Water as solvent
Since our research focus for years has been on bio- and chemocatalytic synthesis in water, I read with great interest “Some Organic Chemists Want to Turn on the Tap of a Familiar Solvent” (C&EN, July 17, 2023, page 20). I particularly enjoyed reading the part highlighting the impressive achievements of Bruce Lipshutz and his group, who led this field of catalysis in water. While this part of the article will certainly encourage organic chemists to consider the use of water as the reaction medium of choice in research, unfortunately other parts of the article focus on the downsides of water, which might give the wrong impression, thereby discouraging its use. These comments include “Enzymes don’t typically make large amounts of compounds. . . . That’s not ideal for industry, which strives to efficiently make large amounts of a compound,” “Enzymatic biocatalysis reactions tend to give higher yields in organic solvents,” and “The answer to this challenge, counterintuitively, is putting enzymes in organic solvents.”
In my view, such statements do not agree with the current state of the art in enzyme catalysis, especially industrial biocatalysis. Moreover, they don’t do justice to the tremendous potential of water as nature’s solvent for synthesis. First, considering TON and TOF, a native enzyme can “make large amounts of compounds” in water with outstanding productivities and excellent technical feasibility. One textbook example is the enzymatic production of 6-aminopenicillanic acid demonstrated at over 10,000 metric tons per year using PenG acylase, also done with negligible loss of activity over multihundred cycles. Given that this and related precedents all run in water with high process efficiency and in the absence of organic solvents, such remarks appear to be misguided and misleading, at best, especially since there are many additional success stories of impressive industrial applications using native enzymes in water (e.g., hydrolases, monooxygenases, and dehydrogenases).
Second, the comment that the “answer . . . is putting enzymes in organic solvents” is not correct. Usually, with the exception of lipases, most enzymes are deactivated in organic solvent. By contrast, water allows the use of all types of enzymes, as they evolved in this medium!
In the final analysis, enzymes in water are destined to play a significant role in the future of organic synthesis. Let’s not forget that directed evolution is part of this story and that the 2018 Nobel Prize in Chemistry is in total agreement.