A theoretical study on the structure of thiazolidine-2,4-dione and its 5-substituted derivatives in the gas phase. Implications for the thiazolidine-2,4-dione -water complex

3.1 Optimized geometries of Thiazolidine-2,4-dione tautomeric forms

Thiazolidine-2.4-dione could exist in different tautomeric forms as shown in Scheme 1. Crystallographic study of Form et al. (Form et al. (1975) and theoretical investigation (Enchev et al., 2002, 1994; Spassova and Enchev, 2004; Ray et al., 2008; Tahmassebi, 2003) showed that the predominant tautomer is the diketo form, structure (A), and there was no evidence supporting thiazoline (oxo-enol) or thiazole (dienol) forms (Scheme 1). In addition, experimental results showed that all the bonds in the molecule show significant multiple character, with the exception of those belonging to the saturated methylene carbon atom, C(5). The calculated optimized geometrical parameters, in accordance with the atom-numbering scheme given in Scheme 1, and the available crystallographic data (Form et al., 1975) the investigated compound are listed in Table 1. A close look at Table 1 indicates that our gas phase theoretical results are agreed with the available experimental data. Plotting of the theoretical data versus the experimental ones indicates a strong linear dependencies (see Fig. 1). These figures suggest that the B3LYP/6–311 + G(d,p) bond lengths and bond angles are well fitted to X-ray experimental data, with the correlation coefficients, respectively, 0.9956 and 0.9785. Nevertheless, it is found that the most substantial deviations from X-ray results are found for the S(1)—C(2) bond which is longer by 0.049 Å. The difference is more substantial for the bond angles. For example, our calculation predicts that S(1)—C(5)—C(4) to be expanded by 4.4° in comparison with the experiment.

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Figure 1

Upper: linear correlation dependencies of Upper: calculated bond lengths vs. Experimental bond lengths (Å) and Lower: calculated bond angle vs. experimental bond angle (degree).

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It is well known that the tautomerization process, in which carbonyl and thiocarbonyl heterocyclic with a hydrogen undergo rabid equilibration with their enol tautomers, is believed to play a crucial role in chemistry of heterocyclic compounds. Moreover, molecular geometries can be specified in terms of bond lengths, bond angles and torsional angles. In the present case, the geometrical structures of the tautomeric forms (A–E) are shown in Fig. 2. It is clearly shown that the keto-enol process is associated by the expected significant changes of the corresponding molecular geometries. For example, the C2⚌O2 bond is elongated by 0.126–0.135 Å. At the same time, there is also an increase in the bond angles S(1)—C(2)—N(3) by 11.5° and a decrease of the bond angles S(1)—C(2)—O(2) and N(3)—C(2)—O(2) by 9.7–1.6°. Same changes are also detected for C(4)⚌O(4) bond. Detailed distances and angles values of A optimized tautomer are given in Table 1. In addition, our results, in accordance with analog rhodanine compound (Al-Sehemi and El-Gogary, 2009), all of the intra-ring distances and angles in the tautomers (A–E) show the pronounced changes. This non-rigid structure of thiazolidine-2,4-dione tautomers gives their ability to fit with the receptors in the biological systems. In addition, our calculations show that all ring atoms of thiazolidine-2,4-dione tautomers (A–E) form planar structures, with all the internal torsion angles are very close to 0°.

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Figure 2

Optimized geometrical structures of the thiazolidine-2,4-dione compound (A) and its tautomers (B-E).

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Furthermore, it is well known that substituents affect the geometrical structures greatly (Raissi et al., 2012, 2013; Al-Sehemi and El-Gogary, 2009). In the present study, some representative 5-substituted thiazolidine-2,4-dione (—CH₃, —NH₂, —Cl, —F, —CN and —NO₂) were chosen to calculate their tautomerization equilibrium. Comparing the geometrical parameters of the 5-substituted thiazolidine-2,4-dione with that of A, B, C, D and E tautomers revealed that, at this level, little effects of substituent type position were observed on the structural parameters. For example, comparing the geometrical parameters of the substituted thiazolidine-2,4-dione with that of A tautomer shows that the C(2)⚌O(2) and C(4)⚌O(4) bonds elongated by ∼0.006 Å when changing from electron-withdrawing groups to electron-releasing group. The S(1)—C(2)—N(3) and N(3)—C(4)—C(5) bond angles are increased in the range of 0.4–0.9° when going from electron-withdrawing groups to electron-donating one.

3.2 Analysis of relative thermodynamic data

Calculated thermodynamic parameters such as relative energies, ΔE, enthalpies, ΔH, Gibbs free energies, ΔG, of the various tautomers of thiazolidine-2,4-dione and its derivatives are presented in Table 2. Total set of energetic data are available in Table S1 of the supplementary materials. The B3LYP/6–311++G(3df,2p)//B3LYP/6–311 + G(d,p) method at 298.15 K and 1 atm pressure was performed to calculate all of these data. ΔE, ΔH and ΔH of each tautomer are defined as the difference between its total energy or enthalpy or Gibbs free energy with respect to the most stable tautomer A.

A cursory examination of Table 2 indicates that in all cases the most stable tautomeric structure corresponds to the diketo structure, tautomer A. The second interesting find is that, in contrast to the hydantoin system (Safi and Abu-Awwad, 2008) and in agreement with the analog rhodanine (Al-Sehemi and El-Gogary, 2009), the next-low lying tautomer corresponds to the C tautomer, which is formed by a 1,3-hydrogen transfer from the hydrogen atom at position 3 to the carbonyl oxygen at position 4. The relative energy difference is ∼60 kJ mol⁻¹. The relative stability order (ΔE in kJ mol⁻¹) of the tautomeric forms of the compound under probe is as follows:

• A > C > B > D > E.

Our results shows that the A tautomer is about 60–106 kJ mol⁻¹ more stable than the other tautomers (B–E); that is, the high positive ΔH demonstrates that tautomerization of the investigated system process is highly endothermic. As it is shown in Fig. 3, the activation barrier requires to get the most stable enolic structure, the C tautomer, through the transition state TS(A–C) is about 196 kJ mol⁻¹. However, the B tautomer, which is formed by a 1,3-hydrogen migration from N3 to O2, is less stable than the tautomer C, the activation barrier requires to achieve this tautomer through the transition state TS(A–B) is found to be ∼5 kJ mol⁻¹ lower than that of tautomer C.

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Figure 3

Energy profile for the prototropic isomerization process of thiazolidine-2,4-dione. All values are in kJ mol⁻¹.

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It is obvious that these large positive ΔG values indicate that the prototropic isomerization process, which leading to the transition from the keto to enol form is quite disfavored, i.e., it is nonspontaneous. It implies, in agreement with analogs polyfunctional heterocyclic systems (Safi and Abu-Awwad, 2008; Safi and Frenking, 2013) that this reaction in gas phase is thermodynamically and kinetically unfavored, meaning that the reverse reaction is both thermodynamically and kinetically favored and the A tautomer is the dominant in gas phase.

3.3 Analysis of the substitution effect

Close inspection to our theoretical results (Table 2) shows that the nature of the substituent groups has no effect on the stability order of thiazolidine-2,4-dione tautomers, except. However, there is some exchange of the stability order of thiazoline (oxo-enol) or thiazole (dienol) forms. According to Table 2, the stability order (ΔE in kJ mol⁻¹) of substituted thiazolidine-2,4-dione tautomers is as follows:

On the other hand, when the substitution takes place, the tautomer C becomes more stable than tautomer B, except for CN and NH₂. The interchange of the stability order can be accounted for by the inductive effect and resonance effect of the amino group, which increases the intrinsic basicity of the oxygen atom attached to position 4.

3.4 Analysis of PA, MEP, and NVAO

We will now discuss the proton affinities (PAs), molecular electrostatic potential (MEP) and natural valence atomic orbital energies (NVAO) of the basic centers (O2, N3 and O4) exist for thiazolidine2-4,dione. The PA is defined as the negative of the enthalpy change associated with the gas phase protonation reaction B + H⁺ → BH⁺. Table 3 displays the PAs of the basic sites (O2, O4 and N3) exist for the heterocyclic system under probe. The PAs have been calculated using B3LYP/6–311++G(3df,2p)//B3LYP6–311 + G(d,p) methods. Total energies, zero point energies and thermal corrections to enthalpies for all the protonated 5-susbtituted derivatives of Thiazolidine-2,4-dione compound are given in Tables S2 of the supplementary materials.

An inspection of Table 3 indicates that in all of the thiazolidine derivatives the most basic center is the carbonyl oxygen atom at position 2, O2. The calculated PA of O2 of the parent thiazolidine-2,4-dione compound is ∼802 kJ mol⁻¹ and it is ∼9 and 100 kJ mol⁻¹ higher than O4 and N3, respectively. Furthermore, it is found that the PA is increased when changing from electron-withdrawing group to electron-releasing group. Our results show that the highest PA corresponds to 5-amino derivatives (∼830 kJ mol⁻¹) where the smallest one corresponds to the 5-cyano derivatives. The electron releasing group makes the electron pairs on the oxygen atom more available by donating the electron to the system. The reverse is true in the case of the electron withdrawing group. These results lead us to classify the compound under probe as a moderate basic compound, and the basic centers in this compound can be arranged in order of its strength as follows: O2 > O4 > N3.

To better understand the PA, we will discuss now the results of the molecular electrostatic potential (MEP) and the valence natural atomic orbital energies (NVAO). It was pointed out that the molecular electrostatic potential (MEP) on the nuclei of a molecule originally invoked to study electrophilic reactivity (Yuang et al., 2013). The MEP of a molecule is a real physical property, and it can be determined experimentally by X-ray diffraction techniques (Suresh, 2006). Yuang et al. proposed a theoretical model to calculate this quantum descriptor can be found in Ref. (Yuang et al., 2013). They suggested that the more negative the MEP value, the stronger the molecular basicity, the larger the proton affinity and gas-phase basicity. Also they proposed that for systems with multiple sites of the same basic element type, the most basic site (largest energy decrease) has the most negative MEP value (Yuang et al., 2013). The numerical values of the MEP on the nuclei of basic centers and the valence natural atomic orbital energies of these centers for all species investigated here are also listed in Table 3.

Our theoretical results show that the MEP values on the nuclei of the two oxygen atoms (O2 and O4) are almost degenerate and they are more negative than that on the nitrogen atom, MEP(N3), by about 4.042–4.045 a.u. The degeneracy in the MEP values of the two oxygen atoms suggests again that there is a competitiveness between the two sites. Based on these findings, one expects that the two oxygen atoms should be the site to preferably bond with the incoming proton. These numerical data lead us to suggest,, in accordance with our studies on benzamide derivatives (Safi and Omar, 2014), that the analysis of MEP on the nuclei of the basic centers can be used as a good descriptor to the intrinsic basicities of the heterocyclic compounds containing different type of the basic centers.

It is worth noticing that the MEP and NVAO values become more negative when changing from electron withdrawing group to electron-releasing one in comparison with the parent thiazolidine2,4-dione compound. The most negative MEP value corresponds to the 5-CH₃ derivatives where the least one belongs to the 5-Cl and 5-NO₂ ones. The least negative NVAO energy value corresponds to substituted methyl derivative (−1.829 a.u.) while the highest one corresponds to the substituted nitro derivative (−1.935 a.u.).

3.5 Analysis of thiazolidine-2,4-dione-water complex

In this section we will now discuss the stability of the cyclic thiazolidine-2,4-dione-water complex as a function of the acidity or the basicity of the different sites of the title compound. The interaction of thiazolidine-2,4-dione with one water molecule is guided by the possibility of the water molecule behaving as a hydrogen-bond donor or as a hydrogen-bond acceptor when respectively interacting with the basic centers (C2⚌O2 and C2⚌O4) and the acidic groups (N3—H and C5—H) existing in these compounds. Three possible structures may exist in which water behaves simultaneously as hydrogen-bond acceptor and donor (A–C). To the best of the author Knowledge, the thiazolidine-2,4-dione-water complexes have not been investigated neither theoretically nor experimentally. However, some systems such as uracil–water (Del Bene, 1983; Nguyen et al., 1998) and triazepine-water (Lamsabhi, 2008) complexes have been studied. The stability of the superwater systems has been explained according to the binding energies. On the other hand, some relevant vibrational frequencies of uracil have also been calculated for the uracil-water (1/2) supersystem (Ghomi et al., 1997). Fig. 4 shows the three stable cyclic structures A, B and C of the thiazolidine-water complexes along with the intermolecular geometrical parameters and the corresponding molecular graphs based on quantum theory of atoms in molecules QTAIM of Bader (Bader, 1990).

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Figure 4

Upper: Optimized structures of the complexes A, B and C between uracil and water from B3LYP/6–311 + G(d,p) calculations (distances (Å), angles (degree)). Lower: Molecular graphs of Thiazolidine-2,4-diones-water complexes. The charge densities at the bond critical points (red) and ring critical points (yellow) are in e au⁻³.

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Our results show that the three complexes are characterized by C1 symmetry, one of the hydrogen atoms of water being out-of-plane of the uracil molecule. Inspection of Table 4 indicates that the A and B complexes are almost degenerate with a difference only of ∼0.1 kJ mol⁻¹ in favor of the B complex. The complex C is found to be ∼8.5 kJ mol⁻¹ less stable than the most stable one (Table 4). The hydration energies of the complexes A, B and C due to the binding with water molecule are ∼ −30.6, −28.5 and −18.4 kJ mol⁻¹, respectively. These results suggest that the thiazolidine-2,4-dione compound is characterized by a weak interaction with water, which allows classification of the strength of the corresponding hydrogen bonds as moderate. It is worth noting that, in the structure A and B, the carbonyl groups at position 2 and 4 act as a hydrogen-bond acceptor with respect to water and both kinds of complexes have in common the N3—H group at position 3 acting as a HB donor. In complex C, the group acting as HB donor is a C5—H group rather than a N3—H group while the carbonyl group at position 4 acts as a hydrogen-bond acceptor with respect to water.

As it is shown in Fig. 4, the N3—H⋯Ow and O6(7)⋯Hw–Ow distances do not markedly differ and this suggests that the two intermolecular hydrogen bonds in the considered complexes have about the same contribution to the total binding energy. Our results show that O6⋯Hw–Ow distance (2.047 Å) is shorter than the O6⋯Hw–Ow one (2.090 Å). This seems to indicate that the carbonyl group at position 4 is a weaker HB acceptor than the carbonyl group at position 2. This is in accordance with our recent findings showing that the carbonyl group at position 2 has a larger intrinsic basicity than the one at position 5. The two N3—H···Ow interaction in both complexes has almost the same distance (1.995(6) Å).

In the C complex, the distances C5—H⋯Ow and O7⋯Hw–Ow are markedly different, suggesting that the two intramolecular hydrogen bonds have not the same contribution to the total binding energy. It is found that the C5—H⋯Ow (2.697 Å) is longer than the O7⋯Hw–Ow one (1.969), suggesting that the O7⋯Hw—Ow hydrogen bond has a more contribution in the total binding energy than the C5—H⋯Ow one.

In order to confirm the above results, the topology of the electron density of the complexes (A–C) based on the AIM analysis of Bader (Bader, 1990) has been studied. The topological parameters of the hydrogen bond interaction (electron densities, ρ_BCP, local electronic potential energy at the corresponding BCPs, hydrogen bond strengths, E_HB = 1/2 V(r) (in kcal/mol), and the electron charge densities at the corresponding ring critical points of the quasirings, ρ_RCP) are given in Table 4. Inspection of these result strongly supports the above finding in which the complex B is the most stable complex among the three cyclic complexes. It is found that the highest ρ_RCP value belongs to the complex B, reflecting that the five-membered quasicyclic structure of the complex B is the most stable one where the analog cyclic structure of the complex is the least stable one. Additionally, inspection of our results reflected in the value of the electron density at the BCP of the corresponding bonds. In fact, as can be shown in Fig. 4 and Table 4, according to ρ_BCP values, the most stable hydrogen bond corresponds to the interaction between the oxygen of water molecule and the amino hydrogen atom, N3—H⋯O_w. Also, importantly, however, O4 is less PA than O2, inspection of our results indicates that the O4⋯H_w interaction (ρ_BCP = 0.0243 au⁻³, complex B) is stronger than the corresponding O2⋯H_w (ρ_BCP = 0.0189 au⁻³, complex A). These findings are in line with those obtained for uracil–water complexes (Nguyen et al., 1998) and triazepine-water complexes (Lamsabhi, 2008).

In order to confirm the above findings, analysis of Natural Bond Orbital (NBO) has been carried out. The electron transfer energies due to the orbital interaction are also included in Table 5. NBO calculations show that the two lone pairs of the O2 and O4 are not equivalent and their overlap interactions with the N3—H antibonding are quite different. Theoretical results revealed, in accordance with the relative energies of the complexes, that the strongest interaction was observed for the B complex. In complex B, the total orbital interaction energy, E_CT, is ∼3 kJ mol⁻¹ higher than that in the A complex. These results indicate, in complex A and B, that the water molecule acts as a hydrogen bond acceptor and the N3-H group acting as a hydrogen bond acceptor.

At last it should be pointed out that the vibrational frequency shifts of the harmonic asymmetric ν^as(OH) and ν^as(C⚌O) and symmetric ν^s(C⚌O) and ν^as(OH) stretching vibrations, together with the ν(NH) stretching vibrations are listed in Table 5. Inspection of the frequency results indicates that the highest frequency shifts are observed for the A complex with respect to the other complexes.