Proximity Effects in Organic Chemistry

Proximity of reactive groups in a chemical transformation allows bond polarization, resulting generally in an acceleration in the rate of the reaction. In nature this is normally achieved by a well-defined alignment of specific amino acid side chains at the active site of an enzyme. 

The first example is the hydrolysis of a glucoside bond. o-Carboxyphenyl jS-D-glucoside (1-1) is hydrolyzed at a rate 10 faster than the corresponding 

This illustrates the fact that the proper positioning of a group (electrophilic or nucleophilic) may accelerate the rate of a reaction. There is thus an analogy to be made with the active site of an enzyme such as lysozyme. Of course the nature of the leaving group is also important in describing the properties. Furthermore, solvation effects can be of paramount importance for the course of the transformation especially in the transition state. Reactions of this type are called assisted hydrolysis and occur by an intramolecular displacement mechanism steric factors may retard the reactions. 

Let us look at another example 2,2 -tolancarboxylic acid (1-4) in ethanol is converted to 3-(2-carboxybenzilidene) phthalide (1-5). The rate of the reaction is 10 faster than with the corresponding 2-tolancarboxylic or 2,4 -tolancarboxylic acid. Consequently, one carboxyl group acts as a general acid catalyst (see Chapter 4) by a mechanism known as complementary bU functional catalysis. 

The ester function of 4-(4 -imidazolyl) butanoic phenyl ester (1-6) is hydrolyzed much faster than the corresponding -butanoic phenyl ester. If a p-nitro group is present on the aryl residue, the rate of hydrolysis is even faster at neutral pH. As expected, the presence of a better leaving group further accelerates the rate of reaction. This hydrolysis involves the formulation of a tetrahedral intermediate (1-7). A detailed discussion of such intermediates 

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