Isodesmic Reaction for Pka Calculations of Common Organic Molecules

Supporting Information

Isodesmic reaction for pKa calculations of common organic molecules

Sebastián Sastre, Rodrigo Casasnovas, Francisco Muñoz and Juan Frau

Table 1. Comparison between calculated and experimental aqueous pKa values of aliphatic alcohols. CPCM SMD Exptl [1] CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Ethanol 15.90 Methanol 15.50 15.67 15.50 15.57 15.63 15.40 15.47 2-chloroethanol 14.30 13.40 13.11 13.08 13.51 13.25 13.18 Propanol 16.10 15.66 15.80 15.61 15.56 15.68 15.49 i-propanol 17.10 16.16 16.43 16.33 15.67 16.02 15.70 2-butanol 17.60 16.48 16.70 17.54 16.14 16.47 15.89 tert-butanol 19.20 17.66 18.15 18.06 16.36 16.93 16.35

MAD 0.85 0.68 0.62 1.20 1.01 1.29 SD 0.49 0.46 0.51 0.96 0.75 0.97 AD max 1.54 1.19 1.22 2.84 2.27 2.85

Table 2. Comparison between calculated and experimental aqueous pKa values of carboxylic acids. CPCM SMD Exptl [2] CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Acetic ac. 4.76 Chloroacetic ac. 2.86 1.91 1.63 1.84 1.94 1.36 0.97 Formic ac. 3.75 3.19 2.76 3.14 2.62 2.21 2.46 3-chlorobutanoic ac. 4.05 4.20 3.44 3.98 3.90 3.74 3.40 Benzoic ac. 4.20 4.00 4.62 4.00 3.37 3.98 3.35 4-chlorobutanoic ac. 4.52 5.10 5.09 5.02 4.57 4.52 4.38 Hexanoic ac. 4.82 5.93 6.08 5.95 5.11 5.24 5.04 Propanoic ac. 4.87 5.89 5.94 5.85 5.48 5.49 5.24 Pentanoic ac. 4.87 5.97 6.09 5.92 4.30 4.40 5.13 Trimethylacetic ac. 5.05 6.37 6.49 6.56 5.62 5.72 5.42

MAD 0.78 0.98 0.79 0.57 0.64 0.67 SD 0.42 0.36 0.47 0.36 0.54 0.59 AD max 1.32 1.44 1.51 1.13 1.54 1.89 Table 3. Comparison between calculated and experimental aqueous pKa values of aliphatic amines. CPCM SMD Exptl [3] CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Ethylamine 10.63 Methylamine 10.62 10.60 10.38 10.58 9.99 9.79 9.91 Propylamine 10.53 10.93 10.95 10.96 10.87 10.91 10.72 i-propylamine 10.63 10.30 10.44 10.28 10.55 10.72 10.39 Butylamine 10.59 11.26 11.04 11.01 10.70 10.76 11.02 2-butylamine 10.56 10.40 10.67 10.55 10.47 10.74 10.65 tert-butylamine 10.55 10.02 10.42 10.10 10.70 11.11 10.77 trimethylamine 9.76 12.27 11.96 12.65 9.58 9.61 9.90 dimethylamine 10.64 12.23 11.99 12.39 10.30 10.20 10.48

MAD** 0.35 0.26 0.28 0.23 0.37 0.31 SD** 0.24 0.14 0.20 0.21 0.28 0.22 AD max** 0.67 0.45 0.45 0.63 0.83 0.71

MAD 0.87 0.72 0.90 0.24 0.35 0.27 SD 0.84 0.74 1.00 0.19 0.25 0.20 AD max 2.51 2.20 2.89 0.63 0.83 0.71 ** Just for primary amines

Table 4. Comparison between calculated and experimental aqueous pKa values of phenols. CPCM SMD Exptl [3] CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Phenol 9.98 p-cyanophenol 7.95 5.79 5.24 5.38 6.29 5.77 5.85 o-chlorophenol 8.56 7.51 7.38 7.46 7.32 7.20 7.22 m-cyanophenol 8.61 7.11 6.94 6.97 7.85 7.54 7.54 m-chlorophenol 9.02 8.17 8.02 8.04 8.24 8.13 8.15 m-fluorophenol 9.28 8.34 8.14 8.07 8.41 8.25 8.17 p-chlorophenol 9.38 8.77 8.70 8.68 8.91 8.87 8.86 p-fluorophenol 9.95 9.72 9.45 9.48 9.91 9.66 9.71 m-methylphenol 10.08 10.43 10.55 9.81 10.43 10.60 10.72 p-methylphenol 10.14 10.67 10.76 10.59 10.65 10.77 10.62 o-methylphenol 10.29 11.02 11.12 11.13 10.58 10.70 10.65

MAD 0.90 1.08 1.02 0.70 0.89 0.87 SD 0.57 0.68 0.68 0.48 0.57 0.56 AD max 2.16 2.71 2.57 1.66 2.18 2.10

Table 5. Comparison between calculated and experimental aqueous pKa values of benzoic acids. CPCM SMD Exptl [4] CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Benzoic ac. 4.20 o-chlorobenzoic ac. 2.93 15.67 15.50 15.57 15.63 15.40 15.47 m-chlorobenzoic ac. 3.83 13.40 13.11 13.08 13.51 13.25 13.18 p-chlorobenzoic ac. 3.99 15.66 15.80 15.61 15.56 15.68 15.49 p-methylbenzoic ac. 4.37 16.16 16.43 16.33 15.67 16.02 15.70 m-methylbenzoic ac. 4.27 16.48 16.70 17.54 16.14 16.47 15.89 p-fluorobenzoic ac. 4.13 17.66 18.15 18.06 16.36 16.93 16.35

MAD 0.45 0.57 0.41 0.41 0.50 0.34 SD 0.29 0.41 0.30 0.35 0.48 0.29 AD max 0.95 1.36 0.82 1.05 1.39 0.69

Table 6. Comparison between calculated and experimental aqueous pKa values of pyridines. CPCM SMD Exptl CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Pyridine 5.23 [5] 2- methylpyridine 5.97 [3] 6.77 6.96 6.90 6.45 6.65 5.78 3-methylpyridine 5.68 [3] 6.02 6.18 6.20 5.72 5.88 6.49 4- methylpyridine 6.02 [3] 6.23 6.44 6.89 6.24 6.42 6.15 2,3-dimethylpyridine 6.57 [5] 7.40 7.68 7.43 7.25 7.54 7.20 2,4-dimethylpyridine 6.99 [5] 8.07 8.44 7.73 7.78 7.54 7.73 3-bromopyridine 2.84 [5] 2.88 2.87 2.60 1.55 1.50 1.29 3-fluoropyridine 2.97 [3] 3.26 3.03 2.89 2.38 2.17 2.02 3-cyanopyridine 1.45 [6] 0.01 -0.72 -0.42 0.78 0.51 0.41 3-chloropyridine 2.81 [5] 2.93 2.87 4.15 1.96 1.50 1.82

MAD 0.57 0.75 0.83 0.62 0.80 0.78 SD 0.48 0.74 0.55 0.36 0.39 0.44 AD max 1.44 2.17 1.87 1.29 1.34 1.55 Table 7. Effect of the reference species on the accuracy of the calculated pKa of pyridines expressed as Mean Absolute Deviation (MAD). CPCM SMD Reference CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Pyridine 0.57 0.75 0.83 0.62 0.80 0.78 2-methylpyridine 0.71 0.95 0.78 0.78 0.99 0.78 3-methylpyridine 0.50 0.74 0.71 0.62 0.82 1.17 4-methylpyridine 0.49 0.72 0.75 0.66 0.87 0.81 2,3-dimethylpyridine 0.73 1.03 0.74 0.92 1.19 1.03 2,4-dimethylpyridine 0.94 1.34 0.71 1.01 1.35 1.11 3-bromopyridine 0.55 0.73 0.97 1.30 1.43 1.45 3-fluoropyridine 0.49 0.72 0.87 0.76 1.00 0.95 3-cyanopyridine 1.85 2.68 2.42 0.79 1.07 1.00 3-chloropyridine 0.51 0.72 1.15 0.91 1.06 0.97

Table 8. Effect of the reference species on the accuracy of the calculated pKa of aliphatic alcochols expressed as Mean Absolute Deviation (MAD). CPCM SMD Reference CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Ethanol 0.85 0.68 0.62 1.20 1.01 1.29 Methanol 0.99 0.69 0.68 1.30 0.93 1.26 2-chloroethanol 0.55 0.71 0.82 0.89 0.66 0.89 Propanol 0.63 0.54 0.52 0.93 0.77 0.97 i-propanol 0.56 0.47 0.57 0.99 0.66 0.93 2-butanol 0.65 0.51 0.59 1.01 0.69 1.09 tert-butanol 1.00 0.59 0.76 2.16 1.64 2.04

Table 9. Effect of the reference species on the accuracy of the calculated pKa of carboxylic acids expressed as Mean Absolute Deviation (MAD). CPCM SMD Reference CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Acetic ac. 0.78 0.98 0.79 0.57 0.64 0.67 Chloroacetic ac. 1.45 1.72 1.50 0.84 1.42 1.70 Formic ac. 1.11 1.51 1.13 1.02 1.45 1.17 3-chlorobutanoic ac. 0.74 1.25 0.80 0.57 0.66 0.79 Benzoic ac. 0.86 0.89 0.86 0.78 0.64 0.88 4-chlorobutanoic ac. 0.74 0.89 0.79 0.58 0.64 0.67 Hexanoic ac. 0.88 1.09 0.98 0.69 0.82 0.72 Propanoic ac. 0.84 1.00 0.89 0.91 0.96 0.82 Pentanoic ac. 0.88 1.06 0.92 0.66 0.73 0.74 Trimethylacetic ac. 1.07 1.25 1.31 0.87 1.01 0.81 Table 10. Effect of the reference species on the accuracy of the calculated pKa aliphatic amines expressed as Mean Absolute Deviation (MAD). CPCM SMD Reference CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Ethylamine 0.87 0.72 0.90 0.24 0.35 0.27 Methylamine 0.61 0.93 0.80 0.61 0.93 0.80 Propylamine 0.35 0.32 0.17 0.35 0.32 0.17 i-propylamine 0.23 0.34 0.38 0.23 0.34 0.38 Butylamine 0.28 0.35 0.48 0.28 0.35 0.48 2-butylamine 0.21 0.35 0.22 0.21 0.35 0.22 tert-butylamine 0.31 0.63 0.30 0.31 0.63 0.30 Trimethylamine 0.27 0.41 0.27 0.27 0.41 0.27 Dimethylamine 0.36 0.58 0.33 0.36 0.58 0.33

Table 11. Effect of the reference species on the accuracy of the calculated pKa of benzoic acids expressed as Mean Absolute Deviation (MAD). CPCM SMD Reference CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Benzoic ac. 0.47 0.46 0.44 0.41 0.50 0.34 o-chlorobenzoic ac. 1.41 1.71 1.42 1.42 1.68 1.17 m-chlorobenzoic ac. 2.06 2.01 1.84 2.12 2.05 1.94 p-chlorobenzoic ac. 1.12 1.19 1.30 1.21 1.21 1.12 p-methylbenzoic ac. 1.12 1.22 1.15 1.12 1.15 1.07 m-methylbenzoic ac. 1.21 1.27 1.18 1.15 1.19 1.16 p-fluorobenzoic ac. 2.92 2.92 3.04 2.73 2.76 2.86

Table 12. Effect of the reference species on the accuracy of the calculated pKa of phenols expressed as Mean Absolute Deviation (MAD). CPCM SMD Reference CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Phenol 0.90 1.08 1.02 0.70 0.89 0.87 p-cyanophenol 1.80 2.28 2.06 1.36 1.82 1.73 o-chlorophenol 0.90 1.01 0.87 0.98 1.09 1.05 m-cyanophenol 1.21 1.34 1.22 0.67 0.88 0.87 m-chlorophenol 0.81 0.94 0.83 0.68 0.82 0.81 m-fluorophenol 0.84 0.98 0.93 0.72 0.86 0.89 p-chlorophenol 0.79 0.91 0.80 0.64 0.78 0.77 p-fluorophenol 0.83 0.93 0.83 0.68 0.80 0.80 m-methylphenol 1.07 1.31 0.89 0.89 1.17 1.28 p-methylphenol 1.20 1.42 1.34 1.03 1.27 1.14 o-methylphenol 1.38 1.60 1.69 0.84 1.09 1.05 Table 13. Comparison between the calculated and experimental pKa values of piridines using ethylamine as the reference species. CPCM SMD Exptl CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Pyridine 5.23 [5] 7.73 6.73 4.14 5.21 4.08 4.14 2-methylpyridine 5.97 [3] 9.46 8.39 5.36 6.63 4.62 5.36 3-methylpyridine 5.68 [3] 8.68 7.69 4.63 5.86 5.33 4.63 4-methylpyridine 6.02 [3] 8.94 8.39 5.15 6.40 4.99 5.15 2,3-dimethylpyridine 6.57 [5] 10.18 8.93 6.16 7.52 6.05 6.16 2,4-dimethylpyridine 6.99 [5] 10.94 9.23 6.68 8.12 6.58 6.68 3-bromopyridine 2.84 [5] 5.37 4.10 0.45 1.48 0.14 0.45 3-fluoropyridine 2.97 [3] 5.53 4.38 1.29 2.15 0.87 1.29 3-cyanopyridine 1.45 [6] 1.78 1.07 -0.31 0.49 -0.75 -0.31 3-chloropyridine 2.81 [5] 5.37 5.65 0.87 1.87 0.66 0.87

MAD 1.83 2.75 1.88 1.21 0.74 1.40

SD 0.69 0.99 0.73 0.70 0.43 0.85 AD max 2.68 3.95 2.84 2.39 1.36 2.70

Table 14. Comparison between the calculated and experimental pKa values of benzoic acids using acètic acidas the reference species. CPCM SMD Exptl [4] CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Benzoic acid 4.20 4.00 4.62 4.00 3.37 3.98 3.35 o-chlorobenzoic 2.93 1.77 1.98 1.90 1.04 1.31 1.39 m-chlorobenzoic 3.83 3.03 3.55 2.94 2.43 2.93 2.28 p-chlorobenzoic 3.99 3.34 3.94 4.02 2.84 3.41 2.79 p-methylbenzoic 4.37 4.38 5.12 4.14 3.35 4.09 3.52 m-methylbenzoic 4.27 4.29 4.96 4.49 3.68 4.39 3.52 p-fluorobenzoic 4.13 3.67 4.23 3.65 3.18 3.71 3.07

MAD 0.47 0.46 0.44 1.12 0.59 1.12 SD 0.43 0.34 0.38 0.42 0.52 0.33 AD max 1.15 0.94 1.03 1.88 1.62 1.55 Table 15. Comparison between the calculated and experimental pKa values of phenols using ethanol as the reference species. CPCM SMD Exptl [3] CBS-4B3* B3LYP M05-2X CBS-4B3* B3LYP M05-2X Phenol 9.98 6.54 6.36 5.73 5.24 4.96 4.10 2.36 1.63 1.13 1.55 0.75 -0.03 p-cyanophenol 7.95 4.07 3.76 3.21 2.58 2.18 1.34 o-chlorophenol 8.56 3.67 3.33 2.73 3.11 2.52 1.66 m-cyanophenol 8.61 4.73 4.40 3.79 3.50 3.11 2.27 m-chlorophenol 9.02 4.90 4.53 3.82 3.67 3.24 2.29 m-fluorophenol 9.28 5.33 5.09 4.44 4.17 3.86 2.98 p-chlorophenol 9.38 6.28 5.83 5.23 5.16 4.65 3.83 p-fluorophenol 9.95 6.99 6.93 5.56 5.69 5.58 4.84 m-methylphenol 10.08 7.23 7.14 6.34 5.91 5.76 4.74 p-methylphenol 10.14 7.58 7.50 6.88 5.83 5.68 4.76 o-methylphenol 10.29

MAD 3.96 4.25 4.94 5.17 5.54 6.41 SD 0.89 1.07 0.96 0.70 0.88 0.86 AD max 5.59 6.32 6.82 6.40 7.20 7.98

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