* no barrier to formation of INT1 from REACT, ** no barrier to formation of PROD from INT2

3.1 General Reaction Scheme

The reaction simulated is described in Scheme 1 where methylamine is used to simulate a generic amine nucleophile. The reaction involves an acid catalyzed process through the inclusion of a methylammonium cation and two water molecules. The first step sees the SN2 based substitution of the carbonyl of the substrate by the methylamine, the breaking of the carbonyl double bond with concomitant proton transfer from the methylammonium cation to give the corresponding carbinolamine. As can be seen from Figure 1, the transition state (TS1) associated with the nucleophilic attack at position-a of compound 22 has a short C-N nucleophilic distance of 2.0 Å. However, it does not involve noticeable proton transfer to the oxyanion being formed, this occurring after the barrier has been traversed. Furthermore, it is found that nucleophilic attack of the carbonyl directly connected to the phenyl ring (position-b) results in a dramatically higher barriers to reaction (9.3 vs 21.3 kcal/mol) as a result of the loss of resonance effects with the carbonyl bond not observed at the other position. This also helps to explain why the corresponding intermediate at position-a is considerably lower in energy (-3 vs 9.9 kcal/mol).
Despite position-a having the lowest barrier to substitution, it is found that position-b has the lowest barrier associated with the elimination of water and the formation of the imine. This can be explained by the resonance stabilization afforded by the phenyl ring attached to position-b. The reaction proceeds with shuttling of a proton from the amine of the carbinolamine intermediate to its hydroxy groupvia a water molecule. The proton transfer step is essentially complete at the transition state with the C-O carbinolamine bond being 1.5 Å. The barrier to reaction for position-a is found to be 26.9 kcal/mol compared to 18.7 kcal/mol for position-b. The final step in the reaction requires the abstraction of the remaining proton on the imine nitrogen to generate the neutral product. This step is found to be a low energy process (~0.1-10 kcal/mol) and sees the regeneration of the methylammonium catalyst.
All compounds simulated follow the same general trends as compound 22 . Two exceptions are compounds 10 and 16 which do not display a barrier to substitution (TS1) for positions containing strongly electron withdrawing groups. Furthermore, 16 forms product directly from INT2 without the formation of INT3. More detailed analysis of the complete reaction profiles of all molecules in Table 1 showed clearly that the barrier to water elimination (TS2) was observed to be the rate determining step for the conversion of the substrates to the corresponding SB. The TS2 barrier heights for the main chemical classes present ranged from ~ 18-25 kcal/mol for 1,3 diones (6), ~21-34 kcal/mol for 1,2 diones (5), ~25-32 kcal/mol for aliphatic aldehydes (7), ~29-30 kcal/mol for aromatic aldehydes and ketones (4).