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Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the enzyme active site accompanied by loss of the carbamate leaving group followed by hydrolysis of the carbamoyl enzyme. This hydrolysis, or decarbamoylation, is relatively slow, and half-lives of carbamoylated AChEs range from 4 min to more than 30 days. Therefore, carbamates are effective AChE inhibitors that have been developed as insecticides and as therapeutic agents. We show here, in contrast to a previous report, that decarbamoylation rate constants are independent of the leaving group for a series of carbamates with the same carbamoyl group. When the alkyl substituents on the carbamoyl group increased in size from N-monomethyl- to N,N-dimethyl-, N-ethyl-N-methyl-, or N,N-diethyl-, the decarbamoylation rate constants decreased by 4-, 70-, and 800-fold, respectively. We suggest that this relationship arises as a result of active site distortion, particularly in the acyl pocket of the active site. Furthermore, solvent deuterium oxide isotope effects for decarbamoylation decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE, indicating a shift in the rate-limiting step from general acid-base catalysis to a likely conformational change in the distorted active site.

415 mum 2.67)5 and the isomerization of 2-aryl-3-methyl-2-butene (2.34),20 both in acetic acid.Whether the maximum theoretical C-H isotope effect is reckoned to be 6.2 (zero-point energy only), 10 (allowing for bending vibrations), or higher still if the tunnel effect is included,21 these are small isotope effects and are therefore indicative of an asymmetric transition state,22 relatively close either to the carbonium ion or to the product. Since the former is of much higher energy, consideration of the Hammond postulate% suggests that the transition state for slow proton transfer will be in fact carbonium ion like. ConclusionThis reaction, the dehydration of 1,l'-diadamantylmethylcarbinol in aqueous acetic acid, is unusual in that variation of the solvent composition causes the deuterium KIE to vary over a wide range. This phenomenon is attributable to the fact that one of the components of the reaction medium, water, causes the intermediate carbonium ion to revert to starting material, while the major component, acetic acid, is apparently inert. A very simple kinetic scheme leads to an equation which expresses the overall KIE in terms of the water concentration. The data Two water-insoluble compounds, bis(4-nitrophenyl) carbonate and p-chlorobenzhydryl chloride, solvolyze in micelles at rapid rates indicative of highly aqueous binding sites. This is used as evidence against the classical Hartley micelle and in support of a "porous cluster" model bearing water-filled regions where guests bind hydrophobically. The conclusions from the kinetic data agree with those from a variety of other approaches used in this laboratory including I3C NMR, gas solubility, ORD, and molecular models.Reactivity inside a micelle generally differs from that in bulk water. This fact has been widely used to probe the 0022-3263/81/1946-0415$01.00/0 nature of micellar enviromnents.lJ Of course, it is seldom easy to interpret small catalytic or inhibitory effects with

The neutral hydrolysis of p-nitrophenyl trifluoroacetate in acetonitrile solvent has been studied by varying the molarities of water from 1.0 to 5.0 at 25 degrees C. The reaction is found to be third order in water. The reaction is also third order in D(2)O and in methanol when D(2)O and methanol replace water as the solvent. The kinetic solvent isotope effect is (kH(2)O/kD(2)O) = 2.90 +/- 0.12. Proton inventories at each molarity of water studied are consistent with an eight-membered cyclic transition state model. In this model, three protons undergo bonding changes. Such an eight-membered transition state model can easily accommodate linear hydrogen bonds for the three transferred protons. These results are consistent with the experimental findings of Bell and Critchlow(1) on the reversible addition of water to 1,3-dichloroacetone in dioxane and the theoretical findings of Wolfe and co-workers(2) on the hydration of formaldehyde.

Substituted phenols serve as general-acid catalysts of leaving-group departure from the adduct of methoxide ion with 7n-N02C6H4N(CH3)COCF3 in methanol at 25 °C. Sufficiently high concentrations of general acid convert methoxide addition to the rate-limiting step, allowing determination of rate constants for methoxide addition to substrate carbonyl (fea = 300 M-1 s-1), for overall solvent-assisted leaving-group departure (fee = kake'/k^= 5.9 M-1 s-1) and for overall general-acid-catalyzed leaving-group departure (fcBH = kJtBB fk^= 2400 ± 1200 M"2 s-1 for five substituted phenols with pKa's from 12.7 to 14.6). Thus the Bronsted a ~0. It is suggested that the general acid is a spectator at spontaneous expulsion of the leaving group, producing catalysis by fast subsequent trapping of CH3NAr-. The Jencks clock shows the tetrahedral intermediate to have a minimum characteristic lifetime of 1-10 ns.

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