substitution at an alkyl carbon is said to alkylate the nucleophile. For example, the above reaction between RI and NMe3 is an alkylation of tri-methylamine. Similarly, nucleophilic substitution at an acyl carbon is an acylation of the nucleophile. 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

Scheme 9.15 Use of isotope exchange in the study of the mechanisms of nucleophilic substitution at alkyl and acyl carbon.

Acid derivatives differ in the nature of the nucleophile bonded to the acyl carbon —OH in the acid, —Cl in the acid chloride, —OR in the ester, and —NH2 (or an amine) in the amide. Nucleophilic acyl substitution is the most common method for interconverting these derivatives. We will see many examples of nucleophilic acyl substitution in this chapter and in Chapter 21 ( Carboxylic Acid Derivatives ). The specific mechanisms depend on the reagents and conditions, but we can group them generally according to whether they take place under acidic or basic conditions. 

The NMR spectrum of complex 18 displayed an acyl carbon at 259.6 ppm, a carbonyl (cyclic CO2 group) at 222.8ppm, and an unresolved broad signal between 207.7 and 209.3ppm for the other CO of the molecule. The resonance of the quaternary carbon of the metallacycle, substituted with an SCH3 group, was observed at 95.5 ppm <20050M1709>. 

As we have said, nucleophilic substitution takes place much more readily at an acyl carbon than at saturated carbon. Thus, toward nucleophilic attack acid chlorides are more reactive than alkyl chlorides, amides are more reactive than amines (RNH2), and esters are more reactive than ethers. 

In the laboratory of D.R. Williams, a carbanion methodology for the alkylations and acylations of substituted oxazoles was investigated. The study showed that the monoalkylation of the dianion generated from 2-(5-oxazolyl)-1,3-dithiane exclusively led to the substitution of the carbon adjacent to sulfur. However, acylation reactions of the dianion afforded 4,5-disubstituted oxazoles. These new products presumably arose from carbonyinitrile ylide intermediates, which were generated by the selective C-acylation of a ring-opened dianion tautomer. This is the first example of a base-induced, low-temperature Cornforth rearrangement. 

Fig. 2.19 Effective methods to generate all-carbon substituted quaternary stereocenters (a) Diels-Alder assembly of a complicated building block for the synthesis of (-tj-aspidospermidine (b) intermolecular C-acylation using a planar nucleophilic ferrocene type catalyst.

Ring cleavage of iV-acyl- and A-(arylsulfonyl)histamines with di-(-butyl carbonate presumably involves quaternizing iV-acylation prior to ring cleavage <84JCS(Pl)59,89S825> (Equation (21)). The use of l-acyl-4-substituted imidazoles as intermediates in the synthesis of sterically hindered 1,5-disubstituted imidazoles has been known for some years (see CHEC-I), and in 1993 was rediscovered <93H(35)433>. 

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