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Trace Metal Catalysis in Water: Enabling Technologies for Environmentally Friendly Organic Synthesis

  • Author(s): Landstrom, Evan Barrett Gam
  • Advisor(s): Lipshutz, Bruce H
  • et al.
Creative Commons 'BY-NC-ND' version 4.0 license
Abstract

Organic synthesis is the cornerstone of small molecule pharmaceutical development and manufacturing. Unfortunately, making these medications still relies on the use of toxic organic solvents as the reaction medium. These solvents represent ~80% of the organic waste stream generated by the pharmaceutical industry. Additionally, key catalytic reactions involve unsustainably high levels of endangered precious metals.

Throughout the course of this research new reaction conditions were developed to address these concerns. With respect to solvents, the designer surfactant TPGS-750-M in water was chosen as the reaction medium. This commercially available surfactant has significant literature track record of enabling organic transformations in aqueous media, often with mild reaction conditions.

There are a plethora of catalysts in the literature that enable critical organic transformations, such as the Suzuki-Miyaura coupling, that can be effective at low catalyst loadings. Unfortunately, they often require harsh reaction conditions involving high heat and organic solvents to achieve optimal yields of the desired product. In light of this, new, more effective catalysts and shrewd implementation of available catalysts was investigated.

By combining aqueous micellar media with judicious catalyst design and implementation, new reaction conditions were developed in good-to-excellent product yields of critical bond-forming reactions that are used extensively in pharmaceutical synthesis, namely C-C, C-N, and “click” reactions. All of these are conducted in an environmentally friendly manner in an aqueous medium with no more than 0.05-0.5 mol % (500-5000 ppm) of metal catalyst.

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