Investigations into the kinetic and thermochemical properties of organic and biological species in the gas phase
Creators: name: Krajewski, Allison E.
Publisher: name: No Publisher Supplied
Year: 2022

description: This dissertation outlines our investigational efforts into kinetic and thermodynamic properties of gas-phase species, both organic and biologic in nature. Gas-phase ion chemistry has long been used to better understand intrinsic reactivity of species without complications from underlying solvent effects. These results are achieved through a combination of computational (density functional theory) and experimental (mass spectrometric) techniques.Hydricity is an important concept in both biological and organic chemistry as hydride transfer plays a vital role in many reactions, such as in the electron transport chain for glycolysis, hydrogen activation, the reduction of carbon dioxide, or in other synthetic processes. While transition-metal hydrides are common, they have the distinct disadvantage of being both less abundant and more toxic than their metal-free hydride counterparts, making the latter more appealing to use; metal-free silicon-based hydrides are one such example. To design reactions efficiently, it becomes of the utmost importance to quantify hydricity. Both thermodynamic and kinetic methods have been employed previously; while the former allows for an absolute value within a given solvent, it can be more difficult to measure experimentally. Although kinetic hydricity is a relative value that changes based on which acceptors are used, it is still an invaluable tool. Kinetic hydricity, synonymous with nucleophilicity, has been studied extensively in the condensed phase by our collaborator, Professor Herbert Mayr, for an extensive range of compounds, including silanes. However, as previously mentioned, solvent effects often mask underlying reactivity. In Chapters 2 and 3, we study reactions in the gas phase to gain insight into the intrinsic kinetic hydricity (nucleophilicity) of silanes.C-F activation is another important class of organic reactions that have been gaining in popularity. Because C(sp3)-F is the strongest single bond between carbon and any other element, it is difficult to break. This is advantageous when considering drug design, as C F bonds are commonly used in the pharmaceutical and agrochemical industries. However, these strong bonds are disadvantageous from an environmental standpoint, as many atmospheric pollutants contain C-F bonds, including carbon tetrafluoride and chlorofluorocarbons. The easiest way to cleave a C-F bond is to convert it to a C-H bond, in what are known as hydrodefluorination (HDF) reactions. While hydrogen (H2) has been used in the past for these reactions, it has the unfortunate result of producing toxic and corrosive HF as a byproduct. Instead, silicon has emerged as promising replacement due to the impressive strength of the Si-F bond. This field is relatively nascent, and the first room-temperature HDF reaction was reported less than 20 years ago in 2005. While there have since been many reactions reported in the condensed phase, there have been no analogous gas phase studies. We rectify this in Chapter 4, where we report our initial results into our systematic study of HDF reactions in vacuo using silyl cations to break C(sp3)-F bonds.In addition to organic reactions, gas-phase studies are also useful when considering biological systems. For example, thymine DNA glycosylase (TDG) is an enzyme that has evolved to excise thymine from DNA when it is incorrectly inserted into the helical structure, most likely as a result of 5-methylcytosine deamination. This enzyme has “broad specificity,” so it is able to not only excise incorrectly-placed thymine (whilst ignoring “normal” thymine) but also a series of other nucleobases, including 5-halogenated uracils. While 5-fluorouracil is a common anti-cancer drug, it can have disastrous consequences if it is misincorporated into healthy DNA. Professor Alexander Drohat from the University of Maryland has studied this enzyme extensively and has measured its excision rate for many common substrates. In Chapter 5, we studied the gas-phase acidic and basic properties of 5-halouracils (5-fluorouracil, 5-chlorouracil, 5-bromouracil, and 5-iodouracil) experimentally; we were not only interested in benchmarking theoretical thermochemical calculations for the first time, but we also wanted to compare our results to the excision rate by TDG to hopefully gain a deeper understanding into the mechanism of this enzyme.Reactive oxygen and nitrogen species (RONS) cause oxidation to healthy DNA, and one of the most common mutations is oxidation of guanine (G) to 8-oxo-7,8-dihydroguanine (OG); if left unremedied, the mispairing of OG:A, rather than G:C, can result in permanent G:C to T:A transversions. MutY is a glycosylase that, unlike TDG, cleaves the glycosidic bond between A paired opposite to OG, rather than that of OG itself. This enzyme has exquisite sensitivity to the structure of A, and any modifications could potentially inhibit the recognition and removal of adenine in OG:A base pairings within the active site. In Chapter 6, we present a collaborative effort with Dr. Sheila David (University of California, Davis). We calculated the gas-phase acidities and basicities for a series of adenine analogues to see if we could determine how structural modifications affected their reactivities.Finally, bifunctional human endonuclease VIII-like 1 (NEIL1) is another enzyme that has evolved to combat oxidative damage. This enzyme has broad specificity, with the ability to recognize and extricate a wide range of oxidized purines, pyrimidines, and hydantoins. NEIL1 is also a unique enzyme in that it has two common isoforms that differ in the identity of the amino acid in position 242: the unedited (UE) form has lysine (K242) and the edited (Ed) has arginine (R242). ADAR1, an adenosine deaminase, causes the change from the UE to Ed form of NEIL1; this change also has a dramatic effect on rate of cleavage. In Chapter 7, we again collaborated with Dr. Sheila David (University of California, Davis). To better understand the differences in UE:Ed NEIL1 ratios, we calculated acidities and proton affinities for several oxidized substrates of NEIL1 to see if we could identify any trends that might lead to this dramatic difference in scission between the two NEIL1 isoforms.