An additive found in foods and medicines lets chemists perform common organic syntheses in water in minutes or seconds (ACS Sustainable Chem. Eng. 2020, DOI: 10.1021/acssuschemeng.0c03975).
“It is a real breakthrough that makes it possible for the first time to envision fast processes, potentially in flow, under the mild conditions associated with the chemistry in water,” says Fabrice Gallou, a Novartis chemist who was not involved in the research.
Organic solvents are the norm in chemistry, from undergraduate labs to industry. But many common solvents are pollutants or health hazards, which has led some chemists to look for ways to do chemistry in water. Wilfried M. Braje of AbbVie and Sachin Handa of the University of Louisville and colleagues discovered that in water, hydroxypropyl methylcellulose (HPMC)—used as a thickening agent in foods and a filler in pills— forms structures that contain hydrophobic pockets where reactions can take place. The concept has similarities to micellar chemistry, which uses surfactant molecules to make spheres in water with hydrophobic interiors. Braje and Handa are both active in that area as well, as is Gallou.
The researchers found that catalytic palladium forms nanoparticles in HPMC’s pockets, which Handa likens to enzymes’ active sites. They demonstrated a number of Pd-catalyzed Buchwald-Hartwig aminations, almost all of which were completed between a few minutes and 1 hr. They also used HPMC in metal-free amid and peptide couplings, the fastest of which took less than 1 min. The group scaled up one peptide coupling to 100 g, and Handa says the researchers have since done a 1 kg reaction, both taking just 1 min.
The technique is “a medicinal chemist’s dream-come-true,” says Bruce Lipshutz of the University of California, Santa Barbara, a micellar chemist pioneer not involved in the research, adding that the work “may represent an entirely new field.”
Braje and Handa used commercially available HPMC, which costs about $0.10 per gram, and Handa says they think they can modify the molecules to make reactions possible in 1 or 2 s. One problem he says they are still working to solve is how to clean the water used in these processes to reduce the environmental impact as much as possible.—.