General base or nucleophilic

The rate constant /ct, determined by means of Eq. (6-47) or (6-48), may describe either general base or nucleophilic catalysis. To distinguish between these possibilities requires additional information. For example, in Section 3.3, we described a kinetic model for the N-methylimidazole-catalyzed acetylation of alcohols and experimental designs for the measurement of catalytic rate constants. These are summarized in Scheme XVIIl of Section 3.3, which we present here in slightly different form. 

The reaction of 14 may remind one of the well-established reaction mechanism for chymotrypsin (Fig. 5) (20). By comparing the acyl-trans-fer reaction of complex 14 with that of chymotrypsin 17, we find that the alcoholic nucleophiles in 14 and 17 are activated by Zn11—OH- and imidazole (in a triad), respectively. Several common features should be pointed out (i) Both reactions proceed via two-step reaction (i.e., double displacement), (ii) The basicity of Zn11—OH (pKa = 7.7) is somewhat similar to that of imidazole (plfa = ca. 7). (iii) The initial acyl-transfer reactions to alcoholic OH groups are rate determining, (iv) In NA hydrolysis with chymotrypsin, the pH dependence of both the acylation (17 — 18) and the deacylation (19 — 17) steps point to the involvement of a general base or nucleophile with a kinetically revealed piFCa value of ca. 7. A major difference here is that while the... 

An often occurring mechanistic problem is the diagnosis of general base or nucleophilic catalysis which give identical kinetics. Imidazole is a well known catalyst for the hydrolysis of 4-nitrophenyl acetate in water and it is known to involve nucleophilic attack because iV-acetylimidazole has been observed from ultraviolet spectral work [17]. The absence of a solvent deuterium isotope effect confirms the operation of the nucleophilic pathway (Table 7) because a primary isotope effect is expected for the general base mechanism. 

Much of the study of kinetics constitutes a study of catalysis. The first goal is the determination of the rate equation, and examples have been given in Chapters 2 and 3, particularly Section 3.3, Model Building. The subsection following this one describes the dependence of rates on pH, and most of this dependence can be ascribed to acid—base catalysis. Here we treat a very simple but widely applicable method for the detection and measurement of general acid-base or nucleophilic catalysis. We consider aqueous solutions where the pH and p/f concepts are well understood, but similar methods can be applied in nonaqueous media. 

On the oxidation side, the primary radical is symmetrically stabilized by addition of a base, or nucleophile, or by expulsion of an acid, in the general... 

In general, there are two immiscible phases in reaction mixture, viz. an aqueous phase which contains a salt (a base or nucleophile) and the other an organic phase containing the substrate which is expected to react with the salt. When a phase transfer catalyst (usually contains a lipophilic cation) is added to the reaction mixture, the lipophilic cation (which has solubility in both aqueous and organic phases), exchanges anions with the excess of anions in the salt solution. 

A similar bait and switch approach has been exploited for acyl-transfer reactions (Janda et al., 1990b, 1991c). The design of hapten [10] incorporates both a transition state mimic and the cationic pyridinium moiety, designed to induce the presence of a potential general acid/base or nucleophilic amino acid residue in the combining site, able to assist in catalysis of the hydrolysis of substrate [11] (Appendix entry 2.6). 

A kinetic smdy of the acylation of ethylenediamine with benzoyl chloride (110) in water-dioxane mixtures at pH 5-7 showed that the reaction involves mainly benzoylation of the monoprotonated form of ethylenediamine. Stopped-flow FT-IR spectroscopy has been used to study the amine-catalysed reactions of benzoyl chloride (110) with either butanol or phenol in dichloromethane at 0 °C. A large isotope effect was observed for butanol versus butanol-O-d, which is consistent with a general-base-catalysed mechanism. An overall reaction order of three and a negligible isotope effect for phenol versus phenol- /6 were observed and are consistent with either a base- or nucleophilic-catalysed mechanism. Mechanistic studies of the aminolysis of substituted phenylacetyl chlorides (111) in acetonitrile at —15 °C have revealed that reactions with anilines point to an associative iSN2 pathway. ... 

Lipscomb has commented that glutamic acid-245 might act either as a general base or a nucleophile. The available mechanistic information has been reviewed by Kaiser and Kaiser (1972), who postulated that the carboxylate anion of glutamic acid-245 acts as a nucleophile forming an anhydride intermediate [equation (29)]. The divergent D2O solvent isotope effects, =... 

Notes This is generally found as a base or nucleophile. 

As discussed above, hydroxide ion is one of the poorest leaving groups, so alkaline hydrolysis can always be classed as nucleophilic catalysis. Thus, even if a given nucleophile cannot catalyze the hydrolysis of an ester directly, it will be able to do so indirectly if it can assist the addition of water. And this is what a nucleophile does when it acts as a general base (or as a general acid). 

The hydrolysis of the more reactive carboxylic esters is catalyzed by a wide range of oxyanions. The mechanism proposed for the neutral hydrolysis of esters on p. 158 involves two molecules of water, one as a nucleophile and one as a general base. In principle an oxyanion or other nucleophile can replace either of these molecules, and both general base and nucleophilic catalysis of ester hydrolysis are well-known. The detailed mechanism of nucleophilic catalysis depends, to some extent, on the type of anion concerned, but the differences occur at a relatively late stage in the reaction, and the similarities are sufficient to allow generalizations about oxyanion reactions as a class. Some of the differences are not normally kinetically significant, and are best mentioned briefly at this point. 

The lower effective concentrations found in intramolecular base catalysis are due to the loose transition states of these reactions. In nucleophilic reactions, the nucleophile and the electrophile are fairly rigidly aligned so that there is a large entropy loss. In general-base or -acid catalysis, there is considerable spatial freedom in the transition state. The position of the catalyst is not as closely defined as in nucleophilic catalysis. There is consequently a smaller loss in entropy in general-base catalysis, so that the intramolecular reactions are not favored as much as their nucleophilic counterparts. 

Thus, by definition, electrophiles are electron-pair acceptors and nucleophiles are electron-pair donors. These definitions correspond closely to definitions used in the generalized theory of acids and bases proposed by G. N. Lewis (1923). According to Lewis, an acid is any substance that can accept an electron pair, and a base is any substance that can donate an electron pair to form a covalent bond. Therefore acids must be electrophiles and bases must be nucleophiles. For example, the methyl cation may be regarded as a Lewis acid, or an electrophile, because it accepts electrons from reagents such as chloride ion or methanol. In turn, because chloride ion and methanol donate electrons to the methyl cation they are classified as Lewis bases, or nucleophiles ... 

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