Nucleophilic and General Base Reactions

B. Discrimination between Nucleophilic and General Base Reactions... 

The single most important factor governing the relative importance of nucleophilic and general base catalysis for a given reaction is the partitioning of the tetrahedral intermediate formed by the addition of the nucleophile to the carbonyl group, viz. 

Catalysis by phosphate buffers of various active acyl compounds (344 X = O, S), (345 X = O, S) and (346) has been examined to assess its role as a nucleophile and general base.313 In water at pH 8.5 phosphate dianion functions as both nucleophile and base towards (344 X = S) the Nu role accounts for about 80-93% of the reaction, hi D2O the process is totally nucleophilic. For (345 X = S), the Nu- role is 40-50% of the reaction and for (346) the phosphate dianion adopts an entirely nucleophilic role, while the monoanion acts as a general base. 

In the above set of acetate esters shown in Fig. 10, the rate equation for the reaction of imidazole with esters contains a term first-order in imidazole (either a nucleophilic or general base reaction), a term second-order in imidazole, and a term first-order in imidazole and first-order in hydroxide. The general rate expression is given in equation (26). 

Neuvonen H. Kinetics and mechanisms of reactions of pyridines and imidazole with phenyl acetates and trifluoroacetates in aqueous acetonitrile with low content of water nucleophilic and general base catalysis in ester hydrolysis. J Chem Soc Perkin Trans II 1987 266 159-67. 

Several pieces of data support the role of certain amines as nucleophiles and others as general-base catalysts in this reaction. First, non-nucleophilic amines follow Bronsted relationships, but those amines that are small enough to be nucleophiles are markedly more active. Furthermore, solvent isotope effects are significantly different for the nucleophilic and general-base pathways. The small nucleophilic amines do not show solvent isotope effects, whereas the amines that act as general-base catalysts do show solvent isotope effects. 

For the intramolecular catalysis in the aminolysis of N-acetyl-imidazole by diamines [68, 69] the catalytic group is in the same molecule as the nucleophile, and the problem of distinguishing between nucleophilic and general base catalysis does not arise. The rate law for the aminolysis of N-acetylimidazole by monoamines has both terms of first and of second order in amine, but in the aminolysis by ethylene diamine the term which is first order in amine is relatively more important. The rate constant for this reaction is 186 times greater than that for a monoamine of comparable basicity and a similar rate enhancement is found for the reaction with 1,3-diaminopropane. Rather smaller rate enhancements are found with 1,4-diaminobutane and 1,5-diaminopentane (see Table 4). Intramolecular catalysis is also found in the aminolysis of methyl formate... 

Hydration is found to be susceptible to both general acid and general base (p. 74) catalysis, i.e. the rate-limiting step of the reaction involves either protonation of the carbonyl compound (general acid, 14), or conversion of H20 into the more nucleophilic OH (general base, 15) ... 

A critical input in unraveling the catalytic mechanism of epoxide hydrolases has come from the identification of essential residues by a variety of techniques such as analysis of amino acid sequence relationships with other hydrolases, functional studies of site-directed mutated enzymes, and X-ray protein crystallography (e.g., [48][53][68 - 74]). As schematized in Fig. 10.6, the reaction mechanism of microsomal EH and cytosolic EH involves a catalytic triad consisting of a nucleophile, a general base, and a charge relay acid, in close analogy to many other hydrolases (see Chapt. 3). 

The pH-rate profile for reaction of nitrosobenzene with A-methylhydroxylamine (to form only 1-methyl 2-phenyldiazene-2-oxide) has been found to exhibit a negative break between pH 0.5 and 3.0. This has been ascribed to a change in ratedetermining step from nucleophilic attack on nitrosobenzene at low pH to dehydration of the A,iV -dihydroxy intermediate at higher pH the dehydration is subject to general-acid catalysis a = 0.34) and specific and general-base catalysis (f) = 0.20). The pH-rate profile is similar to that for reaction of A-methylhydroxylamine with... 

Intramolecular general base catalysis of hycholysis (21a) was unexpected since the ester has a phenolic leaving group. Felton and Bruice (1968, 1969) reasoned that, if nucleophilic attack occurred, the leaving phenolate ion group would be properly positioned to attack the intermediate acylimidazole and thereby reverse the reaction. The normally less efficient general base reaction then becomes the favoured pathway, as in hydrolysis of acetyl salicylate (see Section 4). Likewise, Fife and McMahon (1970) explained bimolecular general base catalysis by imidazole (21b) in hydrolysis of o-(4-nitrophenylene) carbonate 3 49) by reversibility... 

The reaction of an amine with an ester generally produces an amide, and catalysis of hydrolysis occurs only in two special situations. Tertiary amines cannot give amides, and may act as nucleophiles or general bases to catalyze ester hydrolysis, and general base catalysis of hydrolysis may be observed with any amine, as long as competing reactions (in particular aminolysis) are relatively slow. 

Several broad themes recur frequently in enzymatic reaction mechanisms. Among the most important of these are (1) proximity effects, (2) general-acid and general-base catalysis, (3) electrostatic effects, (4) nucleophilic or electro-philic catalysis by enzymatic functional groups, and... 

In nucleophilic catalysis the catalytic properties are a result of the intermediate formation of a 1-acylimidazole (Scheme 27). When the ester has a good leaving group, e.g. p-nitrophenyl acetate, the effective catalyst is the imidazole neutral molecule which increases in effectiveness as the basic pKa of the heterocycle increases. Where, however, the ester has a poor leaving group, e.g. p-cresol acetate, the imidazole anion becomes involved and general base catalysis predominates. Thus, for imidazoles with pjK"a 4 catalysis by the anion is the main reaction. Imidazole is a much more effective nucleophile than other amines in this type of reaction since it is a tertiary amine with little steric hindrance, and it is able to delocalize the positive charge which results from the nucleophilic addition to... 

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