s of Thiols in DMSO - American Chemical Society

Article pubs.acs.org/JPCA

Quantum-Chemical Predictions of pKa’s of Thiols in DMSO Hai-Zhu Yu,† Yi-Meng Yang,† Liang Zhang,† Zhi-Min Dang,*,† and Guo-Hua Hu*,‡ †

Department of Polymer Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China Laboratory of Reactions and Process Engineering (CNRS UMR 7274), CNRS-Université de Lorraine , ENSIC, 1 rue Grandville, BP 20451, 54001 Nancy, France

‡

S Supporting Information *

ABSTRACT: The deprotonation of thiols (on the S−H bond) is widely involved in organic and bio-organic reactions. With the aid of density functional theory (DFT) calculations, the present study focuses on predicting the pKa’s of thiols. Efforts were first put in searching for an appropriate computational method. To achieve this goal, the accuracy of 13 different DFT functionals (i.e., B3LYP, BB1K, PBE, M06, M05, M06-2X, M06-L, M05-2X, TPSS, MPW1K, MPWB1K, MPW3LYP, TPSSLYP1W) and 6 different total electron basis sets (6-31G(d), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p), 6-311++G(d,p), 6-311++G(2df,2p)) (with DMSO solvent and SMD solvation model) were examined. The M06-2X/6-311++G(2df,2p) (M1) method was found to give the best performance in reproducing the reported 16 pKa’s of thiols, with a standard deviation (SD) of about 0.5 pKa unit. Meanwhile, the M1 method was found to be excellent in reproducing the gas phase Gibbs free energies of 17 thiols, providing extra evidence for the reliability of the M1 method in treating thiol systems. On this basis, M1 was then used to predict the pKa’s of 291 thiols whose experimental pKa values remain unknown. Accordingly, the scope of pKa’s of different thiols was constructed.

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pKa’s of 50 chemically diverse compounds including acids, bases, and ampholytes by potentiometric titration.66 Penhoat et al. measured the pKa’s of substituted phenols in H2O, CH3CN, DMF, DMSO and i-PrOH with the nuclear magnetic resonance (NMR) method.67 In addition to the experimental strategies, theoretical calculations have also been frequently used to evaluate the pKa’s of organic compounds. For instance, Cheng and co-workers recently reported the pKa’s of 41 chiral phosphoric acid catalysts in DMSO.68 Fu and Liu et al. reported the pKa’s of a series of organic acids, including organophosphorus/phosphorus heterocycles69 and organosilicons70 (in MeCN/DMSO). Shields et al. calculated the pKa’s of carboxylic acids71 and substituted-phenols,72 and established extensive benchmarking on how DFT methods perform for evaluating ΔG for gas-phase deprotonation, against both high level QM methods and very accurate experimental databases.73,74 Notwithstanding the extensive experimental and theoretical studies on the pKa’s of organic compounds, the pKa values of thiols are relatively scarce. The low acidity and the high instability of thiols result in the difficulty in measuring the pKa’s experimentally.75,76 To the best of our knowledge, there are fewer than 30 thiols whose pKa values have been experimentally measured (vide supra).77,78 In this context, theoretical calculations might represent an alternative strategy to predict the pKa’s of thiols.

INTRODUCTION Thiols widely exist in natural products and drug molecules and have shown great potential in organic/bio-organic synthesis, biological chemistry, and materials science.1−20 In the past decades, much effort has been put in the reactions involving thiols.21−30 For instance, various thiol substrates have been used in protein and peptide chemistry31−44 and the transition metal catalyzed synthesis of sulfides,45,46 S-heterocyclic compounds,47 and other C−S coupling reactions.48 In many of these reactions, the base mediated deprotonation of the related S−H bond is an essential step. For example, in the thiol involved nucleophilic substitution,49−52 Michael addition,53,54 and anti-Markovnikov addition reaction,55,56 the deprotonation of the S−H bond has been frequently proposed as an elementary step. More importantly, the deprotonation of thiols (acidity) has been frequently found to be important in determining the overall reactivity. For example, in the recently reported ligation reaction between peptide-α-thioester and cysteine-peptide, Kent et al.57 found that the substituted thiophenols with pKa > 6 were more active than the other ones (pKa < 6). Therefore, the measurement of pKa values of thiols is of great potential for understanding the reactivity of the thiolinvolved reactions and the development of novel reactions. In recent years, both experimental strategies and theoretical calculations have been used to study the pKa’s of organic compounds. For example, Bordwell and Evans established the acidity scales of a large number of organic compounds (such as acids, alcohols, and amides) in DMSO58−64 and N-methyl-2pyrrolidone solvents.65 Recently, Volgyi et al. measured the © 2014 American Chemical Society

Received: October 16, 2013 Revised: December 13, 2013 Published: January 3, 2014 606

dx.doi.org/10.1021/jp410274n | J. Phys. Chem. A 2014, 118, 606−622

The Journal of Physical Chemistry A

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Figure 1. Selected 16 thiols for evaluation of different DFT functionals.

Considering that different calculation methods may give distinct results for one transformation,79−82 we first examine the reliability of different methods to identify an appropriate one that can accurately reproduce the pKa’s of thiols in DMSO solvent (obtained by experimental methods).78 To achieve this goal, the performances of 13 DFT methods (B3LYP,83,84 BB1K,85 PBE,86,87 M06,88,89 M05,90 M06-2X,88 M06-L,91 M052X,92 TPSS,93 MPW1K,94 MPWB1K,95 MPW3LYP,96 and TPSSLYP1W97) and 6 different total electron basis sets (631G(d), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p), 6-311+ +G(d,p), 6-311++G(2df,2p)) were first compared. We found that the linear correlation coefficients (R) for those methods were all above 0.96. M06-2X/6-311++G(2df,2p) (M1) gives the best performance. With the M1 method, the linear correlation coefficients (R) between 16 calculated pKa and the experimentally obtained ones was 0.9891, the standard deviation (SD) is 0.5539 pKa, and the root-mean-square deviation (RMSD) is 0.5939 pKa. Meanwhile, the gas phase acidities of 17 thiols have also been well reproduced by the M1 method, providing an extra evidence for the reliability of the M1 method in treating thiol systems. On this basis, we used this method to predict the pKa’s of 291 thiols whose experimental pKa’s in DMSO remain unkown, including alkyl, amino, alkoxyl, carbonyl, alkenyl, alkynyl, heteroaryl, and aromatic thiols. We hope the present study will benefit the mechanistic understanding and future development of more powerful synthetic strategies involving thiols.

solvent). The calculations indicated that the linear correlation obtained by the M06-2X/6-311++G(2df,2p)//M06-2X/ 6-31G(d) (M2) method was slightly worse than that calculated by the M1 method. Finally, the M1 method was used to predict the pKa’s of 291 thiols (in DMSO).

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RESULTS AND DISCUSSION Calculation of pKa’s of Thiols in DMSO. Following the previous theoretical studies on pKa calculations,100−105 we first set a compound (1) whose pKa value was well measured experimentally as a reference. In the present study, aniline was chosen as the reference because its pKa has been measured by two or more indicators as 30.6 ± 0.1 pKa (in DMSO solvent).106 On this basis, a proton-exchange reaction between thiols with 1 and the pKa’s of 1 was then used to evaluate the pKa’s of the other concerned thiols (eq 1). This method is used to avoid the significant underestimation of the solvation energy of H+ by theoretical calculations.107 Meanwhile, the number of charged species is conserved, which allows for some cancellation of errors.108,109 As shown in eq 1, the Gibbs free energy change of the proton exchange reaction between thiol and aniline in DMSO is defined as ΔGexchange, and the equilibrium constants defined as Ka. From eqs 1−5, the pKa of the thiol (in DMSO) can be finally obtained by eq 6. RSH + C6H5NH1−1 → RS−1 + C6H5NH 2

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ln K a = −

METHODS All calculations were performed with Gaussian 09 program.98 In examining the performances of different methods (i.e., B3LYP, BB1K, PBE, M06, M05, M06-2X, M06-L, M05-2X, TPSS, MPW1K, MPWB1K, MPW3LYP, TPSSLYP1W), geometry optimizations were performed in DMSO solvent, employing the SMD99 solvation model (with the default settings) and 6-31G(d) basis set. The linear correlations between the experimental results and the calculated ones were found to be better for BB1K and M06-2X methods, and thus the effect of basis sets (6-31G(d), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p), 6-311++G(d,p), 6-311++G(2df,2p)) was examined on the basis of these two methods. It is found that M06-2X/6-311+ +G(2df,2p) (M1) yielded the best performance among those. Nonetheless, considering that the M1 method was relatively time-consuming, we also examined whether the combination of M06-2X/6-31G(d) geometry optimization and the M06-2X/ 6-311++G(2df,2p) single point energy calculation would give comparable results (with SMD solvation model and DMSO

(1)

ΔGexchange (2)

RT

On the basis of eqs 1 and 2, we have e−ΔGexchange / RT =

[RS−1][C6H5NH 2] [RSH][C6H5NH1−1]

(3)

Using the experimental pKa value of aniline in DMSO (i.e., 30.6),106 we have [H+][C6H5NH1−1] = 10−30.6 [C6H5NH 2]

(4)

Using eqs 3 and 4, we obtain K a(RSH) =

[H+][RS−1] = 10−30.6e−ΔGexchange / RT [RSH]

(5)

Thus pK a(RSH) = 30.6 + 607

ΔGexchange 2.303RT

(6)



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Table 1. Comparison between pKa Values Calculated by DFT/6-31G(d) and the Experimental Results of Thiols in DMSOa pKa(calc) RSH C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 Rc SDc RMSDc RSH C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 Rc SDc RMSDc

B3LYP 6.4 7.7 5.0 0.8 15.8 14.9 10.1 14.1 3.7 15.0 12.3 8.7 9.1 6.6 7.1 7.0 0.9787 1.0576 3.1429 M06 6.4 7.3 4.9 0.7 15.5 14.5 10.7 14.0 3.6 15.0 11.8 8.6 10.1 6.1 7.0 6.9 0.9700 1.1745 3.2503

PBE 7.5 8.9 6.1 1.4 17.4 16.6 12.6 15.2 5.2 16.8 13.1 9.9 10.0 7.7 8.1 8.0 0.9720 1.3096 2.1297 M06-L 7.1 8.2 5.7 1.2 16.5 15.5 11.3 14.4 4.7 15.9 12.3 9.3 9.4 7.2 7.5 7.6 0.9755 1.0998 2.6128

TPSS 7.6 9.0 6.1 1.5 17.1 16.3 11.1 15.3 5.1 16.7 13.3 9.7 10.0 7.7 8.2 8.1 0.9747 1.1948 2.1446

BB1K 8.3 9.7 6.8 2.1 18.2 17.4 13.2 16.1 6.1 17.7 13.7 10.5 10.7 8.5 8.9 8.8 0.9717 1.3295 1.6058 pKa(calc)

MPWB1K 8.2 9.6 6.7 2.0 18.1 17.3 13.1 16.0 5.9 17.6 13.6 10.4 10.5 8.3 8.8 8.7 0.9720 1.3286 1.6683

M06-2X 6.2 6.3 4.5 2.0 15.5 13.7 9.6 13.4 2.2 14.4 11.0 7.7 7.7 5.6 7.0 6.6 0.9806 0.9011 3.7618

M05 6.7 6.2 5.2 1.2 16.8 15.8 11.4 14.4 4.8 15.7 12.7 8.8 9.4 7.1 7.3 7.1 0.9600 1.4428 2.9305

MPW3LYP 7.9 9.2 6.4 1.6 17.5 16.6 12.8 15.9 5.9 16.8 13.4 10.3 10.5 8.0 8.5 8.5 0.9684 1.3006 1.8658 TPSSLYP1W 7.9 9.2 6.3 1.6 16.9 16.3 12.2 15.7 5.6 16.5 13.5 9.9 10.3 8.0 8.5 8.4 0.9701 1.1959 1.9462

MPW1K 7.6 8.9 6.1 1.4 17.6 16.6 13.1 15.4 5.3 16.9 13.1 10.0 10.1 7.7 8.1 8.1 0.9701 1.3636 2.0868 M05-2X 5.4 6.5 3.9 0.6 15.0 13.8 10.1 12.4 1.8 14.5 11.5 7.0 7.4 5.2 5.6 5.9 0.9803 1.0863 4.2255

pKa(exp)b 10.3 11.2 9.0 5.5 17.9 17.1 13.0 15.4 5.2 17.1 14.2 12.5 11.4 10.7 10.6 10.8

pKa(exp)b 10.3 11.2 9.0 5.5 17.9 17.1 13.0 15.4 5.2 17.1 14.2 12.5 11.4 10.7 10.6 10.8

The regression slopes for all correlations of calculation and experimental results are fixed at 1.00. bThe data are cited from ref 78. cR: linear correlation coefficient, SD (standard deviation) = [∑(xi − x)̅ 2/(N − 1)]1/2 (N = 16, i = 1−16, xi represents the calculated data for each species, x̅ is the mean of the 16 calculated data). RMSD (root-mean-square deviation) = [∑(xi − yi)2/N]1/2 (N = 16, xi represents the calculated data for each species, and yi represents the experimental data accordingly). a

Figure 2. Correlations between the calculated and experimental pKa values78 in DMSO for 16 thiols with BB1K and M06-2X functionals. 608



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Table 2. Comparison between pKa Values in DMSO Calculated at BB1K/(BS,SMD) and the Experimental Results for the 16 Thiolsa pKa (BB1K/BS,SMD)

a

RSH

6-31G(d)

6-31+G(d)

6-31+ G(d,p)

6-311+ G(d,p)

6-311++ G(d,p)

6-311++ G(2df,2p)

pKa(exp)b

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 R SD RMSD

8.3 9.7 6.8 2.1 18.2 17.4 13.2 16.1 6.1 17.7 13.7 10.5 10.7 8.5 8.9 8.8 0.9717 1.3295 1.6058

11.3 12.5 10.2 5.3 19.7 18.9 15.5 18.3 8.3 19.2 15.9 13.1 13.9 11.8 12.3 12.5 0.9799 0.8525 1.8590

11.3 12.6 10.2 5.3 19.6 18.8 16.3 18.2 8.2 19.2 15.7 13.1 13.9 11.8 12.2 12.0 0.9770 0.9036 1.8741

11.8 13.1 10.6 5.5 20.1 19.3 16.3 18.8 9.0 19.6 16.5 13.6 14.3 12.2 12.5 12.4 0.9754 0.9525 2.2898

11.8 13.1 10.6 5.5 20.1 19.4 16.4 18.8 9.0 19.7 16.4 13.7 14.4 12.2 12.8 12.5 0.9742 0.9630 2.3449

12.5 13.8 11.4 6.8 20.6 20.1 16.0 19.3 9.3 20.2 16.8 14.4 14.8 13.0 13.2 13.4 0.9849 0.7086 2.8158

10.3 11.2 9.0 5.5 17.9 17.1 13.0 15.4 5.2 17.1 14.2 12.5 11.4 10.7 10.6 10.8

The regression slopes for all correlations of calculation and experimental results are fixed at 1.00. bThe data are cited from ref 78.

Table 3. Comparison between pKa Values in DMSO Calculated at M06-2X/(BS/SMD) and the Experimental Results for 16 Thiolsa pKa(M06-2X/BS,SMD)

a

RSH

6-31G(d)

6-31+G(d)

6-31+ G(d,p)

6-311+ G(d,p)

6-311++ G(d,p)

6-311++ G(2df,2p)

pKa(exp)b

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 R SD RMSD

6.2 6.3 4.5 2.0 15.5 13.7 9.6 13.4 2.2 14.4 11.0 7.7 7.7 5.6 7.0 6.6 0.9806 0.9011 3.7618

9.2 9.2 7.7 3.8 17.5 15.6 12.6 15.6 4.6 16.3 13.4 10.6 10.4 8.5 9.7 9.2 0.9878 0.6695 1.3053

9.3 9.2 7.8 3.8 17.7 15.6 12.2 15.5 4.6 16.3 13.4 10.8 10.5 8.6 10.4 9.3 0.9880 0.6451 1.2263

9.3 9.8 8.4 4.8 17.3 16.4 12.5 16.1 5.8 17.0 13.2 11.4 11.7 9.2 9.9 9.7 0.9847 0.6671 0.8790

10.4 9.9 8.4 4.8 17.4 16.4 12.6 16.1 5.9 17.0 13.3 11.2 11.1 9.4 10.8 9.4 0.9840 0.6743 0.8095

10.4 10.7 9.4 6.1 18.0 17.1 13.1 16.6 6.1 17.5 14.8 11.7 12.1 10.0 10.9 11.3 0.9891 0.5539 0.5939

10.3 11.2 9.0 5.5 17.9 17.1 13.0 15.4 5.2 17.1 14.2 12.5 11.4 10.7 10.6 10.8

The regression slopes for all correlations of calculation and experimental results are fixed at 1.00. bThe data are cited from ref 78.

According to Table 1, the linear fit correlation coefficients (R) for all these DFT functionals are above 0.96, and SD values are all around 1 pKa, RMSD values are less than 4 pKa. In addition, BB1K gives the lowest RMSD values (R = 0.9717, SD = 1.3295, RMSD = 1.6058) and M06-2X gives the best R values and SD values (R = 0.9806, SD = 0.9011, RMSD = 3.7618). However, the high RMSD value calculated at M06-2X method indicates the systemic error between calculated and experimental values. In other words, the aforementioned data imply that BB1K is a better choice for predicting the absolute pKa value of thiols, and M06-2X might be more appropriate for

DFT Functionals Effect. The accuracy of 13 different DFT functionals was first examined. The pKa’s of 16 thiols (Figure 1) that were previously reported78 were used to evaluate the performance of different methods. The solution-phase geometry optimizations of all species were calculated in DMSO solvent, corresponding to the experimental conditions. The SMD model and 6-31G(d) basis set were used. The calculation results are given in Table 1. For comparison, the experimentally measured pKa values and the linear correlation parameters (R, SD, RMSD) between the calculation results and experimental ones are also provided in Table 1. 609



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Figure 5. Seventeen thiols for the gas acidities calculation (the experimental data are cited from refs 110−117). Figure 3. Correlation between the calculated (by using M1) and experimental pKa values78 of 16 thiols in DMSO.

Figure 6. Correlation between the experimental and calculated gasphase acidities at M06-2X/6-311++G(2df,2p) (M1). Figure 4. Correlation between calculated (M2) and experimental pKa values78 of 16 thiols in DMSO.

largest basis set (6-311++G(2df,2p)) is used. The high linear coefficient (R = 0.9891) and low deviation (SD = 0.5539, RMSD = 0.5939) indicate the validity of this method. Accordingly, examination of all the 13 DFT functionals and the 6 basis sets leads to the conclusion that M06-2X/6-311+ +G(2df,2p) (M1) is an appropriate method for predicting the pKa’s of thiols. The linear fit correlations between calculation (with the M1 method) and experimental results are shown in Figure 3. Solution Phase Single Point Energy Calculations. Considering the fact that M06-2X/6-311++G(2df,2p) (M1) is relatively time-consuming, an effort was made to find out whether an alternative method could give comparable accuracy with a much lower computational cost. To achieve this goal, we performed single point energy calculations with the M06-2X/ 6-311++G(2df,2p) method at the M06-2X/6-31G(d) optimized structures, and this method is named M2. Figure 4 shows the linear correlation between the calculation results (M2) and the experimental ones (R = 0.9886, SD = 0.5732, RMSD = 2.0584). It is found that although the linear coefficient (R) and the SD values calculated at the M2 method are better than all the other ones in Tables 1−3, the RMSD value is relatively large. Meanwhile, all the three linear factors (R, SD and RMSD) calculated at M2 are worse than those calculated at the M1

predicting the relative acidity of different thiols. For clarity, the linear correlation relationships between the experimental and the theoretical pKa’s calculated with these two methods are given in Figure 2. Basis Sets Effect. We next used the best of two functionals (BB1K and M06-2X) to examine the performances of different basis sets (BS: 6-31G(d), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p), 6-311++G(d,p), 6-311++G(2df,2p)). The calculated pKa’s with different basis sets and the correlation parameters with the experimentally measured pKa’s are given in Tables 2 (BB1K) and 3 (M06-2X), respectively. Inspection of the calculation results in Table 2 shows that the linear correlations between the calculation results and the experimental ones are comparable for different basis sets with the BB1K methods: R becomes better, whereas RMSD becomes worse when the polarization and diffuse functions are taken into account. For example, although the BB1K/6-311++G(2df,2p) gives a slightly better R value, its RMSD value is significantly larger than that calculated at the BB1K/6-31G(d) level. In contrast, on the basis of the M06-2X method, all of the three linear parameters (R, SD, and RMSD) become best when the 610



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Table 4. Calculated pKa’s of Different Thiols in DMSOa

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Table 4. continued

a

These three thiols (i.e., 206, 208, and 209) might be in equilibrium with their thiolketo forms. The details have been provided in the Supporting Information.

acidities ΔGgas110−117 of 17 different thiols (the uncertainty for experimental data is ±2.0−4.0 kcal/mol, Figures 5 and 6). The linear fit relationship is ΔGexp = ΔGcalc + 1.9967, with a high linear coefficient (R = 0.9826) and low SD value (1.0934 kcal/mol, smaller than the experimental uncertainty). Therefore, the additional calculation on gas phase acidities further verifies the reliability of the M1 method in treating thiols.

method. Therefore, it is concluded that M1 is a better choice when the computation cost is acceptable, whereas M2 can be used as an alternative when the concerned thiol molecules are relatively bulky, requiring a high computational cost. Gas-Phase Acidities Calculation with the M1 Method. To verify the proposed M1 method, we further compared the calculation results and the experimental ones on gas phase 617



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Conclusion for Different DFT Functionals and Basis Sets in DMSO Solvent. On the basis of the above calculations and discussion, the M06-2X/6-311++G(2df,2p) (M1) method is recommended for calculating the pKa’s of thiols. The linear correlation relationship between the calculated and experimental results is pKa(exp) = pKa(calc) + 0.2552 (Figure 3), the linear coefficient (R) is 0.9891, SD is 0.5539 pKa, and RMSD is 0.5939 pKa (for 16 thiols). In the following, we choose the M1 method to predict the pKa’s of about 290 organosulfur compounds (vide supra). Note that all these compounds are cited from NIST Standard Reference Database 69117 (compiled by K. Irikura), and their pKa values (currently unknown) might be potentially helpful for the mechanistic understanding of the reactivity of the thiol-involved reactions. Prediction of pKa’s of Other Thiols in DMSO Solvent. In the present study, we classified the thiols into different types, such as alkyl, alkoxyl, carbonyl, alkenyl, amino, heteroaryl, and aromatic thiols. Considering that the M1 method tends to systematically underestimate the experimentally observed pKa’s by about 0.3 pKa (pKa(exp) = pKa(calc) + 0.2552, Figure 3), in the following section we add 0.3 pKa to the calculated pKa value of each species. The detailed calculated structures and the related pKa’s (after the correction of 0.3 pKa) are provided in Table 4. For the sake of clarity, Figure 7 shows the ranges of pKa of different types of thiols.

Figure 8. NBO charge on the S atom of the thiol group (the upper data corresponds to the reactant, the lower data corresponds to the anionic product).

the aromaticity and strengthens the conjugation between the S atom and the CN bond. Indeed, the NBO charge on the S atom of the thiol group (Figure 8) is significantly larger (i.e., more positive in the reactant and less negative in the deprotonated products) than the other heteroaryl thiols (such as 212, 216, and 222 in Figure 8), indicating that the electron density on the S atom of the thiol group is more severely delocalized to a higher degree in 220, 224, and 234 than in the other thiols. The electron delocalization results in a more instable reactant and a more stable deprotonated product. Therefore, the acidity of these compounds is higher, leading to the smaller pKa values. Similarly, the smaller pKa’s of 209 relative to all other alkyl thiols can also be attributed to the high electron-withdrawing substituents. Some other interesting observations can also be noted from the calculation results. For example, a good linear correlation exists between the calculated pKa’s of p- or m-substituted benzenethiol and the Hammett substituent constants σp/ σm.118,119 As shown in Figures 9 and 10, the linear relationship

Figure 7. pKa values of various types of thiols in DMSO.

Different Types of Thiols. From Figure 7, it can be seen that the pKa’s of alkyl thiols/dithiols (12.0−19.3) are relatively larger (with lower acidity) than those of the other types, whereas the pKa’s of α-carbonyl thiols (3.5−9.3) are relatively smaller (with higher acidity). The observations can be understood from the electronic effect: the alkyl group is relatively electron-donating, and thus destabilizing the formed anionic species (lower acidity, larger pKa’s); in contrast, the significant electron-withdrawing carbonyl groups tend to stabilize the formed anionic species, thus resulting in a smaller pKa value (higher acidity). Meanwhile, it is found that the pKa’s of the other types of thiols are 13.1−18.3 for alkoxyl, 8.4−17.8 for carbonyl, 11.8−16.4 for alkyne, 7.2−16.4 for aromatic thiols, and 7.3−16.7 for amino thiols. Herein, it is interesting to note that the pKa’s of heteroaryl thiols always lie in the range 3.9− 15.8, whereas three thiols (i.e., 220, 224, and 234 in Figure 8) are significantly smaller by about 2 pKa (with higher acidity). The reason for such observation was supposed to be related to the presence of the β-S and β-N atoms, which weakens

Figure 9. Correlation between the pKaDMSO(calc) of p-substituted benzenethiol and the Hammett substituent constants (σp).

between the pKa and the related substituent constants are pKaDMSO(calc) = −4.4905σp + 10.0914 (R = 0.9760, N = 10) and pKaDMSO(calc) = −4.8205σm + 10.6227 (R = 0.9943, N = 6). The good linear correlation implies that pKa’s of other similar substituted benzenethiol compounds might be estimated through at least two methods: first, one can calculate the pKa’s of the concerned compound with the M1 method and add this value with 0.3 pKa; second, one can use the linear 618



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ASSOCIATED CONTENT

S Supporting Information *

Full text of ref 98. Electronic energies, thermal correction to Gibbs free energy, and the Cartesian coordinates of the 16 thiols in DMSO and the 17 thiols in the gas phase. Electronic energies (au) and thermal correction to Gibbs free energy of the 291 predicting thiols. Equilibrium between thiols and the thiolketo forms of 206, 208, and 209. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*Z.-M. Dang: e-mail: [email protected]. *G.-H. Hu: e-mail, [email protected]. Notes

The authors declare no competing financial interest.

Figure 10. Correlation between the pKaDMSO(calc) of m-substituted benzenethiol and the Hammett substituent constants (σm).

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ACKNOWLEDGMENTS

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REFERENCES

We thank the Natural Science Foundation of China (No. 21202006, 51303010) and China Postdoctoral Science Foundation (No. 2013T60059) for financial supports and the Shanghai Supercomputer Centre for technical support.

relationships shown in Figures 9 and 10 and the substituent constant for the concerned group in benzenethiol compounds to roughly estimate the pKa’s of the concerned species. The second method is potentially useful for experimental chemists to estimate the acidity of different benzenethiols and understand their reactivity.

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CONCLUSIONS Thiols have shown great potential in organic/bio-organic synthesis, biological chemistry, and material science, and the deprotonation of the S−H bond has been frequently proposed as an elementary step in thiol-involved reactions. The present study aims at using an appropriate density functional theory (DFT) method to predict the pKa’s of thiols in DMSO. The accuracy of different DFT methods is first compared. They include different functionals (B3LYP, BB1K, PBE, M06, M05, M06-2X, M06-L, M05-2X, TPSS, MPW1K, MPWB1K, MPW3LYP, TPSSLYP1W) and different basis sets (6-31G(d), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p), 6-311++G(d,p), 6-311++G(2df,2p)) (solvent = DMSO, SMD model). The M06-2X/6-311++G(2df,2p) (M1) method yields the best performance in reproducing the pKa’s of 16 different thiols reported in the literature: pKa(exp) = pKa(calc) + 0.2552, R = 0.9891, and SD = 0.5539. Moreover, the M1 method can also well reproduce the gas phase acidities ΔGgas of 17 different thiols, which provides evidence in favor of the reliability of M1 in treating thiol systems. Subsequently, the M1 method is used to predict the pKa’s of about 290 thiols whose experimental pKa values in DMSO remain unknown. Thus, the ranges of pKa’s of different types of thiols (including alkyl, alkoxyl, carbonyl, alkenyl, amino, heteroaryl, and aromatic thiols) were constructed for the first time. Interestingly, a good linear correlation between the calculated pKa’s of p- or m-substituted benzenethiols and the Hammett substituent constants σp/σm was found. The observation implies the potential of using computational methods or substituent constant data to predict the unknown pKa’s of novel benzenethiols. We hope the present study will benefit the mechanistic understanding of the reactivity of the thiol-involved reactions and the development of novel reactions. 619



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s of Thiols in DMSO - American Chemical Society

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