Mechanochemistry: Its Unrealized Potential in Natural Product Research

For nearly 150 years, the traditional training of a synthetic chemist has included performing a reaction in a solvent filled round bottom glass flask with heating as required. During this time, it would have been counterintuitive (if not unthinkable) for most chemists to do synthesis in any other way. However, conducting chemistry without a solvent may well date back several thousand years to the extraction of mercury from cinnabar by grinding it in a mortar and pestle. Also, during the nineteenth century, a gradual change of chemistry thinking began to emerge. Early pioneers and practitioners of non-solvent chemistry included the luminary Michael Faraday and his “dry method” of synthesis as well as Matthew Carey Lea, reacting silver halide salts by simply grinding them. Intriguingly, there is currently a renaissance of interest in this non-solvent approach, now commonly termed mechanochemistry and succinctly defined ¹ as “chemical synthesis enabled or sustained by mechanical force.” Instead of heating, the stressful pounding and grinding action of mechanochemistry provides the resulting compression and rubbing forces which energize its synthetic power. This effect can conveniently be achieved by something as sophisticated as a powerful ball mill or as simple as a mortar and pestle.

The field of mechanochemistry has rapidly accelerated in the past several decades with more than 25 000 total mechanochemistry publications to date (Figure 1, using the SciFinder^® chemistry database with the search term “mechanochemistry”). Not surprisingly, the significant growth in mechanochemistry research has closely paralleled the focus and interest in Green Chemistry over the past several decades. ² Besides its obvious simplicity, the advantages of mechanochemistry over conventional solvent reactions are numerous, including reduced environmental impact and waste disposal costs along with improved safety. Mechanochemistry can even result in higher yields, unique product selectivity as well as success for seemingly “impossible” reactions. Small (mmol) scale reactions can also be accommodated by mechanochemistry using the proper devices. ³ The list of well-known organic reactions converted from solvent-based to mechanochemistry continues to diversify and expand. Remarkably, even sensitive organometallic syntheses like the Grignard reaction can be easily accomplished mechanochemically. ⁴ The quickly growing area of cocrystal synthesis has also successfully utilized mechanochemistry. ⁵

Figure 1.

Growth of mechanochemistry publications.

Against this backdrop of rapidly emerging mechanochemistry, it is rather surprising then that natural product synthesis has been only a relatively minor participant. One very practical application which has been routinely exploited is the mechanochemical extraction of natural products from their indigenous sources. Numerous examples of this methodology have recently appeared. ⁶ However, a literature search has revealed that the use of mechanochemistry in actual natural product syntheses has been relatively infrequent if not rare. Two recent successful examples can be cited. The first is the synthesis of bis(indolyl)quinones from indoles and haloquinones ⁷ and the second is the preparation of bis(indolyl)methanes from indoles and carbonyl precursors by mechanochemistry. ⁸ In the latter instance, one of the substances obtained was the marine natural product trisindoline. Both articles also highlight the benefits of simplicity, mild reaction conditions, excellent yields and the benign environmental impact afforded by mechanochemistry.

The preceding examples clearly demonstrate the potential advantages of mechanochemistry as applied to natural product synthesis. In a recent review ⁹ of complex and daunting natural product syntheses, the authors characterized these impressive achievements as an “endless quest for unreachable perfection.” It would seem then that the unique synthetic concept of mechanochemistry could well advance that elusive goal.