A Theoretical Study of the Preferred Reaction Mechanism …
139
4 Conclusions
The reaction of thiourea and chloroacetic acid has been investigated to determine
the preferred geometries of the reactants, the possible transition states, intermediate
and products. The two tautomeric forms of thiourea have been utilised in the study
to determine the tautormer which preferably reacts with chloroacetic acid to form
2-iminothiazolidin-4-one. The study has been performed with both MP2 and DFT
methods and considering both vacuum and water solvent media. The results of the
investigation show that the reaction of ClCH 2 COOH with NH 2 CSNH 2 , in vacuo and
in water solution, is thermodynamically disfavoured because it is both endothermic
and endergonic. The reaction of ClCH 2 COOH and NHCSHNH 2 is favoured in vacuo
and disfavoured in water solution. Therefore, is reasonable to infer that the reaction
of thiourea and chloroacetic acid involves the imidothiol form of thiourea. Since the
in vacuo medium (with dielectric constant, ε = 1) is the most ideal representation of
non-polar media, it is also reasonable to conclude that the reaction between thiourea
and chloroacetic acid is best carried out in non-polar media. A rationalisation for
the difference in the behaviour of the two tautomers can be explained as follows;
in practice, NHCSHNH 2 is likely to behave more like a zwitterionic form. In such
a case, the S atom in NHCSHNH 2 has a negative charge and is therefore a better
nucleophile than the S atom in NH 2 CSNH 2 .
In the reaction between thiourea and chloroacetic acid, the formation of the TS3
products is a result of the concerted reaction step involving asynchronous bondformation and bond-breaking processes. However, the formation of the product from
TS3 is both concerted and synchronous bond breaking (during the removal of the
water molecule) and bond formation (the restoration of the carbonyl O2 atom).
Investigation of the reaction of ClCH 2 COOH with either of the tautomer of
thiourea in water solution indicates that the reaction is endothermic and therefore
not thermodynamically favoured. Moreover, while in vacuo the by-products for the
reaction include water and hydrogen chloride, in water solution the by-products are
the hydronium ion and the chloride ion. The difference in the by-products may be
related to the interaction between the solvent molecules and the chloride ions.
A comparison of the results across methods (MP2 and DFT) suggests similar
trends are obtained, in terms of energetic and electronic properties, for the species
involved in the investigated mechanisms; this is true in all the media.
References
1. Skyler JS (2004) Diabetes mellitus: pathogenesi and treatment strategies. J Med Chem 47:4113–
4117
2. Kaminskyy O, Bednarczyk-Cwynar B, Vasylenko O, Kazakova O, Zimenkovsky B, Zaprutko
L, Lesyk R (2012) Synthesis of new potential anticancer agents based on 4-thiazolidinone and
oleanane scaffolds. Med Chem Res 21:3568–3580
139
4 Conclusions
The reaction of thiourea and chloroacetic acid has been investigated to determine
the preferred geometries of the reactants, the possible transition states, intermediate
and products. The two tautomeric forms of thiourea have been utilised in the study
to determine the tautormer which preferably reacts with chloroacetic acid to form
2-iminothiazolidin-4-one. The study has been performed with both MP2 and DFT
methods and considering both vacuum and water solvent media. The results of the
investigation show that the reaction of ClCH 2 COOH with NH 2 CSNH 2 , in vacuo and
in water solution, is thermodynamically disfavoured because it is both endothermic
and endergonic. The reaction of ClCH 2 COOH and NHCSHNH 2 is favoured in vacuo
and disfavoured in water solution. Therefore, is reasonable to infer that the reaction
of thiourea and chloroacetic acid involves the imidothiol form of thiourea. Since the
in vacuo medium (with dielectric constant, ε = 1) is the most ideal representation of
non-polar media, it is also reasonable to conclude that the reaction between thiourea
and chloroacetic acid is best carried out in non-polar media. A rationalisation for
the difference in the behaviour of the two tautomers can be explained as follows;
in practice, NHCSHNH 2 is likely to behave more like a zwitterionic form. In such
a case, the S atom in NHCSHNH 2 has a negative charge and is therefore a better
nucleophile than the S atom in NH 2 CSNH 2 .
In the reaction between thiourea and chloroacetic acid, the formation of the TS3
products is a result of the concerted reaction step involving asynchronous bondformation and bond-breaking processes. However, the formation of the product from
TS3 is both concerted and synchronous bond breaking (during the removal of the
water molecule) and bond formation (the restoration of the carbonyl O2 atom).
Investigation of the reaction of ClCH 2 COOH with either of the tautomer of
thiourea in water solution indicates that the reaction is endothermic and therefore
not thermodynamically favoured. Moreover, while in vacuo the by-products for the
reaction include water and hydrogen chloride, in water solution the by-products are
the hydronium ion and the chloride ion. The difference in the by-products may be
related to the interaction between the solvent molecules and the chloride ions.
A comparison of the results across methods (MP2 and DFT) suggests similar
trends are obtained, in terms of energetic and electronic properties, for the species
involved in the investigated mechanisms; this is true in all the media.
References
1. Skyler JS (2004) Diabetes mellitus: pathogenesi and treatment strategies. J Med Chem 47:4113–
4117
2. Kaminskyy O, Bednarczyk-Cwynar B, Vasylenko O, Kazakova O, Zimenkovsky B, Zaprutko
L, Lesyk R (2012) Synthesis of new potential anticancer agents based on 4-thiazolidinone and
oleanane scaffolds. Med Chem Res 21:3568–3580