The pKa's of substituted thiols are important for understanding their properties and reactivities in applications in chemistry, biochemistry, and material chemistry. For a collection of 175 different density functionals and the SMD implicit solvation model, the average errors in the calculated pKa's of methanethiol and ethanethiol are almost 10 pKa units higher than for imidazole. A test set of 45 substituted thiols with pKa's ranging from 4 to 12 has been used to assess the performance of 8 functionals with 3 different basis sets. As expected, the basis set needs to include polarization functions on the hydrogens and diffuse functions on the heavy atoms. Solvent cavity scaling was ineffective in correcting the errors in the calculated pKa's. Inclusion of an explicit water molecule that is hydrogen bonded with the H of the thiol group (in neutral) or S(-) (in thiolates) lowers error by an average of 3.5 pKa units. With one explicit water and the SMD solvation model, pKa's calculated with the M06-2X, PBEPBE, BP86, and LC-BLYP functionals are found to deviate from the experimental values by about 1.5-2.0 pKa units whereas pKa's with the B3LYP, ωB97XD and PBEVWN5 functionals are still in error by more than 3 pKa units. The inclusion of three explicit water molecules lowers the calculated pKa further by about 4.5 pKa units. With the B3LYP and ωB97XD functionals, the calculated pKa's are within one unit of the experimental values whereas most other functionals used in this study underestimate the pKa's. This study shows that the ωB97XD functional with the 6-31+G(d,p) and 6-311++G(d,p) basis sets, and the SMD solvation model with three explicit water molecules hydrogen bonded to the sulfur produces the best result for the test set (average error -0.11 ± 0.50 and +0.15 ± 0.58, respectively). The B3LYP functional also performs well (average error -1.11 ± 0.82 and -0.78 ± 0.79, respectively).

The SMD implicit solvation model augmented with one and four explicit water molecules was used to calculate pKa's and redox potentials of N-methyl-substituted nucleic acid bases guanine, adenine, cytosine, thymine, and uracil. Calculations were carried out with the B3LYP/6-31+G(d,p) level of theory. The same numbers of water molecules were hydrogen bonded to the neutral, protonated, and deprotonated nucleobases in their unoxidized and oxidized forms. The improvement in pKa1 involving neutrals and cations was modest. By contrast, the improvement in pKa2 involving neutrals and anions was quite significant, reducing the mean absolute error from 4.6 pKa units with no waters, to 2.6 with one water and 1.7 with four waters. For the oxidation of nucleobases, adding explicit waters did little to improve E(X(•),H(+)/XH), possibly because both species in the redox couple are neutral molecules at pH 7.

Acid dissociation constants (pK's) are key physicochemical properties that are needed to understand the structure and reactivity of molecules in solution. Theoretical pK's have been calculated for a set of 72 organic compounds with -OH and -OOH groups (48 with known experimental pK's). This test set includes 17 aliphatic alcohols, 25 substituted phenols, and 30 hydroperoxides. Calculations in aqueous medium have been carried out with SMD implicit solvation and three hybrid DFT functionals (B3LYP, ωB97XD, and M06-2X) with two basis sets (6-31+G(d,p) and 6-311++G(d,p)). The effect of explicit water molecules on calculated pK's was assessed by including up to three water molecules. pK's calculated with only SMD implicit solvation are found to have average errors greater than 6 pK units. Including one explicit water reduces the error by about 3 pK units, but the error is still far from chemical accuracy. With B3LYP/6-311++G(d,p) and three explicit water molecules in SMD solvation, the mean signed error and standard deviation are only -0.02 ± 0.55; a linear fit with zero intercept has a slope of 1.005 and R = 0.97. Thus, this level of theory can be used to calculate pK's directly without the need for linear correlations or thermodynamic cycles. Estimated pK values are reported for 24 hydroperoxides that have not yet been determined experimentally.

Oxidation of guanine in the presence of lysine can lead to guanine-lysine cross-links. The ratio of the C4, C5 and C8 crosslinks depends on the manner of oxidation. Type II photosensitizers such as Rose Bengal and methylene blue can generate singlet oxygen, which leads to a different ratio of products than oxidation by type I photosensitizers or by one electron oxidants. Modeling reactions of singlet oxygen can be quite challenging. Reactions have been explored using CASSCF, NEVPT2, DFT, CCSD(T), and BD(T) calculations with SMD implicit solvation. The spin contamination in open-shell calculations were corrected by Yamaguchi's approximate spin projection method. The addition of singlet oxygen to guanine to form guanine endo- peroxide proceeds step-wise via a zwitterionic peroxyl intermediate. The subsequent barrier for ring closure is smaller than the initial barrier for singlet oxygen addition. Ring opening of the endoperoxide by protonation at C4-O is followed by loss of a proton from C8 and dehydration to produce 8-oxoG . The addition of lysine (modelled by methylamine) or water across the C5=N7 double bond of 8-oxoG is followed by acyl migration to form the final spiro products. The barrier for methylamine addition is significantly lower than for water addition and should be the dominant reaction channel. These results are in good agreement with the experimental results for the formation of guanine-lysine cross-links by oxidation by type II photosensitizers.

Despite the numerous computational efforts on estimating acid dissociation constant (pK a’s), an accurate estimation of pK a’s of bio-organic molecules in the aqueous medium is still a challenge. The major difficulty lies in the accurate description of the aqueous environment and the cost and accuracy of quantum mechanical (QM) methods. Herein, we report a well-defined quantum chemical protocol for accurately calculating pK a’s of a wide range of bio-organic molecules in aqueous media. The performance of our method has been assessed using test sets containing molecules with a range of sizes and a variety of functional groups, including alcohols, phenols, amines, and carboxylic acids, and obtained an impressive mean absolute accuracy of 0.5 pK a units. For the smaller molecules, we use a high-level QM method (CBS-QB3) and a calibrated explicit–implicit solvation model that yields accurate pK a values for a range of functional groups. For the larger molecules, we combine this approach with an efficient error-cancellation scheme that eliminates the systematic errors in different density functional methods to yield accurate pK a values for simple to complex molecular systems. Our protocol is efficient, applicable to large molecules, covers all the common functional groups present in bio-organic molecules, and should find widespread applications in diverse research areas including drug–protein binding, catalysis, and chemical synthesis.