Applications of Redox Processes to Molybdenum and Tungsten Dearomatization Agents

Dakermanji, Steven, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Harman, W. Dean, Department of Chemistry, University of Virginia

In contrast to the large number of unsaturated rings present in molecular libraries, many medicinal chemists are looking for ways to synthesize molecules with higher levels of three-dimensional complexity. While aromatic molecules are attractive precursors for these compounds due to the large number of sites of unsaturation in a cyclic framework, their utility is reduced due to aromatic stability. Dearomatization methodologies involving dihapto-coordination to an electron-rich metal center allows for modification of common aromatic molecules. Through this coordination, the conjugation is broken, causing the unbound portion of the ring to resemble a non-aromatic alkene system, both in its structure and reactivity. The steric and electronic effects of coordination to the metal can facilitate additions to the aromatic with high regio- and stereoselectivity.
The goal of this research is to investigate electron-transfer reactions for synthesis and reactivity changes with complexes of {MoTp(NO)(DMAP)} and {WTp(NO)(PMe3)}. From a halide precursor for each system, a one electron reduction with sodium generates the proper electronic state of the metal to coordinate aromatics in a dihapto fashion. Synthesis of complexes with labile dihapto-coordinated ligands affords the ability to exchange the labile ligand for a range of aromatic ligands.
The rate of the ligand exchanges for the dihapto-coordinated ligands was found to be accelerated by the addition of an oxidant. Uncatalyzed exchanges for these systems occur by an initial slow dissociation of the dihapto-coordinated ligand follow by fast coordination of the incoming ligand. Through addition of an oxidant catalyst, it has been shown that an alternate electron chain transfer pathway precludes normal dissociation. This pathway allows for shorter substitution half-lives with higher yields for the molybdenum system. In addition, exchanges occur through a purported Mo(I) intermediate. allowing for retention of the stereochemistry of the metal. This effect was used in enantioenrichment efforts for the molybdenum system.
The coordination of asymmetric alkene compounds results in the possible formation of coordination diastereomers, with some species favored over others based on steric and electronic factors. Typically, these dihapto-coordinated nonaromatic alkene complexes are synthesized as a mixture of kinetic isomers. Efforts to resolve the different coordination diastereomers found that addition of an oxidant catalyst increases the rate of isomerization between different coordination diastereomers. Addition of substoichiometric amounts of catalyst allowed for isolation of a single, thermodynamically-favored diastereomer from mixtures of up to ten different coordination diastereomers.
In addition to the application of electron transfer properties for ligand exchange and coordination isomerization, it was found that similar reactivity could be used for the formation of dihapto complexes of these metal systems directly from the M(I) precursor complexes. Investigations on a κ1-amide complex of the Mo(I) metal fragment provided evidence of a η2-amide complex in equilibrium. Reduction of the Mo(I) dihapto isomer is much more facile, allowing for the use of the weaker reducing agent magnesium metal as compared to the sodium metal needed for reduction of halide complexes of both metal fragments. In the case of the molybdenum system, it was shown that the reductions with magnesium could outperform the analogues sodium reduction. Work is still ongoing to optimize the reduction of the tungsten system with magnesium.

PHD (Doctor of Philosophy)
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