Bac2 mechanisms hydrolysis

In basic solution, a mechanism similar to the Bac2 mechanism for ester hydrolysis is believed to operate ... 

Fig. 43 Carbamate prodrugs [129a,b] are targets for abzyme cleavage to release a mustard [130] of enhanced cytotoxicity. ElcB hydrolysis of aryl carbonates involves the anion [131]. TSAs [132] and [133] were used to generate antibodies to catalyse a BAc2 mechanism for hydrolysis whose kinetic behaviour was evaluated with ester [134].

The acid-catalysed hydrolysis of the acylal, 1-phenoxyethyl propionate (13), has been studied using the PM3 method in the gas phase. The kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl and tetrahydropyran-2-yl alkanoates (14) in water and water-20% ethanol have been reported. In acidic and neutral media, kinetics, activation parameters, isotope-exchange studies, substituent effects, solvent effects and the lack of buffer catalysis pointed clearly to an Aai-1 mechanism with formation of the tetrahydro-2-furyl or tetrahydropyran-2-yl carbocation as the rate-limiting step (Scheme 1). There is no evidence of a base-promoted Bac2 mechanism up to pH 12. ... 

A dissociative elimination-addition pathway has also been proposed to account for the kinetics of alkaline hydrolysis of 2,4-dinitrophenyl 4 -hydroxyphenylpropionitrile in 40% (v/v) dioxane-water, although participation of the associative Bac2 mechanism cannot be ruled out since it may be facilitated by the electronic effect of the triple bond. Formation of intermediate (15), having a conjugated and cumulated double-bond system, should favour the ElcB mechanism and thereby account for the contrasting entropies of activation found for hydrolysis of (14) and the corresponding 4 -methoxyphenylpropionate. 

Further evidence for this mechanism is that a small but detectable amount of 180 exchange (see p. 332) has been found in the acid-catalyzed hydrolysis of benzamide.551 (180 exchange has also been detected for the base-catalyzed process,562 in accord with the Bac2 mechanism). Kinetic data have shown that three molecules of water are involved in the ratedetermining step,563 suggesting that, as in the Aac2 mechanism for ester hydrolysis (0-10), additional water molecules take part in a process such as... 

Rates of reactivity of HO- and H02- towards / -nitrophenyl /V,/V-dimcthylcarba-mate in ROH-H2O mixtures increased with increasing concentrations of IVOil and Bu OII, but the reverse was true for (CH20H)2.43 Kinetic studies of the alkaline hydrolysis of a series of secondary A -thiazolylcarbamates (19 R = H) and tertiary A-methyl-iV-thiazolylcarbamates (19 R = Me) have shown that they proceed by an ElcB and a BAc2 mechanism, respectively 44... 

The basic hydrolysis of a series of aryl AM4-X-benzenesull onyl)-/V-methyldithiocarbamates (65 X = MeO, Me, H, Cl, N02, CF3) in 30% aqueous dioxane at 25 °C proceeded via a BAc2 mechanism to give thiophenol, COS, and the corresponding (V-methyIsuI lonamidc, 4-X-CeH4S02NHMe.56... 

The total hydrolysis of phenylacetonitrile (Formula A in Figure 7.9) to phenylacetic acid (C) can be performed in one or two steps and both under acidic (following the mechanism in Figure 7.8) and basic conditions. In the latter case, the nucleophilic addition of a hydroxide ion to the nitrile carbon atom is the rate-determining step. This is how the imidic acid anion D is formed. Protonation (—> F), deprotonation (—> E) and reprotonation yield the amide B, which one can isolate or further hydrolyse under harsher conditions via the usual BAC2 mechanism (cf. Figure 6.24). 

Fig. 6.21. Bac2 mechanism of the basic hydrolysis of carboxylic esters.

That a single solvent molecule clustered to a nucleophile can drastically change the reaction pathway has been demonstrated by studying the reaction of phenyl acetate with methoxide ion in the gas phase [671, 672]. Alkaline hydrolysis of esters in solution is known to proceed by attack of the nucleophile at the carbonyl carbon atom to form a tetrahedral intermediate, followed by cleavage of the acyl-oxygen bond (Bac2 mechanism) cf. Eq. (5-138a). 

Studies of reaction kinetics, and use of isotopic labelling (180) [3], have established the general mechanism for base-catalysed hydrolysis of esters (i) of most primary and secondary alcohols (Bac2 mechanism [3]) shown in Fig. 7. 

Evidence for the Bac2 mechanism has come from isotopic labeling studies. Hydrolysis of ethyl, isopropyl, or f-butyl benzoate labeled with... 

It is possible to shift ester hydrolyses away from the normal Aac2 or Bac2 mechanisms by structural changes in the substrate. When the ester is derived from a tertiary alcohol, acid-catalyzed hydrolysis often shifts to a mechanism involving alkyl-oxygen fission. This shift is due to the stability of the carbonium ion that can be formed by C-O heterolysis, and probably also to a decrease in the rate of nucleophilic attack at the carbonyl group because of steric factors. Alkenes, as well as alcohols, may be produced from the carbonium ion, since water can function either as a nucleophile or as a Br0nsted base. 

Tertiary benzoyloxymethylsulfonamides (17) undergo hydrolysis via pH-independent and acid- and base-catalysed processes. Reactions are also buffer catalysed for buffer species with pXa values > 10.5. For the pH-independent pathway, hydrolysis takes place via formation of an Al-sulfonyliminium ion (Scheme 2). The mechanism of the acid-catalysed process involves pre-equilibrium protonation of the substrate followed by iminium ion formation. The base-catalysed pathway involves the normal Bac2 mechanism of ester hydrolysis. The buffer-catalysed reaction gives rise to a curved Brpnsted plot, with values of 1.6 and 0.25 for nucleophiles with pXa values <12.5 and >13, respectively. This is indicative of nucleophilic catalysis associated with a change in rate-limiting step from formation of the tetrahedral intermediate for buffer species with pXa > 13 to decomposition of the tetrahedral intermediate for buffer species with pXa < 12.5. ... 

The dissociative mechanism of acyl transfer ElcB), which prevails for the alkaline hydrolysis of 2,4-dinitrophenyl 4-hydroxybenzoate, could not be detected in a series of extended analogues. Thus, kinetic studies of the alkaline hydrolysis of the 2,4-dinitrophenyl esters of 4-(4 -hydroxyphenyl)benzoic acid (24), 4-(4 -hydroxyphenyl) azobenzoate (26 Z = Y = N), Al-(4 -hydroxybenzylidene)-4-aminobenzoate (26 Z = CH, Y = N) and 4 -hydroxy-fran5-stilbene-4-carboxylate (26 Z = Y = CH) showed that these compounds did not form the corresponding ElcB intermediates (25) and (27), but instead reacted through the usual Bac2 mechanism. ... 

---