For organic chemists, micellar chemistry offers water as a solvent

Water is called the universal solvent for its ability to dissolve a broad range of chemicals. But you wouldn’t know that from spending time in chemistry labs, where the solvents of choice are almost exclusively organic. Water can react with so many different types of molecules that it can prevent scientists from getting good results out of complex reactions. So, many synthetic chemists see water as a hazard.

Many, but not all.

In the past several years, a small group of chemists has been experimenting with a technique that makes synthetic chemistry possible in water. Using surfactant molecules like detergents, these researchers can form microscopic spheres in water called micelles. The insides of these particles have an environment that’s friendly to greasy organic molecules. They are like tiny flasks, perfect for hosting organic reactions and shielding them from surrounding water molecules.

Micellar chemistry—and chemistry in water in general—is often pitched as being more environmentally friendly than doing the same reactions in organic solvents, many of which are toxic. Solvents account for a huge portion of the waste chemistry produces. Proponents of micellar chemistry say its benefits go further than being green. It also enables reactions with higher yields, milder conditions, and fewer side products. And they’re convinced that it can change the synthetic chemistry world.

Born in academic labs, micellar chemistry is now catching on at several pharmaceutical companies and may soon reach other industries. At the same time, much of what scientists know about micellar chemistry comes from trial and error rather than fundamental knowledge about how these systems work, and some think this lack of basic information is impeding progress and wider adoption.

Tiny flasks

Making molecules in water is hardly a new idea. It even predates humans. “Nature has been optimizing reactions in water for billions of years,” says Wilfried Braje, a chemist at the pharmaceutical company AbbVie who is developing micellar chemistry processes. For instance, the Krebs cycle has evolved in cells, which are mostly water, to create chemical fuel by breaking down organic molecules.

Comparatively, human chemists have had only a century or two to optimize the chemical reactions they’ve invented. Still, a lot of time, effort, and money have gone into understanding and perfecting those reactions in organic solvents. Solvents have a sort of inertia in chemistry labs. “Making change happen is extremely difficult,” says Fabrice Gallou, who leads micellar chemistry efforts at drugmaker Novartis. This is true in chemistry labs, not just because synthetic chemists are familiar with organic solvents but also because companies and regulators have built a world tailored to these solvents.

Bruce Lipshutz has made it his mission to show that synthetic chemistry can be adapted to micelles. The University of California, Santa Barbara, chemist started in 2008 by demonstrating micellar chemistry is compatible with olefin cross-metathesis reactions, which are typically performed in an organic solvent like dichloromethane (Org. Lett. 2007, DOI: 10.1021/ol800028x). Since then he’s ticked off a number of other common synthetic reactions, like Sonogashira couplings (Org. Lett. 2008, DOI: 10.1021/ol801471f), Suzuki-Miyaura cross-couplings (Org. Lett. 2008, DOI: 10.1021/ol801712e), and photocatalytic reactions (Green Chem. 2018, DOI: 10.1039/C7GC03866F). Others, like Sachin Handa of the University of Louisville, who did postdoctoral work in Lipshutz’s lab, have expanded the list further. Handa has used micellar chemistry to perform Buchwald-Hartwig aminations (ACS Catal. 2019, DOI: 10.1021/acscatal.9b02622) and has done reactions with carbanion intermediates (ACS Catal. 2020, DOI: 10.1021/acscatal.0c01196). Typical instructions for all these reactions require organic solvents. That’s because some of their components, like carbanions (anions with a negative charge on a carbon atom), are usually thought to be incompatible with water.

The micelles these chemists use self-assemble from surfactants, molecules with water-soluble heads and oil-soluble tails. In water, surfactants form spheres with their water-soluble heads pointing outward and their oil-soluble tails pointing inward, forming a compartment where organic molecules can react without water interfering. Chemists are learning that these micelles can play other useful roles as well, like concentrating reactants and catalysts in the same place. That can speed up syntheses or result in reactions that use less catalyst than standard processes, which can be especially important when the catalyst is an expensive metal like palladium.

Micellar chemists initially used available surfactants like laboratory detergents to carry out their tests. As they have pushed further into the catalog of named organic reactions, they have started designing new surfactants with different sizes, shapes, and substituents to optimize micelles for specific reactions. For instance, Shenlin Huang, a chemist at Nanjing Forestry University who is another graduate of Lipshutz’s group, is experimenting with plant-derived chiral surfactants that could enable enantioselective micellar reactions, although he hasn’t been able to make it work yet.

Early adopters

These efforts have caught the attention of pharmaceutical companies. Micellar chemistry could help them reduce waste; organic solvents account for 50% to 80% of the waste produced during the making of a drug molecule, according to various sources. Eliminating waste is good for the environment, but firms are interested in ditching organic solvents because it can reduce costs too. Regulations like Europe’s Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH), provide another impetus by forcing companies to stop using common types of organic solvents.

Gallou’s employer Novartis was an early adopter of micellar chemistry. He credits REACH and other regulations for pushing the pharmaceutical company starting around 2008 to look for alternatives to organic solvents, but it was two years before Gallou found micellar techniques that would work for Novartis’s products.

In 2016, Gallou and other Novartis scientists reported a micellar process to make an undisclosed active pharmaceutical ingredient (API) the company was investigating (Green Chem. 2016, DOI: 10.1039/C5GC02371H). The sequence included Suzuki-Miyaura cross-coupling, arylation, and amide bond–forming reactions, and the researchers reported that they were able to make the API faster, more cheaply, in higher yield, and with less solvent than the optimized process in traditional organic solvents. They even used less water, surprising as that may sound, because they were able to use higher concentrations of reagents in their reactions and they optimized their protocol.

AbbVie’s Braje says the Novartis paper was key to drumming up interest in micellar chemistry because it “showed this approach has major benefits” for pharmaceutical companies. At the Green Chemistry and Engineering (GC&E) Conference happening online this month, Braje will present work from a collaboration with Handa on amide coupling—“the most important reaction” in the pharmaceutical industry, he says—that works in seconds without needing any organic solvent to isolate their products. The process the scientists developed uses hydroxypropyl methylcellulose as the surfactant, which is a polymer found in many pills and also ketchup. Braje says this molecule doesn’t form micelles, however. Instead of forming fully-enclosed spheres, it makes structures with lipophilic pockets.

The firm Takeda has gotten in on the act, too. Company scientist Dan Bailey will also present efforts to make an API with micellar chemistry at GC&E. Like Novartis’s 2016 effort, the Takeda group’s process improved the API’s yield and reduced both solvent and water use. Bailey says the potential environmental benefits are what make micellar chemistry attractive to him personally, but he says the improvements in efficiency, selectivity, and productivity are what catch the attention of most chemists.

Pharmaceutical companies aren’t the only ones interested in micellar chemistry. Lipshutz and collaborators at Corteva Agriscience describe micellar methods for making two biaryl molecules found in the herbicides Rinskor and Arylex (Org. Lett. 2020, DOI: 10.1021/acs.orglett.0c01625). Researchers at the agrochemical company Syngenta have also worked with Lipshutz, and they have replaced dioxane, a probable carcinogen, in some Suzuki-Miyaura reactions.

Barriers to entry

Even with micellar chemistry’s tantalizing selling points, problems may stand in the way of wider adoption. Some micellar processes still require organic solvents to isolate and purify reaction products. “If we extract with solvent how much do we gain? Not much,” says David Leahy, Bailey’s micellar chemistry collaborator at Takeda.

Another issue Leahy raises is cleaning leftover organic and inorganic compounds from the water used in these processes. This water can’t be released untreated. But these steps are not yet efficient or cost-effective, Leahy says.

And there’s an even more fundamental barrier to expanding the field. Champions of micellar chemistry readily admit that scientists still know very little about its basic rules, relying on empirical understanding of how to make individual reactions work. “It’s still too much driven by trial and error,” Gallou says, which makes it difficult to adapt micellar processes for synthesizing existing drugs and other products.

Handa emphasizes that the synthetic chemistry rules most people learn are not universal. They apply to reactions in organic chemistry, he says, but “chemistry in water obeys different rules.”

Alessandro Scarso of Ca’ Foscari University of Venice says now is the time for micellar chemists to start learning those rules: “So far people just mix things and the catalysis works. Now we need more precise understanding of what’s going on in micellar aggregates.” He wants to see investigations pinpoint where reactants and catalysts go in micellar systems—do they react in the micelles’ cores, on their surfaces, or somewhere else?—and he wants to see mechanistic studies of these reactions.

One chemist trying to uncover the rules of micellar chemistry is Luca Beverina of the University of Milano–Bicocca. He’s a process chemist focused on organic semiconductors, materials that could be useful in displays or photovoltaics. Beverina has designed new surfactants with aromatic elements that stabilize organic semiconductor molecules and make their synthesis more efficient (Green Chem. 2019, DOI: 10.1039/C9GC01071H). These molecules are quite different from pharmaceutical or agrochemical compounds previously synthesized with micellar chemistry, meaning he’s had to discover his own rules for micellar chemistry. That’s led him to believe that these systems may be more complex than the spherical micelles Lipshutz and others describe. He thinks the surfactants may be playing other roles, creating emulsions or dispersions and surface tension effects that may not be fully appreciated yet. “I think sometimes why the processes are problematic is because ‘micelle’ is not the right term,” he says.

Lipshutz says he doesn’t dispute Beverina’s claims that reactions in these systems may not always take place within micelles. And he points out that he and Beverina are pursuing two different kinds of chemistry, which may explain Beverina’s observations. He and others, Beverina included, return to the fact that at this stage, chemists just don’t know very much about micellar chemistry.

That doesn’t make them any less optimistic. “At the beginning I wasn’t convinced” micellar chemistry could work, Beverina says. “But it does.” He adds that micellar chemistry is a “strategy we can use even if we don’t totally understand it.”

The small group of micellar chemists hope to see these techniques spread, even knowing it will be hard to fight organic solvents’ inertia. “It’s really hard to overcome preconceived ideas,” says Margery Cortes-Clerget, a postdoctoral researcher who began working with Gallou after finishing a postdoctoral fellowship with Lipshutz. Chemists who believe water and synthesis don’t mix sometimes don’t see all the possible benefits of micellar chemistry, she says. “Have an open mind.”