Title page for ETD etd-05152012-225340

Type of Document Dissertation
Author Patwardhan, Neeraj Narendra
URN etd-05152012-225340
Title Study of synthesis, reactions and enantiomerization of Cα- chiral Grignard reagents
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Carlier, Paul R. Committee Chair
Kingston, David G. I. Committee Member
Santos, Webster L. Committee Member
Tanko, James M. Committee Member
  • Keywords: enantiomerization
  • kinetics
  • chiral Grignard reagents
  • solvent effects
  • reaction order
  • ion-pair separation
  • entropy of activation
  • electrostriction
  • DFT calculations
Date of Defense 2015-05-02
Availability restricted
The development of chiral organometallics for asymmetric synthesis is a topic of significant research in the recent past. The most studied in this class are the chiral organolithium reagents with many reported examples. The primary focus of our research is the development of Cα-chiral Grignard reagents, where the metal bearing α-carbon is the sole source of chirality. Examples of such Grignard reagents are rare owing to the problems associated with their synthesis, and their low configurational stability. We have studied these problems in three different modules of this project.

Reactions of 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile with carbon electrophiles are first attempted in order to expand the utility of this configurationally stable Cα-chiral Grignard reagent in asymmetric synthesis. This reagent has been shown to be non-reactive towards carbon electrophiles at low temperatures. Consequently, we attempt to enhance the reactivity of this compound through two different approaches, Lewis-base activation and the “ate-complex” generation. The Magnesium/Halogen (Mg/X) exchange reactions have been shown to be extremely useful in the synthesis of complex Aryl, alkenyl (sp2) and alkynyl (sp) Grignard reagents. Examples of Mg/X exchange reactions of Alkyl (sp3) halides are, however, rare. Even more rare are such examples with secondary and tertiary alkyl halides, justifying the relative paucity of chiral Grignard reagents. In this module of our project, we study the Mg/X exchange reactions on secondary alkyl halides possessing a γ-hydroxyl group, as an internal activator for such Mg/X exchange reactions.

Enantiomerization pathways of chiral organolithium compounds have been widely studied. However, few such studies have been performed on chiral Grignard reagents. In this module of the project, we studied the solvent assisted enantiomerization mechanism of the Cα-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile. Rate constant for the enantiomerization of this compound was measured in three different ethereal solvents to study the effect of solvent on the configurational stability. Finally, the order of the enantiomerization process with respect to [Et2O] was studied in order to predict the mechanism of this process in Et2O solvent.

Our kinetic studies on the enantiomerization process provided us with a definitive picture for the enantiomerization of the Cα-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile, where solvation of the Grignard reagent preceded an ion-pair separation step which eventually lead to enantiomerization of the Grignard species. However, the precise structure of all the involved solvated intermediates could not be determined as kinetics was not able to distinguish between these intermediates. We next performed computational calculations to study the effect of solvation on the analogous 1-magnesio-cyclopropylcarbonitrile in order to address the unanswered questions from our kinetic studies.

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