Multiple changes in rate-determining step in the acid and base catalyzed cyclizations of ethyl N-(p-nitraphenyl)hydantoates caused by methyl substitution

The slopes of the pH-rate profiles for the cyclization of 2-methyl- and 2,3 -dimethyl hydantoates 1-NPU and 2-NPU between pH 1 and 7 change from 1 to 0 and then back to 1. A reaction first order in H+ was observed with the lat ter compound. The 2,2,3-trimethyl derivative 3-NPU showed only one reaction first order in OH-, but complex acid catalysis is described by slopes 0, - 1, 0, and finally -1 again. The cyclizations were general base catalyzed, w ith Bronsted beta values of 0.5-0.6. The OH- catalysis at higher pH for 1-N PU and 2-NPU showed inverse solvent kinetic isotope effects and deviated fr om the Bronsted relationships, while that for 3-NPU showed a normal effect and complied with the Bronsted relationship. The accelerations due to the g em-dimethyl effect were lost with the OH- and general base-catalyzed reacti ons of 3-NPU. This behaviour is due to a change from the rate-determining f ormation of the tetrahedral intermediate with 1-NPU and 2-NPU to the rate-d etermining breakdown with 3-NPU, due to steric hindrance to protonation of the leaving ethoxy group. The OH- reaction at higher pH involves attack of the ureide anion with 1-NPU and 2- NPU, becoming concerted with deprotonati on when catalyzed by general bases and changing to acid inhibition of the a nion of the tetrahedral intermediate at low pH. With 3-NPU at higher pH, T- is in equilibrium and the conjugate acids of the general bases accelerate its breakdown by protonating the ethoxy group. Acid catalysis of the cycliz ation of 3-NPU at higher pH is also protonation of the leaving group from T O changing to the rate-determining formation of T at lower pH. The latter m echanism is preferred for the cyclization of 2-NPU.