2008 Academic Award

Professors Robert E. Maleczka, Jr. and Milton R. Smith, III of Michigan State University

 

Green Chemistry for Preparing Boronic Esters

 

Innovation and Benefits: One way to build complex molecules, such as pharmaceuticals and pesticides, is with a Suzuki "coupling" reaction. This versatile coupling reaction requires precursors with a carbon-boron bond. Making these precursors, however, typically requires harsh conditions and generates significant amounts of hazardous waste. Professors Maleczka and Smith developed a new catalytic method to make these compounds under mild conditions and with minimal waste and hazard. Their discovery allows the rapid, green manufacture of chemical building blocks, including some that had been commercially unavailable or environmentally unattractive.

Summary of Technology: One way to build valuable molecules, such as pharmaceuticals, pesticides and similar complex substances, is through "coupling" reactions. Coupling reactions connect two smaller molecules, usually through a new carbon-carbon (C–C) bond. A particularly powerful coupling reaction is the Suzuki coupling, which uses a molecule containing a carbon-boron bond to make a larger molecule through a new C–C bond. In fact, the Suzuki coupling is a well-established, mild, and versatile method for constructing C–C bonds and has been reported to be the third most common C–C bond-forming reaction used to prepare drug candidates.

Chemical compounds with a carbon-boron bond (called organoboron compounds) are often prepared from the corresponding halides by Grignard or lithiate formation followed by reaction with trialkyl borate esters and hydrolytic workup. Miyaura developed an alternative using a palladium catalyst, but even this improved reaction requires a halide precursor.

Several years ago, Professors Milton R. Smith, III and Robert E. Maleczka, Jr. began collaborating to find a "halogen-free" way to prepare organoboron compounds, specifically the aryl and heteroaryl boronic esters that are the key building blocks for Suzuki couplings. Their collaboration builds upon Smith's invention of the first thermal, catalytic arene carbon–hydrogen bond (C–H) activation/borylation reaction. This led to transformations using iridium catalysts that are efficient, have high yields, and are tolerant of a variety of functional groups (alkyl, halo-, carboxy, alkoxy-, amino, etc.). Sterics, not electronics dictate the regiochemistry of the reactions. As a consequence, 1,3-substituted arenes give only 5-boryl (i.e., meta-substituted) products, even when both the 1- and 3-substituents are ortho/para directing. Just as significantly, the reactions are inherently clean as they can often be run without solvent, and they occur with hydrogen being the only coproduct. The success of these reactions has led Miyaura, Ishiyama, Hartwig, and other researchers to use them as well.

In brief, catalytic C–H activation/borylation allows the direct construction of aryl boronic esters from hydrocarbon feedstocks in a single step, without an aryl halide intermediate, without the limitations of the normal rules of aromatic substitution chemistry, and without many common functional group restrictions. Moreover, given its mildness, the borylation chemistry can be readily combined in situ with subsequent chemical reactions.

This technology allows for rapid, low-impact preparations of new chemical building blocks that currently are commercially unavailable or only accessible by protracted, costly, and environmentally unattractive routes. Indeed, most recently, Michigan State University licensed the nominated technology to BoroPharm, Inc, which is using these catalytic borylations to produce much of the company's product line. Thus, the nominated technology is proving to be practical green chemistry at the laboratory bench and beyond.


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