Tautomerization of formamide, 2-pyridone, and 4-pyridone: an ab initio study

Abstract

The tautomerism of formamide, 2-pyridone, and 4-pyridone has been investigated by ab initio calculations using minimal, extended, and polarization basis sets. When the effects of geometry optimization, polarization functions, correlation energy (estimated by second-order Merller-Plesset perturbation theory), and zero-point vibration energy are combined, the following theoretical estimates are obtained: formimidic acid is 12 kcal/mol less stable than formamide, 2-pyridone is 0.3 kcal/mol more stable than 2-hydroxypyridine and 4-hydroxypyridine is 2.4 kcal/mol more stable than 4-pyridone. Only the 2-pyridone tautomerism has been observed directly in the gas phase, and theory is in good agreement with all three experimental values (0.3 f 0.3,O.l & 0.6,0.6 f 0.1 kcal/mol). In the case of 4-pyridone, the theoretical value may be closer to the actual tautomerization energy than the 7 kcal/mol in favor of hydroxypyridine obtained from indirect experiments. For the heterocycles, relative geometries of tautomers optimized with a minimal basis or semiempirical methods are as satisfactory as structural changes obtained at extended basis set levels. Relative tautomerization energies are reproduced well with the minimal or extended bases, while absolute tautomerization energies require consideration of polarization functions, correlation energy, and zero-point vibration. Tautomerism such as displayed by pyridone/hydroxypyridine plays a role in many areas of chemistry and biochemistry: e.g., the rationalization of structures, properties, and reactivities in heterocyclic chemistry;'*2 concepts and probes of aromaticity;3 measures of intrinsic stabilities vs. solvent mechanisms of enzymatic catalysis and receptor interactions;6 and possibly even mutations during DNA replicati~n.~.~ Investigations of tautom- erism of 2-pyridone date from 1907.8 Most studies since then have dealt with the equilibrium in liquid media,'v9 where the pyridone tautomer is preferred by a factor of 1000. X-ray crystallography shows that pyridone is also favored in the solid.'*I2 The dominance of the pyridone tautomer in solution, neat liquid, and solids has been shown to be the result of strong solvent effects, ion binding, and self- association^.'^^^^^^^'^ In contrast, recent IR and UV measurements have established that the two tautomers are nearly equal in energy when unassociated in the vap~r.~,'~J~ Similar gas-phase tautomerizations have since been investigated for a number of lactam/lactim pairs by using IR,I9 UV,zo pho- toelectron,21*22 ion cyclotron resonan~e,~~-~~ and mass spectros- copy.26*27 All of these gas-phase equilibria show marked dif- ferences from solution data.'*2,9,'3-'7*z8 Numerous theoretical studies with almost every available method have attempted to reproduce the tautomerization energy for pyridone/hydroxypyridine and similar heterocyclic systems2- Simulations of hydrogen bonding and solvent interactions re- produce qualitatively the shift in the equilibrium toward pyridone in condensed However, quantitative agreement with the tautomerization energy in the vapor has been difficult to obtain. Geometry optimization, basis-set flexibility, correlation energy, and zero-point vibration have been recognized as important contributors to these and related45-55 isomerization reactions. In this paper, we report an extensive series of ab initio computations on formamide, 2-pyridone, 4-pyridone, and their tautomers that take these factors into account. Method Ab initio calculations were carried out with the GAUSSIANBO series of programss6 by using minimal (STO-3G), extended(3-21G and 6- 31G),5*~~~ and polarization (6-31G*) basis sets. The extended basis sets are of the split-valence. type, and the polarization basis set is an extended basis augmented by a shell of six Cartesian d-type Gaussians on each non-hydrogen atom. Energies were calculated in the Hartree-Fock (HF) approximation, and correlation effects were estimated via second-order