Stabilisation of intermediates by proton transfer

The extent of catalysis depends critically upon the stability of the intermediate 1. If the rate of expulsion of H20 from 1 (rate constant 7c i) is slower than proton transfer to solvent water, the rate of formation of the intermediate (rate constant ki) will be the rate-limiting step and no catalysis will be observed. The rate constant for protonation of the amine nitrogen of 1 by solvent water, 7cHa (HA = H20), depends on the basicity of the nitrogen and is given by kAKw/Ka, where kA represents the rate constant for diffusion-controlled abstraction of a proton by hydroxide ion, with a value of approximately 1010 M-1 s 1, and 

Ka is the acid dissociation constant of the ammonium group of 2. If the rate of expulsion of H2O from 1 to regenerate reactants is faster than (or similar to) the rate at which 1 is trapped by proton abstraction from water, the rate-limiting step occurs after the formation of intermediate 1, and the addition of general acids (i.e. other proton donors) may increase the observed rate. 

The rate constant for expulsion of RNH2 to regenerate the reactants, k 1, is between 106 and 109 s-1 and much faster than that for proton transfer to water (B = H20), which is between 10-1 and 102 s 1. When the general base catalyst is a second molecule of amine 

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