Acidity in DMSO from the embedded cluster integral equation quantum solvation model

  • Jochen Heil
  • Daniel Tomazic
  • Simon Egbers
  • Stefan M. KastEmail author
Original Paper
Part of the following topical collections:
  1. Topical Collection on the occasion of Prof. Tim Clark’s 65th birthday


The embedded cluster reference interaction site model (EC-RISM) is applied to the prediction of acidity constants of organic molecules in dimethyl sulfoxide (DMSO) solution. EC-RISM is based on a self-consistent treatment of the solute’s electronic structure and the solvent’s structure by coupling quantum-chemical calculations with three-dimensional (3D) RISM integral equation theory. We compare available DMSO force fields with reference calculations obtained using the polarizable continuum model (PCM). The results are evaluated statistically using two different approaches to eliminating the proton contribution: a linear regression model and an analysis of pK a shifts for compound pairs. Suitable levels of theory for the integral equation methodology are benchmarked. The results are further analyzed and illustrated by visualizing solvent site distribution functions and comparing them with an aqueous environment.


Solvent site distribution of DMSO around 3-methylphenole and pK a regression result for the EC-RISM quantum solvation model


Embedded cluster 3D RISM EC-RISM pKa prediction DMSO solvent 



We thank the German Federal Ministry of Education and Research (BMBF) and the Deutsche Forschungsgemeinschaft (DFG) for financial support, and the IT and Media Center (ITMC) of the TU Dortmund for computational support.

Supplementary material

894_2014_2161_MOESM1_ESM.txt (95 kb)
ESM 1 (TXT 94 kb)
894_2014_2161_MOESM2_ESM.txt (62 kb)
ESM 2 (TXT 61 kb)


  1. 1.
    Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3093CrossRefGoogle Scholar
  2. 2.
    Cramer CJ, Truhlar DG (1999) Implicit solvation models: equilibria, structure, spectra, and dynamics. Chem Rev 99:2161–2200CrossRefGoogle Scholar
  3. 3.
    Tomasi J, Persico M (1994) Molecular interactions in solution: an overview of methods based on continuous distributions of the solvent. Chem Rev 94:2027–2094CrossRefGoogle Scholar
  4. 4.
    Hansen JP, Mcdonald IR (2006) Theory of simple liquids, 3rd edn. Academic, LondonGoogle Scholar
  5. 5.
    Kloss T, Heil J, Kast SM (2008) Quantum chemistry in solution by combining 3D integral equation theory with a cluster embedding approach. J Phys Chem B 112:4337–4343CrossRefGoogle Scholar
  6. 6.
    Beglov D, Roux B (1997) An integral equation to describe the solvation of polar molecules in liquid water. J Phys Chem B 101:7821–7826CrossRefGoogle Scholar
  7. 7.
    Kovalenko A, Hirata F (1998) Three-dimensional density profiles of water in contact with a solute of arbitrary shape: a RISM approach. Chem Phys Lett 290:237–244CrossRefGoogle Scholar
  8. 8.
    Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general Amber force field. J Comput Chem 25:1157–1174CrossRefGoogle Scholar
  9. 9.
    Kast SM, Heil J, Güssregen S, Schmidt KF (2010) Prediction of tautomer ratios by embedded-cluster integral equation theory. J Comput-Aided Mol Des 24:343–353CrossRefGoogle Scholar
  10. 10.
    Hoffgaard F, Heil J, Kast SM (2013) Three-dimensional RISM integral equation theory for polarizable solute models. J Chem Theory Comput 9:4718–4726CrossRefGoogle Scholar
  11. 11.
    Balakin KV, Savchuk NP, Tetko IV (2006) In silico approaches to prediction of aqueous and DMSO solubility of drug-like compounds: trends, problems and solutions. Curr Med Chem 13:223–241CrossRefGoogle Scholar
  12. 12.
    Tsuzuki W, Ue A, Kitamura Y (2001) Effect of dimethylsulfoxide on hydrolysis of lipase. Biosci Biotechnol Biochem 65:2078–2082CrossRefGoogle Scholar
  13. 13.
    Tsuzuki W, Ue A, Nagao A (2003) Polar organic solvent added to an aqueous solution changes hydrolytic property of lipase. Biosci Biotechnol Biochem 67:1660–1666CrossRefGoogle Scholar
  14. 14.
    Watanabe E, Sudo R, Takahashi M, Hayashi M (2000) Evaluation of absorbability of poorly water-soluble drugs: validity of the use of additives. Biol Pharm Bull 23:838–843CrossRefGoogle Scholar
  15. 15.
    Magill AM, Cavell KJ, Yates BF (2004) Basicity of nucleophilic carbenes in aqueous and nonaqueous solvents—theoretical predictions. J Am Chem Soc 126:8717–8724Google Scholar
  16. 16.
    Trummal A, Rummel A, Lippmaa E, Burk P, Koppel IA (2009) IEF-PCM calculations of absolute pK a for substituted phenols in dimethyl sulfoxide and acetonitrile solutions. J Phys Chem A 113:6206–6212CrossRefGoogle Scholar
  17. 17.
    Yang C, Xue XS, Jin JL, Li X, Cheng JP (2013) Theoretical study on the acidities of chiral phosphoric acids in dimethyl sulfoxide: hints for organocatalysis. J Org Chem 78:7076–7085CrossRefGoogle Scholar
  18. 18.
    Klamt A, Eckert F, Diedenhofen M, Beck ME (2003) First principles calculations of aqueous pK a values for organic and inorganic acids using COSMO-RS reveal an inconsistency in the slope of the pK a scale. J Phys Chem A 108:9380–9386CrossRefGoogle Scholar
  19. 19.
    Almerindo GI, Tondo DW, Pliego JR Jr (2004) Ionization of organic acids in dimethyl sulfoxide solution: a theoretical ab initio calculation of the pKa using a new parametrization of the polarizable continuum model. J Phys Chem A 108:166–171Google Scholar
  20. 20.
    Yu A, Liu Y, Li Z, Cheng JP (2007) Computation of pK a values of substituted aniline radical cations in dimethylsulfoxide solution. J Phys Chem A 111:9978–9987CrossRefGoogle Scholar
  21. 21.
    Fu Y, Liu L, Wang YM, Li JN, Yu TQ, Guo QX (2006) Quantum-chemical predictions of redox potentials of organic anions in dimethyl sulfoxide and reevaluation of bond dissociation enthalpies measured by the electrochemical methods. J Phys Chem A 110:5874–5886CrossRefGoogle Scholar
  22. 22.
    Fu Y, Liu L, Li RQ, Liu R, Guo QX (2004) First-principle predictions of absolute pK a’s of organic acids in dimethyl sulfoxide solution. J Am Chem Soc 126:814–822CrossRefGoogle Scholar
  23. 23.
    Ding F, Smith JM, Wang H (2009) First-principles calculation of pK a values for organic acids in nonaqueous solution. J Org Chem 74:2679–2691CrossRefGoogle Scholar
  24. 24.
    Kast SM, Kloss T (2008) Closed-form expressions of the chemical potential for integral equation closures with certain bridge functions. J Chem Phys 129:2008–2010CrossRefGoogle Scholar
  25. 25.
    Kovalenko A, Hirata F (1999) Self-consistent description of a metal–water interface by the Kohn–Sham density functional theory and the three-dimensional reference interaction site model. J Chem Phys 110:10095–10112CrossRefGoogle Scholar
  26. 26.
    Morita T, Hiroike KA (1960) New approach to the theory of classical fluids. I. Prog Theor Phys 23:1003–1027CrossRefGoogle Scholar
  27. 27.
    Singer SJ, Chandler D (1985) Free energy functions in the extended RISM approximation. Mol Phys 55:621–625CrossRefGoogle Scholar
  28. 28.
    Joung S, Luchko T, Case DA (2013) Simple electrolyte solutions: comparison of DRISM and molecular dynamics results for alkali halide solutions. J Chem Phys 138:044103Google Scholar
  29. 29.
    Perkyns JS, Pettitt BM (1992) A site–site theory for finite concentration saline solutions. J Chem Phys 97:7656–7666CrossRefGoogle Scholar
  30. 30.
    Perkyns JS, Pettitt BM (1992) A dielectrically consistent interaction site theory for solvent–electrolyte mixtures. Chem Phys Lett 190:626–630Google Scholar
  31. 31.
    Luzar A, Soper K, Chandler D (1993) Combined neutron diffraction and computer simulation study of liquid dimethyl sulphoxide. J Chem Phys 99:6836–6847CrossRefGoogle Scholar
  32. 32.
    Liu H, Müller-Plathe F, van Gunsteren WF (1995) A force field for liquid dimethyl sulfoxide and physical properties of liquid dimethyl sulfoxide calculated using molecular dynamics simulation. J Am Chem Soc 117:4363–4366CrossRefGoogle Scholar
  33. 33.
    Klemenkova ZS, Novskova TA, Lyashchenko AK (2008) The IR absorption spectra of aqueous solutions of dimethylsulfoxide over the frequency range 50–300 cm−1 and the mobility of water molecules. Rus J Phys Chem 82:571–575Google Scholar
  34. 34.
    Ritzoulis G (1989) Excess properties of the binary liquid systems dimethylsulfoxide + isopropanol and propylene carbonate + isopropanol. Can J Chem 67:1105–1108CrossRefGoogle Scholar
  35. 35.
    Talman JD (1978) Numerical Fourier and Bessel transforms in logarithmic variables. J Comput Phys 29:35–48CrossRefGoogle Scholar
  36. 36.
    Rossky PJ, Friedman HL (1980) Accurate solutions to integral equations describing weakly screened ionic systems. J Chem Phys 72:5694–5700CrossRefGoogle Scholar
  37. 37.
    Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR (2012) Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform 4:1–17CrossRefGoogle Scholar
  38. 38.
    Halgren TA (1996) Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94*. J Comput Chem 17:490–519CrossRefGoogle Scholar
  39. 39.
    Bordwell FG, Algrim DJ (1988) Acidities of anilines in dimethyl sulfoxide solution. J Am Chem Soc 110:2964–2968CrossRefGoogle Scholar
  40. 40.
    Bordwell FG, Hughes DL (1982) Thiol acidities and thiolate ion reactivities toward butyl chloride in dimethyl sulfoxide solution. The question of curvature in Broensted plots. J Org Chem 47:3224–3232Google Scholar
  41. 41.
    Frisch MJ, et al. (2004) Gaussian 03, revision C.02. Gaussian Inc., WallingfordGoogle Scholar
  42. 42.
    Cancès E, Menucci B, Tomasi J (1997) A new integral equation formalism for the polarizable continuum model: theoretical background and applications to isotropic and anisotropic dielectrics. J Chem Phys 107:3032–3041Google Scholar
  43. 43.
    Menucci B, Tomasi J (1997) Continuum solvation models: a new approach to the problem of solute’s charge distribution and cavity boundaries. J Chem Phys 106:5151–5158Google Scholar
  44. 44.
    Menucci B, Cancès E, Tomasi J (1997) Evaluation of solvent effects in isotropic and anisotropic dielectrics and in ionic solutions with a unified integral equation method: theoretical bases, computational implementation, and numerical applications. J Phys Chem B 101:10506–10517Google Scholar
  45. 45.
    Tomasi J, Menucci B, Cancès E (1997) The IEF version of the PCM solvation method: an overview of a new method addressed to study molecular solutes at the QM ab initio level. J Mol Struct (Theochem) 464:211–226CrossRefGoogle Scholar
  46. 46.
    Kovalenko A, Ten-no S, Hirata F (1999) Solution of three-dimensional reference interaction site model and hypernetted chain equations for simple point charge water by modified method of direct inversion in iterative subspace. J Comput Chem 20:928–936CrossRefGoogle Scholar
  47. 47.
    Chirlian LE, Francl MM (1987) Atomic charges derived from electrostatic potentials: a detailed study. J Comput Chem 8:894–905Google Scholar
  48. 48.
    Breneman CM, Wiberg KB (1990) Determining atom-centered monopoles from molecular electrostatic potentials. The need for high sampling density in formamide conformational analysis. J Comput Chem 11:361–373CrossRefGoogle Scholar
  49. 49.
    Huffman LM, Casitas A, Font M, Canta M, Costas M, Ribas X, Stahl SS (2011) Observation and mechanistic study of facile C–O bond formation between a well-defined aryl–copper(III) complex and oxygen nucleophiles. Chem Eur J 17:10643–10650Google Scholar
  50. 50.
    Molcad GmbH (2013) Homepage.

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jochen Heil
    • 1
  • Daniel Tomazic
    • 1
  • Simon Egbers
    • 1
  • Stefan M. Kast
    • 1
    Email author
  1. 1.Physikalische Chemie III, Technische Universität DortmundDortmundGermany

Personalised recommendations