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1 Comment on the Correct Use of Continuum Solvent Models Junming Ho a, Andreas Klamt b,c and Michelle L. Coote 1,a a ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Research School of Chemistry, Australian National University, Canberra ACT 0200, Australia b COSMOlogic GmbH&CoKG, Burscheider Str. 515, Leverkusen, Germany c Institute of Physical and Theoretical Chemistry, University of Regensburg, Regensburg, Germany SUPPPORTING INFORMATION 1 Correspondence author. mcoote@rsc.anu.edu.au S1

2 Table S1. B3LYP/6-31+G(d) thermal corrections (Hartrees) to the free energy of the solute obtained in the gas and solution phase (CPCM-UAKS) based on the harmonic oscillator rigid rotor approximation. Acid Gcorr,gas Gcorr,aq Δ (kcal mol -1 ) Conjugate base Gcorr,gas Gcorr,aq Δ (kcal mol -1 ) ch3oh ch3oh ch3ch2oh ch3ch2oh phenol phenol hcooh hcooh ch3cooh ch3cooh cf3cooh cf3cooh hf hf hcl hcl hooh hooh hocl hocl hno hno h2so h2so ch3coch ch3coch hcn hcn ch3cooch2ch ch3cooch2ch f-phenol f-phenol hno hno hn hn pyruvic pyruvic cf3ch2oh cf3ch2oh no2-phenol no2-phenol ch2(cn) ch2(cn) ch3ch2cn ch3ch2cn ch3so3h ch3so3h (cf3)2coh (cf3)2coh propanol propanol (ch3)3coh (ch3)3coh MAD 0.7 MAD 0.4 S2

3 Table S2. The experimental and calculated solvation free energies a (kcal mol -1 ) of 50 neutral and ionic solutes. Expt PCM-UAHF b ΔG solv PCM-UAHF (HF/6-31+G*) MP2 (PCM-UAHF) PCM-UAHF (MP2/6-311+G(3df,2p) c MP2 (Gas) PCM-UAHF (HF/6-31+G*) d ΔG solv = E soln + G nes - G gas PCM-UAHF (HF/6-31+G*) e ΔG solv = G soln (Freq)-G gas ΔG nes ΔG solv E soln + G nes G gas ΔG solv G soln (Freq) ΔG solv c5h5n c6h ch2ch ch3ch ch3cho ch3cl ch3cn ch3coch ch3conh ch3cooch ch3cooh-base ch3cooh ch3f ch3nh ch3och ch3oh-base ch3oh ch3sh ch chch-base chch h+ch3coch f - f h+ch3nh h+ch3och f - f h+ch3oh h+ch3sh f - f h+h2o E h+h2s h+me3n S3

4 h+nh h+phnh h2co h2o-base f - f h2o h2s-base h2s hcn-base hcn hcooh-base hcooh me3n f - f nh phcho phcl phnh phno phoh-base phoh phsh-base e phsh MAD 1.4 MAD 2.0 MAD 29.5 MAD 2.9 AD max 7.1 AD max 12.3 AD max 77.3 AD max 16.3 a Experimental values are adopted from reference 17, and all solvation free energies refer to a standard state of 1 mol L -1 in both gas and solution phase. b PCM-UAHF solvation free energies computed at the HF/6-31+G* level on corresponding gas phase optimised geometries (in accordance with parameterisation) c PCM-UAHF solvation free energies but with the electrostatic component computed at the MP2/6-311+G(3df,2p) level of theory. d Manual calculation of solvation free energies by using PCM-UAHF/HF/6-31+G* E soln + G nes (assumed to have a standard state of 1 mol L -1 ) in place of G soln in equation (2). G gas is obtained via a frequency calculation at the HF/6-31+G* level. e Manual calculation of solvation free energies by using PCM-UAHF/HF/6-31+G* G soln obtained from a frequency calculation on the solution optimised geometry. G gas is obtained via a frequency calculation at the HF/6-31+G* level. f Convergence problems during geometry optimisation in solution. S4

5 Table S3. Complete references 8 and 9. (8) Frisch, M. J.; G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A. Gaussian 03, Revision E.01 Gaussian, Inc., Wallingford CT, (9) Higashi, M.; M., A. V.; Olson, R. M.; Chamberlin, A. C.; Pu, J.; Kelly, C. P.; Thompson, J. ; D.; Xidos, J. D. L., J.; Zhu, T.; Hawkins, G. D.; Chuang, Y.-Y.; Fast, P. L.; Lynch, B. J.; Liotard, ; D. A.; Rinaldi, D. G., J.; Cramer, C. J.; Truhlar, D. G. GAMESSPLUS version , ; University of Minnesota, M., 2008, based on the General Atomic and Molecular ; Electronic Structure System (GAMESS) as described in Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comp. Chem. 1993, 14, S5

6 Table S4. The gas phase geometries of all the species appearing in Table S2. NOTE: All species had zero imaginary frequencies, as determined from frequency calculations at the HF/6-31+G(d) level. c5h5n 1\1\GINC-X101\FOpt\RHF\6-31+G(d)\C5H5N1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\n, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \\Version=EM64L-G03Re ve.01\state=1-a1\hf= \rmsd=5.627e-09\rmsf=9.880e-05\thermal =0.\Dipole= ,0., \PG=C02V c6h6 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\C6H6\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \\Version=EM64L-G03RevE.01\State=1-A1G\HF= \ RMSD=8.088e-09\RMSF=8.834e-05\Thermal=0.\Dipole=0.,0.,0.\PG=D06H [3C2' ch2ch2 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\C2H4\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c,0.,0., \C,0.,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \\Version=EM64L-G03RevE.01\State=1-AG\HF= \ RMSD=6.856e-09\RMSF=5.281e-05\Thermal=0.\Dipole=0.,0.,0.\PG=D02H [C2"( ch3ch3 1\1\GINC-X127\FOpt\RHF\6-31+G(d)\C2H6\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \H, , , \C, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.0 1\State=1-A1G\HF= \RMSD=8.358e-09\RMSF=5.977e-05\Thermal=0.\ Dipole=0.,0.,0.\PG=D03D ch3cho 1\1\GINC-X101\FOpt\RHF\6-31+G(d)\C2H4O1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \O, , , \C, , , \H, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A\HF= \RMSD=7.632 e-09\rmsf=4.216e-05\thermal=0.\dipole= , , \p G=C01 ch3cl 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\C1H3Cl1\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \Cl, , , \H, , , \\Version =EM64L-G03RevE.01\State=1-A1\HF= \RMSD=8.629e-09\RMSF=7.097e S6

7 -05\Thermal=0.\Dipole= , , \PG=C03V [C3(C1Cl1), ch3cn 1\1\GINC-X134\FOpt\RHF\6-31+G(d)\C2H3N1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c,0.,0., \c,0.,0., \n,0.,0., \h, ,0., \h, , , \h, , , \\Version=EM64L-G03RevE.01\State=1-A1\HF = \RMSD=6.106e-09\RMSF=4.143e-05\Thermal=0.\Dipole=0.,0., \PG=C03V ch3coch3 1\1\GINC-X136\FOpt\RHF\6-31+G(d)\C3H6O1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c,0.,0., \O,0.,0., \C, ,0., \C, ,0., \H, , , \H, ,0., \H, , , \H, , , \H, ,0., \H, , , \\Version=EM64L-G 03RevE.01\State=1-A1\HF= \RMSD=5.348e-09\RMSF=4.817e-05\The rmal=0.\dipole=0.,0., \pg=c02v ch3conh2 1\1\GINC-X100\FOpt\RHF\6-31+G(d)\C2H5N1O1\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\n, , , \C, , , \C, , , \O, , , \H, , , \H, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A\HF= \RMSD=5.966e-09\RMSF=3.472e-06\Thermal=0.\Dipole= , , \PG=C01 ch3cooch3 1\1\GINC-X137\FOpt\RHF\6-31+G(d)\C3H6O2\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \H, , , \C, , , \O, , , \O, , , \C, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State= 1-A'\HF= \RMSD=8.194e-09\RMSF=9.792e-05\Thermal=0.\Dipole= , , \PG=CS ch3cooh-base 1\1\GINC-X101\FOpt\RHF\6-31+G(d)\C2H3O2(1-)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\c, , , \O, , , \O, , , \C, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A\HF= \RMSD =5.220e-09\RMSF=6.333e-05\Thermal=0.\Dipole= , , \PG=C01 ch3cooh 1\1\GINC-X138\FOpt\RHF\6-31+G(d)\C2H4O2\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \H, , , \C, , , \O, , , \O, , , \H, , , \\Version=EM64L-G03RevE.0 1\State=1-A'\HF= \RMSD=6.042e-09\RMSF=1.114e-04\Thermal=0.\ S7

8 Dipole= , , \PG=CS ch3f 1\1\GINC-X138\FOpt\RHF\6-31+G(d)\C1H3F1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \F, , , \H, , , \\Version=E M64L-G03RevE.01\State=1-A1\HF= \RMSD=2.032e-09\RMSF=1.217e- 05\Thermal=0.\Dipole= , , \PG=C03V [C3(C1F1),3S ch3nh2 1\1\GINC-X139\FOpt\RHF\6-31+G(d)\C1H5N1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \N, , , \H, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=4.0 51e-09\RMSF=6.508e-05\Thermal=0.\Dipole= , , \PG=CS ch3och3 1\1\GINC-X140\FOpt\RHF\6-31+G(d)\C2H6O1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \O, , , \H, , , \C, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A1\HF= \RMSD=4.443e-09\RMSF=8.703e-05\Thermal=0.\Dipole= , , \PG=C02V ch3oh-base 1\1\GINC-X140\FOpt\RHF\6-31+G(d)\C1H3O1(1-)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\o,0., 0., \C,0.,0., \H, ,0., \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A1\HF= \RMS D=9.406e-09\RMSF=7.305e-06\Thermal=0.\Dipole=0.,0., \PG=C03V [ C3(C1O1),3SGV(H1)]\\@ ch3oh 1\1\GINC-X141\FOpt\RHF\6-31+G(d)\C1H4O1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \O, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State= 1-A'\HF= \RMSD=2.854e-09\RMSF=6.152e-05\Thermal=0.\Dipole= , , \PG=CS [SG(C1H2O1),X(H2)]\\@ ch3sh 1\1\GINC-X141\FOpt\RHF\6-31+G(d)\C1H4S1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \H, , , \S, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A'\HF = \RMSD=5.446e-09\RMSF=2.395e-05\Thermal=0.\Dipole= , , \PG=CS [SG(C1H2S1),X(H2)]\\@ ch4 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\C1H4\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c,0.,0.,0.\h,0.,0., \h, ,0., \h, ,-0 S8

9 , \H, , , \\ Version=EM64L-G03RevE.01\State=1-A1\HF= \RMSD=7.467e-10\RMSF =1.863e-04\Thermal=0.\Dipole=0.,0.,0.\PG=TD chch-base 1\1\GINC-X142\FOpt\RHF\6-31+G(d)\C2H1(1-)\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\c,0.,0., \c,0.,0., \h,0.,0., \\version=em64 L-G03RevE.01\State=1-SG\HF= \RMSD=6.245e-09\RMSF=9.552e-06\T hermal=0.\dipole=0.,0., \pg=c*v chch 1\1\GINC-X143\FOpt\RHF\6-31+G(d)\C2H2\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c,0.,0., \C,0.,0., \H,0.,0., \H,0.,0., \\Version=EM64L-G03RevE.01\State=1-SGG\HF= \RMSD=4.359e-09 \RMSF=3.884e-05\Thermal=0.\Dipole=0.,0.,0.\PG=D*H h+ch3coch3 1\1\GINC-X89\FOpt\RHF\6-31+G(d)\C3H7O1(1+)\JMH502\09-Jul-2010\0\\# HF/ 6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\c, , , \O, , , \C, , , \C, , , \H, , , \H, , , \H, , , \H, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\Stat e=1-a\hf= \rmsd=5.763e-09\rmsf=9.141e-06\thermal=0.\dipole= , , \PG=C01 h+ch3nh2 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\C1H6N1(1+)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\n, , , \H, , , \H, , , \H, , , \C, , , \H, , , \H, , , \H, , , \\Version=EM64L-G 03RevE.01\State=1-A'\HF= \RMSD=7.753e-09\RMSF=3.365e-05\Ther mal=0.\dipole= , , \pg=cs h+ch3och3 1\1\GINC-X143\FOpt\RHF\6-31+G(d)\C2H7O1(1+)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\c, , , \H, , , \H, , , \O, , , \H, , , \C, , , \H, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=6.460e-09 \RMSF=4.728e-05\Thermal=0.\Dipole= , , \PG=CS h+ch3oh 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\C1H5O1(1+)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\c, , , \H, , , \H, , , \H, , , \O, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A\HF= \RMSD=3.316e-09\RMSF=1.328e-04\Thermal=0.\Dipole= , , \PG=C01 h+ch3sh 1\1\GINC-X127\FOpt\RHF\6-31+G(d)\C1H5S1(1+)\JMH502\09-Jul-2010\0\\# HF S9

10 /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\s, , , \H, , , \C, , , \H, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A\HF= \RMSD=1. 597e-09\RMSF=1.055e-04\Thermal=0.\Dipole= , , \PG=C01 h+h2o 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\H3O1(1+)\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\o, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=1. 634e-09\RMSF=3.779e-05\Thermal=0.\Dipole= , , \PG=CS h+h2s 1\1\GINC-X144\FOpt\RHF\6-31+G(d)\H3S1(1+)\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\s, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=3.696e-09\RMSF=1.504e-04\Thermal=0.\Dipole= , , \PG=CS h+me3n 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\C3H10N1(1+)\JMH502\09-Jul-2010\0\\# H F/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\n, ,0., \C, ,0., \H, ,0., \C, , , \C, , , \H, , , \H, , , \H, , , \H, ,0., \H, , , \H, , , \ H, , , \H, , , \H, , , \\Version=EM6 4L-G03RevE.01\State=1-A1\HF= \RMSD=3.256e-09\RMSF=1.219e-04 \Thermal=0.\Dipole= ,0., \PG=C03V [C3(N1H1),3SGV(C1H1 ),X(H6)]\\@ h+nh3 1\1\GINC-X136\FOpt\RHF\6-31+G(d)\H4N1(1+)\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\n, , , \H, , , \H, , , \H, , , \H, , , \\ Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=7.822e-10\RMSF =7.329e-05\Thermal=0.\Dipole= , , \PG=CS [S G(H2N1),X(H2)]\\@ h+phnh2 1\1\GINC-X141\FOpt\RHF\6-31+G(d)\C6H8N1(1+)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\1,1\c, ,0., \C, ,0., \C, , 0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \N, ,0., \H, ,0., \H, , , \H, , , \\V ersion=em64l-g03reve.01\state=1-a'\hf= \rmsd=4.815e-09\rmsf =1.037e-04\Thermal=0.\Dipole= ,0., \PG=CS [SG(C6H6N1),X(H2)]\\@ h2co 1\1\GINC-X141\FOpt\RHF\6-31+G(d)\C1H2O1\JMH502\09-Jul-2010\0\\# HF/6-3 S10

11 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c,0.,0., \O,0.,0., \H, ,0., \H, ,0., \\Version=EM64L-G03RevE.01\State=1-A1\HF= \RMSD=3.401e-09\RMSF=1.966e-05\Thermal=0.\Dipole=0.,0., \PG=C02V h2o-base 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\H1O1(1-)\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\o,0.,0., \h,0.,0., \\version=em64l-g03reve.01\state=1- SG\HF= \RMSD=2.134e-09\RMSF=4.117e-05\Thermal=0.\Dipole=0.,0., \PG=C*V h2o 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\H2O1\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\o, ,0., \H, ,0., \H, ,0., \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD =2.146e-09\RMSF=1.272e-05\Thermal=0.\Dipole= ,0., \PG= CS h2s-base 1\1\GINC-X134\FOpt\RHF\6-31+G(d)\H1S1(1-)\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\s,0.,0., \h,0.,0., \\version=em64l-g03reve.01\state=1- SG\HF= \RMSD=4.201e-09\RMSF=1.380e-08\Thermal=0.\Dipole=0., 0., \PG=C*V h2s 1\1\GINC-X136\FOpt\RHF\6-31+G(d)\H2S1\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\s, ,0., \H, ,0., \H, ,0., \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RM SD=6.093e-09\RMSF=1.673e-04\Thermal=0.\Dipole= ,0., \P G=CS hcn-base 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\C1N1(1-)\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\n,0.,0., \c,0.,0., \\version=em64l-g03reve.01\state=1- SG\HF= \RMSD=3.657e-09\RMSF=1.055e-04\Thermal=0.\Dipole=0.,0., \PG=C*V hcn 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\C1H1N1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\h,0.,0., \C,0.,0., \N,0.,0., \\Version=EM64L-G0 3RevE.01\State=1-SG\HF= \RMSD=4.519e-09\RMSF=3.576e-05\Therm al=0.\dipole=0.,0., \pg=c*v hcooh-base 1\1\GINC-X127\FOpt\RHF\6-31+G(d)\C1H1O2(1-)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\c, ,0., \H, ,0., \O, ,0., \O, ,0., \\Version=EM64L-G0 3RevE.01\State=1-A'\HF= \RMSD=7.914e-09\RMSF=8.365e-05\Ther mal=0.\dipole= ,0., \pg=cs hcooh 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\C1H2O2\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, ,0., \H, ,0., \O, ,0., \O, ,0., \H, ,0., \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=8.828e-09\RMSF=3.583e-05\Thermal=0.\Dipole= ,0., \PG=CS me3n S11

12 1\1\GINC-X101\FOpt\RHF\6-31+G(d)\C3H9N1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \H, , , \N, , , \H, , , \H, , , \C, , , \C, , , \H, , , \H, , , \H, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\ State=1-A1\HF= \RMSD=8.191e-09\RMSF=2.717e-05\Thermal=0.\Di pole= , , \pg=c03v [C3(N1),3SGV(C1H1),X(H6)]\ nh3 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\H3N1\JMH502\09-Jul-2010\0\\# HF/6-31+ G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\n, , , \H, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=5.154e-09\RMSF=3.469e-04\Thermal=0.\Dipole= , , \PG=CS phcho 1\1\GINC-X128\FOpt\RHF\6-31+G(d)\C7H6O1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \C, ,0., \O, ,0., \H, ,0., \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD=4.756e-09\RMSF=1.161e-04\Thermal=0.\Dipole= ,0., \PG=CS phcl 1\1\GINC-X136\FOpt\RHF\6-31+G(d)\C6H5Cl1\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \Cl, ,0., \\Version=EM64L-G03RevE.01\State=1-A1\HF= \RMSD=8.017e-10\RMSF=2.121e-05\Thermal=0.\Dipole= ,0., \PG=C02V phnh2 1\1\GINC-X89\FOpt\RHF\6-31+G(d)\C6H7N1\JMH502\09-Jul-2010\0\\# HF/6-31 +G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \C, , , \C, , , \C, , , \C, , , \C, , , \H, , , \H, , , \H, , , \H, , , \H, , , \N, , , \H, , , \H, , , \\Version=EM64L-G03RevE.01\State=1-A\HF= \RMS D=8.624e-09\RMSF=1.522e-04\Thermal=0.\Dipole= , , \PG=C01 phno2 1\1\GINC-X126\FOpt\RHF\6-31+G(d)\C6H5N1O2\JMH502\09-Jul-2010\0\\# HF/6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., S12

13 21486\C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \N, ,0., \O, ,0., \O, ,0., \\Version=EM64L-G03RevE.01\State=1-A'\HF= \RMSD= 6.281e-09\RMSF=3.313e-05\Thermal=0.\Dipole= ,0., \PG=C S [SG(C6H5N1O2)]\\@ phoh-base 1\1\GINC-X136\FOpt\RHF\6-31+G(d)\C6H5O1(1-)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\c, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \O, ,0., \\Version=EM64L-G03RevE.01\State=1-A1\HF= \RMSD=7.967e-09\RMSF=3.558e-05\Thermal=0.\Dipole= ,0., \PG=C02V [C2(H1C1C1O1),SGV(C4H4)]\\@ phoh 1\1\GINC-X137\FOpt\RHF\6-31+G(d)\C6H6O1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \ H, ,0., \H, ,0., \H, ,0., \H, ,0., \O, ,0., \H, ,0., \\Version=EM64L-G03R eve.01\state=1-a'\hf= \rmsd=9.572e-09\rmsf=9.516e-05\therma l=0.\dipole= ,0., \pg=cs [SG(C6H6O1)]\\@ phsh-base 1\1\GINC-X138\FOpt\RHF\6-31+G(d)\C6H5S1(1-)\JMH502\09-Jul-2010\0\\# HF /6-31+G(d) opt freq=noraman maxdisk= \\hf geom opt\\-1,1\c, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \C, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \H, ,0., \S, ,0., \\Version=EM64L-G03RevE.01\State=1-A1\HF= \RMSD=5.227e-09\RMSF=1.080e-04\Thermal=0.\Dipole= ,0., \PG=C02V [C2(H1C1C1S1),SGV(C4H4)]\\@ phsh 1\1\GINC-X101\FOpt\RHF\6-31+G(d)\C6H6S1\JMH502\09-Jul-2010\0\\# HF/6-3 1+G(d) opt freq=noraman maxdisk= \\hf geom opt\\0,1\c, , , \C, , , \C, , , \C, , , \C, , , \C, , , \H, , , \H, , , \H, , , \H, , , \H, , , \S, , , \H, , , \\Version=EM64L-G03RevE.01\ State=1-A\HF= \RMSD=9.489e-09\RMSF=1.084e-05\Thermal=0.\Dipol e= , , \pg=c01 [X(C6H6S1)]\\@ S13

14 Table S5. Some Typical Output Summaries for CSM Calculations Example 1. Output from a PCM calculation in Gaussian Variational C-PCM results ========================= <psi(0) H psi(0)> (a.u.) = <psi(0) H+V(0)/2 psi(0)> (a.u.) = <psi(0) H+V(f)/2 psi(0)> (a.u.) = <psi(f) H psi(f)> (a.u.) = <psi(f) H+V(f)/2 psi(f)> (a.u.) = Total free energy in solution: with all non electrostatic terms (a.u.) = (Unpolarized solute)-solvent (kcal/mol) = (Polarized solute)-solvent (kcal/mol) = Solute polarization (kcal/mol) = 0.86 Total electrostatic (kcal/mol) = Cavitation energy (kcal/mol) = 4.45 Dispersion energy (kcal/mol) = Repulsion energy (kcal/mol) = 1.45 Total non electrostatic (kcal/mol) = 0.72 DeltaG (solv) (kcal/mol) = This term is actually E soln + G nes not the actual G soln as indicated Example 2. Output from an SM6 solvation calculation in GAMESSPLUS. Summary of SM6 solvation calculation by GAMESSPLUS version 2008 at 298 K Options: ISCRF = 2, IGAS = 0, ICMD =418, ICDS =418, IAQU = 1, DIELEC = (0) E-EN(g) gas-phase B3LYP3 elect-nuc energy a.u. (1) E-EN(liq) elect-nuc B3LYP3 energy of solute a.u. (2) G-P(liq) polarization free energy of solvation kcal/mol (3) G-ENP(liq) elect-nuc-pol free energy of system a.u. (4) G-CDS(liq) cavity-dispersion-solvent structure kcal/mol (5) G-P-CDS(liq) = G-P(liq) + G-CDS(liq) = (2) + (4) kcal/mol (6) G-S(liq) free energy of system = (1) + (5) a.u. (7) DeltaE-EN(liq) elect-nuc reorganization energy of solute molecule (7) = (1) - (0) kcal/mol (8) DeltaG-ENP(liq) elect-nuc-pol free energy of solvation (8) = (3) - (0) kcal/mol (9) DeltaG-S(liq) free energy of solvation (9) = (6) - (0) kcal/mol This term is actually E soln + G nes not the actual G soln as indicated S14

15 Example 3. Output from a PCM calculation in GAMESS RESULTS OF PCM CALCULATION FREE ENERGY IN SOLVENT = <PSI H(0)+V/2 PSI> = A.U. INTERNAL ENERGY IN SOLVENT = <PSI H(0) PSI> = A.U. DELTA INTERNAL ENERGY = <D-PSI H(0) D-PSI> = A.U. ELECTROSTATIC INTERACTION = A.U. PIEROTTI CAVITATION ENERGY = A.U. DISPERSION FREE ENERGY = A.U. REPULSION FREE ENERGY = A.U. TOTAL INTERACTION (DELTA + ES + CAV + DISP + REP) = A.U. TOTAL FREE ENERGY IN SOLVENT = A.U. FREE ENERGY IN SOLVENT = KCAL/MOL INTERNAL ENERGY IN SOLVENT = KCAL/MOL DELTA INTERNAL ENERGY = 0.00 KCAL/MOL ELECTROSTATIC INTERACTION = KCAL/MOL PIEROTTI CAVITATION ENERGY = 0.00 KCAL/MOL DISPERSION FREE ENERGY = 0.00 KCAL/MOL REPULSION FREE ENERGY = 0.00 KCAL/MOL TOTAL INTERACTION = KCAL/MOL TOTAL FREE ENERGY IN SOLVENT = KCAL/MOL This term is actually E soln + G nes not the actual G soln as indicated -INTERNAL ENERGY IN SOLVENT- OMITS ES,CAV,DISP,REP (USES SOLVATED ORBITALS IN THE GAS PHASE HAMILTONIAN) -FREE ENERGY IN SOLVENT- INCLUDES ES+DISP+REP WHICH ARE IN THE SELF-CONSISTENT WAVEFUNCTION. -TOTAL FREE ENERGY IN SOLVENT- INCLUDES ES+DISP+REP+CAV, MEANING CAVITATION IS NOT IN THE SCF ENERGY. S15