Dissertations / Theses on the topic 'Hydride Transfer Chemistry'

The secondary kinetic isotope effects for the hydride transfer reactions from aliphatic alcohols to four carbocations (NAD⁺ models) in acetonitrile were determined. The results suggest that the hydride transfer takes place by tunneling and that the rehybridizations of both donor and acceptor carbons lag behind the H-tunneling. This is quite contrary to the observations in alcohol dehydrogenases where the importance of enzyme motions in catalysis is manifested.

It has been accepted that hydrogen-transfer reactions take place through a quantum mechanical tunneling mechanism, where H tunnels through its classical energy barrier in light of its wave form. There are several H-tunneling models proposed, including the contemporary Marcus-like H-tunneling model, which explains that the donor-acceptor distance (DAD) in the tunneling ready state (TRS) is shorter for a heavier isotope (e.g. deuterium (D)) then a lighter isotope (e.g., protium (H)). This model has been used to explain the kinetic isotopic effect observations in H-tunneling processes to provide mechanistic role of protein in enzyme catalysis. The purpose of the research is to test the hypothesis of “isotopically different DAD” concept by studying the hydrogen/deuterium-transfer reactions in solutions, given that hydride-transfer reactions account for over 50% of biological reactions. Our group’s previous results showed that the steric hindrance and hydrogen-bonding effect played a significant role in the different hydrogen vs deuterium tunneling-ready states. In general, the shorter DAD creates more spatial crowding effect which will affect the 2° C-H vibrations and decrease the 2° KIEs. In this thesis, different reaction systems were designed to test these effects by studying the 1° isotope dependence of 2° KIEs at the near and remote positions from the reaction center. It was found that the results are consistent with the hypothesis of the “isotopically different TRS structures”.

The nucleotide 2'-deoxythymidine 5'-monophosphate (thymidylate, dTMP) is phosphorylated twice to become a substrate for DNA polymerases, which copy a cell’s genetic information in advance of cell division. The main route to dTMP is mediated by the enzyme thymidylate synthase (TSase) and goes through 2'-deoxyuridine 5'-monophosphate (dUMP); dUMP’s heterocyclic aromatic pyrimidine ring loses a proton from its C5 position and gains a methylene and a hydride from the other reactant, methylene tetrahydrofolate (MTHF). In general, intricate knowledge of an enzyme’s mechanism can yield insight that leads to the development of precision-targeted inhibitors tailored exactly to thymidylate synthase. In fact, even more careful targeting could be achievable: Although E. coli TSase has served as a model system, investigators have increasingly been directing their lines of inquiry toward human TSase. A general enzymatic catalytic cascade is complex, comprising substrate binding, the chemical steps and product release; typically, the product release step is rate-limiting. TSase, however, is partially rate-limited by the chemistry portion of the process. The enzymatic mechanism has been considered for decades, yet recently has undergone a reassessment. After substrate binding – for which there is strong evidence for preference to dUMP as the first ligand in the wild-type E. coli enzyme – the important events are methylene transfer from MTHF to dUMP, proton abstraction and hydride transfer. The last of these – hydride transfer – is irreversible and rate-limiting (to a large degree without Mg2+, and to a small but noticeable degree with Mg2+). The studies described here are aimed at three therapeutically relevant questions: (a) determining the extent of negative charge accumulation at the O4 position of the hydride transfer acceptor; (b) expanding knowledge of the differential properties of E. coli and human TSase; and (c) gaining insight into the molecular origin of the drug resistance seen in a clinically relevant human TSase mutant. The properties touched on in this work include steady-state kinetics; inhibition constants toward 5-fluoro dUMP, substrate binding sequence and the temperature dependency of intrinsic hydride transfer kinetic isotope effects (KIEs). Intrinsic KIEs are a specialized measurement that permits the investigator to examine a particular hydrogen transfer step in isolation; it is achieved by labeling the bond to hydrogen broken in the reaction with protium (1H, also written as H), deuterium (2H, also written as D) or tritium (3H, also written as T). The latter is radioactive. The reaction is conducted with a mixture of two hydrogen isotopes at a time, and the extent to which the heavier isotope is disfavored against reaction is assessed; this covers multiple steps. Heavier isotopes directly participating in a chemical step react slower both because of zero-point vibrational energies if a semi-classical view is taken and because of the mass-dependence of tunneling probabilities if a quantum-mechanical view is taken. Each of the two-way isotopic comparisons mentioned above furnishes an observed KIE for that competition between two isotopes. Mathematical combination of two isotopic comparisons cancels out the effect of isotopically insensitive steps and provides rich insight into the hydride transfer alone. The ultimate result is the ratio of rate constants for the isotopologues; this ratio’s magnitude and variation with temperature report on the compactness of the active site and its resistance to thermal fluctuation, respectively. Our results reveal a possible role for E. coli asparagine 177 (N177) in the hydride transfer transition state (TS) stabilization, as revealed by its disruption in the aspartate mutant, N177D. This disruption was found to be alleviated to a high extent when the substrate was changed to dCMP, consistent with the N177 stabilizing partial negative charge at the TS for hydride transfer. This has drug design implications. Our work on human TSase underscores slightly weaker substrate binding preference, insensitivity to Mg2+ and mild alteration of hydride transfer TS when compared with E. coli TSase. Finally, analysis of the Y33H mutant of human TSase – the affected residue being remote from the active site – indicated the drug resistance was because of a higher inhibition constant for 5F-dUMP and that the hydride transfer step is disrupted, with a wider variation among donor-acceptor distances (between the two carbons involved in the hydride transfer at the TS for that step). Other researchers’ crystallographic evidence reveals greater positional uncertainty for a set of active-site side chains in the E. coli equivalent mutant. In totality, the data available implicate enzyme motions as relevant to drug binding and to catalysis for human TSase. In summary, the research described herein enriches the understanding of several aspects of the behavior of multiple TSase variants – the overall performance as seen via steady-state kinetics; the pattern of substrate binding as seen with observed KIEs for the proton abstraction step; and the efficiency of active site preparation for hydride transfer as evidenced in the temperature dependency of intrinsic hydride transfer KIEs.

Choline oxidase catalyzes the two-step oxidation of choline to glycine betaine, one of limited osmoprotectants, with the formation of betaine aldehyde as an enzyme bound intermediate. Glycine betaine accumulates in the cytoplasm of plants and bacteria as a defensive mechanism to withstand hyperosmolarity and elevated temperatures. This makes the genetic engineering of relevant plants which lack the property of salt accumulation of economic interest, and the biosynthetic pathway of the osmolyte a potential drug target in microbial infections. The reaction of alcohol oxidation occurs via a hydride ion tunneling transfer from the substrate donor to a flavin acceptor within a highly preorganized active site environment in which choline and FAD are in a rigidly close proximity. In this dissertation, factors contributing to the enzyme-substrate preorganization which is required for the hydride ion tunneling reaction mechanism in choline oxidase have been investigated. Crystallographic studies of wild-type choline oxidase revealed a covalent linkage between C8M atom of the FAD isoalloxazine ring and the N(3) atom of the side chain of a histidine at position 99, and a solvent excluded cavity in the substrate binding domain containing glutamic acid at position 312 as the only negatively charged amino acid residue in the active site of the enzyme. The role of the histidine residue and the contribution of the 8á-N(3)-histidyl covalent linkage of the flavin cofactor to the reaction of alcohol oxidation was investigated in a variant form of choline oxidase in which the histidine residue was replaced with an asparagine. The role of the glutamate residue and the importance of the spatial location of the negative charge at position 312 was investigated in variant forms of choline oxidase in which the negatively charged residue was replaced with glutamine and aspartate. Mechanistic data obtained for the variant enzymes and their comparison to previous data obtained for wild-type choline oxidase are consistent with the residues at positions 99 and 312 being important for relative positioning of the hydride ion donor and acceptor. The residues are important for the enzyme-substrate preorganization that is required for the hydride tunneling reaction in choline oxidase.

Enzymes direct chemical reactions with precision and speed, making life as we know it possible. How they do this is still not completely understood, but the relatively recent discovery of subpicosecond protein motion coupled to the reaction coordinate has provided a crucial piece of the puzzle. This type of motion is called a rate-promoting vibration (RPV) and has been seen in a number of different enzymatic systems. It typically involves a compression of the active site of the enzyme which lowers the barrier for the reaction to occur. In this work we present a number of studies that probe these motions in two dehydrogenase enzymes, yeast alcohol dehydrogenase (YADH) and homologs of lactate dehydrogenase (LDH). The goal of the study on the reaction of YADH was to probe the role of the protein in proton tunneling in the enzyme, which was suggested to occur from experimental kinetic isotope effect studies. We did this using transition path sampling (TPS), which perturbatively generates ensembles of reactive trajectories to observe transitions between stable states, such as chemical reactions. By applying a quantum method that can account for proton tunneling, centroid molecular dynamics, and generating reactive trajectory ensembles with and without the method, we were able to observe the change in barrier to proton transfer upon application of the tunneling method. We found that there was little change in the barrier, showing that classical over-the-barrier transfer is dominant over tunneling in the proton transfer in YADH. We also applied the knowledge of RPVs to identify a new class of allosteric molecules, which modulate enzymatic reaction not by changing a binding affinity, but by disrupting the reactive motion of enzymes. We showed, through design of a novel allosteric effector for human heart LDH, applying TPS to a system with and without the small molecule bound, and analysis of the reaction coordinate of the reactive trajectory ensemble, that the molecule was able to disrupt the motion of the protein such that it was no longer coupled to the reaction. We also examined the subpicosecond motions of two other LDHs, from Plasmodium falciparum and Cryptosporidium parvum, which evolved separately from previously studied LDHs. We found, using TPS and reaction coordinate identification, that while the LDH from C. parvum had similar dynamics to the earlier LDHs, the LDH from P. falciparum had a earlier transition-state associated with proton transfer, not hydride transfer. This is likely due to this LDH having a larger active site pocket, increasing the amount of motion necessary for proton transfer, and, thus, the barrier to proton transfer. More work is necessary in this system to determine whether the protein is coupled with the search for the reactive conformation for proton transfer. Protein motion coupled to the particle transfer in dehydrogenases plays an important role in their reactions and there is still much work to be done to understand the extent and role of RPVs.

Choline oxidase catalyzes the flavin-dependent, two-step oxidation of choline to glycine betaine via the formation of an aldehyde intermediate. The oxidation of choline includes two reductive half-reactions followed by oxidative half-reactions. In the first oxidation reaction, the alcohol substrate is activated to its alkoxide via proton abstraction and oxidized via transfer of a hydride from the alkoxide α-carbon to the N(5) atom of the enzyme-bound flavin. In the wild-type enzyme, proton and hydride transfers are mechanistically and kinetically uncoupled. The role of Ser101 was investigated in this dissertation. Replacement of Ser101 with threonine, alanine, cysteine, or valine demonstrated the importance of the hydroxyl group of Ser101 in proton abstraction and in hydride transfer. Moreover, the kinetic studies on the Ser101Ala variant have revealed the importance of a specific residue for the optimization of the overall turnover of choline oxidase. The UV-visbible absorbance of Ser101Cys suggests Cys101 can form an adduct with the C4a atom of the flavin. The mechanism of formation of the C4a-cysteinyl adduct has been elucidated. D-arginine dehydrogenase (DADH) catalyzes the oxidation of D-amino acids to the corresponding imino acids, which are non-enzymatically hydrolyzed to α-keto acids and ammonia. The enzyme is strick dehrogenase and deoesnot react with molecular oxygen. Steady state kinetic studies wirh D-arginine and D-histidine as a substrate and PMS as the electron acceptor has been investigated. The enzyme has broad substrate specificity for D-amino acids except aspartate, glutamate and glycine, with preference for arginine and lysine. Leucine is the slowest substrate in which steady state kinetic parameters can be obtained. The chemical mechanism of leucine dehydrogenation catalyzed by DADH was explored with a combination of pH, substrate and solvent kinetic isotope effects (KIE) and proton inventories by using rapid kinetics in a stopped-flow spectrophotometer. The data are discussed in the context of the crystallographic structures at high resolutions (<1.3 Å) of the enzyme in complex with iminoarginine or iminohistidine.

Nowadays, the modern chemical industry has to deal with increasing environmental concerns, including the disposal of waste and its economic impact, or the diminution of important worldwide resources such as transition metals. In this Ph.D. thesis, we aimed to bring improvement in this area by the development of green processes, based on the use of recyclable heterogeneous catalysts. By combining the catalytic properties of several metal cations with the properties of solid catalysts such as polyoxometalates or zeolites, we were able to set up new tools for organic synthesis. Silver-doped polyoxometalates proved to be very efficient catalysts in the rearrangement of alkynyloxiranes to furans. Acetals and spiroketals were synthetized by dihydroalkoxylation of alkynediols under catalysis with silver-zeolites. As a perspective, we highlighted the potential applications of such green procedures in the total synthesis of more complex molecules. The first results suggested that these environmental friendly processes should gain increasing interest in the future.

De nos jours, l’industrie chimique est de plus en plus confrontée à la question de son impact environnemental. Dans le même temps, elle doit faire face à la diminution des ressources de matières premières importantes tels que les métaux de transition, tout en respectant des contraintes économiques. Ces travaux de thèse avaient pour but de tenter de répondre à ces exigences, par le développement de méthodologies de synthèse basées sur l’utilisation de catalyseurs hétérogènes recyclables. En combinant les propriétés catalytiques de certains ions métalliques avec les propriétés de catalyseurs solides tels que les polyoxométallates ou les zéolithes, nous avons pu mettre au point de nouveaux outils pour la synthèse organique. Les polyoxométallates dopés à l’argent ont démontré leur efficacité dans le réarrangement d’alcynyloxiranes en furanes. La synthèse de spiroacétals et d’acétals par dihydroalkoxylation d’alcyne diols a été effectuée pour la première fois en catalyse à l’argent, via l’utilisation de zéolithes. En perspective, nous avons mis en évidence les applications potentielles de ces procédés verts dans la synthèse totale de molécules plus complexes. Les premiers résultats suggèrent que de telles synthèses plus respectueuses de l’environnement ont tout intérêt à être davantage utilisées à l’avenir
Nowadays, the modern chemical industry has to deal with increasing environmental concerns, including the disposal of waste and its economic impact, or the diminution of important worldwide resources such as transition metals. In this Ph.D. thesis, we aimed to bring improvement in this area by the development of green processes, based on the use of recyclable heterogeneous catalysts. By combining the catalytic properties of several metal cations with the properties of solid catalysts such as polyoxometalates or zeolites, we were able to set up new tools for organic synthesis. Silver-doped polyoxometalates proved to be very efficient catalysts in the rearrangement of alkynyloxiranes to furans. Acetals and spiroketals were synthetized by dihydroalkoxylation of alkynediols under catalysis with silver-zeolites. As a perspective, we highlighted the potential applications of such green procedures in the total synthesis of more complex molecules. The first results suggested that these environmental friendly processes should gain increasing interest in the future

All organisms must maintain an adequate level of thymidylate, which gets phosphorylated twice and then utilized by DNA polymerases for DNA replication that must precede cell division. Most organisms rely on classical thymidylate synthase (TSase) for this function. However, a subset of microorganisms – including a number of notable, widespread human pathogens – relies on an enzyme with a distinct structure and catalytic strategy. This enzyme is termed flavin-dependent thymidylate synthase (FDTS), as the flavin is required for thymidylate production. Because of this considerable orthogonality between FDTS and classical TSase, FDTS serves as a promising target for new therapeutics – one that could have only mild adverse effects on the host organism. FDTS catalyzes the reductive methylation of uridylate (2′-deoxyuridine-5′-monophosphate; dUMP) to yield thymidylate (2′-deoxythymidine-5′-monophosphate; dTMP). The methylene originally resides on CH2H4folate and is eventually transferred to the nucleotide. This methylene’s route to dUMP is unique in enzymology, and our experiments described herein strive to gain an understanding of the molecular details of its transfer. Compounds that mimic intermediates and transition states along this path are likely to bind FDTS tightly and could be leads for drugs, and our new insights could facilitate this. After methylene transfer is complete, a hydride transfer from flavin to the nucleotide occurs. We utilized rapid quench flow techniques in heavy water to follow the hydrogen transfers in FDTS; solvent isotope effects were measured and analyzed, furnishing evidence that the hydride transfer contributes to rate limitation. Reconstitution of the enzyme with unnatural flavins both reinforced these conclusions and suggested new hypotheses and experiments.

La notion de transfert d'hydrogène métallo-catalysé étudiée dans ce manuscrit consiste à générer un hydrure métallique actif à partir d'un donneur d'hydrogène (alcool) et à le transférer vers un produit insaturé dans un objectif d'augmentation de la complexité moléculaire. Une large gamme de produits peut être synthétisée grâce à ce concept et à ses diverses variantes. Le ligand phosphinito-acide phosphineux (PAP) qui est un ligand chargé négativement, permet de former des complexes robustes avec le palladium ou le platine et de générer en présence d'un alcool des hydrures métalliques remarquablement actifs. Dans la première partie de ce travail, un nouveau système d'oxydation d'alcool en milieu anaérobie particulièrement chimiosélectif a été développé. Les études complémentaires mises en œuvre ont permis une bonne compréhension du mécanisme de transfert d'hydrogène. Elles ont également mis en lumière l'intéressante aptitude du ligand PAP à auto-adapter ses propriétés électroniques spécifiquement à chaque étape d'un cycle catalytique. Dans un deuxième temps, une cascade réactionnelle oxydation - double activation de liaison C(sp3)-N débouchant sur la production d'amines primaires libres sans purification a été présentée. Il a été démontré à cette occasion que les complexes M/PAP pouvaient jouer le rôle d'acides de Lewis faible. Enfin, un processus de transfert d'hydrogène énantiosélectif a été étudié à travers l'isomérisation énantiosélective des alcools allyliques
The notion of metal catalyzed hydrogen transfer presented in this manuscript relies in generating an active metal hydride from an hydrogen donor (alcohol) and transferring it toward an unsaturated product with a view to molecular complexity increasing. A broad variety of product could be targeted with this concept and its variants. The phosphinito-phosphinous acid ligand which is negatively charged ligand is capable to generate strikingly active palladium and platinum hydride. In the first part of this work, a new anaerobic alcohol oxidation system with remarkable properties of chemioselectivity has been developed. Complementary studies have allowed a good understanding of the hydride transfer mechanism. Moreover it highlighted the interesting ability of the PAP ligand to self adapt its own electronic properties specifically to each steps of the catalytic cycle. In a second stage, a cascade process oxidation - double C(sp3)-N bond activation has been presented. It has been shown that M/PAP complexes could act as a weak Lewis acid. Finally, an enantioselective version of hydride transfer processes has been studied through enantioselective isomerization of allylic alcohols. The effect of the combination of a P - stereogenic ligand and new secondary chirality inductors (central chirality borne by the X-type ligand and inherent chirality borne by a supramolecular C1 symmetric moiety) has been evaluated

Highthroughput methods have been increasingly applied to catalyst screening, however, efforts to use these for enantioselective measures are still lacking. We propose to apply Fluorescence Resonance Energy Transfer (FRET) as a highthroughput screening method to fulfill such a purpose. This concept is applied to the desymmetrization of meso substrates. The meso compound will be equipped with a recognition element for catalyst binding, two different fluorescence donor molecules to distinguish between the chiral centres and also a fluorescence acceptor molecule to suppress fluorescence. Upon catalytic hydrolysis, the fluorescence acceptor molecules will be discharged into solution and thus can be detected by use of a spectrophotometer. As each donor molecule has a characteristic fluorescence emission wavelength, measuring the respective fluorescence intensities will ultimately allow for one to rapidly determine the enantiomeric excess. Efforts towards establishing this FRET based assay are discussed herein.* *Please refer to dissertation for diagrams.

Copper hydrides such as [Ph₃PCuH]₆ (Stryker’s Reagent) are textbook reagents in organic chemistry for the selective hydrogenation of α,β-unsaturated carbonyl compounds. Despite their widespread use both stoichiometrically and catalytically, there are many important questions about polynuclear copper hydrides that have not been answered. I have investigated the electron transfer chemistry of [Ph₃PCuH]₆ and related copper hydrides. Copper hydrides (E₁/₂ = –1.0 to –1.2 V vs FcH/FcH⁺) are good one-electron reducing agents. Stopped-flow techniques have allowed the detection of electron transfer intermediates in copper hydride reactions. The fate of the copper containing products after electron transfer or hydride transfer reactions has been investigated. An unusual cationic copper hydride, [(Ph₃P)₇Cu₇H₆]⁺ was found to be the major product of these reactions. Methods of converting this species back to [Ph₃PCuH]₆ have been investigated. The chemistry of this cationic species plays an important role in catalytic use of copper hydrides.

This thesis, largely describing diverse studies in organic synthesis, is divided into three parts. Part I, titled ‘Heterocycles’, describes in two chapters studies directed towards elaborating certain thiazole and oxazole derivatives as useful synthons. Part II, titled ‘Hydride transfers’, describes in two chapters synthetic and some mechanistic studies involving the Cannizzaro and Tishchenko reactions, apart from work with chirally-modified alumino and borohydride reagents. Finally, Part III, titled ‘Miscellaneous studies’, describes structural studies on cyclic carbonates. (For structural formula see the abstract.pdf file.)

Part I of this thesis focuses on the development of novel synthetic methods and investigations into their incorporation into multicatalytic reactions. The first chapter describes the development of a bismuth(III)triflate catalyzed hydrocarboxylation reaction of unactivated alkenes to synthesize lactones. Efforts toward applying this new methodology in multicatalytic sequences are described. In the second chapter, the development of palladium(II) mediated oxidative formylation and ketonylation methods to construct complex aldehydes and ketones is presented. Investigations into the oxidative formylation mechanism revealed the formation of a stable acylpalladium hydride intermediate that could be manipulated in situ allowing for the formation of other functionality. These methods were shown to be compatible in multi-transformation processes leading to the synthesis of complex heterocyclic products in a single reaction vessel. The third chapter describes the total synthesis of members of the Tylophora alkaloid family of molecules using a key oxidative carbonylation step. Application of a tandem palladium(II) catalyzed aminochlorocarbonylation / indium(III) catalyzed Friedel-Crafts acylation led to the rapid construction of the key intermediate in these syntheses in a one-pot reaction. The concise syntheses of both 13a,alpha-secoantofine and antofine using this multicatalytic strategy are presented. The second part of this thesis describes the study of stable carbocations as catalysts for hydride transfer reactions. Both cyclopropenium and trityl catalysts are investigated in a reductive etherification method. A study of trityl catalyst structure and initial investigations into the development of chiral trityl catalysts are presented.

The synthesis of metal-redox active ligand complexes is described, along with reactivity studies aimed at facilitating novel C-N bond forming reactions. A copper bis(iminosemiquinone) structure is characterized, analyzed and its reduction series are characterized and the reactivity of the Cu(II) bis(amidophenolate) analog is investigated with tosyl azide. The identification of the major reaction product and its characterization is detailed, with reaction sensitivities and heavily distorted x-ray diffraction single crystal structure generating a complex data set. The characterization of the isolated product is ongoing, with EPR studies aimed at identifying the radical nature of the complex. Unusual solvent effects and solubility issues have been noted with these initial EPR studies and more data is necessary before analysis can be properly attempted. An ytterbium bis(amidophenolate) complex was synthesized and its reactivity studied with aryl azides. Initial reactivities generate the first documented lanthanide tetrazenes in-lieu of the targeted ytterbium imido. Reactivities and characterization of these complexes support a stable, heavily ionic tetrazene-metal complex with no observed redox nature, UV light sensitivities, or imido azide-tetrazene equilibrium observed in various tetrazene transition metal complexes. Synthesis of a sterically blocked ytterbium imido was attempted, utilizing DMAP. Initial isolation was achieved with characterization and reactivity studies supporting the imido nature of the complex. The weak coordinating of the DMAP provided instability that proved in opposition to crystallization, however, so the imido could not be confirmed. Initial reactions using alternative steric hinderance from triphenylphosphine oxide and pyridine N-oxide prove promising to increasing the stability of the presumed ytterbium imido. Organic synthesis was performed generating a potential antibacterial agent. The synthesis of cyclopropenes was initiated as antagonists for ETR proteins in fruits and plants. The intermediates proved highly sensitive to harsh chemical conditions, which was overcome utilizing a tin-mediated Barbier allylation. The cyclopropene alcohol synthon was synthesized, though protecting group optimization is necessary.

Radical cyclizations are important reactions in organic chemistry. However, they are seldom used industrially due to their reliance on neurotoxic trialkyltin hydride. Many substitutes for tin hydrides have been developed but none have provided a general solution to the problem. Transition metal hydrides with weak M-H bonds can generate carbon centered radicals by hydrogen atom transfer (HAT) to olefins. This metal to olefin hydrogen atom transfer (MOHAT) reaction has been postulated as the initial step in many hydrogenation and hydroformylation reactions. The Norton group has shown MOHAT can mediate radical cyclizations of ɑ,ω dienes to form five and six membered rings. The reaction can be done catalytically if 1) the product metalloradical reacts with hydrogen gas to reform the hydride and 2) the hydride can perform MOHAT reactions. The Norton group has shown that both CpCr(CO)₃H and Co(dmgBF₂)₂(H₂O)₂ can catalyze radical cyclizations. However, both have significant draw backs. In an effort to improve the catalytic efficiency of these reactions we have studied several potential catalyst candidates to test their viability as radical cyclization catalysts. I investigate the hydride CpFe(CO)₂H (FpH). FpH has been shown to transfer hydrogen atoms to dienes and styrenes. I measured the Fe-H bond dissociation free energy (BDFE) to be 63 kcal/mol (much higher than previously thought) and showed that this hydride is not a good candidate for catalytic radical cyclizations. I have investigated the dynamics of Co(dmgBF₂)₂(H₂O)₂ under hydrogen gas to attempt to observe its hypothesized cobalt hydride. Under large pressures up to 70 atm we see two species one which we assign as the cobalt hydride and one which we assign as a ligand protonated Co(I) complex. These are supported by high pressure NMR studies of the same complexes. By varying the H₂ pressure, we can calculate the hydrogen atom donor ability of the mixture formed under H₂ as 50 kcal/mol. This makes this mixture a very good H• donor. The Norton group has shown that vanadium hydrides have very weak V-H bonds that donate H* rapidly. However, they cannot be made catalytic under hydrogen gas. I have attempted to regenerate these vanadium hydrides by a sequential reduction then protonation of the metalloradical. With HV(CO)₄dppe this only produced hydrogen gas, presumably by one electron reduction of HV(CO)₄dppe. However, with HV(CO)₄dppf this does not readily occur and this hydride could potentially be a catalyst for radical cyclizations. Many radical cyclizations involve vinyl (sp²) radicals. I have shown that both the CpCr(CO)₃H and the Co(dmgBF₂)₂(H₂O)₂ systems can catalytically perform metal to alkyne hydrogen atom transfers (MAHAT's) and that these reactions can be used to perform radical cyclizations very efficiently.