Quantum Chemical Calculation ofTautomeric Equilibria

Frequently, energy differences are quite small and hence require very accurate calculations which can be fiendishly difficult Thus, the choice of an appropriate electronic structure procedure is very important. Furthermore, environmental influences (solvent) have a profound effect on the position of tautomeric equilibria. Consequently, a proper description of solvation is essential. Alternatively, some property that might be useful to distinguish between tautomers could be 

Tautomerism Methods and Theories, First Edition. Edited by Liudmil Antonov. 

An apparently trivial but important point to be considered is the generation of structures. Although for simple systems all the possible tautomeric forms can be easily drawn, in other cases the situation is less clear for example, 15 sttuctures for xanthine were provided to the participants in the SAMPL2 challenge as many as 40 sttuctures (tautomers and conformers) have been considered for warfarin [8]. Several tools exist to handle the tautomer enumeration problem [9], but these rely on experimental data and/or empirical rules (mosdy pJC values) and hence not all types of tautomerism might be described correctly. 

This chapter is intended to present an overview and critical evaluation of available computational procedures for treating tautomeric equilibria. It is not intended to provide an introduction to computational chemistry. Several excellent books on this topic exist (10, 11]. Applications to a variety of problems in organic chemistry, including tautomeric equilibria, are described by Bachrach [12]. 

Available methods are based on either classical mechanics (force field methods) or quantum mechanics. Force fields are important in the context of quantum mechanics/molecular mechanics (QM/MM) procedures and hence were described in detail in Chapter 10. A short mention will be made here in the paragraph on 

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