Bis-ortho-substitution by methyl groups dramatically increases the racemization barrier of Tröger bases

We have shown through racemization kinetics studies that the enantiomerization barriers of the bis-ortho-methyl substituted Tröger bases 2 and 3 in acidic media are raised by 30 kJ mol(-1) relative to the parent compound 1, that is 130.4(4) and 131.6(4) kJ mol(-1), respectively (105 degrees C, pH 1, ethylene glycol). The enantiomerization barrier of para-methoxy-para-nitro substituted Tröger base 4 was determined by dynamic capillary electrophoresis to 96.3(2) kJ mol(-1) (25 degrees C, pH 2.2, H(2)O), which is lower by 5 kJ mol(-1) relative to 1. The influence of deutero-substitution on the racemization rates was also studied. The influence of steric and electronic factors on the enantiomerization barrier was investigated by quantum-mechanical (DFT) calculations. It is shown that enantiomerization takes place in two steps: ring-opening and further interconversion of the monocyclic intermediate. For the interconversion to occur a transition state has to be passed which is sensitive to steric effects. Ortho-substitution by methyl groups significantly increases the energy of this state. Thus, compounds 2 and 3 are the simplest Tröger bases which are configurationally stable in acidic media.