Acid catalysis nucleophilic acyl substitution

The metabolic breakdown of triacylglycerols begins with their hydrolysis to yield glycerol plus fatty acids. The reaction is catalyzed by a lipase, whose mechanism of action is shown in Figure 29.2. The active site of the enzyme contains a catalytic triad of aspartic acid, histidine, and serine residues, which act cooperatively to provide the necessary acid and base catalysis for the individual steps. Hydrolysis is accomplished by two sequential nucleophilic acyl substitution reactions, one that covalently binds an acyl group to the side chain -OH of a serine residue on the enzyme and a second that frees the fatty acid from the enzyme. 

An acid-base reaction (Reaction [1]) occurs with OH, NH3, and amines, all common nucleophiles used in nucleophilic acyl substitution reactions. Nonetheless, carboxyhc acids can be converted to a variety of other acyl derivatives using special reagents, with acid catalysis, or sometimes, by using rather forcing reaction conditions. These reactions are summarized in Figure 22.2 and detailed in Sections 22.10A—22.10D. 

The most common use of In(III) salts in the catalysis of nucleophilic substitutions is in nucleophilic acyl substitutions, specifically esterifications and transesterifications. The traditional acetylation of alcohols using strong acids or bases are often plagued by problems of substrate compatibility with the reaction conditions, especially for tertiary alcohols with their low Sn2 reactivity and propensity to eliminate instead of undergoing SnI reactions. Thus, the use of mild conditions offered by In(III) salts provided solutions to these problems. 

Controlled oxidation of A-acyl-piperidines and -pyrrolidines can be used to prepare 2-alkoxy derivatives or the equivalent enamides, which are useful general synthetic intermediates. The former are susceptible to nucleophilic substitution under Lewis-acid catalysis, via Mannich-type intermediates, and the latter can undergo electrophilic substitution at C-3 or addition to the double bond. 

This is the most useful method of amide formation (equation 2). An activated carboxylic acid acylates aiiunonia, primary or secondary amines by a formal Sn2 substitution of leaving group X. The reactivity of the acylating reagent depend on the acidity of HX, and dierefore the order of reactivity is RCOHal > (RC0)20 = RCONs > RCChR > RCONH2 > RCOR. Moreover, the reaction rate increases with higher nucleophilicity of the amine as well as base or acid catalysis. 

The decarboxylative acylation of ortho-substituted benzoic acids involving nucleophilic addition to nitriles occurs under palladium catalysis (Scheme 4.35) [40]. 

The mechanism of nucleophihc acyl substitution reactions depends on the identity of the nucleophile and the leaving group. The mechanisms for acid and base catalysis are not the same. We now consider both acid- and base-cataly2ed nucleophihc acyl substitution. 

Figure 37.2. Catalysis by the enzyme chymotrypsin of the cleavage of one peptide bond in a protein a proposed mechanism. Histidine and pro-tonated histidine act as general base and acid in two successive nucleophilic substitution reactions (a) cleavage of protein with formation of acyl enzyme and liberation of one protein fragment (6) hydrolysis of acyl enzyme with regeneration of the enzyme and liberation of the other protein fragment.

The role of the metal ion in ester hydrolysis catalysed by CPA has been examined with both Zn +- and Co +-substituted enzymes. When the terminal carboxyl of the substrate is electrostatically linked to argenine-145 and the aromatic side-chain lies in a hydrophobic pocket, the only residues close enough to the substrate to enter catalysis are glutamate-270, tyrosine-248, the metal ion, and its associated water. Low-temperature studies aid the elucidation of the mechanism. Between - 25 and - 45 °C in ethylene glycol-water mixtures two kinetically discrete processes are detected, the slower of which corresponds to the catalytic rate constant. The faster reaction is interpreted as deacylation of a mixed anhydride acyl-enzyme intermediate formed by nucleophilic attack by glutamate-270 on the substrate (Scheme 6). Differences in the acidity dependences of the catalytic rate constant with the metal ions Zn + (p STa 6.1) and Co +-(pATa 4.9) suggest that ionization of the metal-bound water molecule occurs and is involved in the decay of the anhydride. The catalytic rate constant shows an isotope effect in DgO. 

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