136
M. M. Kabanda and K. P. Otukile
are weaker in water solution compared to vacuum. The exceptions are TS2 and IM2,
where the interaction distances are slightly shorter for the geometries optimized in
aqueous solution. Among the TSs and IMs presenting H-bond like interactions, the
shortest distance correspond to the N–H···Cl5 bond in IM1, corresponding to the
process of abstraction of the H13 proton by the Cl ion.
The E and G values suggest that the reaction is endothermic and endergonic. In
addition, the calculated energy barriers for the formation of IM1 from RC-t and the
formation of the product complex from TS3 are significantly reduced in solution.
Although the reaction appears to have lower barrier heights in water solution as
compared to the results in vacuo, it is still overall not a spontaneous reaction in water
solution, as evidenced by its G value.
3.3 NH 2 CSNH 2 + ClCH 2 COOH Reaction Mechanism
in Vacuo
The relative energies of the isolated reactant molecules, pre-association complexes, transition state (TS) structures, intermediates and products of the reaction
of ClCH 2 COOH with NH 2 CSNH 2 are shown in Table 1b and the corresponding
optimised geometries are shown in Fig. 7. The relative energies refer to the sum
of the energies of the separate reactants (R). Selected bond distances necessary
for the discussion are indicated in Fig. 7. The potential energy diagram depicting
the reaction mechanism for the cyclisation is shown in Fig. 4b. As in the previous
case, relative energies and bond distances referred to in the discussion correspond to
M06-2X/6-311++G(3df,2p) results.
In the first step, the pre-association complex is formed from ClCH 2 COOH and
NH 2 CSNH 2 . This is a barrier-less weakly bound pre-association reactant complex
(RC) stabilised by two simultaneous intermolecular H-bonds involving the COOH
group of chloroacetic acid and the amino (NH 2 ) group of NH 2 CSNH 2 . In this geometry, the OH group of ClCH 2 COOH is the H-bond donor to the S atom and the C=O
group is the H-bond acceptor to the NH 2 in thiourea. The O2···H11–N10 intermolecular H-bond is shorter than the S7···H6–O3. RC is 14.526 kcal/mol more stable than
the sum of the energies of the starting reactant molecules.
The cyclisation reaction starts when the most nucleophilic centre in one of the
starting molecules attacks the most electrophilic centre in the second molecule. In
the two starting molecules, there are four possible nucleophilic centres, which are
O, S, N and Cl. Among these possible centres, S is the most nucleophilic because
it has lower electronegativity value (2.5) than both O (3.5) and N (3.0) and because
it is a largest atom (atomic size effect) so that its lone pair of electrons are farthest
from the nucleus in comparison with O, N and Cl (i.e., it is the most polarisable atom
among the possible nucleophiles). The most electrophilic centre is the α-position C4
atom of ClCH 2 COOH. Therefore, an attack by the soft nucleophilic S atom on the
soft electrophilic C atom leads to an SN 2 nucleophilic reaction (with S replacing
M. M. Kabanda and K. P. Otukile
are weaker in water solution compared to vacuum. The exceptions are TS2 and IM2,
where the interaction distances are slightly shorter for the geometries optimized in
aqueous solution. Among the TSs and IMs presenting H-bond like interactions, the
shortest distance correspond to the N–H···Cl5 bond in IM1, corresponding to the
process of abstraction of the H13 proton by the Cl ion.
The E and G values suggest that the reaction is endothermic and endergonic. In
addition, the calculated energy barriers for the formation of IM1 from RC-t and the
formation of the product complex from TS3 are significantly reduced in solution.
Although the reaction appears to have lower barrier heights in water solution as
compared to the results in vacuo, it is still overall not a spontaneous reaction in water
solution, as evidenced by its G value.
3.3 NH 2 CSNH 2 + ClCH 2 COOH Reaction Mechanism
in Vacuo
The relative energies of the isolated reactant molecules, pre-association complexes, transition state (TS) structures, intermediates and products of the reaction
of ClCH 2 COOH with NH 2 CSNH 2 are shown in Table 1b and the corresponding
optimised geometries are shown in Fig. 7. The relative energies refer to the sum
of the energies of the separate reactants (R). Selected bond distances necessary
for the discussion are indicated in Fig. 7. The potential energy diagram depicting
the reaction mechanism for the cyclisation is shown in Fig. 4b. As in the previous
case, relative energies and bond distances referred to in the discussion correspond to
M06-2X/6-311++G(3df,2p) results.
In the first step, the pre-association complex is formed from ClCH 2 COOH and
NH 2 CSNH 2 . This is a barrier-less weakly bound pre-association reactant complex
(RC) stabilised by two simultaneous intermolecular H-bonds involving the COOH
group of chloroacetic acid and the amino (NH 2 ) group of NH 2 CSNH 2 . In this geometry, the OH group of ClCH 2 COOH is the H-bond donor to the S atom and the C=O
group is the H-bond acceptor to the NH 2 in thiourea. The O2···H11–N10 intermolecular H-bond is shorter than the S7···H6–O3. RC is 14.526 kcal/mol more stable than
the sum of the energies of the starting reactant molecules.
The cyclisation reaction starts when the most nucleophilic centre in one of the
starting molecules attacks the most electrophilic centre in the second molecule. In
the two starting molecules, there are four possible nucleophilic centres, which are
O, S, N and Cl. Among these possible centres, S is the most nucleophilic because
it has lower electronegativity value (2.5) than both O (3.5) and N (3.0) and because
it is a largest atom (atomic size effect) so that its lone pair of electrons are farthest
from the nucleus in comparison with O, N and Cl (i.e., it is the most polarisable atom
among the possible nucleophiles). The most electrophilic centre is the α-position C4
atom of ClCH 2 COOH. Therefore, an attack by the soft nucleophilic S atom on the
soft electrophilic C atom leads to an SN 2 nucleophilic reaction (with S replacing