HYDROLYSIS OF GENOTOXIC METHYL-SUBSTITUTED OXIRANES - EXPERIMENTAL KINETIC AND SEMIEMPIRICAL STUDIES

The kinetics of acid-catalyzed hydrolysis of seven methylated aliphati c epoxides-(RRC)-R-1-C-2(O)(CRR4)-R-3 (A: R-1=R-2=R-3=R-4,H; B: R-1=R- 2=R-3=H, R-4=Me; C: R-1=R-2 H, R-3=R-4=Me; D: R-1=R-3=H, R-2=R-4=Me(tr ans); E: R-1=R-3=H, R-2=R-4=Me(cis); F: R-1=R-3-R-4=Me, R-2=H; G: R-1= R-2=R-3=R-4=Me)-has been studied at 36 +/- 1.5 degrees C. Compounds wi th two methyl groups at the same carbon atom of the oxirane ring exhib it highest rate constants (k(eff) in reciprocal molar concentration pe r second: 11.0 +/- 1.3 for C, 10.7 +/- 2.1 for F, and 8.7 +/- 0.7 for G as opposed to 0.124 +/- 0.003 for B, 0.305 +/- 0.003 for D, and 0.63 5 +/- 0.036 for E). Ethylene oxide (A) displays the lowest rate of hyd rolysis (0.027 M-1 s(-1)). The results are consistent with literature data available for compounds A, B, and C. To model the reactivities we have employed quantum chemical calculations (MNDO, AM1, PM3, and MIND O/3) of the main reaction species. There is a correlation of the logar ithm k(eff) with the total energy of epoxide ring opening. The best co rrelation coefficients (r) were obtained using the AM1 and MNDO method s (0.966 and 0.957, respectively). However, unlike MNDO, AM 1 predicts approximately zero energy barriers for the oxirane ring opening of co mpounds B, C, F, and G, which is not consistent with published kinetic data. Thus, the MNDO method provides a preferential means of modeling the acidic hydrolysis of the series of methylated oxiranes. The gener al ranking of mutagenicity in vitro, A > B > C, is in line with the co ncept that this sequence also gradually leaves the expoxide reactivity optimal for genotoxicity toward reactivities leading to higher biolog ical detoxifications.