QUANTUM CHEMICAL pKa ESTIMATION OF CARBON ACIDS, SATURATED ALCOHOLS, AND KETONES VIA QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By COREY ADAM BALDASARE B.S., Wright State University, 2018 Wright State University 2020 WRIGHT STATE UNIVERSITY GRADUATE SCHOOL July 23rd, 2020 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Corey Adam Baldasare ENTITLED Quantum Chemical pKa Estimation of Carbon Acids, Saturated Alcohols, and Ketones via Quantitative Structure- Activity Relationships BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science. __________________________ Paul Seybold, Ph.D. Thesis Director __________________________ Audrey McGowin, Ph.D. Chair, Department of Chemistry Committee on Final Examination: ________________________________ Paul Seybold, Ph.D. ________________________________ Eric Fossum, Ph.D. ________________________________ David Dolson, Ph.D. ________________________________ Barry Milligan, Ph.D. Interim Dean of the Graduate School ABSTRACT Baldasare, Corey Adam. M.S., Department of Chemistry, Wright State University, 2020. Quantum Chemical pKa Estimation of Carbon Acids, Saturated Alcohols, and Ketones via Quantitative Structure-Activity Relationships Acid dissociation constants, often expressed as pKa values, afford vital information with regards to molecular behavior in various environments and are of significance in fields of organic, inorganic, and medicinal chemistry. Several quantitative structure-activity relationships (QSARs) were developed that correlate experimental pKas for a given class of compounds with a descriptor(s) calculated using density functional theory at the B3LYP/6-31+G** level utilizing the CPCM solvent model. A set of carbon 2 acids provided a good final QSAR model of experimental aqueous pKas versus ΔEH2O (R = 0.9647) upon removal of three aldehydes as outliers. A study of saturated alcohols offered a final QSAR model with R2 = 0.9594, which was employed to confirm the behavior of the three aldehydes as hydrated species in aqueous solution. Finally, a study restricted to ketones was conducted to estimate their pKas in dimethyl sulfoxide solution. QSAR models of experimental pKas versus ΔEDMSO for the keto and enol tautomers were modest at best (R2 = 0.8477 and 0.7694, respectively). A binary linear regression was employed to incorporate descriptors representing both the keto and enol tautomers, improving the final R2 to 0.9670 upon removal of one outlier. The QSAR models presented may be utilized to estimate pKas for related compounds not offered in the existing literature or that are challenging to measure experimentally. iii Table of Contents Chapter 1 – A Brief Introduction into Estimating Molecular Acidities Computationally 1.1 Gas Phase versus Solution Phase Acidities ................................................................. 1 1.2 Quantitative Structure-Activity Relationships ............................................................ 7 1.3 First-Principles Calculations and Other pKa Estimation Techniques ........................ 11 1.4 Quantum Chemical Calculations: Density Functional Theory .................................. 13 1.5 Modeling Solvation ................................................................................................. 19 1.6 References ............................................................................................................... 21 Chapter 2 – Computational Estimation of the Gas-Phase and Aqueous Acidities of Carbon Acids 2.1 Abstract ................................................................................................................... 24 2.2 Introduction ............................................................................................................. 25 2.3 Methods ................................................................................................................... 27 2.4 Results ..................................................................................................................... 29 2.5 Structural Features Affecting Carbon Acid Acidities ............................................... 37 2.6 Conclusions ............................................................................................................. 43 2.7 References ............................................................................................................... 44 Chapter 3 – Theoretical Estimation of the pKas of Saturated Alcohols in Aqueous Solution 3.1 Abstract ................................................................................................................... 48 3.2 Introduction ............................................................................................................. 48 3.3 Computational Methods ........................................................................................... 51 3.4 Results and Discussion ............................................................................................ 52 3.5 Conclusions ............................................................................................................. 61 3.6 References ............................................................................................................... 61 Chapter 4 – Estimation of Ketone Molecular Acidities in Dimethyl Sulfoxide using QSAR 4.1 Abstract ................................................................................................................... 64 iv 4.2 Introduction ............................................................................................................. 65 4.3 Computational Methodology .................................................................................... 68 4.4 Results and Discussion ............................................................................................ 69 4.5 Conclusions ............................................................................................................. 85 4.6 References ............................................................................................................... 86 v List of Figures Chapter 1 1.1 Common thermodynamic cycle for an ionization reaction ........................................ 11 Chapter 2 2.1 DFT calculated gas phase ΔG° values versus literature gas phase ΔG° values for the acid dissociation reactions of the 33 carbon acids with data available in NIST (triacetylmethane removed as an outlier)........................................................................ 32 2.2 Experimental aqueous pKa values versus aqueous energy difference values (ΔEH2O) for all 42 carbon acids in his study, computed using the CPCM implicit solvent model .. 33 2.3 Plot of equation (3): experimental aqueous pKa values versus energy differences calculated in aqueous solvent model for 38 carbon acids (upon removal of three hydrates and 2-nitropropane) ....................................................................................................... 34 2.4 Hybridization effects in C2HX compounds and their effect on pKa values ................. 38 2.5 Changes of the acidities of substituted methanes resulting from the electron- withdrawing powers of F, CN, and NO2 substituents...................................................... 39 2.6 The series of carbon acids toluene, diphenylmethane, and triphenylmethane illustrating the effects of aromatic rings on the molecular pKa values ............................. 41 2.7 Electron delocalization due to adjacent carbonyls in a series of carbon acids ............ 43 Chapter 3 3.1 DFT (B3LYP/6-31+G**) calculated ΔG° values in vacuum versus literature gas phase ΔG° values for the proton transfer reactions of 16 saturated alcohols with data available in NIST. .......................................................................................................... 54 3.2 Plot of experimental aqueous pKa values versus calculated gas phase ΔE quantities, including all alcohols in the study except trinitroethanol. ............................................... 56 3.3 Plot of experimental aqueous pKas versus calculated ∆E(H2O) values for all 30 saturated alcohols in this study....................................................................................... 57 vi Chapter 4 4.1 Plot of experimental pKas (DMSO) versus ΔEDMSO (kJ/mol) for the keto tautomers of the thirty different ketones ............................................................................................. 74 4.2 Plot of experimental pKas (DMSO) versus ΔEDMSO (kJ/mol) for the enol tautomers of the thirty different ketones ............................................................................................. 75 4.3 Graph of experimental DMSO pKas for all 30 ketones versus the calculated pKas within CPCM-DMSO solvent model ............................................................................. 77 4.4 Final QSAR model of experimental DMSO pKas for 29 ketones versus the calculated pKas within CPCM-DMSO solvent model ..................................................................... 78 4.5 QSAR model of ΔE(DMSO) versus experimental carbon acid pKa values in DMSO. ...................................................................................................................................... 81 4.6 QSAR model of ΔE(DMSO) versus experimental alcohol pKa values in DMSO ...... 84 vii List of Tables Chapter 2 2.1 Experimental Aqueous pKa values