Abstract
In Chapter 1, the kinetics and mechanism of the detritiation of various azoles namely, [2-[3]H]thiazole, [2-[3]H]benzothiazole, [2-[3]H]benzo-xazole and [3(5)-[3]H]-1,2,4-triazole have been studied at a temperature of 85.0° over the pH range 0-12. The pH-rate profiles indicate that, in general, two reaction mechanisms are in operation. Firstly, rate-determining attack of hydroxide ion on the protonated form of the substrates giving rise to ylide intermediates - this is predominant at pH values lower than 5. Secondly, rate-determining attack of hydroxide ion on the netural form of the substrate giving rise to carbanions -this mechanism becomes predominant at high pH values. The good agreement between the experimental and theoretical pH-rate profiles, the latter having been constructed on the basis that one or other, or both, of these mechansims are operative, provided good support for the above interpretation. Similarly the effects of position and type of heteratom(s) on the rates of detritiation are consitent with these mechanisms. However the pH-rate profile for [5-3H]tetrazole was different from the other azoles, suggesting that other exchange pathways are involved in this case. In Chapter 2, the rate of detritiation of histidine derivatives, namely, [2-[3]H]histamine, glycyl-2-[-[3]H]-L-histidine and glycyl-[2-[3]H]-L-histidyl-glycine were also measured as a function of pH at 85. 0. The pH-dependence of the detritiation rates is consistent with rate-determining attack of hydroxide ion on the protonated form of the substrate. The presence of neighbouring ionisable groups (NH[3+], COO[-]) affects the rates of exchange in a manner depending on the proximity of these groups to the reaction centre. In Chapter 3, the detritiation of the antibiotic [8-[3]H]puromycin and the anti-leukemia agents [8-[3]H]-6-mercaptopurine and [8-[3]H]-6-mercaptopurine riboside have been studied as a function of pH at 85.0. Similar exchange pathways to those proposed for the detritiation of simple azoles are involved. In the case of 6-mercaptopurine riboside an additional pathway involving hydroxide ion attack on the anion is predominant at high pH values.