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Presidential Green Chemistry Challenge: 2014 Academic Award

Professor Shannon S. Stahl, University of Wisconsin-Madison


Aerobic Oxidation Methods for Pharmaceutical Synthesis

Innovation and Benefits: Oxidation reactions are widely used in the production of organic chemicals, but they often form wasteful byproducts. Professor Stahl has developed catalytic methods that replace hazardous chemicals with oxygen from air as an environmentally benign oxidant. The methods operate under mild conditions, can be performed safely on a large scale, and are highly selective, even with complex building blocks for pharmaceuticals, potentially saving time and money and reducing hazardous waste.

Summary of Technology: Molecular oxygen (O2) is the least expensive and most environmentally benign chemical oxidant available, but it is rarely used because of safety concerns and poor reaction selectivity. Rather than using oxygen, industrial chemists typically choose between using more toxic oxidizing agents or employing alternative synthetic routes that avoid oxidation altogether, even if the routes are less efficient.

Professor Stahl and his group specialize in the development and investigation of catalytic aerobic oxidation reactions, and they recently developed several practical and synthetically useful aerobic alcohol oxidation methods. In 2011, post-doctoral researcher Dr. Jessica Hoover showed that a copper(I) salt and TEMPO (2,2,6,6-tetramethylpiperidinyl-N-oxyl) mediate selective oxidation of primary alcohols to aldehydes at room temperature with ambient air as the oxidant. The method is compatible with both activated and unactivated alcohols, tolerates heterocycles and diverse oxygen-, nitrogen-, and sulfur-containing functional groups, and enables selective oxidation of primary alcohols within the molecules containing unprotected secondary alcohols. Mechanistic studies of these reactions led to the subsequent discovery of a new catalyst system by graduate student Janelle Steves that exhibits broader scope and efficiently oxidizes both primary and secondary alcohols. The simplicity of these catalyst systems and lack of stoichiometric reagents other than oxygen greatly simplifies product isolation and reduces waste. Chlorinated solvents, which are commonly needed with other classes of oxidation reactions, are not required.

Professor Stahl has partnered with Professor Thatcher Root (Dept. of Chemical and Biological Engineering, University of Wisconsin-Madison) and scientists at several pharmaceutical companies (Drs. Matthew Yates, Martin Johnson, Joseph Martinelli at Eli Lilly; Dr. Christopher Welch at Merck; Dr. Joel Hawkins at Pfizer) to explore strategies for safe and scalable implementation of aerobic oxidation reactions for pharmaceutical synthesis. One approach involves a continuous-flow process, which has been used to achieve aerobic oxidation of alcohols to aldehydes in near-quantitative yields with reactor residence times as low as five minutes.

The development of practical, safe, and scalable oxidation methods of this type provides a foundation for widespread adoption of oxidations using molecular oxygen by pharmaceutical, fine, and specialty chemical manufacturers.

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