The Influence of Unsaturation and of Fluorine Substitution on Ketone-Alcohol Equilibrium Constants. A Measure od α,β-Unsaturated Ketone Resonance Energy and of Halogen Destabilization

Metabolism of 11-oxygenated steroids. Metabolism in vitro by preparations of liver

“…Effect of 12cc-fluorine. The enhancement of reduction rates of cc-haloketones has now been observed in the steroids with 2a-fluoro saturated 3-ketones, with 4-fluoro-, 6,-fluoro-, and 6a-fluoro-A4-3-ketones (Ringold et al 1964a), with 16-fluoro-17-ketones (Offner, Ryan, Smith, Fried & Munson, 1962) and with a sizable range of 9cc-fluoro-11ketones.…”

“…A. Eschenmoser & J. Schreiber (personal communication) supposed that this was mainly due to stabilization of the 1 l,B-hydroxy group by the negative inductive effect of the 9a-halogen (see also Ro6ek, Westheimer, Eschenmoser, Moldovanyi & Schreiber, 1962). In a study of the influence of fluorine substitution on the redox equilibria of steroid 3-ketone-3a-ol pairs catalysed by 3a-hydroxy steroid dehydrogenase, Ringold, Lawrence & Graves (1964a) found that (equatorial) 2a-fluorine substitution increased the free energy of reduction of saturated 5a-hydrogen-3ketones from 5-8 to 8-5kcal./mole, corresponding to 100-fold decrease in the equilibrium constant expressed as ketone/alcohol. They attributed this to destabilization of the ketone group on the basis of the well established bathochromic shift of the carbonyl stretching frequency in the infrared spectrum and other chemical findings.…”

“…The situation is rather different in the 9aand 12a-halo-11-oxo steroids, because in both cases the halogen is an axial substituent and the reduction product is a tran8-1,2-diaxial halohydrin. However, Ringold, Ramachandran & Forchielli (1964b) found that the substitution of (axial) 6,8-fluorine produced a larger effect than the substitution of (equatorial) 6a-fluorine on the enzymic reduction of A4-3-oxo steroids, an effect complicated by two factors: (a) an inhibition of polarization of the C-4-C-5 double bond; (b) facilitation of hydride transfer from NADPH (Ringold et al 1964a).…”