Nucleophilic acyl substitution position

Oxidation converts the hemithioacetal into a thiol ester—an acyl enzyme. Like other esters, this one is prone to nucleophilic acyl substitution. It is cleaved, with phosphate ion as nucleophile, to regenerate the sulfhydryl group in the enzyme. The other product is 1,3-diphosphoglycerate. The molecule is (still) a phosphate ester at the 3-position, and has become a mixed anhydride at the 1-position. 

Nucleophilic acyl substitution can be initiated by a negative or neutral nucleophile attacking the partially positive carbonyl carbon. In this two-step mechanism, a tetrahedral intermediate is formed loss of the leaving group produces the new acid derivative. Alternatively,... 

Claisen Condensation (Section 19.3A) The product of a Claisen condensation is a j8-ketoester. Condensation occurs by nucleophilic acyl substitution in which the attacking nucleophile is the enolate anion of an ester. The Claisen condensation mechanism involves reaction of one ester molecule with base to form an enolate anion, which reacts as a nucleophile with another molecule of ester to give a tetrahedral carbonyl addition intermediate, in which the RO" group is lost to give a /3-ketoester, which is deprotonated at the a position by the RO". 

Since we know the relative stabilities of acyl derivatives, we can predict the position of a nucleophilic acyl substitution reaction. The same factors that affect the relative reactivity of acyl derivatives also control their stabilities. The identity of the groups bonded to the tetrahedral carbon atom affects the stabilities of the reactants and products. Thus, destabilizing the reactant and stabilizing the product increase the equihbrium constant. We conclude that the less stable acyl derivative is more reactive and can be converted into a more stable, less reactive acyl derivative. The relative stabihties of acyl derivatives enable us to understand most of the chemical reactions discussed in this chapter. 

Methoxide functions as a base and deprotonates the most acidic position, leading to a doubly-stabilized enolate. This enolate then functions as a nucleophile and attacks the ester in an intramolecular nucleophilic acyl substitution reaction. The resulting tetrahedral intermediate loses methoxide to reform the carbonyl group. The OH... 

Vinyl sulfides have found numerous applications in synthesis in the recent literature. Vinyl sulfides unsubstituted in the 1-position are metallated readily, and the resulting 1-phenythio- or 1-alkylthiovinyllithium reagents have been utilized for nucleophilic acylation and other applications. " The phenylthio-substituted... 

If the anodic oxidation of N-alkylanilines is performed in the presence of nucleophiles like enol ethers, nucleophilic substitution in the of-position to nitrogen by the enol ether can be observed in low yields. The electrophilic intermediate is the N-aryl iminium ion or the N-aryl imine after loss of two electrons and one or two protons. These intermediates add to the enol ether to give acetals (up to 26%) as addition products, or the first addition step is followed by an electrophilic aromatic substitution to form tetrahydroqui-nolines (13-39%) [47]. It should be noted at this point that better results for the nucleophilic a-substitution to nitrogen can be obtained with N,N-dialkylanilines (see next subsection). Optimum results, however, are obtained with N-acylated compounds via the intermediate N-acyl iminium ions (see Ref. 8). 

Benzene rings with substituents other than halo, nitro, sulfonic acid, alkyl, and acyl can be prepared by first synthesizing one of these substituted benzenes and then chemically changing the substituent. The kinds of substituents that can be placed on benzene rings are greatly expanded by reactions of arene dia-zonium salts, nucleophilic aromatic substitution reactions, and reactions involving a benzyne intermediate. The relative positions of two substituents on a benzene ring are indicated either by numbers or by the prefixes ortho, meta, and para. 

When acid derivative 2 reacts with sulfuric acid, the oxygen atom is the base and the conjugate acid product of this acid-base reaction is oxocarbenium ion 3, which is resonance stabilized. When 2 is an acid chloride, anhydride, ester, or amide, a heteroatom is attached to the positive carbon in 3. As in Chapter 18 (Section 18.1), the acid-base reaction of the carbonyl unit in 2 to give 3 facilitates reactions with nucleophiles. The reaction of intermediate 3 with a nucleophile ( Y) gives tetrahedral intermediate 4 contrary to acyl addition, reaction 4 contains an X group that can function as a leaving group. Loss of X leads to the final product of this reaction 5. If the nucleophile ( Y) is hydroxide, compormd 5 is the carboxylic acid (X = OH). If the nucleophile Y is an alcohol, the product 5 is an ester, and if Y is an amine, the product 5 is an amide. This first reaction is therefore the acid-catalyzed acyl substitution reaction of acid derivatives. 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

Hubbard and Kirsch (1972) have recently proposed that histidine may act as a nucleophile in a-chymotrypsin acylation reactions of esters having a good leaving group (jO-nitrophenol). This suggestion was based on a similarity in p-value for acylation by p-substituted nitrophenyl and dinitrophenyl benzoates and nucleophilic attack on these compounds by imidazole, in contrast with less positive p-values for hydroxide ion catalysis. Hammett p-values for hydrolysis of substituted phenyl esters are given in Table 6 and show little apparent trend. The values for hydroxide ion and alcoholate ions are... 

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