Conf igurational Stability of 2-Benzoylcyclohexanone: Unexpected Solvent Effects on the Rate of Racemization GILBERT E. TUMAMBAC, CHRISTOPHER J. FRANCIS, and CHRISTIAN WOLF* Department of Chemistry, Georgetown University, Washington, DC ABSTRACT The kinetics of the racemization of 2-benzoylcyclohexanone 1 in hex- anes, ethanol, and mixtures thereof have been investigated by time dependence of enantiomeric purity using enantioselective HPLC. In pure hexanes and ethanol, the racemization half-lives were determined as 552 and 23.8 min, respectively, at 66jC. Surprisingly, racemization of 1 in mixtures of hexanes and ethanol was found to involve an induction period followed by a sigmoidal decrease of the enantiomeric excess with half-lives varying between 11.5 and 24.0 min. This unexpected solvent influence on the rate of racemization of 1 was attributed to complex isomerization mechanisms involving three possibly interconverting enol tautomers of 1. Chirality 17:171 – 176, 2005. A 2005 Wiley-Liss, Inc. KEY WORDS: benzoylcyclohexanone; racemization; tautomerization; enantioselec- tive HPLC The keto – enol tautomerism of b-diketones and b-keto esters plays a significant role in organic and organometal- lic chemistry 1 and has therefore been studied extensively using chromatographic 2 and spectroscopic techniques 3 as well as calorimetry 4 and X-ray crystallography. 5 Gas-phase studies performed with a variety of b-diketones and b-keto esters including acetylacetone, a-haloacetylacetones, ben- zoylacetone, and ethyl acetoacetate revealed a preference for the enol tautomer which has been attributed to intra- molecular hydrogen bonding. 6,7a In solution, keto – enol tautomerization has been found to depend on solvent com- position, temperature and concentration. 2,6 – 8 In general, enol formation is favored in nonpolar and aprotic solvents that do not disrupt intramolecular hydrogen-bonding. For a given solvent, the keto/enol ratio of b-diketones and b-keto esters has been reported to decrease with in- creasing temperature and concentration. X-ray and neu- tron diffraction experiments revealed a preference for the enol form and fast tautomerization between isomeric keto – enol structures of b-diketones and b-keto esters in the solid state, which was attributed to resonance-assisted intramolecular and intermolecular hydrogen bonding. 5 Diffraction studies conducted under cryogenic conditions have shown that the migrating proton is asymmetrically placed between both oxygens of the keto – enol isomers, i.e., both carbonyls undergo enolization. Enolization of ketones that have a chiral center bearing a hydrogen in the a-position results in racemization. Despite the numerous studies on keto – enol tautomerism and enol formation, few kinetic details of racemization reactions proceeding via an achiral enol intermediate can be found in the literature. In particular, racemization of chiral b-dicarbonyl compounds have not received much attention. Steric and electronic effects on the keto – enol equilibrium of 2-benzoylcyclanones have been studied by Campbell and Gilow. 9 The keto/enol ratio was reported to depend on the degree of coplanarity between the benzoyl moiety and the cycloalkyl ring. Based on UV and IR spec- troscopy and halogen titration experiments, it was con- cluded that deviation from a coplanar arrangement destabilizes the enol form in the case of 2-benzoylcyclo- hexanone and 2-benzoylcycloheptanone, showing 3% and 7% enol content in methanol, respectively. 9b According to Spencer and co-workers, the surprisingly low enol content of these b-keto esters can be attributed to the disruption of the intramolecular hydrogen bonding in methanol and formation of intermolecular hydrogen bonds with the sol- vent resulting in unfavorable entropic change. 4 Since enolization of chiral b-diketones and b-keto esters results in racemization, the study of the stereochemical stability of these compounds may be of importance to asymmetric synthesis, dynamic kinetic resolution, and chi- ral chromatography. It may also be important for the de- termination of the pharmacological and pharmacokinetic integrity of pharmaceuticals exhibiting a chiral center that can undergo tautomerization and thus racemization. We therefore decided to study the kinetics of the racemization of 2-benzoylcyclohexanone, 1 (Scheme 1). It should be noted that the interconversion of the enantiomers of 1 via enol 2 involves two consecutive reversible reaction steps that proceed via an achiral intermediate, while racemiza- tion of a pure or enantioenriched enantiomer is generally considered an irreversible process. 10 The kinetics of other *Correspondence to: Christian Wolf, Department of Chemistry, George- town University, Washington, DC, 20057. E-mail: cw27@georgetown.edu Received for publication 3 November 2004; Accepted 20 January 2005 A 2005 Wiley-Liss, Inc. CHIRALITY 17:171–176 (2005) DOI: 10.1002/chir.20148 Published online in Wiley InterScience (www.interscience.wiley.com).