* 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).