Strategies Toward Nucleophilic Additions to eta-2 Bound Arenes

Smith, Jacob, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Harman, Walter, AS-Chemistry, University of Virginia

Chapter 1 details the concepts of aromaticity and the importance of aromatic molecules in a variety of industrial and medicinal contexts. Speculation is included with regard to the potential value of aromatic molecules as a largely untapped source in drug development given the difficulties in realizing dearomatized manifolds. Common dearomatization methodologies are examined and the development of dihapto-coordinate enabled dearomatization is discussed. Existing limitations of dearomatization methodologies promoted by electron-rich metals are presented, particularly within the context of aromatics with electron withdrawing groups (EWGs) and in the dearomatization of benzene itself.

Chapter 2 investigates the protonation of benzene itself once bound to the tungsten scaffold. An estimate of the pKa of the resulting tungsten benzenium is provided and the selectivity of the initial protonation is examined. The selective formation of 1,3-cyclohexadiene and cyclohexene is presented and mechanistic considerations are presented. Importantly, the success and stability of the dearomatized benzene enables comparison to other heavy metal analogs with data consistent with the postulation that the tungsten fragment is the most activating of developed dearomatization scaffolds.

Chapter 3 details how the dearomatization of benzene can be used to generate regio- and stereo-specific isotopologues of cyclohexene. This is an extension of the mechanistic work presented in Chapter 2 and details the synthesis of novel cyclohexene isotopologues (including those of substituted cyclohexenes). Support for the resulting stereochemical assignments is supported through NMR and molecular rotational resonance (MRR) spectroscopic techniques along with neutron diffraction.

Chapter 4 continues to investigate the nuances of the complex WTp(NO)(PMe3)(η2-cyclohexene). Topics include the ability to distinguish isomerization mechanisms operative for isotopologues, inferring mechanisms by products determined by molecular rotational resonance spectroscopy (MRR) and attempts derivatize the dihapto-bound alkene bond. Attempts to access agostic complexes and the potential to recycle the tungsten dearomatization fragment is also presented.

Chapter 5 reports on the ability of molybdenum to bind the first substituted benzene (α,α,α-trifluorotoluene). Much of this work was initially pioneered by Dr. Jeffery Myers. The resulting molybdenum-trifluorotoluene complex can be synthesized via direct reduction and optimized conditions are presented. The substituted benzene is exceptionally labile and readily undergoes substitution reactions with a variety of unsaturated ligands. The kinetics of this process are investigated and a proof of concept is detailed to show the substitution route to a dihapto-coordinate molybdenum benzene complex. This is the first isolatable monomeric molybdenum benzene complex of which we are aware.

Chapter 6 looks to examine the compatibility with molybdenum and tungsten scaffolds together with electron deficient arenes. A survey of aromatics with π-bond containing EWGs supports concerns that dihapto coordination of the EWG pre-empts coordination of the aromatic ring. While -CF3 groups appear to be compatible with both systems, aryl C-F bonds are only tolerated by the molybdenum scaffold. Energies and isomerization dynamics of the resulting dearomatized π-ligands are investigated.

Chapter 7 looks to generate exceptionally electron-deficient π-ligands from the double protonation of anisole once bound to the potent tungsten π-base. The resulting dicationic fragment is moderately stable in solution and reacts with a variety of weak aromatic nucleophiles. The resulting substituted oxonium containing ligands can be treated with a range of reagents and provide a synthetic route to a series of novel 1,4-cyclohexene complexes.

Chapter 8 extends the methodology of double protonation to benzene which can be enabled by complexation to either the tungsten or molybdenum dearomatization agents. The resulting electrophilic organometallic scaffolds can then be treated with weak aromatic nucleophiles. An examination in the selectivity of the addition process is analyzed, as well as the ability for the metal to direct both of the initial protonations.

Chapter 9 details the development of the tri-n-butyl-phosphine ligand (P(n-Bu)3) as a cost efficient alternative to the PMe3 ligand initially developed on the tungsten scaffold. We report on the ability of the {WTpNO P(n-Bu)3} synthon to form dihapto-coordinate complexes with a variety of unsaturated ligands. Notably, for molecules highly stabilized by aromaticity (i.e benzene and benzene derivatives), a significant amount of C-H activated product is shown to be in equilibrium with the η2-isomer. Extensive computational work is presented to evaluate the mechanisms associated with this novel equilibrium, investigating the intermediates between the oxidative addition and reductively eliminated products. The computational work was done in collaboration with Anna Schouten and Professor Daniel Ess from Brigham Young University.

PHD (Doctor of Philosophy)
dearomatization, isotopologue, tungsten, molybdenum, benzene, nucleophilic addition
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