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M. M. Kabanda and K. P. Otukile
1 Introduction
Thiazolidin-4-one derivatives are known for their biological activities such as antidiabetic [1], anti-cancer [2], anti-HIV and platelet activating factor antagonist [3,
4]. In particular, functionalised 2-iminothiazolidin-4-one heterocyclic derivatives
exhibit several biological activities such as anti-tuberculosis [5], anti-convulsant [6],
anti-fungal [7], antibacterial [8], antimicrobial [9], antiviral [10] and immunodulation
properties [11]. Recent studies have shown that 2-iminothiazolidin-4-one derivatives
are already considered as potential prodrug compounds because of their potent, orally
active Sphingosine-1-phosphate (S1P 1 ) receptor agonist [12]. The potentiality of
their applications in the design of pharmaceutical drugs has been the driving force for
the large number of synthetic protocols leading to the synthesis of 2-iminothiazolidin4-ones [13–15]. The traditional approach for the synthesis of 2-iminothiazolidin-4ones involved cyclization from thioureas with chloroacetic acid derivatives via using
various catalysts, such as sodium acetate, sodium hydride, and pyridine [10, 11, 16–
19]. Several studies have recently reported on the possible green pathways in the
preparation of 2-iminothiazolidin-4-ones [14, 15].
To our knowledge, the mechanism for the reaction of chloroacetic acid
(ClCH 2 COOH) with thiourea to form 2-iminothiazolidin-4-one has been studied
through experimental techniques [13, 14] and has not yet been studied through theoretical methods. Therefore, to shed light on this point, this study presents a detailed
computational investigation into the mechanism of formation of 2-iminothiazolidin4-one. The specific objectives of the study are to identify the intermediate and transition structures and to characterise their geometric features. In experimental conditions, the synthesis of 2-iminothiazolidin-4-ones has been reported to occur preferably in water solution [15]. To simulate such conditions, the study reported here is
performed in vacuo and in water solution in order to analyze the specific influences
of the solvent on the process as a medium, but also its possible interaction with the
reactants and its role on the mechanistic pathway.
To model the mechanism of the process in the gas phase and in aqueous solution,
two density functional theory (DFT) methods and an MP2 method were selected. DFT
with hybrid GGA functionals, such as MPWB1K, and meta-hybrid functionals (e.g.
M06-2X) are increasingly utilised for the study of reaction mechanisms for organic
compounds and for characterising the kinetic features of chemical reactions [20–27].
Moreover, because of their computational affordability, DFT with hybrid meta-GGA
functionals are also increasingly providing benchmark results for systems where
MP2 and its variations or CCSD(T) methods are too expensive to afford [23–26]. In
this work, two functionals, the M06-2X (a global-hybrid meta-GGA) and M11-L (a
meta-nonseparable gradient approximations functional) are utilised throughout the
study.
The schematic representation of the starting reactant molecules, chloroacetic acid
and thiourea, and the atom numbering utilised in this work are shown in Fig. 1. The
reaction mechanism hypothesised and investigated in the present study is illustrated
in Fig. 2. Thiourea can exist in two tautomeric forms, the thione and iminothiol, as
M. M. Kabanda and K. P. Otukile
1 Introduction
Thiazolidin-4-one derivatives are known for their biological activities such as antidiabetic [1], anti-cancer [2], anti-HIV and platelet activating factor antagonist [3,
4]. In particular, functionalised 2-iminothiazolidin-4-one heterocyclic derivatives
exhibit several biological activities such as anti-tuberculosis [5], anti-convulsant [6],
anti-fungal [7], antibacterial [8], antimicrobial [9], antiviral [10] and immunodulation
properties [11]. Recent studies have shown that 2-iminothiazolidin-4-one derivatives
are already considered as potential prodrug compounds because of their potent, orally
active Sphingosine-1-phosphate (S1P 1 ) receptor agonist [12]. The potentiality of
their applications in the design of pharmaceutical drugs has been the driving force for
the large number of synthetic protocols leading to the synthesis of 2-iminothiazolidin4-ones [13–15]. The traditional approach for the synthesis of 2-iminothiazolidin-4ones involved cyclization from thioureas with chloroacetic acid derivatives via using
various catalysts, such as sodium acetate, sodium hydride, and pyridine [10, 11, 16–
19]. Several studies have recently reported on the possible green pathways in the
preparation of 2-iminothiazolidin-4-ones [14, 15].
To our knowledge, the mechanism for the reaction of chloroacetic acid
(ClCH 2 COOH) with thiourea to form 2-iminothiazolidin-4-one has been studied
through experimental techniques [13, 14] and has not yet been studied through theoretical methods. Therefore, to shed light on this point, this study presents a detailed
computational investigation into the mechanism of formation of 2-iminothiazolidin4-one. The specific objectives of the study are to identify the intermediate and transition structures and to characterise their geometric features. In experimental conditions, the synthesis of 2-iminothiazolidin-4-ones has been reported to occur preferably in water solution [15]. To simulate such conditions, the study reported here is
performed in vacuo and in water solution in order to analyze the specific influences
of the solvent on the process as a medium, but also its possible interaction with the
reactants and its role on the mechanistic pathway.
To model the mechanism of the process in the gas phase and in aqueous solution,
two density functional theory (DFT) methods and an MP2 method were selected. DFT
with hybrid GGA functionals, such as MPWB1K, and meta-hybrid functionals (e.g.
M06-2X) are increasingly utilised for the study of reaction mechanisms for organic
compounds and for characterising the kinetic features of chemical reactions [20–27].
Moreover, because of their computational affordability, DFT with hybrid meta-GGA
functionals are also increasingly providing benchmark results for systems where
MP2 and its variations or CCSD(T) methods are too expensive to afford [23–26]. In
this work, two functionals, the M06-2X (a global-hybrid meta-GGA) and M11-L (a
meta-nonseparable gradient approximations functional) are utilised throughout the
study.
The schematic representation of the starting reactant molecules, chloroacetic acid
and thiourea, and the atom numbering utilised in this work are shown in Fig. 1. The
reaction mechanism hypothesised and investigated in the present study is illustrated
in Fig. 2. Thiourea can exist in two tautomeric forms, the thione and iminothiol, as