{A simple computational approach for pKa calculation of organosulfur compounds} J. Serb. Chem. Soc. 86 (2) 165–170 (2021) Short communication JSCS–5412 165 SHORT COMMUNICATION A simple computational approach for pKa calculation of organosulfur compounds SYED TAHIR ALI*, ANEESA CHOUDHARY1, SYED MAJID KHALIL2 and ARIF ZUBAIR3 1Department of Chemistry, Federal Urdu University of Arts Science and Technology, Karachi, Pakistan, 2Bosch Pharmaceutical Private Limited, Plot No. 209, Sector 23, Korangi Industrial Area, Karachi, Pakistan and 3Department of Environmental Science, Federal Urdu University of Arts Science and Technology, Karachi, Pakistan (Received 18 May, accepted 7 July 2020) Abstract: The present work is related to predicting the pKa values of organo- sulfur compounds through the density functional theory (DFT). In this study, 22 organosulfur compounds were considered to calculate the theoretical pKa values. The main emphasis was given on the substitution of different groups on the sulfur atom. The computations were performed in the presence of dimethyl sulfoxide (DMSO) as solvent. Experimentally, the order of increase of acidity is; sulfides < sulfoxides < sulfones. The herein computed pKa values also fol- low the same order. The theoretical pKa values were computed using the DFT method B3LYP, with the basis sets 6-31G(d), 6-31+G(d,p) and the IEFPCM bulk solvation model. The majority of the pKa values computed through the diffuse function basis set were in excellent agreement with the experimental ones. Hence this computational approach, B3LYP/6-31+G(d,p)/IEFPCM, could be utilized to predict the pKa values of these types of organosulfur com- pounds. Keywords: DFT method; diffuse function basis set; DMSO solvent. INTRODUCTION The acid dissociation constant (pKa) is an important property of many organic compounds and it is strongly related to their applications. Fast and accurate methods for determining aqueous pKa values of organic compounds would have a wide range of applications. Aside from experimental measure- ments, theoretical determination of the acidity of a compound has been an imp- ortant and challenging objective of computational chemistry.1,2 The comput- ations (theoretical calculations) are a reconfirmation of experimental results. A * Corresponding author. E-mail: stahir.ali@fuuast.edu.pk https://doi.org/10.2298/JSC200518042A ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ 166 ALI et al. computation provides an idea of the structural information of a molecule in vacuum (gas phase), which is difficult to obtain through experiments. Theoretical calculations are also helpful in providing information for the determination of the preferred protonation site when more than one site is available.3 Organosulfur compounds have many important applications, which have already been reported in literature.4–7 In this communication, we are presenting a very easy computational approach for theoretical calculation of pKa values. This theoretical model is employed for three types of organosulfur compounds, i.e., sulfides, sulfoxides and sulfones. Different kinds of substituents were selected that were attached on both sides of the sulfur atom. The structures of compounds considered for pKa calculation are shown in Fig. 1. The significance of this com- putational model is that it could be uniformly applied for sulfides, sulfoxides and sulfones. Fig. 1. Compounds considered for the theoretical pKa calculations. This computational protocol was developed in previous studies related to pKa calculations.8,9 In these studies, it was shown that the theoretically calcul- ated pKa values could be utilized to resolve discrepancies in experimental pKa values. These computational studies were performed with different solvation models but only water was used as the solvent. ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ THEORETICAL CALCULATION OF DISSOCIATION CONSTANT 167 EXPERIMENTAL The experimental pKa values of different derivatives of sulfide, sulfoxide and sulfone were obtained from literature.10-13 These experimental pKa values are determined in DMSO as solvent. The series starts with the simple forms, i.e., dimethyl sulfide, dimethyl sulfoxide and dimethyl sulfone. Other derivatives were set by variation of different groups (see Fig. 1). First, the geometries of all the considered compounds were drawn with the help of GaussView 6.14 Then the molecular modeling software Gaussian 1615 was employed for all quantum calcul- ations. For the computation of the pKa values, the Gibbs energy changes in the gas phase (∆Ggas) were calculated through the DFT method, B3LYP, with the basis sets 6-31G(d) and 6-31+G(d,p). Solvation free energy changes (∆Gsolv) in DMSO have been obtained by single point computations on gas phase geometries, using the bulk solvation model – integral equat- ion formalism polarizable continuum model (IEFPCM). The calculations of pKa values is per- formed by using a well known thermodynamic cycle (Scheme 1; Eqs. (1) and (2)).16 The Gibbs energy of the gas phase proton17 was taken from the Sackur–Tetrode Equation as Ggas(H+) = –6.28 kcal* mol-1; for the Gibbs energy change of hydration of the proton, the experimental value,18 ΔGsolv(H+) = –270.0 kcal mol-1, was used. The usual correction term of 1.9 kcal mol-1 was applied for standard state conversion between 1 atm in the gas phase and 1 mol L-1 in solution.19 Scheme 1. The thermodynamic cycle utilized for Eqs. (1) and (2). pKa = ΔG/(2.303RT) (1) ΔG = ΔGgas + ΔGsolv(A-) + ΔGsolv(H+) – ΔGsolv(HA) (2) RESULTS AND DISCUSSION The data set of experimental pKa values shows that changing the methyl group with a phenyl or a benzyl group increases the acidity of the considered organosulfur compounds. Electron withdrawing substituents also have the same effect (see Table I). Addition of oxygen atoms on sulfur also increases the acidity from sulfide to sulfoxides and sulfones (see Fig. 2). Initially all structures were fully optimized with frequency calculations, by the B3LYP method using the basis set, 6-31G(d). Solvation energies were obtained by single point computations with the same basis set. The calculated pKa values obtained through this computational approach and the experimental pKa values are summarized in Table I. * 1 kcal = 4184 J ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ 168 ALI et al. TABLE I. Comparison of experimental and calculated pKa values Sulfide Sulfoxide Sulfone Comp. Exp. Calcd.a Calcd.b Comp. Exp. Calcd.a Calcd.b Comp. Exp. Calcd.a Calcd.b 1a 45.0 55.7 45.7 2a 35.1 46.9 35.1 3a 31.1 38.2 31.3 1b 42.4 51.3 43.2 2b 29.0 35.3 28.6 3b 25.4 30.2 24.4 1c 30.8 37.6 32.0 2c 33.0 53.5 34.1 3c 29.0 36.5 28.6 1d 26.7 32.0 27.7 2d 27.2 33.8 27.6 3d 23.4 29.8 24.1 1e 20.8 24.5 18.6 2e 24.5 30.3 25.3 3e 22.3 32.1 23.4 1f 18.7 24.9 21.7 2f 15.1 21.9 12.8 3f 12.0 15.2 9.4 1g 16.9 25.2 15.4 3g 11.4 24.5 17.0 1h 11.8 15.7 8.7 3h 7.1 10.1 3.0 MAD 6.8 1.7 9.6 0.83 6.8 1.9 R2 0.99 0.98 0.83 0.99 0.89 0.91 aB3LYP/6-31G(d)/IECPCM; bB3LYP/6-31+G(d,p)/IECPCM Fig. 2. Addition of oxygen atoms increases the acidity. A comparison of the experimental and computed pKa values shows that the pKa values computed through B3LYP/6-31G(d)/IEFPCM procedure are large than experimental pKa values. The mean absolute deviations (MAD) are also large (<7pKa – units) in sulfide, (<9pKa – units) in sulfoxide and (<7pKa – units) in sulfone. However, the correlation coefficients (R2) are somehow better in each series (>0.8). Addition of a diffuse function in the basis set subsequently improved the results. The MAD values decreased significantly in each series (<2pKa – unit) and the R2 values also improved (>0.9). The data obtained through the B3LYP/6- -31+G(d,p)/IEFPCM computational approach shows an excellent agreement between the experimental and computed pKa values (see Table I). Hence, this computational model is excellent in predicting the pKa values of these kinds of organosulfur compounds. All investigated data obtained through B3LYP/6- -31+G(d,p)/IEFPCM computational model are presented in Fig. 3. CONCLUSIONS The DFT method was employed to calculate theoretical pKa values of org- anosulfur compounds using two different basis sets. The diffuse function basis set provided the best calculated pKa values and these are in excellent agreement with ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ THEORETICAL CALCULATION OF DISSOCIATION CONSTANT 169 Fig. 3. Plot of experimental and computed pKa through B3LYP/6-31+G(d,p)/IEFPCM. the majority of the experimental pKa values. Oxidation of sulfur and substitution of electron withdrawing and aromatic groups increase the acidity of considered organosulfur compounds. The predicted pKa values showed the same phenom- enon regarding the acidity of organosulfur compounds. Finally it was concluded that the proposed computational approach B3LYP/6-31+G(d,p)/IEFPCM is pre- dictive and could be utilized to calculate theoretical pKa values of these kinds of small organosulfur compounds. For large and flexible organosulfur compounds, conformational analysis will be required. Acknowledgement. The authors are thankful to Higher Education Commission (HEC), Pakistan, for financial support. И З В О Д ЈЕДНОСТАВАН РАЧУНАРСКИ ПРИСТУП ИЗРАЧУНАВАЊУ pKa ОРГАНОСУМПОРНИХ ЈЕДИЊЕЊА SYED TAHIR ALI, ANEESA CHOUDHARY1, SYED MAJID KHALI2 и ARIF ZUBAIR3 1 Department of Chemistry, Federal Urdu University of Arts Science and Technology, Karachi, Pakistan, 2 Bosch Pharmaceutical Private Limited, Plot No. 209, Sector 23, Korangi Industrial Area, Karachi, Pakistan и 3 Department of Environmental Science, Federal Urdu University of Arts Science and Technology, Karachi, Pakistan Овај рад се односи на предвиђање pKa вредности органосумпорних једињења помоћу теорије функционала густине (DFT). У овој студији су разматрана 22 органо- сумпорна једињења за израчунавање теоријских pKa вредности. Нагласак је стављен на супституцију различитих група на атому сумпора. Израчунавања су урађена за при- суство диметил-сулфоксида (DMSO) као растварача. Експеримeнтални редослед порас- та киселости је: сулфиди < сулфоксиди < сулфони. Наше израчунате pKa вредности такође следе овај поредак. Теоријске pKa вредности израчунате су користећи DFT метод B3LYP, са базисима 6-31G(d), 6-31+G(d,p) и IEFPCM помоћни солватациони модел. Већина pKa вредности, израчунатих помоћу дифузног базиса, су у изврсној сагласности са експерименталним. Отуда се овај рачунарски приступ, B3LYP/6-31+G(d,p)/IEFPCM, може користити за предвиђање pKa вредности овог типа органосумпорних једињења. (Примљено 18. маја, прихваћено 7. јула 2020) REFERENCES 1. A. Onufriev, D. A. Case, G. M. Ullmann, Biochemistry 40 (2001) 3413 (https://doi.org/10.1021/bi002740q) ________________________________________________________________________________________________________________________ (CC) 2021 SCS. Available on line at www.shd.org.rs/JSCS/ 170 ALI et al. 2. K. S. Alongi, G. C. Shields, Ann. Rep. Comp. Chem. 6 (2010) 113 (https://doi.org/10.1016/S1574-1400(10)06008-1) 3. G. J. Paul, J. S. Walter, J. Chem. Phys. 83 (1985) 2984 (https://doi.org/10.1063/1.449201) 4. M. K. Syed, C. Murray, M. Casey, Eur. J. Org. 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