Comparison of the gas-phase basicities and relative methylation nucleophilicities of carbonyl-containing compounds

The gas-phase basicities and relative methylation nucleophilicities of a series of simple cyclic carbonyl-containing compounds were evaluated in order to understand the low reactivities of some barbiturates and anti-convulsants in the gas phase. The gas-phase basicities were determined by the bracketing method, and the relative methylation nucleophilicities were characterized by monitoring ion-molecule reactions with CH3OCH2+ ions from dimethyl ether. Heats of formation were calculated for the protonated and methylated structures in order to estimate the favored sites of protonation and methylation. As shown in this paper, the positions of the carbonyl groups have a striking effect on the relative gas-phase basicities and methylation rates within a related series of compounds. For those compounds with two carbonyl groups in 1,2 positions, the methylation efficiency is enhanced by a factor of 100 over those compounds with two carbonyl groups in the 1,3 or 1,4 positions. This large difference is attributed to the variation in molecular dipole moments of the three cyclohexanediones and the relative positions of the two carbonyl groups. Cyclohexane-1,2-dione has the greatest dipole moment, leading to the highest interaction energy with the CH3OCH2+ reactant, and has the capability for cooperative interaction during the attack on CH3OCH2+ and subsequent rapid methyl cation transfer between the two carbonyl groups, thus enhancing the reaction rate and product stability. The order of gas-phase basicities is also strongly influenced by the number and positions of the carbonyl groups and the presence of a nitrogen atom in the ring. For example, glutarimide, which has two carbonyl groups surrounding a nitrogen atom in the ring, has a gas-phase basicity that is about 10 kcal mol-1 less than that of cyclohexane-1,3-dione. This result is attributed to the restriction of partial hydrogen-bond formation between the two carbonyl groups in glutarimide because of increased planarity of the ring due to the nitrogen atom.