NMR SPECTROSCOPIC AND THEORETICAL CHEMISTRY STUDIES ON THE INTERNAL ACYL MIGRATION REACTIONS OF THE 1-O-ACYL-BETA-D-GLUCOPYRANURONATE CONJUGATES OF 2-(TRIFLUOROMETHYL)BENZOIC, 3-(TRIFLUOROMETHYL)BENZOIC, AND 4-(TRIFLUOROMETHYL)BENZOIC ACIDS

High resolution F-19 NMR spectroscopy has been used to investigate the kinetics of internal acyl migration and hydrolysis of the synthetic b eta-1-O-acyl-D-glucopyranuronates of 2-, 3-, and 4-(trifluoromethyl)be nzoic acids (TFMBAs) in phosphate buffer solutions at (30 degrees C) a s models of drug ester glucuronides. Apparent first-order degradation of the 1-O-acyl glucuronide and the sequential appearance of 2-, 3-, a nd 4-O-acyl isomers as both alpha- and beta-anomeric forms were observ ed fur each TFMBA isomer. The overall degradation rate constants of th e 2-, 3-, and 4-TFMBA 1-O-acyl isomers were 0.065 h(-1), 0.25 h(-1), a nd 0.52 h(-1). In order to probe the reasons for these differences in reactivity, theoretical structural and electronic parameters for the b eta-anomers of the 1-O-acyl glucuronides, their beta-2-O-acyl isomers, and both structures of the postulated ortho-acid ester intermediate w ere computed using semiempirical molecular orbital (AM1 and PM3) metho ds. The distinction between the slowly reacting 2-TFMBA glucuronide an d the much faster reacting 3- and 4-TFMBA glucuronides could be observ ed by calculation of the relative bond order of the C-O bonds in the o rtho-acid ester intermediates. The slow internal acyl migration rate o fthe 2-TFMBA isomer was also partly attributed to the high degree of s teric hindrance of the trifluoromethyl group obstructing attack by the glucuronic acid 2-hydroxy group on the carbonyl carbon to form the or tho-acid ester intermediate. Some calculated molecular orbital propel- ties, namely, dipole moment, energy of the lowest unoccupied molecular orbital (LUMO), LUMO density, and nucleophilic frontier density on th e carbonyl carbon, were also shown to be related to the measured half- lives. This work gives insight into the molecular physicochemical prop erties that influence the acyl migration kinetics of simple model drug glucuronides and is of potential importance in understanding more com plex drug glucuronide acyl migration reactions of toxicological intere st.