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Enolization reactions mediated by s-block metal amide reagents

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posted on 2008-04-03, 00:00 authored by Xuyang He
The enolization of ketonic substrates is a cornerstone reaction in modern organic synthesis. The research in this dissertation is split into three main sections, with the investigation of s-block metal enolate chemistry being the underlying theme. The first section focuses on the synthesis and characterization of a series of homo- and heterobimetallic potassium and calcium enolates. This set of compounds was generated from the enolization of 2', 4', 6'-trimethylacetophenone using potassium hexamethyldisilazide (KHMDS) and calcium bis(hexamethyldisilazide) (Ca(HMDS)2). The section details the crystallographic characterization of a tetrameric potassium enolate, a dimeric amidocalcium enolate, a mixed-metal K/Ca amide, a solvent-separated K/Ca complex with a [Ca(HMDS)3]Ìâåø anion, and three mixed-metal enolate complexes containing 1:1, 2:1 and 2:2 stoichiometries of K and Ca. This set of complexes has allowed a comparison of the bonding between the two periodic neighbors within single complexes. The reactivities of magnesium bis(hexamethyldisilazide) Mg(HMDS)2, KHMDS, Ca(HMDS)2, several mixed-metal K/Ca amide combinations in enolization reactions are reported. The second section concentrates on an investigation into the utility of Ca(HMDS)2 to mediate the enolization of ketonic substrates. These studies demonstrate that Ca(HMDS)2 clearly deprotonates a variety of ketones in good to quantitative yields under mild conditions. Furthermore, this reagent is significantly more reactive than its magnesium analogue, which is a practical advantage. The regioselectivity of this calcium bisamide has been tested by reaction with a series of unsymmetrical ketones. These studies show that Ca(HMDS)2 is a highly kinetically selective base. The stereoselectivity of the base was also investigated and found to be strongly solvent-dependent. E-enolates are the major products in weakly polar solvents like toluene, while Z-enolates are the major products in donor solvents such as THF or pyridine. A group of amidocalcium enolates derived from a subset of the ketones used in the selectivity studies were isolated from various solvent mixtures, and characterized in the solid state. Crystallographic analyses revealed the formation for monomers, dimers, and charge-separated complexes. NMR spectroscopic studies in pyridine solution indicate the establishment of complex equilibria between amidocalcium enolate, charge-separated species, bisenolate and bisamide. The final section outlines a detailed mechanistic study for the enolization of propiophenone mediated by Mg(HMDS)2 in toluene. A combination of NMR spectroscopy, kinetic studies, crystallographic analyses and theoretical investigations has been used to elucidate the mechanism for ketone enolization. This investigation indicates that a key intermediate prior to the enolization is a three-coordinated precomplex formed between the amide and the ketone. A large primary isotope effect indicates that deprotonation is the rate-determining step, and that a tunneling effect may be in operation. From these data, a six-membered transition state has been proposed that aids in rationalizing the observed selectivity of the enolization.

History

Date Modified

2017-06-05

Defense Date

2008-03-27

Research Director(s)

Gregory R. Madey

Committee Members

Kenneth W. Henderson Seth N. Brown Marya Lieberman Slavi Sevov

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Language

  • English

Alternate Identifier

etd-04032008-165235

Publisher

University of Notre Dame

Program Name

  • Chemistry and Biochemistry

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