Kinetic investigation of the nucleophilic cleavage of spiroactivated cyclopropanes

Stephen S Templin, Marquette University


Part I. The kinetics of the ring cleavage reaction of 6,6-dimehtyl-1-phenylspiro (2.5) octan-4,8-dione (6a) with pyridine was investigated. Mechanistic insight was gained by determining the reactivity under conditions of various media, substituents, nucleophiles and temperatures and interpreting the results. The solvent effects on the reaction rates of the previously studied systems 6,6-dimethyl-1-phenyl-5,7-dioxaspiro (2.5) octan-4,8-dione$\sp1$ (4a) and 3,3,10,10-tetramethyldispiro ( -trideca-1,5,8,12-tetraone (TACP)$\sp2$ gave conflicting results. The rate of the reaction of the mono-spiroactivated system (4a), in which the activating group is a diester functionality, with pyridine increased with increasing solvent polarity, as expected for this S$\sb{\rm N}$2 reaction. The rate of the reaction of the di-spiroactivated system (TACP), in which the activating groups are both diketone functionalities, with pyridine did not exhibit normal solvent effects. The rate of the reaction of the present system (6a), which contains only one spiroactivating group as does 4a but the group is a diketone functionality as in TACP, exhibited normal solvent effects. Therefore, the unusual solvent effects observed for the reaction of TACP are due to the presence of two activating groups and not the nature of the group itself. Part II. The solvolysis of 1-methyl-4,6-di-t-butylspiro (2.5) octa-3,6-dien-5-one (11b) was studied in order to interpret the effects of varying the substituents and the solvent pH on the reaction rate. The mechanisms of the hydrolysis of 11b in neutral and acid media are of importance due to the relationship to the biologically active compound CC-1065$\sp3$. Acid catalyzed and neutral hydrolysis studies on CC-1065 reactive site analogues$\sp{4,5}$ have been utilized in conflicting reports on the involvement of the spiroactivated ring cleavage in the antitumor activity of CC-1065 and its analogues. Solvent isotope effects of the neutral hydrolysis of 11b indicate that the reaction follows an S$\sb{\rm N}$2 mechanism. Solvent isotope effects in acidic media and the presence of general acid catalysis indicate that the reaction proceeds by an A-2 mechanism in acid.

Recommended Citation

Templin, Stephen S, "Kinetic investigation of the nucleophilic cleavage of spiroactivated cyclopropanes" (1991). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI9226224.