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Fragmentation of 1,4,2-Oxathiazole Derivative to Provide Anticancer Isothiocyanates Product: Is the C-5 and C-3 Substituent Responsible?

  • Abdelilah BenallouEmail author
  • Habib El Alaoui El Abdallaoui
Original Article

Abstract

Isothiocyanates (ITCs) was recognized as anticancer properties, few attempts that were performed to prepare this product through exploiting the relative sensitivity of 1,4,2-oxathiazole derivative utilizing fragmentation process, for which some pertinent features as temperature and substituent were considered as a key role of such procedure. With the aid of most appropriate theoretical methods, we have remarked that the presence of electron-releasing substituents such as, N > O > S > C, at C-5 as well as electron-releasing substituents corresponding to an aliphatic group at the position C-3 are in high performance on the fragmentation of 1,4,2-oxathiazole derivatives. At this stage, we suggest that the substituent at the position C-5 should be responsible for the lengthening and weakening of C–S and O–N interatomic bond, while the substituents at the position C-3 play a principal factor to stability of the ITCs products, besides both substituents have successfully reduced the involved temperature. Likewise, ELF analysis shows that the weakening and cleavage of C–S bond is a direct consequence of the lone pairs electron donation associated with the nucleophilic atom substituent to the C5–S σ* orbital.

Keywords

Isothiocyanates 1,4,2-Oxathiazole fragmentation Theoretical chemistry ELF analysis Anticancer properties 

1 Introduction

Well-known as a class of compounds with a wide range of biological activities, isothiocyanates (ITCs) is highly recognized as anticancer and antimicrobial properties [1] as well as a pesticidal activity [2]. Furthermore, there is significant evidence proposing that isothiocyanates include the aptitude to inhibit the processes of carcinogenesis [3] and tumorigenesis [4]. Historically, ITCs compounds were frequently generated by using of unsafe reagents such as thiophosgene and a carbon disulfide [5, 6] or by another prevalent procedure which employed a polymer-supported catch-and-release method [7] (see Scheme 1).
Scheme 1

Synthesis of ITCs via catch-and-release approach initiated by thiophosgene and carbon disulfide reagent

It is worth noting that 1,4,2-oxathiazole in situ generated from a classical [3 + 2] cycloaddition reaction between nitrile oxides 1 and a thiocarbonyl-containing compound 2, firstly reported by Huisgen and co-workers [8] (Scheme 2). Recently, due to sensitiveness response of the 1,4,2-oxathiazole 3 towards thermal environments [9]. Serious efforts have been made to exploit this issue, by the fact their synthesis for many years is infrequent. To this end, the sensitive thermal of 1,4,2-oxathiazole has been employed for the synthetic of ITCs derivatives, as explored by Battaglia et al. [10].
Scheme 2

Fragmentation and rearrangement of the heterocyclic core of 1,4,2-oxathiazoles 3 in situ generated from a classical [3 + 2] cycloaddition reaction between nitrile oxides 1 and a thiocarbonyl-containing compound 2 to give isothiocyanates (ITCs) and a carbonyl-containing equivalent 5

Very little works were performed to study the fragmentation of 1,4,2-oxathiazole, in this sense. Hewitt and co-workers have shown that the temperature and the substituent at the position C-5 are responsible for the fragmentation responsiveness [11]. To the best of our knowledge, only one evident theoretical study that was concerned with the fragmentation of 5,5-diamino-substituted 1,4,2-oxathiazoles to give ITCs derivatives employing ab initio method [12], that study strongly revealed the role of C-5 substituent on the fragmentation of 1,4,2-oxathiazole to yielding ITCs. Thereafter, two principal factors could be responsible for governing the fragmentation of 1,4,2-oxathiazoles to provide ITCs compounds, such as the temperature as long as the C-5 and/or C-3 substituent effect (Scheme 2).

Over the course of our study, the fragmentation of 1,4,2-Oxathiazoles to affording ITCs derivative will be performed, several levels of temperature and several of electron-releasing groups as a substituent at the position 5 and 3 should be inspected. To this end, C-, O-, S-, and N-alkyl substituents will be used, in this context, certain studies revealed that the presence of electron-releasing substituents (N-, O-, and S substituent) at C-5 requires a lower temperature than a C substituted group (> 180 °C) to effect fragmentation [11].

In our ongoing goal, the present work will be aimed to rationalize and characterize the effect of the temperature and the electron-releasing substituent at the position 5 on the fragmentation and rearrangement procedures to yielding the ITCs derivatives, from a 1,4,2-oxathiazoles prototype, experimentally taken into oversee by Hewitt et al. [11], as displayed in Scheme 3. Herein, to provide an overall explanation, our study will be widened to the substituent at the position 3, both attractors and donor’s substituents have to be experienced. For that purpose, the electron localization function (ELF) method [13], quantum theory of atoms-in molecules (QTAIM) [14, 15], bonding evolution theory (BET) [16], and the conceptual density functional theory (CDFT) [17, 18, 19], have emerged to analyze the chemistry proprieties of an element and the reaction mechanism [20, 21, 22, 23, 24, 25], within a new reactivity model namely Molecular Electron Density Theory (MEDT) [26]. Considering this fact, a complete investigation will be achieved.
Scheme 3

Fragmentation of 1,4,2-oxathiazoles via two possible mechanistic pathway to construct ITCs and a carbonyl-containing equivalent

2 Computational Methods

All electronic structure calculations were performed using the B3LYP exchange–correlation functional [27], some studies have proved that B3LYP hybrid leads to an underestimation in the reaction thermochemistry and thermochemical kinetics [28, 29], together with the standard basis set, 6-311g(d). The optimizations of stationary points were performed using the Berny analytical gradient method [30] and also, the IRC paths [31] were traced in order to check the energy profiles connecting the transition state (TS) to the two associated minima using the second order Gonzalez–Schlegel integration method [32]. The electronic structures of stationary points were analyzed by employing the natural bond orbital (NBO) method [33] and by ELF topological analysis [13] together with the bonding evolution theory (BET) [14]. The ELF study was carried out with the Multiwfn program [34] using the corresponding mono determinant wave functions of the selected structures. The calculation was performed with the Gaussian 09 suite of programs [35].

3 Results and Discussions

To shed light on the fragmentation process, the present work will be detailed in three-structured parts. First, (1) a geometrical parameters investigation of 1,4,2-oxathiazoles fragmentation towards the C-5 and C-3 substituent at the ground state (GS) will be achieved, and then, (2) the PES paths energetic profile exploration analysis associated with the 1,4,2-oxathiazoles derivatives fragmentation to yielding isothiocyanates derivatives (ITCs) and a carbonyl-containing equivalent are explored. Finally, (3) an ELF electron population topology analysis of the most preferred valence basin densities integrated in the fragmentation process of 1,4,2-oxathiazoles derivatives will be characterized.

3.1 Geometrical Parameters Analysis of 1,4,2-Oxathiazoles Fragmentation with Respect to the C-5 and C-3 Substituents

In order to highlight the influence of C-5- and/or C-3-substituent on the aptitude fragmentation of 1,4,2-oxathiazoles, a number of aryl and alkyl substituents were employed at the R1, R2 and R3 positions as displayed in Fig. 1 and Table 1. In this study, R1 and R2 substituents were selected as an increased electron releasing groups corresponding to the SR, OR and NR (R = alkyl) substituent as well as a functional electron attractor, while R3 substituent at the position C-3 was chosen as an aliphatic, functionalized groups or aryl ones, the found results are portrayed in Table 1
Fig. 1

Atom numbering of 1,4,2-Oxathiazoles derivatives

Table 1

Geometrical parameters of 1,4,2-oxathiazoles derivatives with respect to the R1, R2 and R3 substituents

Entry

Substituents

Distances in Å

R1

R2

R3

O1–C5

S4–C5

O1–N2

1

Me

Me

Ph

1.446

1.867

1.395

2

Me

Me

OMe

1.438

1.881

1.416

3

Me

Me

NMe2

1.427

1.879

1.420

4

Me

Me

Me

1.445

1.782

1.403

5

Et

Et

Ph

1.455

1.870

1.393

6

Et

Et

Et

1.453

1.873

1.401

7

Et

Et

Pr

1.453

1.873

1.401

8

Et

Et

CH3

1.453

1.874

1.400

9

Ph

Ph

Me

1.440

1.892

1.411

10

Et

SEt

Ph

1.429

1.855

1.399

11

SMe

SMe

Ph

1.443

1.864

1.391

12

SEt

SEt

CH3

1.425

1.874

1.411

13

SEt

SEt

Ph

1.427

1.867

1.404

14

Et

OEt

Ph

1.489

1.887

1.340

15

OMe

OMe

CH3

1.414

1.932

1.405

16

OMe

OMe

Ph

1.443

1.913

1.390

17

OEt

OEt

Ph

1.417

1.923

1.397

18

Et

NMe2

Ph

1.442

1.940

1.394

19

NMe2

NMe2

CH3

1.312

2.939

1.507

20

NMe2

NMe2

Ph

1.410

2.158

1.413

In this part, the influence of the C-5-heteroatom substituent on the lengthening and cleavage of C5-S4 bond is highly appreciated. In this sense, we have distinguished that the fragmentation of 1,4,2-Oxathiazoles derivatives became more accessible, as a direct consequence to the presence of increased electron-releasing group. Accordingly, C5-S4 bond distance increases as the electron-releasing substituent increases. At this context, we have remarked that C5-S4 bond distance changes from 1.867, to 1.923 Å and 2.939 Å in the presence of an aliphatic feeble electron donor CH3 substituent (entry 1), moderate electron-releasing oxygen atom substituent (entry 17) and a noticeable electron-releasing nitrogen atom substituent (entry 19), respectively. Thus, the weakening of C5–S4 bond has been completely increased with the employment of high electron donor substituent, especially at the presence of an influencing mesomeric group. On the other hand, the C5 heteroatom substituent does not have significant consequence on the O1–N2 bond, which is changes in narrow range with the variation of R1 and R2 substituent. It should be emphasized that the fragmentation process is a direct consequence to the C5–S4 and O1–N2 bond dissociation. Therefore, the substituent associated with the position 5 cannot generate veritable impact on the cleavage of O1–N2 bond, which strongly indicates that the nature of such substituent is effectively marginal to have sufficient effect on the fragmentation process, in complete disagreement with the findings of Hewitt et al. [11]. However, once the substituent at C-3 is taken into account, a very convinced results were remarked, for which a relative elongation associated with the O1–N2 bond is peculiarly portrayed, mainly in the employment of an alkyl or another electron-donor substituent group; i.e.; OMe, NMe2,…Conversely, the presence of electron attractor substituent as phenyl at C3 gives undesirable consequence. It is worthy to note that the substituent at the position 3 strengthens the C–O carbonyl in the subsequent ITCs product, which prevents an eventual dissociation of such moiety, otherwise the presence of a cyclic inductive electron-attractor (–I) like phenyl substituent at C-3 could affect negatively the stability of ITCs product. Usually, the phenyl substituent commonly recognized as in a stabilizing molecule, for which their utilization as substituent can be disagreeably affected the weakening of S4–C5 and O1–N2 bonds. Therefore, from this preliminary analysis, the C-5 and C-3-substituent are in significant impact on the rate fragmentation of 1,4,2-Oxathiazoles derivatives through weakening and lengthening the C5–S4 and O1–N2 bonds, as far as the influential electron donor of such substituent is significantly considered. Subsequently, either inductive or mesomeric electron-donor substituent at C-5 and C-3 (entry 19) have been revealed as the most valuable route to generate ITCs compounds.

Some conclusion can be drawn from this geometrical study; the electron-releasing group at the position 5 will be weakening the S4-C5 bond. Similarly, an electron- releasing group related to the mesomeric or inductive effect at C-3 will expanse and break the O1–N2 bond as well as will strengthen the O1–C5 bond associated with the ITCs product.

3.2 PES Paths Exploration Analysis Associated with the 1,4,2-Oxathiazoles Derivatives Fragmentation to Yielding Isothiocyanates Derivatives (ITCs) and a Carbonyl-Containing Equivalent

To deeply evaluate the fragmentation process, the thermodynamic characterization of great interest greatly appreciated, the thermochemistry exploration could provide an explication of 1,4,2-Oxathiazoles fragmentation corresponding to the C-5 and C-3 substituents effect, and certainly will confirm the chemical structure parameters. Likewise, this impressive study should have two goals, firstly will estimate the influence of donor or attractor substituent on the rapidity and feasibility of fragmentation and secondly, make it into consideration the temperature and fragmentation relationships. To this end, we envision to determinate the thermodynamic parameters in order to check the energy profiles connecting the transition state (TS) into two associated minima, whereas this thermodynamic investigation was performed in the temperature of 30 °C and 90 °C at 1.0 atm. At this context, Hewitt and co-workers have recently shown that two reactions route, stepwise and a concerted pathways mechanism reaction are possible [12] (Scheme 3). Thus, in a conventional arbitrary choice, our study will be focused on route A, for which the fragmentation processes will take place via a concerted pathways mechanism reaction over TSs structure. Route A as given in Scheme 3, was taken as a prototype model in the subsequent study, therefore each fragmentation process of 1,4,2-oxathiazoles derivatives at the temperature of 30 °C and 90 °C was successfully carried out. Table 2 displays the found results.
Table 2

The gas phase relative energies ΔE, enthalpies ΔH, Gibbs free energies ΔG and Gibbs free energies activation ΔGa with respect to the substituent and temperature at 1.0 atm

Entry

Substituent

Temperature in °C

Energy (kcal/mol)

R1

R2

R3

ΔE

ΔH

ΔG

ΔGa

1

Me

Me

Ph

30

− 32.8

− 30.7

− 39.3

30.0

90

− 30.5

− 41.0

29.4

2

Me

Me

OMe

30

14.6

15.1

10.7

34.4

90

14.9

9.9

33.4

3

Me

Me

NMe2

30

− 6.08

− 3.9

− 14.4

29.9

90

− 3.7

− 16.5

29.5

4

Me

Me

Me

30

− 29.9

− 27.7

− 36.0

29.7

90

− 27.5

− 37.7

29.0

5

Et

Et

Ph

30

− 37.9

− 36.0

− 43.6

28.9

90

− 35.8

− 45.2

28.3

6

Et

Et

Et

30

− 35.0

− 33.3

− 40.2

26.8

90

− 33.1

− 41.6

26.1

7

Et

Et

Pr

30

− 35.3

− 33.5

− 41.0

26.8

90

− 33.3

− 42.4

26.1

8

Et

Et

CH3

30

− 32.6

− 30.5

− 39.0

27.8

90

− 30.3

− 40.7

26.9

9

Ph

Ph

Me

30

− 36.9

− 35.1

− 42.9

25.2

90

− 35.0

− 44.5

24.7

10

Et

SEt

Ph

30

− 43.2

− 41.4

− 48.9

25.2

90

− 41.2

− 50.1

24.5

11

SMe

SMe

Ph

30

− 47.8

− 46.4

− 53.0

31.5

90

− 46.3

− 54.3

31.3

12

SEt

SEt

CH3

30

− 40.8

− 40.4

− 42.8

26.5

90

− 40.5

− 43.2

26.1

13

SEt

SEt

Ph

30

− 49.1

− 47.6

− 54.7

28.4

90

− 47.5

− 56.2

28.1

14

Et

OEt

Ph

30

− 46.3

− 44.6

− 51.4

22.1

90

− 44.4

− 52.8

21.6

15

OMe

OMe

CH3

30

− 48.2

− 46.3

− 54.5

19.8

90

− 46.2

− 56.2

19.5

16

OMe

OMe

Ph

30

− 50.3

− 48.8

− 54.6

21.5

90

− 48.7

− 55.7

21.4

17

OEt

OEt

Ph

30

− 51.0

− 49.6

− 55.6

19.8

90

− 49.5

− 56.8

19.6

18

Et

NMe2

Ph

30

− 48.8

− 47.0

− 54.6

14.4

90

− 46.8

− 56.1

13.7

19

NMe2

NMe2

CH3

30

− 51.4

− 49.9

− 56.7

8.4

90

− 49.8

− 58.1

8.0

20

NMe2

NMe2

Ph

30

11.3

9.8

11.0

4.2

90

9.2

11.2

3.6

As can see in Table 2, the temperature and substituent in both C-5 and C-3 positions significantly have the most important influence on the fragmentation of 1,4,2-oxathiazoles derivatives and completely agree with the analysis of geometrical structure parameters. This will be detailed as given below:
  • The presence of an increased electron-donating at C-5 substituent has improved the fragmentation of 1,4,2-oxathiazoles derivatives. Since the activation Gibbs free energies have been considerably reduced, when using an electron-releasing group; N > O > S > C;

  • The presence of –CH3, –C2H5…, as an aliphatic substituent at C-3 has fascinatedly improved the fragmentation procedure, considering the generated inductive donor effect (+ I), which vastly helps the stability of the products, such as the fragmentation process becomes more exergonic (exothermic), Gibbs free energies ΔG < 0, such a high exothermic characters make the generation of these products quite irreversible;

  • A significant equilibrium between product and reagent was observed. The presence of a noticeable mesomeric donor substituent (+ M) at C-3 relative to the OMe and NMe2 groups (entry: 2, 3) have to be precious. This behavior generates an ITC product less stable (ΔG ≈ 0 and/or ΔG > 0), which then provokes the transformation of product to the initial component in a lapse of time, in conformity with the reversible reaction (Entry: 2, 3 and 20);

  • The presence of phenyl group as an inductive attractor substituent (− I) at the position C-3 will increase the barrier energy required for the fragmentation to take place, in contrast with an aliphatic inductive electron donor substituent (+ I);

  • In all studied cases, the increase of temperature from 30 to 90 °C has successfully reduced the activation energy.

  • It seems that a mesomeric donor substituent group at the position C-3 accelerates the fragmentation by increasing the distance of S4–C5 bond, but produces an unstable isothiocyanates ITCs product.

  • The use of releasing-electron groups at the position C-3 and C-5 in the following order N > O > S > C, considerably improved the fragmentation and reactivity of 1,4,2-oxathiazoles derivatives in low temperature.

From this perceptible analysis, we have concluded that the most adequate ingredient for a perfect fragmentation is:
  • R1 and R2 substituent at the position C-5 has to be categorized as the most releasing electron donor

  • R3 substituent at the position C-3 has to be inductive electron donor (+ I)

  • Temperature should be consistent with the employed substituent to avoid an eventual regeneration to the started 1,4,2-oxathiazoles derivatives,

  • Entry 19 represents the most appropriate fragmentation process in our study, for which such procedure appears to be directed via a feeble barrier activation, 8.0 kcal/mol with significant stability to the products; ΔG = − 58.1 kcal/mol at 90 °C (irreversible reaction). Consequently, the generation of ITCs products will be more suitable at this condition.

3.3 ELF Topological Analysis of the Most Included Valence Basin Associated with the 1,4,2-Oxathiazoles Derivatives Fragmentation

ELF quantum topological acknowledged as a technique that offers a suitable framework for the study of the changes of pair electron density [36], in a reason that ELF is a density-based function that can be interpreted in terms of the relative local excess of kinetic energy density. The highest values associated with the ELF quantum topological being related to the spatial position having a higher relative electron localization which varies in the range interval [0, 1] [37]. For instance, the gradient field associated with the ELF analysis provides a partition of the molecular space into basins of attractors, which empirically connected to chemically significant concepts, which conceptually rationalize the chemical bonding such as lone pairs, valence (V) bonds and atomic cores (C) [38]. Importantly, the attractor’s basins are commonly associated with the spatial regions, where the probability of finding an electron pair supposed maximal. Therefore, an integration of the one electron or the two-electron density possibilities in the spatial volume presents the basis of ELF electron populations. It is worth noting that within the ELF illustration of bonding, valence basin densities are delocalized among those associated with the internal atomic core basins. In this regards, the attractor positions for the most significant valence basins associated with the 1,4,2-oxathiazoles derivatives are shown in Fig. 2, while the electronic populations of the most pertinent ELF valence basins of the twenty studied compounds are schematized in Fig. 3 (see electronic populations values in Table S62, Supplementary information).
Fig. 2

ELF basin attractors of some selected studied compounds associated with the fragmentation of the 1,4,2-oxathiazoles derivatives, the most significant valence basins are displayed as a to l, for simplifying. (See Table S62 for details, Supplementary Information)

Fig. 3

Electronic population in e of the most significant attractors concerning the R1, R2 and R3 substituents associated with the 20 studied examples given in Table 1 (for more information, see table S62 in SI)

In this paragraph, we aim at illustrating effective substituent in both positions is responsible for the fragmentation processes, at this stage, the influence of electron-releasing or withdrawing groups will be examined, and thus, each variation in electron density will be directly considered at the principle S4–C5, O1–N2 and O1–C5 interatomic bond by means of the ELF quantum topological.

Considering the results displayed in Fig. 3 (Table S62 in SI), a lot of valuable conclusions should be highlighted;
  • The change in electron density has to be marked mainly at the disynaptic basin V (S4, C5) associated with the S4–C5 bond.

  • Electronic population derived from ELF analysis relative to the disynaptic basin V (S4, C5) increases with respect to the increase of electron-releasing R1 and R2 substituent

  • Electron density associated with the disynaptic basin V (S4, C5) increases, once electron-withdrawing R3 substituent increases

  • The presence of electron attractor substituent in R1 and R2 position diminishes the electronic population of disynaptic basin V (S4, C5) associated with the S4–C5 bond (entry 9)

  • The change in electron density relative to the disynaptic basin V (O1, N2) associated with the O1–N2 bond is somewhat marginal to compare with those of S4–C5 bond, in full reliability as well.

  • The lack of electron density relative to the S4–C5 bond, can be attributed to the presence of highly electron-donating substituent in R1 and R2 positions (entry: 18, 19 and 20). This outcome encourage us to conclude that this bond is completely fragmented or largely lengthened. Two reasonable reasons are evaluated; (1) disappear of the disynaptic basin V (S4, C5) related to the S4–C5 bond, (entry 19), and (2) the emergence of two monosynaptic basin V(S4) and V(C5) associated with the S4 and C5 atom, whose integrate 0.59e and 0.71e, respectively (entry 20).

  • The presence of an impressive electron-donor at the position C-3 is an inefficient to provoke an efficacious fragmentation.

Accordingly, in order to obtain a further explanation of these outcomes, we will compare the electron density of disynaptic basin V (C5, R1), V (C5, R2) and V (C3, R3) with the change of R1, R2 and R3 substituent, we remark that:
  • The phenyl substituent at the position C-3 and/or C-5 acts as an electron attractor, unveiled by the increase of electronic population of disynaptic basin V (C5, R1), V (C5, R2) and V (C3, R3) at the presence of such substituent, therefore the inductive attractor effect (− I) of phenyl substituent is preferred beyond the mesomeric electron-donor effect (+ M),

  • The SR, OR and NR substituents have an enormous electron-releasing effect to compare with the CH3 inductive electron donor (+ I) substituent, explained by the depopulation of disynaptic basin V(C5,R1), V(C5,R2) at the presence of R1 and/or R2 = SR, OR and NR groups, such as R = alkyl;

Importantly, the presence of an electron-releasing group at R1 and R2 substituent as well as an electron-releasing group at R3 (aliphatic substituent) are in high impact on the fragmentation of 1,4,2-oxathiazoles derivatives through weakening the S5–C5 and O1–N2 bond. And thus, the overlap lone pairs electron interaction of C–5–S, C–5–O and C–5–N substituent toward C5–Sσ* orbital has assisted for the lengthening and weakening of the C5–S4 bond, and then has provided mesomeric stabilization of the carbocations, this proposed mechanism suitably accepted for the formation of ITCs products. Most significantly, we have noted that the substituent at C-3 position has a small influence on the temperature sensitivity of 1,4,2-oxathiazoles derivatives, principally with the aliphatic C-3 substituent, which more prominent than aryl ones. These results are in good agreement with the geometrical parameters and the activation barrier analysis.

Five cases are the most probably overlap orbital interaction for explaining the fragmentation of 1,4,2-oxathiazoles derivatives, as demonstrated in Fig. 4.
Fig. 4

Different type overlap orbital interaction related to the 1,4,2-oxathiazoles derivatives fragmentation

4 Conclusion

As anticancer and antimicrobial proprieties, the isothiocyanate ITCs products taken considerable interest in the last decade; however, few studies that have tried to achieve with a practical method to generate ITCs. In our ambition to exploit the sensitivity of 1,4,2-oxathiazoles derivatives in situ prepared via [3 + 2] cycloaddition reaction, a computational study will be performed. Having been known as the most suitable method for that analysis; the DFT/B3LYP functional hybrid together with the 6-311(d) basis set have been applied, conjoined with a complete investigation by means of ELF topological quantum.

The preliminary analysis implemented at the geometrical parameter shows that the influence of substituent at C-5 and C-3 positions are in dissimilarity on the fragmentation of 1,4,2-oxathiazoles derivatives. On the one hand, the major effect is principally located at the S4–C5 bond, which again reveals that R1 and R2 substituent at the position 5 corresponding to the nucleophilic character have an excessive impact on the lengthening and weakening of such bond. On the other hand, the R3 substituent at the position C-3 which was described as an electron-donating effect has notable stability on the isothiocyanates ITCs products and vice versa.

Accordingly, the potential energy surface paths exploration obviously proves that the barrier activation completely reduced in the presence of releasing electron substituent at C-5 and C-3 position at a reasonable temperature. Note that the thermodynamic analysis exposes that the position C-3 has a major sensitivity towards the stability of isothiocyanates ITCs products, for which the exergonicity (exothermicity) markedly improved with an aliphatic electron donor substituent, make it the ITCs products more favorable with a slight heating.

Another analysis was carried out, the ELF investigation reveals that the functionalized electron-releasing substituent at C-5 and C-3 position improves the electronic density at the S4–C5 and O1–N2 bond. Therefore, a remarkable donation of lone pair electrons of nucleophilic O, N and S atom towards C5–S σ* orbital, which is assisted for the lengthening and weakening of C5–S4 bond. In general, those established results generated by these three investigations are extra consistent.

Consequently, according to the achieved work, the noted substituent at C-5 and C-3 position makes 1,4,2-oxathiazoles potentially useful as thermally responsive, for providing the ITCs as anticancer properties.

Supplementary material

42250_2019_116_MOESM1_ESM.docx (132 kb)
Supplementary material 1 (DOCX 131 kb)

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Copyright information

© The Tunisian Chemical Society and Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Abdelilah Benallou
    • 1
    Email author
  • Habib El Alaoui El Abdallaoui
    • 1
  1. 1.Team of Chemoinformatics Research and Spectroscopy and Quantum Chemistry, Physical and Chemistry Lab, Faculty of ScienceUniversity Chouaib DoukkaliEl JadidaMorocco

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