Kemp decarboxylation hydrogen bonds

Kemp et al., 1978). The rate is slowest in an aqueous solution and is enhanced in aprotic and/or dipolar solvents. The rate augmentation of 106—108 is attainable in dipolar aprotic solvents such as dimethyl sulfoxide and hexamethylphosphoramide (HMPA). Interestingly, the decarboxylation rate of 4-hydroxybenzisoxazole-3-carboxylate [53], a substance which contains its own protic environment, is very slow and hardly subject to a solvent effect (1.3 x 10-6 s-1 in water and 8.9 x 10-6 s-1 in dimethylformamide Kemp et al., 1975). The result is consistent with the fact that hydrogen-bonding with solvent molecules suppresses the decarboxylation. 

The effect of additives betrays the intricacy of the balance of rate effects even more. The addition of cholesterol to catalytic bilayers has been found to be beneficial for the Kemp eleminiation but to inhibit the decarboxylation of 6-NBIC. In general, the effects of additives on the decarboxylation of 6-NBIC appear to subtly depend on the structure of the hydrophobic tail and hydrophilic headgroup of additives. Similarly subtle effects were found for the Kemp elimination and nucleophilic attack by Br and water on aromatic alkylsulfonates depending on the choice of additive, hydrogen bonding effects, reactivity of partially dehydrated OH , and local water concentrations all played a role and vesicular catalysis could be increased or decreased. 

To estimate the impact of these molecular solvent effects the division of solvents into protic (H-bond donor and acceptor) and aprotic (at most H-bond acceptor) ones is very helpful since the formation of specific hydrogen bonds often increases or decreases the reaction rate drastically. The rate for Kemp decarboxylations of benzisoxazole-3-carboxylic acid derivatives accelerate by a factor of about 10 when the solvent character changes from polar protic to polar aprotic. Hydrogen bonds between the reacting anion and the protic solvent were determined to be the most important factor for this acceleration [655, 656]. 

Acevedo O, Jorgensen WL (2005) Influence of inter- and intramolecular hydrogen bonding on Kemp decarboxylations from QM/MM simulations. J Am Chem Soc 127 8829-8834... 

In addition to multiparametric equations, mixed quantum and molecular mechanics simulations reproduced the observed solvent effects quite well. These simulations also support the conclusion from previous work about the anticatalytic role of hydrogen bonds in the Kemp decarboxylation. 

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