Induced intramolecularity in the reference reaction can be responsible for the low effective molarity of intramolecular general acid–base catalysis

Abstract

AbstractWhereas intramolecular catalysis by nucleophilic groups can be associated with values of effective molarities ranging from 105 to 108 M in the absence of strain, values below 10 M are usually observed for general acid–base catalysis. Based on the grounds that the efficiency of intramolecular reactions is related to the entropic disadvantage of bimolecular reactions, this low efficiency is usually explained by a loose transition state for proton transfer that is diffusion limited in the thermodynamically favorable direction. However, the transient formation of a hydrogen bond at an electronegative center provides another possibility that can account for the low efficiency of general acid–base catalysis when the reaction is not diffusion limited. Any proton transfer at a site that forms hydrogen bonds to the solvent and that is concerted with a slower process is likely to take place along a hydrogen bond with the catalyst and thus to have an intramolecular character. As a result, low benefits can be earned from further intramolecularity. This analysis has important consequences for intramolecular and enzymatic proton transfers to and from carbon atoms. Owing to the absence or the weak strength of hydrogen bonds capable of inducing intramolecularity in the non‐catalyzed mechanism, high effective molarities could be recovered. As a result, the existence of strong hydrogen bonds with carbon acids would no longer be needed to account for the high effective molarities that have been observed in some cases for intramolecular proton transfer to or from carbon. Moreover, the introduction of new concepts such as short, strong hydrogen bonds (low‐barrier hydrogen bonds) to account for the high efficiency of enzymatic proton abstraction from carbon would not be necessary. Copyright © 2002 John Wiley & Sons, Ltd.