Wright State University CORE Scholar Browse all Theses and Dissertations Theses and Dissertations 2015 Computational Estimation of the PKa's of Purines and Related Compounds Kara L. Geremia Wright State University Follow this and additional works at: https://corescholar.libraries.wright.edu/etd_all Part of the Chemistry Commons Repository Citation Geremia, Kara L., "Computational Estimation of the PKa's of Purines and Related Compounds" (2015). Browse all Theses and Dissertations. 1610. https://corescholar.libraries.wright.edu/etd_all/1610 This Thesis is brought to you for free and open access by the Theses and Dissertations at CORE Scholar. It has been accepted for inclusion in Browse all Theses and Dissertations by an authorized administrator of CORE Scholar. For more information, please contact [email protected]. Computational Estimation of the pKa’s of Purines and Related Compounds A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By Kara L Geremia B.S., Wright State University, 2014 2015 Wright State University i WRIGHT STATE UNIVERSITY GRADUATE SCHOOL November 23, 2015 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Kara Geremia ENTITLED Computation Estimation of the pKa’s of Purines and Related Compounds BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIRMENTS FOR THE DEGREE OF Master of Science. _______________________________ Paul Seybold, Ph.D. Thesis Director __________________________________ Eric Fossum, Ph.D. Thesis Co-Director _______________________________ David A. Grossie, Ph.D. Chair, Department of Chemistry Committee on Final Examination ________________________________ Paul Seybold, Ph.D. _________________________________ Eric Fossum, Ph.D. _________________________________ Kenneth Turnbull, Ph.D. _________________________________ Rachel Aga, Ph.D. _________________________________ Robert E. W. Fyffe, Ph.D. Vice President for Research and Dean of Graduate School ii ABSTRACT Kara L. Geremia M.S., Department of Chemistry, Wright State University, 2015. Computational Estimation of the pKa’s of Purines and Related Compounds. The acid dissociation value pKa of a compound provides important information regarding the neutral and ionic forms of the compound present under different conditions. However, for many compounds experimental pKa values are not available, and for others the measured values are sometimes uncertain. Consequently, having a computational means for estimating pKa values can be of benefit for biochemical, pharmaceutical, polymer, and many other studies. Purines form a key group of bioactive compounds whose acid/base activities are of considerable interest. The purine class includes such diverse compounds as the nucleic acid bases adenine and guanine, the gout-related compound uric acid, the stimulant caffeine, and the leukemia drug 6- mercaptopurine. We have developed a computational method for estimating purine pKas using a quantitative structure property relationship (QSAR) approach. A group of 31 purines and related compounds was first assembled and then examined using the semi-empirical quantum chemical method RM1. This was followed by an ab initio analysis based on density functional theory at the B3LYP/ 6-31+G** level. iii Table of Contents Chapter 1—Purines and Related Compounds 1.1 Introduction.................................................................................................................... [1] 1.2 Historical Background................................................................................................... [1] 1.3 Profiles of the Compounds Studied.............................................................................. [2] 1.4 References....................................................................................................................... [13] Chapter 2--Computational Analysis of Cationic, Neutral, and Anionic Purine Tautomers 2.1 Abstract........................................................................................................................... [20] 2.2 Introduction.................................................................................................................... [20] 2.3 Computational Methods................................................................................................ [22] 2.4 Results and Discussion................................................................................................... [23] 2.4.1 Purine............................................................................................................................ [23] 2.4.2 Hypoxanthine............................................................................................................... [27] 2.4.3 6-Mercaptopurine........................................................................................................ [31] 2.4.4 Xanthine....................................................................................................................... [35] 2.4.5 Adenine......................................................................................................................... [39] 2.4.6 Guanine........................................................................................................................ [42] 2.5 Conclusion....................................................................................................................... [45] 2.6 References........................................................................................................................ [45] Chapter 3-- Computational Analysis of Tautomers for Indole and Related Compounds 3.1 Abstract.......................................................................................................................... [48] 3.2 Introduction................................................................................................................... [48] 3.3 Computational Method................................................................................................. [49] iv 3.4 Results and Discussion.................................................................................................. [49] 3.4.1 Indole ..................................................................................................................... [49] 3.4.1a. Neutral Tautomers...................................................................................... [49] 3.4.1b. Cationic Tautomers..................................................................................... [50] 3.4.2. Isoindole................................................................................................................. [52] 3.4.2a. Neutral Tautomers...................................................................................... [52] 3.4.2b. Cationic Tautomers..................................................................................... [55] 3.4.3 Indazole................................................................................................................... [56] 3.4.3a. Neutral Tautomers...................................................................................... [56] 3.4.3b. Cationic Tautomers..................................................................................... [57] 3.4.4 Benzimidazole......................................................................................................... [59] 3.4.4a. Neutral Tautomers....................................................................................... [59] 3.4.4b. Cationic Tautomers...................................................................................... [60] 3.4.5 7-Azaindole.............................................................................................................. [61] 3.4.5a. Neutral Tautomers....................................................................................... [61] 3.4.5b. Cationic Tautomers...................................................................................... [62] 3.4.6 Caffeine.................................................................................................................... [63] 3.4.6a. Neutral Species.............................................................................................. [63] 3.4.6b. Cationic Species............................................................................................ [63] 3.4.6c. Anionic Species.............................................................................................. [64] 3.5 Conclusion....................................................................................................................... [66] 3.6 References........................................................................................................................ [66] Chapter 4-- Computational Estimation of the pKa’s of Purine and Purine Related Compounds 4.1 Abstract........................................................................................................................... [69] v 4.2 Introduction.................................................................................................................... [69] 4.3 Computational Methods................................................................................................ [71] 4.4 Results and Discussion................................................................................................... [74] 4.5 Conclusion......................................................................................................................