Analysis of the pKas of Aliphatic Amines Using Quantum Chemical Descriptors

PAUL G. SEYBOLD
Department of Chemistry, Wright State University, Dayton, OH 45435 Received 14 April 2008; accepted 7 May 2008 Published online 11 July 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/qua.21809

ABSTRACT: Previous theoretical studies (Gross and Seybold, Int J Quantum Chem 2000, 80, 1107; Gross et al., J Org Chem 2001, 66, 6919; Gross et al., Int J Quantum Chem 2002, 90, 445) demonstrated that variations in several quantum chemical charge and energy indices for substituted anilines were strongly correlated with the experimentally observed pKa variations of these compounds. The present study examines whether a similar analysis can be extended to the pKas of nonaromatic amines. A particular interest will lie in assessing the role of the aqueous solvent in inuencing the pKas. It is found that, in general, the quantum chemical indices obtained for the isolated molecules in the aliphatic amines do not correlate strongly with the experimental pKas. However, addition of a solvent model (SM5.4A, Chambers et al., J Phys Chem 1996, 100, 16385) leads to good correlations between the experimental pKas and the energy differences (Eaq) between the neutral amines and their cations. The calculations in this study were performed at both the semiempirical RM1 and density functional B3LYP/6-31G* levels. 2008 Wiley Periodicals, Inc. Int J Quantum Chem 108:
2849 2855, 2008

Key words: aliphatic amines; quantum chemical descriptors; RM1 method; B3LYP/631G*; solvent effects

Introduction
he acid dissociation constants of organic compounds, as represented by their pKas, are among the most important features of these compounds. In many cases, the acid base behaviors are

Correspondence to: P.G. Seybold; e-mail: paul.seybold@wright.edu

central to the performances of the compounds in their biochemical, pharmaceutical, industrial, or environmental roles [1]. The aliphatic amines, a class which includes a number of important drugs, neurotransmitters, and other biologically active compounds, are of particular interest in this regard [2, 3]. In earlier studies, we examined correlations between the experimental aqueous-phase pKas of substituted anilines and a variety of quantum chemical

International Journal of Quantum Chemistry, Vol 108, 2849 2855 (2008) 2008 Wiley Periodicals, Inc.

SEYBOLD parameters [4 6]. These studies of substituent effects on the aromatic framework showed that several electronic features of the dissociating amino groups were strongly correlated with the variations in the pKas. The quantum chemical descriptors employed in these earlier studies included group partial atomic charges, highest occupied molecular orbital (HOMO) energies, energies of dissociation, and parameters related to the molecular electrostatic potentials. This report examines whether a similar quantum chemical analysis can be applied to the pKas of aliphatic amines. Compared with the substituted anilines, the aliphatic amines pose some new challenges for attempts to model the pKas using relatively simple quantum chemical indices. Most importantly, whereas the common aromatic framework present in the substituted anilines caused the solventsolute interactions within the series to be roughly constantand thus permitted solvent effects to be neglected in the calculationsthe greater diversity of structures found in the aliphatic amines suggests that for this class such a simplication may no longer be valid. In fact, it is well known that in the gas-phase the basicities of the methylamines increase regularly with methyl substitution [7], and in aqueous solution these basicities occur in the irregular order [8, 9]. NH 3 NH2Me NHMe2 NMe3. This phase difference is generally attributed to hydration effects in solution, and several earlier studies have looked at this problem [9 13]. (Analogous gas-phase/solution differences in acidity and basicity are also observed for aliphatic alcohols [14] and carboxylic acids [15].) In addition, the aqueous solvent environment may cause some of the amine structures to differ substantially from those found in the gas phase, and the greater diversity of the compounds in the aliphatic class can itself be expected to lead to less successful results than those obtained in studies of compounds possessing a common skeleton. Some quite interesting variations in pKa are observed for the aliphatic amines. For example, uorine substitution has been found to have important pharmaceutical applications [16], and it has been found that uorine substitution can cause dramatic changes in amine pKas. In the ethylamine series, the experimental pKas decrease regularly in the order CH3CH2NH2 (10.7), CFH2CH2NH2 (9.0), CF2HCH2NH2 TABLE I ______________________________________
Experimental pKa data for the amines studied in this work. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 15 17 18 19 20 21 22 23 24 25 26 27 28 Compound Ammonia Methylamine Ethylamine Fluoroethylamine Diuoroethylamine Triuoroethylamine n-Propylamine i-Propylamine Fluoropropylamine Triuoropropylamine n-Butylamine sec-Butylamine tert-Butylamine Triuorobutylamine Neo-pentylamine Ethyleneamine Acetamide Urea Ethanediamine Ethanolamine Cyclohexylamine-eq Cyclohexylmethylamine-eq Hydroxylamine Methoxyamine Allylamine Benzylamine Phenylethylamine Phenypropylamine pKa(exp) 9.2a, 9.25b, 9.21c 10.6a, 10.66b, 10.62c 10.7a, 10.70b, 10.63c 9.0a 7.3a, 7.52c 5.7a 10.7a, 10.54b, 10.53c 10.63b, 10.63c 9.9a 8.7a 10.7a, 10.43c 10.56c 10.43c 9.7a 10.21c 8.01b 0.63b 0.1b 10.71b 9.50b, 9.50c 10.64c 10.49c 5.97c 4.60c 9.49b, 9.49c 9.34c 9.83c 10.20c

Where more than one experimental value is listed, the underlined value was used in the regressions. a Ref. [3]. b Ref. [17]. c Ref. [18].

(7.3), CF3CH2NH2 (5.7) [3]. This progression might be reasonably attributed primarily to inductive/electronic effects on the dissociating amine moiety, and a quantum chemical approach to aliphatic amine pKa analysis should hopefully provide a model for this and similar variations within the series.

Methods
The nonaromatic amines studied are listed in Table I with their experimental pKa values. The pKas were taken from literature compilations [3, 17, 18]; the values used for regression analysis are un-

2850 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY

DOI 10.1002/qua

VOL. 108, NO. 15

ANALYSIS OF THE pKas OF ALIPHATIC AMINES TABLE II _____________________________________________________________________________________________

Quantum chemical parameters obtained from the RM1 method. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 15 17 18 19 20 21 22 23 24 25 26 27 28 Compound Ammonia Methylamine Ethylamine Fluoroethylamine Diuoroethylamine Triuoroethylamine n-Propylamine i-Propylamine Fluoropropylamine Triuoropropylamine n-Butylamine sec-Butylamine tert-Butylamine Triuorobutylamine Neo-pentylamine Ethyleneamine Acetamide Urea Ethanediamine Ethanolamine Cyclohexylamine Cyclohexylmethylamine Hydroxylamine Methoxyamine Allylamine Benzylamine Phenylethylamine Phenypropylamine Q(NH2) 0.172 0.066 0.118 0.101 0.082 0.046 0.114 0.123 0.11 0.096 0.118 0.118 0.12 0.106 0.115 0.029 0.038 0.035 0.116 0.178 0.122 0.117 0.002 0.041 0.108 0.114 0.117 0.117
Q(NH3 )

E (kJ/mol) 553.3 619.6 589.9 627.8 647.1 682.9 594.6 575.0 606.0 644.9 587.2 582.8 568.7 620.3 578.5 630.9 685.1 684.6 586.5 608.0 576.5 581.9 641.1 668.4 591.1 574.3 585.3 586.3

Eaq (kJ/mol) 273.0 328.8 313.1 323.1 339.8 368.5 320.8 308.2 324.9 332.5 314.3 308.9 311.8 317.0 312.7 345.8 412.3 400.2 313.1 325.3 317.9 314.7 306.5 374.1 322.9 315.2 314.0 314.2

0.727 0.706 0.665 0.7 0.723 0.744 0.666 0.638 0.673 0.691 0.666 0.669 0.621 0.681 0.669 0.726 0.577 0.606 0.689 0.668 0.636 0.665 0.869 0.822 0.655 0.641 0.66 0.665

derlined in Table I. All calculations were performed using the Spartan06 software program [19]. The calculations reported here used the recently introduced RM1 semiempirical method [20] as well as density functional theory calculations at the B3LYP/6-31G* level. The parameters examined were those found useful in our earlier studies [4, 6], namely the natural charges [21] Qn(NH2) on the neutral amino groups, the natural charges Qn(NH 3 ) on the cationic ammonium groups, and the energy differences E (gas phase) and Eaq (aqueous phase) between the neutral amines and their cationic forms. The pKas considered here involved the transitions from the cations to the neutral forms: R-NH 3 3 R-NH2. Calculations of the aqueous solvation energies were carried out using the SM5.4A solvent model of Chambers et al. [22]. This model calculates solvation energies based on the AM1 [23] semiempirical model. Statistical stud-

ies were performed using the Microsoft EXCEL software program.

Results and Discussion

RM1 CALCULATIONS The quantum chemical amine parameters obtained using the RM1 semiempirical method for the aliphatic amines in this study are summarized in Table II. The rst examination involved applying the RM1-derived parameters to the variations observed in the uorinated ethylamines, as described in the Introduction. Within this quite limited series all three quantum chemical indices showed strong correlations with the experimental pKas: p Ka 2.10 1.02 72.1 11.6QNH2

VOL. 108, NO. 15

DOI 10.1002/qua

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY 2851

SEYBOLD n 4, r 2 0.951, s 0.58, F 39

p Ka 52.4 2.5 62.5 3.6QNH3

n 4, r 2 0.994, s 0.21, F 310 p Ka 43.3 3.1 0.0552 0.0048E n 4, r 2 0.985, s 0.33, F 130 Here n is the number of compounds; r2, the coefcient of determination (i.e., the square of the correlation coefcient); s, the standard error, and F, the Fisher statistic. These results suggest that, at least for this specic congeneric series, the gas-phase RM1 calculations provide an accurate account of the electronic/inductive features affecting the pKas. Presumably, solvation effects are either sensibly constant within this limited series or vary in a regular manner. When applied to the entire set of 28 amines in Table I the correlations with these parameters were, however, not impressive. The electronic charge indices Q(NH2) and Q(NH 3 ) showed essentially no correlation with the experimental pKas, and the energy index E showed only a quite modest correlation: p Ka 47.6 4.9 0.064 0.008E n 28, r 2 0.712, s 1.57, F 64 Examination of the residuals showed three large negative outliers (predictions higher than the experimental values) in this series: compounds 1 (ammonia), 17 (acetamide), and 18 (urea). Application of the SM5.4A solvent model did not greatly change the overall statistics of the pKa versus E regression for the complete set of amines: p Ka 36.4 3.2 0.0845 0.0098Eaq n 28, r 2 0.741, s 1.49, F 74 However, results for the individual compounds were changed considerably, and there were now just two notable outliers (both negative): compounds 1 (ammonia) and 23 (hydroxylamine). It is to be noted that both of these compounds are for two reasons unrepresentative of the larger sample of aliphatic amines, being the smallest compounds in the sample set and the only two compounds

FIGURE 1. Plot of pKa versus Eaq for 26 amines using values obtained using the RM1 semiempirical method.

lacking carbon atoms. When these two unrepresentative compounds were removed from the regression, the correlation with the pKas improved dramatically: p Ka 42.64 1.62 0.1024 0.0049Eaq n 26, r 2 0.948, s 0.68, F 438 These results are plotted in Figure 1. It should be noted that the great majority of compounds are clustered in the pKa range 9 11, and future studies would certainly benet from a greater availability of experimental examples falling outside this range. In some instances one can reasonably question the accuracy of the experimental values reported for outliers in this type of analysis [24], but there appears to be no cause to do so in the present case [25]. Rather, it is possible that the two excluded compounds, because of their unique features, should not be grouped with the more representative aliphatic amines in the present analysis. Alternatively, it may be that the two outliers are poorly treated by the SM5.4A solvent model or may require the employment of a more elaborate solvent model, possibly including explicit water molecules [26, 27]. In his early examination of aliphatic amine pKas Hall [18] found that, whereas the pKas of tertiary amines correlated well with the sums of corresponding Taft constants (*), the data for the primary and secondary amines, as well as for ammonia, did not follow single lines. He attributed

2852 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY

DOI 10.1002/qua

VOL. 108, NO. 15

ANALYSIS OF THE pKas OF ALIPHATIC AMINES TABLE III ____________________________________________________________________________________________

Quantum chemical parameters calculated using the B3LYP/6-31G* method. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 15 17 18 19 20 21 22 23 24 25 26 27 28 Compound Ammonia Methylamine Ethylamine Fluoroethylamine Diuoroethylamine Triuoroethylamine n-Propylamine i-Propylamine Fluoropropylamine Triuoropropylamine n-Butylamine sec-Butylamine tert-Butylamine Triuorobutylamine Neo-pentylamine Ethyleneamine Acetamide Urea Ethanediamine Ethanolamine Cyclohexylamine Cyclohexylmethylamine Hydroxylamine Methoxyamine Allylamine Benzylamine Phenylethylamine Phenypropylamine Q(NH2) 0.369 0.153 0.157 0.147 0.136 0.121 0.155 0.158 0.15 0.141 0.153 0.155 0.157 0.145 0.15 0.045 0.046 0.072 0.154 0.15 0.153 0.153 0.117 0.143 0.14 0.143 0.152 0.15
Q(NH3 )

E (a.u.) 0.3460 0.3829 0.3673 0.3519 0.3484 0.3414 0.3686 0.3717 0.3644 0.3527 0.3706 0.3739 0.3758 0.3599 0.3726 0.3479 0.3226 0.3312 0.3686 0.3609 0.3760 0.3741 0.3634 0.3390 0.3667 0.3728 0.3703 0.4711

Eaq (a.u.) 0.47491 0.47166 0.47309 0.46669 0.46235 0.45747 0.47331 0.47314 0.47132 0.46867 0.47490 0.47438 0.47322 0.47329 0.47325 0.45638 0.42249 0.43745 0.47527 0.46958 0.47469 0.47568 0.49183 0.45408 0.46939 0.47168 0.47460 0.47540

0.505 0.654 0.636 0.649 0.658 0.67 0.639 0.625 0.644 0.653 0.636 0.626 0.616 0.647 0.637 0.655 0.539 0.568 0.633 0.64 0.628 0.635 0.973 0.648 0.632 0.623 0.631 0.637

this difference largely to differences in the hydrations of the ammonium ions. (Note that the amines examined in the present work are all primary amines.) It was of interest to examine the solvation energies for the neutral compounds, Esolv(R-NH2) E(R-NH2) Eaq(R-NH2), and the cations, Esolv(R NH 3 ) E(R-NH3 ) Eaq(R-NH3 ), as determined by the SM5.4A model. The values of Esolv(R-NH2) for the 28 compounds averaged 23 kJ/mol, and ranged from 10 kJ/mol for neopentylamine to just over 50 kJ/mol for urea. As expected, the cations were much more strongly solvated than the neutral species, normally by more than an order of magnitude: Esolv(R-NH 3 ) averaged 306 kJ/mol and ranged from 268 kJ/mol for tert-butylamine to 364 kJ/mol for hydroxylamine. Chambers et al. [22] report the experimental free energies of solvation for NH 4 and CH3NH3 to be roughly 331 kJ/mol

and 293 kJ/mol, respectively; in the present work, the calculated Esolv(R-NH 3 ) values for these species are 338 kJ/mol and 315 kJ/mol, respectively.

B3LYP/6-31G* CALCULATIONS Calculated quantum chemical parameters obtained using the density functional theory B3LYP/ 6-31G* method are shown in Table III. In some respects, the results for the B3LYP/6-31G* calculations closely coincided with those obtained using the RM1 method. For the uoroethylamines both Q(NH2) (r2 0.987) and E (r2 0.922) correlated strongly with the pKas, with the best t being with Q(NH 3 ):
p Ka 106.0 4.8 149.8 7.4QNH3

VOL. 108, NO. 15

DOI 10.1002/qua

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY 2853

SEYBOLD n 26, r 2 0.915, s 0.69, F 257 These results are plotted in Figure 2. Here too, the clustering of the experimental values in the higher pKa range limits the robustness of the regression results reported.

Conclusions
In contrast to the earlier studies of the anilines, where solvent inuences on the pKas could be ignored, for the nonaromatic amines examined in this study inclusion of a solvent model was essential for proper analysis of the pKa variations. For the great majority of compounds in the present series, the SM5.4A solvent model [22] appears to provide an adequate description of the inuence of hydration on the dissociation of the ammonium ions. Perhaps surprisingly, the semiempirical RM1 method [20] produced somewhat better results for this set of compounds than the more elaborate density functional theory B3LYP/6-31G* method. This may be because the RM1 method, which represents an extension of the original AM1 approach [23], is more compatible with the SM5.4A solvent model, which is also based on the AM1 approach. Considering the relatively good ts obtained using the present solvent-assisted model, a similar approach may prove useful in the future in examining the acid/ base behaviors of additional, biologically active aliphatic amines.

FIGURE 2. Plot of pKa versus Eaq for 26 amines using values obtained using the density functional theory B3LYP/6-31G* method.

n 4, r 2 0.995, s 0.18, F 415 In this series, solvation correction energies for the parent amines fell uniformly from 0.00793 a.u. for ethylamine to 0.00642 a.u. in triuoroethylyamine, whereas the solvent corrections for the ammonium ions varied from 0.1137 a.u. for ethylamine to 0.1225 au for triethylamine. For the full set of 28 aliphatic amines neither Q(NH2) nor Q(NH 3 ) showed meaningful correlations with the experimental pKas. The parameter E (the energy here in hartrees) showed only a very modest correlation: p Ka 51.4 6.7 166.5 18.5E n 28, r 0.758, s 1.44, F 81
2

References
1. Perrin, D. D.; Dempsey, B.; Serjeant, E. P. pKa Determination for Organic Acids and Bases; Chapman and Hall: New York, 1981. 2. Upthagrove, A. L.; Nelson, W. L. Drug Metab Dispos 2001, 29, 1377. 3. Morgenthaler, M.; Schweizer, E.; Hoffman-Ro der, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Mu ller, K. Chem Med Chem 2007, 2, 1100. 4. Gross, K. C.; Seybold, P. G. Int J Quantum Chem 2000, 80, 1107. 5. Gross, K. C.; Seybold, P. G.; Peralta-Inga, Z.; Murray, J. S.; Politzer, P. J Org Chem 2001, 66, 6919. 6. Gross, K. C.; Seybold, P. G.; Hadad, C. M. Int J Quantum Chem 2002, 90, 445. 7. Aue, D. H.; Webb, H. M.; Bowers, M. T. J Am Chem Soc 1976, 98, 311. 8. King, E. J. Acid Base Equilibria; Pergamon Press: New York, 1965.

Here addition of the solvent model for the full set of compounds produced even poorer results: p Ka 74.7 11.6 178 25Eaq n 28, r 2 0.664, s 1.69, F 51 In this case, however, the only signicant outliers were now urea (compound 18) and hydroxylamine [23]. Ammonia was fairly well tted. When the two outliers were removed from the regression, the results once more improved dramatically; p Ka 84.1 5.8 198.9 12.4Eaq

2854 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY

DOI 10.1002/qua

VOL. 108, NO. 15

ANALYSIS OF THE pKas OF ALIPHATIC AMINES

9. Tun o n, I.; Silla, E.; Tomasi, J. J Phys Chem 1992, 96, 9043. 10. Nagy, P. J Mol Struct (Theochem) 1989, 201, 271. 11. Aue, D. H.; Webb, H. M.; Bowers, M. T. J Am Chem Soc 1976, 98, 318. 12. Rizzo, R. C.; Jorgensen, W. L. J Am Chem Soc 1999, 121, 4927. 13. Da Silva, E. F.; Svendsen, H. F. Ind Eng Chem Res 2003, 42, 4414. 14. Brauman, J. I.; Blair, L. K. J Am Chem Soc 1970, 92, 5986. 15. Wiberg, K. B.; Clifford, S.; Jorgensen, W. L.; Frisch, M. J. J Phys Chem A 2000, 104, 7625. 16. Mu ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. 17. Lide, D. R., Ed. CRC Handbook of Chemistry and Physics, 88th Ed.; CRC Press: Boca Raton, FL, 2007-8. 18. Hall, H. K., Jr. J Am Chem Soc 1957, 79, 5441. 19. Spartan06, Wavefunction, Inc.: Irvine, CA, 92612. 20. Rocha, G. B.; Freire, R. O.; Simas, A.; Stewart, J. J. P. J Comput Chem 2006, 27, 1101. 21. Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. J Chem Phys 1985, 91, 165. 22. Chambers, C. C.; Hawkins, G. D.; Cramer, C. J.; Truhlar, D. G. J Phys Chem 1996, 100, 16385. 23. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J Am Chem Soc 1985, 107, 3902. 24. Gauch, H. G., Jr. Am Scientist 1993, 81, 468. 25. Robinson, R. A.; Bower, V. E. J Phys Chem 1961, 65, 1279. 26. Pliego, J. R., Jr.; Riveros, J. M. J Phys Chem A 2002, 106, 7434. 27. Jia, Z.-K.; Du, D.-M.; Zhou, Z.-Y.; Zhang, A.-G.; Hou, R.-Y. Chem Phys Lett 2007, 439, 374.

VOL. 108, NO. 15

DOI 10.1002/qua

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY 2855