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A variety of biological and organic reaction mechanisms are studied using powerful tools from experimental and theoretical chemistry. These tools include the precise measurement of kinetic isotope effects (KIEs) and the use of theoretical calculations to predict KIEs as well as determine factors that contribute to reaction acceleration and selectivity. Theoretical analysis of the Swain-Schaad relationship involves the prediction of a large number of isotope effects and establishes the semiclassical boundaries of the relationship. Studies on the mechanism of oxidosqualene cyclase involve the determination of a large number of precise KIEs simultaneously. Transition state models for the Sharpless asymmetric epoxidation have been developed that explain the versatility, high selectivities, and ligand accelerated catalysis of the reaction. Theoretical predictions on the proposed enzymatic mechanism of flavin dependent amine oxidation suggest a hydride transfer mechanism and rules out mechanisms involving covalent intermediates. Finally, a theoretical analysis of Diels-Alder reactions successfully describes the unexpected exo selectivity in some of these reactions.
Several organic reactions that could potentially involve coarctate transition states were investigated by a combination of experimental and theoretical studies. In the thermal fragmentation of [delta]-1,3,4-oxadiazolines, the mechanism supported by kinetic isotope effects and theoretical calculations is a three-step process that does not demonstrate any special stabilization in coarctate transition states. Rather than undergoing a direct coarctate conversion to product, the mechanism avoids coarctate steps. The last step is a concerted coarctate reaction, but being concerted may be viewed as being enforced by the necessity to avoid high-energy intermediates. In the deoxygenation of epoxides with dichlorocarbene, the stabilization from the transition state aromaticity is not great enough to compete with the preference for asynchronous bonding changes. KIEs and calculations suggested that the reaction occurs in a concerted manner but with a highly asynchronous early transition state with much more C[alpha]-O bond breaking than C[beta]-O bond breaking. In the Shi epoxidation, a large [beta]-olefinic 13C isotope effect and small [alpha-carbon isotope effect indicated an asynchronous transition state with more advanced formation of the C-O bond to the [beta]-olefinic carbon. The calculated lowest-energy transition structures are generally those in which the differential formation of the incipient C-O bonds, the "asynchronicity," resembles that of an unhindered model, and the imposition of greater or less asynchronicity leads to higher barriers. In reactions of cis-disubstituted and terminal alkenes using Shi's oxazolidinone catalyst, the asynchronicity of the epoxidation transition state leads to increased steric interaction with the oxazolidinone when a [pi]-conjugating substituent is distal to the oxazolidinone but decreased steric interaction when the [pi]-conjugating substituent is proximal to the oxazolidinone. Dynamic effects were studied in Diels-Alder reaction between acrolein and methyl vinyl ketone. This reaction yields two products in a ratio of 3.0 " 0.5. Theoretical studies shows that only one transition structure is involved in the formation of both. Quasiclassical trajectory calculations on an MP2 surface give a prediction of a product ratio of 45:14 (3.2:1), which is in good agreement with the experimental observation.
Isotope effects have become one of the most powerful tools available to the enzymologist for probing enzymic mechanisms. Enzyme Mechanism from Isotope Effects presents the basic theory underlying isotope effects, including the latest findings on proton tunneling and coupled atomic notions. Specific theoretical applications are emphasized in regard to the types of information that can be obtained using isotope effects. The book also examines recent theoretical treatments of the product dependence of deuterium isotope effects, multiple isotope effects and isotope effects on intermediate partitioning. Other topics include a complete discussion of methods for measuring isotope effects, including a detailed description of the use of the isotope ratio mass spectrometer to obtain isotope effects, and a review of the literature regarding mechanistic information obtained from isotope effects for individual classes of enzyme-catalyzed reactions. Enzyme Mechanism from Isotope Effects is an excellent reference source for investigators using isotope effects in their research. The book is also valuable for reference libraries and instructors teaching courses in enzyme mechanism.
The field of isotope effects has expanded exponentially in the last decade, and researchers are finding isotopes increasingly useful in their studies. Bringing literature on the subject up to date, Isotope Effects in Chemistry and Biology covers current principles, methods, and a broad range of applications of isotope effects in the physical, biolo
In this dissertation, experimental probes and theoretical calculations have been applied to delineate mechanisms of various [2+2] cycloadditions. Besides common experimental observations and transition state theories, this dissertation focuses on the application of kinetic isotope effects (KIEs) and dynamic effects for a better understanding of the mechanisms. The studies of dimerization of allene and [2+2] cycloaddition between 1,1-dimethyl allene and dimethyl maleate showed significant intramolecular KIEs and important reaction intermediates. These experimental observations strongly support a stepwise mechanism via a diradical intermediate. Based on this proposal, theoretical calculations gave excellent predictions of experimental observations. The controversy from previous literatures was well resolved by carefully analyzing the experimental observations. Research on Lewis acid catalyzed [2+2] cycloaddition between allene and alkenes were conducted via a combination of product studies, experimental kinetic isotope effects, common theoretical calculations and quasiclassical trajectory simulations. The results identified two important dynamic effects in these reactions, the bifurcating energy surface and the non-statistical recrossing. These dynamic effects explained the inverse KIEs in the reaction between allene and tetramethylethylene and the regioselectivity in the reaction between allene and isopropylidenecyclohexane. In stabilized Wittig olefination, the betaine was proposed to be an intermediate in the formation of the oxaphophetane as opposed to modern undertandings of a concerted mechanism. Experimental KIEs were consisted with a two-step mechanism and theoretical calculations located an intermediate along the reaction pathway. Trajectory simulations also showed significant amount of recrossing at the transition state and a possible hidden entropic intermediate in the reaction. These results provided a unique angle to understand the mechanism and the selectivity in the stabilized Wittig olefinations. Dynamic effects not only play important roles in common organic reactions, but also in complicated enzynamic reactions, such as the transannular Diels-Alder reaction catalyzed by the corresponding "Diels-Alderase" SpnF. This reaction includes the role of a [6+4] cycloaddition, a bispericyclic transition state, a bifurcating energy surface, a dynamically stepwise cycloaddition, an entropically-delineated intermediate, and transition state recrossing in the mechanism. The reaction is not its caricature from classical mechanistic analysis and it is not well described by either concerted or stepwise labels. Instead, the mechanism is richer and can only be understood by consideration of dynamics. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/151885
Experimental Analysis of Enzyme Mechanism Using Isotope Effects, Volume 596, the latest release in the Methods in Enzymology series, continues the legacy of this premier serial with quality chapters authored by leaders in the field. Chapters in this comprehensive update include Measurement of enzyme binding isotope effects, Chemical ligation and isotope labeling to locate dynamic effects, Measurement of heavy enzyme isotope effects, Extracting kinetic isotope effects from a global analysis of reaction progress curves, KIE of metabolic flux and enzymes, Solvent and Primary KIE on Flavin Enzymes, and The Rapid Determination of Primary Deuterium Isotope Effects on Enzyme-Catalyzed Proton Transfer at Carbon in 50/50 HOH/DOD. Readers who are interested in applying or understanding this research will find useful methods currently used for measuring isotope effects on solution and enzyme reactions. Written by pioneers of modern isotope effect research Is the only collection of modern kinetic isotope effect methods currently available
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.
Focuses on measurements and calculations of isotope effects in chemical reactions and photodissociation. Covers a variety of processes, ranging from the very simple (atom-diatom reactions) to the complex (multiligand coordination compounds) and includes both neutral and ionic species. Examines a variety of applications, including those to astrophysical, planetary, and atmospheric science. Both light- and heavy-atom isotope effects are covered.