Pharmaceutical and Commodity Chemical Synthesis in High-Temperature Water

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ABSTRACTPI: Philip E. Savage Institution: University of MichiganProposal Number: 0625641Title: Pharmaceutical and Commodity Chemical Synthesis in High-Temperature WaterIntellectual Merit: High-temperature liquid water (HTW) is attractive as a reaction medium for organic chemical synthesis because it is inexpensive, abundant, non-toxic, renewable, environmentally benign, and has desirable chemical properties. Several different commercially relevant syntheses have been demonstrated in HTW, but many more targets of opportunity exist. Pharmaceutical reactions, for instance, are attractive targets because this sector of the chemical industry generally produces more waste per unit mass of product than any other sector. After discussions with chemists at Pfizer, the PI has decided to explore three especially attractive chemical reactions in HTW. These are a Friedel-Crafts reaction with "green" Lewis acids catalysts to synthesize tetralone, the deprotection of phenolic methyl ethers, and Suzuki coupling to make new C-C bonds. These three reactions are relevant to the manufacture of several different pharmaceutical products. In addition to the research noted above that examines new chemistries in HTW, he will also revisit syntheses that have already been demonstrated in HTW. These systems include the partial oxidation of p-xylene to make terephthalic acid (in collaboration with BP), aldol condensation, and Friedel-Crafts alkylation. The purpose here is to improve these HTW syntheses so they might become economically competitive with current processes. A limitation currently restraining implementation of HTW-based reaction technologies is that the solubilities of organic reactants are often too low to give volumetric production rates that can compete economically with existing processes. A recent advance, however, has suggested a possible route for overcoming this barrier and increasing the productivity of HTW-based processes without sacrificing the environmental benefits. This advance is the demonstration that solubility in water is not required to get fast reaction rates in water. In fact, for some reactions, heterogeneous aqueous-organic systems (vigorously stirred immiscible aqueous and organic phases) provided greatly accelerated reaction rates relative to the homogeneous conditions typically employed. To date, this effect has only been demonstrated at near ambient temperatures. The PI will explore whether it can be employed in HTW.This project will examine the partial oxidation of p-xylene to make terephthalic acid, aldol condensation, Friedel-Crafts reactions, Suzuki coupling, and ether hydrolysis. If successful, the research will lead to chemical reaction processes that are at least as productive as current ones, but are significantly more environmentally friendly. Removing the current barrier of low reactant concentrations in HTW will allow these technological advances to occur. Broad Impact:The PI will work with the UM Technology Transfer Office to make available the technological advances. The benefit of this work will extend to the chemical industry and the general public (by having less environmental risk associated with the manufacture of chemical products). The project will also provide training for a graduate student and about six undergraduate students. Additionally, the PI will continue his practice of incorporating his research results into the undergraduate and graduate classes he teaches at Michigan, so there will be benefits related to the integration of teaching and research.