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Theoretical Estimation of Pka's of Pyrimidines and Related Heterocycles

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Theoretical Estimation of Pka's of Pyrimidines and Related Heterocycles Wright State University CORE Scholar Browse all Theses and Dissertations Theses and Dissertations 2016 Theoretical Estimation of pKa's of Pyrimidines and Related Heterocycles Rachael Ann Wessner Wright State University Follow this and additional works at: https://corescholar.libraries.wright.edu/etd_all Part of the Chemistry Commons Repository Citation Wessner, Rachael Ann, "Theoretical Estimation of pKa's of Pyrimidines and Related Heterocycles" (2016). Browse all Theses and Dissertations. 1543. https://corescholar.libraries.wright.edu/etd_all/1543 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]. Theoretical Estimation of pKa’s of Pyrimidines and Related Heterocycles A thesis submitted in partial fulfillment of the requirements for the degree of Master in Science By Rachael Ann Wessner B.S., Northern Kentucky University, 2014 2016 Wright State University Wright State University Graduate School June 1, 2016 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Rachael Ann Wessner ENTITLED Theoretical Estimation of pKa’s of Pyrimidines and Related Heterocycles BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER of SCIENCE. ____________________ Paul G. Seybold, Ph.D. Thesis Director ________________________ David A. Grossie, Ph.D. Department Chair Committee on Final Examination ________________________ Paul G. Seybold, Ph.D. ________________________ Eric Fossum, Ph.D. ________________________ David A. Dolson, Ph.D. ________________________ Robert E. W Fyffe, Ph.D. Vice President for Research and Dean of the Graduate School Abstract Wessner, Rachael Ann. MS., Department of Chemistry, Wright State University, 2016. Theoretical Estimation of pKa’s of Pyrimidines and Related Heterocycles. Pyrimidines and related heterocycles are an important class of compounds with a wide variety of applications. As a result, there is great interest in the chemical properties of these compounds, specifically their pKa’s. Despite the importance of these compounds their reported pKa’s are often only approximations or are completely absent from literature. Experimentally measuring pKa’s can be challenging, especially if the pKa is below zero. Alternatively, pKa’s can be estimated computationally using a Quantitative Structure-Activity Relationship (QSAR). However, most of the compounds included in this study exist as two or more forms that arise from tautomerism. Tautomerism complicates the estimation of pKa’s because proton transfers result in a rearrangement of electron density that alters chemical behavior. As a result, pKa’s are unique to each tautomeric species. This research identifies the most stable tautomer associated with each of the compounds included in this study. From here QSAR models have been constructed using a variety of molecular descriptors. The resulting QSAR models are then used to estimate the pKa’s of compounds for which there are currently no literature values. ii Table of Contents An Introduction to Pyrimidines and Related Heterocycles ..................................................................... 1 1.1 This research project .......................................................................................................................... 1 1.2 An introduction to quantum chemical methods ............................................................................... 2 1.3 An introduction to solvent models .................................................................................................... 3 1.4 Biochemical roles and applications of pyrimidines and related heterocycles ................................. 4 Analysis of Uracil Tautomers................................................................................................................... 13 2.1 What are tautomers and why are they important in this study? ................................................... 13 2.2 What factors influence the stability of a tautomer? ....................................................................... 14 2.3 The importance of uracil and its derivatives ................................................................................... 17 2.4 Methods ............................................................................................................................................ 17 2.5 Results .............................................................................................................................................. 18 Analysis of Cytosine Tautomers .............................................................................................................. 43 3.1 An introduction to cytosine ............................................................................................................. 43 3.2 Methods ............................................................................................................................................ 43 3.3 Results .............................................................................................................................................. 43 Theoretical Estimation of pKa’s ............................................................................................................... 51 4.1 An introduction to pKa’s and the value of computational estimation ........................................... 51 4.2 Methods ............................................................................................................................................ 54 4.3 Results .............................................................................................................................................. 55 4.4 Appendix ........................................................................................................................................... 69 References .................................................................................................................................................. 70 iii List of Figures Figure 1: Pyrimidines and related heterocycles examined in this study. ...................................................... 5 Figure 2: An example of keto-enol tautomerism in maleimide. ................................................................. 13 Figure 3: Intrinsic and solvation energies of two tautomeric species. ........................................................ 15 Figure 4: An example of amine-imine tautomerism in neutral uracil and the relative energies of each form in vacuum. ................................................................................................................................................... 16 Figure 5: Two possible sites of protonation in pyrimidine showing the hybridization of each product. The cation on the right is more stable than the cation on the left. ...................................................................... 17 Figure 6: Pyrimidine numbering scheme. ................................................................................................... 18 Figure 7: Neutral uracil tautomers. ............................................................................................................. 19 Figure 8: Comparison of electrostatic potential maps of U-1 and U-4. ...................................................... 20 Figure 9: Natural charges on the atoms in U-1. .......................................................................................... 20 Figure 10: Zwitterionic contribution to the structure of uracil. .................................................................. 20 Figure 11: Low-energy cationic tautomers of uracil. .................................................................................. 21 Figure 12: Low-energy anionic tautomers of uracil. ................................................................................... 22 Figure 13: Electrostatic potential maps of the anionic forms U--1 and U--2. .............................................. 22 Figure 14: Neutral azauracil tautomers. ...................................................................................................... 23 Figure 15: Natural charges on the heavy atoms in AZ-1. ........................................................................... 24 Figure 16: Low-energy cationic tautomers of azauracil. ............................................................................ 24 Figure 17: Low-energy anionic tautomers of azauracil. ............................................................................. 25 Figure 18: Molecular electrostatic potential maps of AZ--1 and AZ--2. ..................................................... 25 Figure 19: Neutral 5-bromouracil tautomers. ............................................................................................. 26 Figure 20: Natural charges on the heavy atoms in BrU-1. .......................................................................... 27 Figure 21: Low-energy cationic tautomers of 5-bromouracil. .................................................................... 27 Figure 22: Low-energy anionic tautomers of 5-bromouracil. ..................................................................... 28 Figure 23: Neutral 5-chlorouracil tautomers. .............................................................................................
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