This award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports Professor Frederick Luzzio at the University of Louisville to investigate alkynylogation in order to promote the transmission of electronic effects between a nucleophilic or electrophilic center through the intermediacy of a triple bond, and the conversion of hydrofluorocarbons (HFCs) into functionalized fluorinated building blocks through C-F activation of some fluorines within the molecule. The alkynylogation effects will be studied using a triple bond extended aldol (alkynylogous aldol) reaction as a working model, utilizing modern synthetic tools capable of controlling the regio- and stereochemistry. Specifically, the effect of size and Lewis acidity of the cation counterion of a base on the gamma-directed alkynylogous aldol reaction will be investigated; the effects of Lewis acid on the regio- and stereoselectivity of Mukaiyama type alkynylogous aldol reaction, and the reaction of silylketene acetals with electrophiles. Transformative fluorination will be pursued through the functionalization of industrially available, ecologically benign, three- or four-carbon HFCs by selectively removing fluorine, utilizing C-F bond activation reactions. A second generation of difluoropropargyl synthons will also be developed utilizing environmentally friendly reagents and conditions, capable of engendering cyclic precursors fitted with synthetic handles that maximize structural diversity.
This research aims for practical approaches, and environmentally friendly uses of materials and for organic synthesis. The project will train a younger generation of chemists in synthesis and organofluorine chemistry and advance the education of underrepresented minorities.
Project Outcome: The group of Professor Hammond has developed an alkynylogation strategy as a method to promote the transmission of electronic effects between a nucleophilic or electrophilic center through the intermediacy of a triple bond. Gold catalysis has had a major focus in this research. Prior to Hammond’s work on gold catalysis, scientists could only assumed that a nucleophile attacks a gold-activated carbon-carbon multiple bond to give a vinyl-Au intermediate. Hammond’s group reported the first room-temperature stable γ-lactone gold(I) complex through the reaction of cationic Au(I) with allenoates and unraveled its mechanism of formation. Based on this mechanistic understanding, the gold-mediated nucleophilic addition to alkynes has given rise to synthetically useful variations, including the transformation of fluorine from its traditional role of substituent into an enabling synthetic tool. In addition, we have implemented a new smart filter with the potential to streamline chemical operations, as well as a pellet-based nanopalladium catalyst that may improve efficiency in the chemical industry. Impact & Benefits: Modern drug discovery often involves screening small lead molecules for their ability to bind to a preselected target. Chemical synthesis is the tool that provides the hit-to-lead support. Yet, despite the drive for efficient and selective chemical reactions, many practical aspects of performing a reaction are labor intensive and time-consuming. Furthermore, chemical synthesis can be uneconomical because of its reliance on non-recyclable reagents and solvents or short-lived commercial catalysts. Our research has contributed to the development of simple, efficient multi-component synthesis of organic compounds from readily available starting materials, employing reaction conditions that are amenable to the medicinal chemist.
