Thesis (Ph. D.)--University of Wisconsin--Madison, 1975. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 301-311).

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Enzyme dynamics occur on a wide range of length and timescales. This work is focused on understanding enzyme dynamic at the fs-ps timescale as this is the dynamic range at which bonds are typically made and broken during chemical reactions. Our work focuses on enzymes that catalyze hydride transfer between two carbon atoms - a fundamental reaction in biology. Primary kinetic isotope effects and their temperature dependence have implied that fast dynamics of the enzyme are important in facilitating hydride transfer, however these experiments do not measure any such motions directly. We make use of two-dimensional infrared spectroscopy (2D IR), a technique that interrogates the vibrations of molecules to extract dynamic information from the surrounding environment with 100 fs resolution. A model system, formate dehydrogenase (FDH), is an excellent probe of dynamics at the fs-ps timescale. Azide bound to the ternary complex of FDH offers the ability to measure dynamics of an analog structure of the reactive complex using 2D IR, while also studying the reaction directly with and KIE’s and their temperature dependence. By altering various parts of the structure of FDH via mutagenesis and other techniques, we investigate the role of structure and dynamics to determine how fast dynamics of the active site influence the the kinetics of hydride transfer. These experiments are the first means of providing a dynamic interpretation of KIEs and their temperature dependence.

The results of kinetic isotope determination and computational studies on Noyori-type catalytic systems for the hydrogenation of ketones are presented. The catalysts examined include RuH2(NHCMe2CMe2NH2)(R-binap) and RuH(NHCMe2CMe2NH2)(PPh3)2. These complexes are active catalysts for ketone hydrogenation in benzene without addition of an external base. The kinetic isotope effect (KIE) for catalysis by RuH2(NHCMe2CMe2NH2)(R-binap) was determined to be 2.0 ± (0.1). The calculated KIE for the model system RuH(NHCH2CH2NH2)(PH3)2 was 1.3, which is smaller than the experimentally observed value but does not include tunneling effects. The complex OsH(NHCMe2CMe2NH2)(PPh3)2 is known to display autocatalytic behaviour when it catalyzes the hydrogenation of acetophenone in benzene. Pseudo first-order reaction conditions are obtained via addition of the product alcohol at the beginning of each kinetic experiment. The KIE determined using various combinations of deuterium-labeled gas, alcohol and ketone was found to be 1.1 ± (0.2). DFT calculations were used to explore the effect of the alcohol and the KIE. An induction period is observed at the start of the hydrogenation that is attributed to the formation of an alkoxide complex. A novel, diamine-orchestrated hydrogen-bonding network is proposed based on DFT calculations to explain how the alkoxide is converted back to the active catalyst. The tetradentate complexes trans-RuHCl[PPh2(ortho-C6H4)CH2NHCH2)]2 and RuHCl[PPh2(ortho-C6H4)CH2NHCMe2)]2 are known to be catalysts for the hydrogenation of acetophenone and benzonitrile in toluene when activated by KOtBu/KH. DFT studies were performed and a mechanism is proposed. The calculated rate limiting step for acetone hydrogenation was found to be heterolytic splitting of dihydrogen, which agrees well with experiment. The novel outer-sphere sequential hydrogenation of a CN triple bond and then a C=N double bond is proposed. A mechanism is proposed, which is supported by DFT studies, to explain the selectivity observed in the nucleophilic attack of amines or aziridines on palladium -prenyl phosphines complexes. Calculations on based on a palladium complex with two phosphorus donor ligands indicated that the observed selectivity would not be produced. Using two new model intermediates with either THF or aziridine substituted for a phosphine ligand trans to the unhindered side of the prenyl ligand did predict the experimentally observed selectivity.

The results of kinetic isotope determination and computational studies on Noyori-type catalytic systems for the hydrogenation of ketones are presented. The catalysts examined include RuH2(NHCMe2CMe2NH2)(R-binap) and RuH(NHCMe2CMe2NH2)(PPh3)2. These complexes are active catalysts for ketone hydrogenation in benzene without addition of an external base. The kinetic isotope effect (KIE) for catalysis by RuH2(NHCMe2CMe2NH2)(R-binap) was determined to be 2.0 ± (0.1). The calculated KIE for the model system RuH(NHCH2CH2NH2)(PH3)2 was 1.3, which is smaller than the experimentally observed value but does not include tunneling effects. The complex OsH(NHCMe2CMe2NH2)(PPh3)2 is known to display autocatalytic behaviour when it catalyzes the hydrogenation of acetophenone in benzene. Pseudo first-order reaction conditions are obtained via addition of the product alcohol at the beginning of each kinetic experiment. The KIE determined using various combinations of deuterium-labeled gas, alcohol and ketone was found to be 1.1 ± (0.2). DFT calculations were used to explore the effect of the alcohol and the KIE. An induction period is observed at the start of the hydrogenation that is attributed to the formation of an alkoxide complex. A novel, diamine-orchestrated hydrogen-bonding network is proposed based on DFT calculations to explain how the alkoxide is converted back to the active catalyst. The tetradentate complexes trans-RuHCl[PPh2(ortho-C6H4)CH2NHCH2)]2 and RuHCl[PPh2(ortho-C6H4)CH2NHCMe2)]2 are known to be catalysts for the hydrogenation of acetophenone and benzonitrile in toluene when activated by KOtBu/KH. DFT studies were performed and a mechanism is proposed. The calculated rate limiting step for acetone hydrogenation was found to be heterolytic splitting of dihydrogen, which agrees well with experiment. The novel outer-sphere sequential hydrogenation of a CN triple bond and then a C=N double bond is proposed. A mechanism is proposed, which is supported by DFT studies, to explain the selectivity observed in the nucleophilic attack of amines or aziridines on palladium -prenyl phosphines complexes. Calculations on based on a palladium complex with two phosphorus donor ligands indicated that the observed selectivity would not be produced. Using two new model intermediates with either THF or aziridine substituted for a phosphine ligand trans to the unhindered side of the prenyl ligand did predict the experimentally observed selectivity.

An effiecient stoichiometric amount system has been developed for the synthesis of N-phenylpyridin-2-amine Palladacycle, and then reation with aryl trifluoroborate to 9-(pyridine-2-yl)-9H-carbazoles by C-H bond activation/ C-C bond formation and C-N bond formation. The subsitutent effect of the aryl trifluoroborate with N-phenylpyridin-2-amine Palladacycle intermediate was observed. Mechanistic studies of C-H bond cleavaged, including trapping of reaction intermediates and kinetic isotope effect experiments, are also presented.

The mechanism of three important aldol reactions and a biomimetic transamination is investigated using a combination of experimental kinetic isotope effects (KIEs), standard theoretical calculations and dynamics trajectory simulations. This powerful mechanistic probe is found to be invaluable in understanding intricate details of the mechanism of these reactions. The successful application of variational transition state theory including multidimensional tunneling to theoretically predict isotope effects, described in this dissertation, represents a significant advance in our research methodology. The role of dynamic effects in aldol reactions is examined in great detail. The study of the proline catalyzed aldol reaction has revealed an intriguing new dynamic effect - quasiclassical corner cutting - where reactive trajectories cut the corner between reactant and product valleys and avoid the saddle point. This phenomenon affects the KIEs observed in this reaction in a way that is not predictable by transition state theory. The study of the Roush allylboration of aldehydes presents an example where recrossing affects experimental observations. The comparative study of the allylboration of two electronically different aldehydes, which are predicted to have different amounts of recrossing, suggests a complex interplay of tunneling and recrossing affecting the observed KIEs. The Mukaiyama aldol reaction has been investigated and the results unequivocally rule out the key carbon-carbon bond forming step as rate-limiting. This raises several interesting mechanistic scenarios - an electron transfer mechanism with two different rate-limiting steps for the two components, emerges as the most probable possibility. Finally, labeling studies of the base catalyzed 1,3- proton transfer reaction of fluorinated imines point to a stepwise process involving an azomethine ylide intermediate. It is found that dynamic effects play a role in determining the product ratio in this reaction.

Organic reactions are systematically examined experimentally and theoretically to determine the role dynamics plays in the outcome of the reaction. It is shown that trajectory studies are of vital importance in understanding reactions influenced by dynamical motion. This dissertation discusses how a combination of kinetic isotope effects, theoretical calculations, and quasiclassical dynamics trajectories aid in the understanding of the solvolysis of p-tolyldiazonium cation in water, the cycloadditions of cyclopentadiene with diphenylketene and dichloroketene, and the cycloaddition of 2- methyl-2-butene with dichloroketene. In the solvolysis of p-tolyldiazonium cation, significant 13C kinetic isotope effects are qualitatively consistent with a transition state leading to formation of an aryl cation, but on a quantitative basis, the isotope effects are not adequately accounted for by simple SN1 heterolysis to the aryl cation. The best predictions of the 13C isotope effects for the heterolytic process arise from transition structures solvated by clusters of water molecules. Dynamic trajectories starting from these transition structures afford products very slowly. The nucleophilic displacement process for aryldiazonium ions in water is determined to be at the boundary of the SN2Ar and SN1 mechanisms. The reaction of cyclopentadiene with diphenylketene affords both [4 + 2] and [2 + 2] cycloadducts directly. This is surprising. There is only one low-energy transition structure for adduct formation. Investigation of this reaction indicates that quasiclassical trajectories started from a single transition structure afford both [4 + 2] and [2 + 2] products. Overall, an understanding of the products, rates, selectivities, isotope effects, and mechanism in these reactions requires the explicit consideration of dynamic trajectories.

Non-statistical recrossing in ketene cycloadditions with alkenes, heavy-atom tunneling and the mechanism of the decarboxylation of Mandelylthiamin is investigated in this dissertation. A combination of experimental kinetic isotope effects and theoretical models and kinetic isotope effects is utilized for this endeavor. This dissertation also describes how the use of quasiclassical dynamic trajectories, microcanonical RRKM calculations, and canonical variational transition state theory in combination with small-curvature tunneling approximations is utilized to help advance our research methodology to better understand mechanism. In the cycloaddition of dichloroketene with cis-2-butene, significant amounts of recrossing is observed using quasiclassical dynamic trajectories. An unusual inverse 13C intramolecular KIE lead us to investigate the role that heavy atoms play in non-statistical recrossing. More importantly, this discovery has uncovered a new phenomena of entropic intermediates that not only applies to ketene cycloadditions, but can also be applicable to other "concerted" reactions such as Diels-Alder reactions. The ring-opening of cyclopropylcarbinyl radical has revealed that heavy-atom tunneling plays a major role. The intramolecular 13C kinetic isotope effects for the ring-opening of cyclopropylcarbinyl radical were unprecedentedly large and in combination with theoretical predictions and multidimensional tunneling corrections, the role of tunneling in this reaction can be better understood. The mechanism decarboxylation of mandelylthiamin has been extensively studied in the literature. However, until the use of theoretically predicted KIEs and theoretical binding motifs the rate-limiting step of this reaction has been hotly debated. In this dissertation, a discussion of how the theoretical KIEs indicate the initial C-C bond as the rate-limiting step and chelating binding motifs of pyridinium and mandelylthiamin to explain the observed catalysis is given.

<p> Deuterium tracer studies, kinetic isotope effect measurements and product composition studies in both ammonia and ammonia-d3 have been used to elucidate the mechanism of the y-elimination reaction of 3-phenylpropyltrimethylammonium iodide with potassium amide in liquid ammonia at -55°. Deuterium tracer studies involving the products from the reaction of 3,3-dideutero-3-phenylpropyltrimethylammonium iodide have excluded the carbene and ylide mechanism. A deuterium exchange test involving the deuterated quaternary salt in ammonia demonstrated that a y-carbanion is formed during the reaction. In addition, a large y-hydrogen isotope effect (kH/kD > 22) and a large nitrogen isotope effect (k^14/K^15 = 1.022) were observed for the reaction. These results are consistent with either an Elcb mechanism in which the rates of ring closure and of return of the carbanion are of comparable magnitudes or a concerted mechanism accompanied by an irrelevant exchange reaction at the y-carbon. The latter has been eliminated on the basis of a deuterium exchange test involving the undeuterated quaternary salt in ammonia-d3 and the relative rates of y- and aelimination of the deuterated and undeuterated quaternary salts in both ammonia and ammonia-d3. </p> / Thesis / Doctor of Philosophy (PhD)