A theoretical study of the reactivity and regioselectivity of thiosemicarbazide (TSC) condensation toward some carbonyl triterpenes was carried out using density functional theory with B3LYP/6-31G(d,p). The relative reactivity of these systems was rationalized by means of the global electrophilicity index. Positional selectivity, namely C3, C7 and C11, were evaluated using difference index Rk, Parr functions and difference of Parr function. The present study showed that the experimental results of the relative reactivity and regioselectivity of these reactions were correctly predicted using difference index Rk, Parr functions and difference of Parr function

Benharref, A.

El Hajbi, A.

Hammal, R.

Mazoir, N.

Zeroual, A.

English

Revues Scientifiques Marocaines

Moroccan Journal of Chemistry ISSN: 2351-812X http://revues.imist.ma/?journal=morjchem&page=login A. Zeroual / Mor. J. Chem. 4N°4 (2016) 938-944  Mor. J. Chem. 4N°4 (2016) 938-944 938    A theoretical investigation of the reactivity and regioselectivity of triterpene derivatives using difference local index, Parr functions.  A. Zerouala . R. Hammala . A. Benharrefb . A. El Hajbia . N. Mazoirb,c    (a) Laboratory of Physical Chemistry, Department of Chemistry, Faculty of Science El Jadida, Chouaib Doukkali University, P.O. Box 20, 24000 El Jadida, Morocco (b) Laboratory of Biomolecular Chemistry, Natural Substances and Reactivity, URAC 16, Faculty of Sciences Semlalia, Cadi Ayyad University, P.O. Box 2390, Marrakech, Morocco. (c) Department of Chemistry, Faculty of Sciences El Jadida, Chouaib Doukkali University, P.O. Box 20, 24000 El Jadida, Morocco         * Corresponding author: zeroual19@yahoo.fr   Received 27 July 2016, Revised 10 Aug 2016, Accepted  08 Jan 2017 Abstract A theoretical study of the reactivity and regioselectivity of thiosemicarbazide (TSC) condensation toward some carbonyl triterpenes was carried out using density functional theory with B3LYP/6-31G(d,p). The relative reactivity of these systems was rationalized by means of the global electrophilicity index. Positional selectivity, namely C3, C7 and C11, were evaluated using difference index Rk, Parr functions and difference of Parr function. The present study showed that the experimental results of the relative reactivity and regioselectivity of these reactions were correctly predicted using difference index Rk, Parr functions and difference of Parr function   Keywords: Triterpene, thiosemicarbazide (TSC) condensation, regioselectivity, DFT, Parr function.                Mor. J. Chem. 4N°4 (2016) 938-944 939  1. Introduction  Heterocyclic chemistry is an integral part of the chemical sciences and constitutes a considerable part of the modern researches that are occurring presently throughout the world. The synthesis of novel heterocyclic derivatives [1] and investigation of their chemical and biological behavior have gained more importance in recent decades. A limited number of natural and synthetic products have served directly as therapeutic agents although lack of specificity frequently limits their application in human and veterinary medicines and in analogous pesticide and other uses in agriculture. The study of heterocyclic systems is of great interest both from the theoretical and practical point of view. Heterocycles also play an important role in the design and discovery of new pharmacologically active compounds [2-5]. In order to prepare new heterocyclic triterpene derivatives, we were interested to the reactivity of the ketones 1 and 2 hemisynthesized from Euphorbia officinarum [6-8] and 3 resulting from Euphorbia resinifera [9] using thiosemicarbazide (TSC) condensation.[10-12] Thus, treatment with equimolecular quantity of compounds 1, 2 and thiosemicarbazide in the presence of hydrogen chloride in  ethanol, yielded respectively, after heating at reflux during 5h, to thiosemicarbazone derivatives 4 and 5. Compound 3 afforded, under the same conditions previously described, product 6 (scheme 1).  Scheme 1. Thiosemicarbazide condensation on compounds 1, 2 and 3. (a) NH2CSNHNH2, EtOH, HCl.  2. Materials and methods  Computational chemistry DFT computations have been realized using the B3LYP functional, [13] together with the standard 6-31(d, p) basis set. [14] The optimizations were carried out using the Berny analytical gradient optimization method. [15] All computations have been shown with the Gaussian 09 suite of programs. [16] The global electrophilicity index [17] ω,   Mor. J. Chem. 4N°4 (2016) 938-944 940  was given by the following expression, ω = (µ2/2η), in terms of the electronic chemical potential µ and the chemical hardness η. Both quantities may be approached in terms of the one-electron energies of the frontier molecular orbital HOMO and LUMO, eH and eL, as µ = (eH - eL)/2 and η = (eL - eH), respectively. [18] The empirical (relative) nucleophilicity index N, [19] based on the HOMO energies obtained within the Kohn–Sham scheme, [20] and defined as N = EHOMO(Nu) - EHOMO(TCE). The nucleophilicity was referred to tetracyanoethylene (TCE). Electrophylic  and nucleophilic Parr functions, [21] were obtained through the analysis of the Mulliken atomic spin density (ASD) of the radical anion and radial cation of the reagents. The local electrophilicity and nucleophilicity indices, [21] were evaluated using the following expressions: ωk = ω  , Nk = N  .. [21] The difference between nucleophilic and electrophilic Parr functions like as the difference Fukui function [22]. . When P2 > 0, the process was driven by a nucleophilic attack on atom k which acted as an electrophilic species; conversely, when P2 < 0, the process was evaluated by an electrophilic attack over atom k which played then as a nucleophilic species. The definition of Rk was given by the following three conditions to identity the centers with electrophilic (Rk = + n.nn) or nucleophilic (Rk = − n.nn) behavior as well as the ambiphilic (Rk = ± n.nn) behavior in addition to eliminate the centers with marginal reactivity: R_k= (Wk-Nk). [23] Where Rk > 0 → electrophilic (Rk = + n.nn) and Rk < 0 → nucleophilic (Rk = − n.nn).  3. Results and Discussions  3.1. Frontier molecular orbital analysis (HOMO-LUMO). The frontier molecular orbitals (HOMO-LUMO) and frontier orbital gap allowed to exemplify the chemical reactivity and kinetic stability of the molecules, and were the important parameters for quantum chemistry [24]. The band gaps in conjugated terpenes were governed by their chemical structures. Therefore, the detailed band gap theoretical calculations were carried out by using B3LYP/6-31+G (d,p) level .  Figure 1.  HOMO-LUMO energy gap for the triterpenes used in this work.    Mor. J. Chem. 4N°4 (2016) 938-944 941  The band gap could sometimes serve as a measure of the excitability of the molecule as well as the energy; the more easily of molecules electron will be excited. The HOMO-LUMO energy gap was an important stability index and a large energy gap which implied high stability for the molecule. Therefore, thiosemicarbazone 3 (ΔE = 3.5149 eV) characterized the highest stability when compared to other triterpenes. The Lower in the HOMO-LUMO energy gap has shown that the intramolecular charge transfer must occur within the molecule and eventual charge transfer interaction placed within the molecule. HOMO-LUMO shapes and band gap of triterpene derivatives were illustrated in Figure 1  3.2. DFT analysis based on the global and local reactivity indexes. The static global properties, namely electronic chemical potential μ, chemical hardness η, global electrophilicity index ω and global nucleophilicity index N of compound 1 and thiosemicarbazide were the chemical properties which we used to analyze the reactivity at various sites in the reactants (Table1).  Table 1. DFT/B3LYP/6-31G (d,p) Electronic chemical potential µ, chemical hardness η, electrophilicity ω, and nucleophilicity N values, in ev.    µ η N  Triterpene 1 -3.844 3.087 4.641 3.539 Triterpene 2 -4.012 2.862 4.086 2.812 Triterpene 3 -4.421 3.510 3.353 2.785 Thiosemicarbazide (TSC) -3.011 5.533 3.751 0.819 We can deduce from table 1 that: •The electronic chemical potential of starting material (TSC) was greater than the triterpenes 1, 2 and 3 which implied that electron transfer have taken place from thiosemicarbazide to triterpenes. •The electrophilicity index of the TSC (0.819 eV) was smaller than the triterpenes 1, 2 and 3: 3.539, 2.812 and 2.785 eV, respectively and implying that in this reaction, the thiosemicarbazide behaved as a nucleophile while 1, 2 and 3 as electrophiles.  3.3. Prediction of the regioselectivity of the reaction using difference local index, Parr functions and a difference of Parr function. Along a polar reaction involving the participation of unsymmetrical reagents, the most favorable reactive channel was that involving the initial two-centre interaction between the most electrophilic  and nucleophilic  centre of both reagents. Recently, we have applied the electrophilic and nucleophilic Parr functions derived from the excess of spin electron density reached via the GEDT process from the nucleophile to the electrophile in order to establish the most favorable nucleophilic-electrophilic interaction in polar processes [21].  Accordingly, in order to characterize the most nucleophilic and electrophilic centers of the species involved in these reactions, the Parr functions the difference electrophilic -nucleophilic and the dual descriptor of Parr function of the triterpenes were analyzed. The four compounds given in Table 1 were ordered according to decreasing electrophilicity (ω) values. For most of them, presenting a single substitution, the global nucleophilicity N index increased on going towards the bottom of Table 1. A first analysis of the Rk values given in Table 2 showed that triterpenes presenting electrophilic activated centers (green color) were located on the top of the table 2, in clear   Mor. J. Chem. 4N°4 (2016) 938-944 942  agreement with the global electrophilic/nucleophilic behavior of these molecules. A comparison of the total absolute values of ΔP at the most electrophilic C7 and C11 center of triterpenes 1 and 2, we showed that ΔP (C7) was smaller than ΔP (C11). This difference was due to the presence of attractive group (ketone and tosyl) in carbon C3, while we have used a donor group (acetyl) ΔP (C11) became greater than ΔP (C7) in clear agreement with the experimental data. The analysis of the electrophilic  Parr functions of triterpenes 1 and 2 showed that C7 carbon presented the maximum values,   0.385 and 0.27, respectively, indicating that these sites are the most electrophilic centers of the species studied (see Scheme 1 for atom numbering). However, the electrophilic  Parr functions of compound 3 showed that the C11 carbon presented the maximum value   0.412. From these values, two appealing conclusions could be obtained: i) the triterpenes 1 and 2 experienced a strong electrophilic activation at the C7 carbon, (ii) for triterpene 3, the electrophilic Parr functions were concentrated at the C11 carbon, in agreement with the experimental data.  Table 2. DFT/B3LYP/6-31G(d,p) the difference local index, Parr functions and a dual descriptor of Parr functions.         experimental attack P1 C7 C11 0.110 0.055 0.001 -0.019 0.109 0.074 0.389 0.194 0.004 -0.088 0.385 0.282 C7 C11  P2 C3 C7 C11 0.0003 0.18 -0.004 -0.05 0.058 -0.05 0.0503 0.122 -0.046 0.0008 0.506 -0.011 -0.204 0.236 -0.204 0.204 0.270 0.193 C3 C7 C11 P3 C7 C11 0.083 0.152 -0.041 0.003 0.109 0.145 0.231 0.423 -0.137 0.010 0.368 0.412 C7 C11  3.4. NMR spectra. The experimental and calculated 13C chemical shifts (δ calc) of compound 3 using the GIAO in gas and solvent approach are given in Table 3. According to these results, the calculated chemical shifts are in accord with the experimental data. As shown in Table 3, the agreement between the experimental and the calculated chemical shifts From the data in table 3, we can draw a curve of experimental chemical shifts according to the theoretical chemical shifts (figure 2). The analysis of the linear regression gave a slope of 1.094, 1.077 and 1.079 respectively with the corresponding gaseous phases, CH2Cl2 and CHCl3. This analysis showed the linearity between theoretical and experimental values. The regression coefficient is R2 = 0.992, 0.993 and 0.9033, respectively to gaseous phases, CH2Cl2 and CHCl3. It indicated a good match between the curve and the data. Indeed, it’s finding that the correlation was even better for GIAO method with chloroform as solvent.           Mor. J. Chem. 4N°4 (2016) 938-944 943  Table 3 : The calculated and experimental chemical shifts δ (ppm) of compound 3 using GIAO method Carbon    δ calc (ppm) δ exp (ppm) δ gas  δ dichloromethane δ chloroform  1 42.37 42.97 42.87 36.1 2 40.75 41.69 41.54 37.5 3 199.16 204.01 203.36 210.5 4 50.06 50.50 50.42 51.7 5 53.98 54.03 54 49.3 6 46.46 46.82 46.75 39.7 7 194.12 196.77 196.26 200.2 8 148.47 149.88 149.69 151.3 9 146.92 148.49 148.28 151.6 10 41.17 42.24 42.13 36.7 11 195.85 198.33 198 202.4 12 55.58 55.94 55.88 44.6 13 52.7 53.27 53.18 37.5 14 53.61 54.35 54.22 36.5 15 35.86 36.45 36,33 28.4 16 33.34 33.58 33.53 29.8 17 57.89 57.95 57.93 48.7 18 22.64 22.85 22.8 17.8 19 24.76 25.13 25.06 18.9 20 42.47 42.84 42.78 37.8 21 27.06 27.24 27.2 17.5 22 44.42 44.74 44.68 27.7 23 39.58 39.89 39.83 26.3 24 44.98 45.33 45.26 27.5 25 36.24 36.65 36.58 29.1 26 27.41 27.60 27.56 16.6 27 24.62 24.78 24.74 17.3 28 30.53 30.99 30.91 24.2 29 16.98 17.20 17.15 15.5    Fig. 2. Correlation between the experimental and the calculated chemical shifts in gaseous phase (in CH2Cl2 and CH3Cl).     Mor. J. Chem. 4N°4 (2016) 938-944 944  4. Conclusion The high reactivity and regioselectivity of the triterpene derivatives 1, 2 and 3 towards thiosemicarbazone derivatives, have been studied using DFT methods at the B3LYP/6-31G(d,p) computational level. Analysis of the DFT reactivity indices for these compounds clearly accounts for its high electrophilic character, entirely at the C7 carbon for 1 and 2 whereas for compound 3, the electrophilic character was at the C11 carbon. These behaviors have explained the high regioselectivity of these reactions. We can therefore conclude that difference local index, Parr functions and a difference of Parr function could adequately predict regioselectivity in organic reactions.  References [1] N. Mazoir, M. Dakir, M. Tebbaa, M. Loughzail, A. Benharref, Tetrahedron letters 57 (2016) 278-280 [2] C-H. Oh, H-W. Cho, D. 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A theoretical investigation of the reactivity and regioselectivity of triterpene derivatives using difference local index, Parr functions.

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A theoretical investigation of the reactivity and regioselectivity of triterpene derivatives using difference local index, Parr functions.

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