Vetticatt, Mathew J. (2009-12). Aldol Reactions - Isotope Effects, Mechanism and Dynamic Effects. Doctoral Dissertation. Thesis uri icon

abstract

  • 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.
  • 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.

publication date

  • December 2009