Making molecules makes a lot of organic-solvent waste, which can harm people’s health and the environment. One solution might be switching to a more benign solvent: water. But how can chemists coax greasy organic compounds to go into polar water? Mimicking nature by using enzymes is one solution. Chemists have also developed a number of tricks to make organic compounds and water mix. Doing organic chemistry in water works for organic molecules that have some aqueous solubility. On-water reactions happen at the interface between water and an organic compound. And with-water reactions rely on additives such as surfactants to entice organic molecules and water to mingle.
Organic chemist Bruce Lipshutz had a bit of a rude awakening. It was around 2007, and the head of environmental health and safety (EH&S) at the University of California, Santa Barbara, sat Lipshutz down to deliver some sobering news.
“I was told, in no uncertain terms, . . . that my group was the number 1 polluter in all of Santa Barbara County,” he says. “Not the campus, not the city, but in the entire county, we were number 1.” The EH&S head, Dave Vandenberg, was in charge of collecting and disposing of the waste that came out of chemistry labs at the university. And Lipshutz’s group, which focused on traditional organometallic synthesis, produced enough solvent waste to make Vandenberg notice. “I realized back then that this could not continue,” Lipshutz says.
Organic solvents are organic compounds in the liquid state. To react, molecules need to bump into one another, and dissolving compounds in a liquid is the most common way to make that happen. With few exceptions, solvents are indispensable in organic chemistry. Chemists run reactions in solvents. They often have to purify the products, which means using more solvent in chromatography columns, separatory funnels, distillation equipment, or other lab tools.
But most organic solvents are safety and health hazards. Toluene, for example, is flammable, a skin irritant, and a health hazard. It’s dangerous to inhale and touch. Repeated exposure can damage people’s organs, cause fertility issues, harm unborn babies, and kill aquatic life. Other common organic solvents are carcinogenic, and overexposure can cause brain damage and death.
Using organic solvents calls for numerous safety measures, including working in a chemical fume hood, wearing personal protective equipment, and arranging special disposal. There are a number of ways to deal with solvent waste at scale, but EH&S agents typically send waste organic liquids to treatment facilities, where they are incinerated, sending greenhouse gases into the air.
“Nobody talks about this, but we organic chemists obviously are contributing to climate change,” Lipshutz says. “We’re generating CO2 by burning that organic solvent.”
Lipshutz realized that if just his group put out so much solvent waste, “just imagine how much waste was being created” worldwide, he says. “It’s beyond our ken to even realize those numbers,” Lipshutz says. “So that drove me to realize that there must be another way.”
This other way can take a lot of forms. Chemists can switch to renewable and nontoxic solvents, such as supercritical carbon dioxide, a liquid-like pressurized form of the gas. Other options are solvents made from biomass or based on ionic liquids or molten salts. These all have safety or supply issues, though. Pressurized liquids such as supercritical CO2 can be an explosion hazard, molten salts can be heat hazards, and solvents made from biomass and ionic liquids can be hard to source. There are other methods that don’t use solvents at all, such as mechanochemistry in a ball mill. And although these methods are growing in popularity, they are not yet at a point that they can be used in a widespread way.
But there is another solvent that’s very common, easily accessible, and nontoxic and definitely has a good safety profile. It’s water.
Scientists estimate that RNA formed on Earth more than 4 billion years ago. Those reactions were probably happening in the oceans, which means organic reactions were happening in water. But how?
Anyone who’s ever seen a lava lamp in action or tried to mix balsamic-and-olive-oil salad dressing knows that oil and water don’t mix. When added together, organic and aqueous liquids tend to separate, forming distinct layers. Shake the mixture, and it may form blobs, with the oily, neutral parts retreating into themselves to get away from the incompatible polar water. But clearly, the two parts can be coerced together.
“The chemistry happening in the human body is not 100% in water,” Lipshutz says. “And all the chemistry that happens in nature doesn’t occur in organic solvents.” This means that organic compounds and water can get together in some situations. In addition, chemists have developed tricks to wheedle organic compounds into aqueous solutions.
When first hearing about running synthetic chemistry reactions in water, most chemists express skepticism that it can work. But chemistry in water doesn’t actually have a solubility problem, Lipshutz says. “Nature provided all the answers,” he says. “Our contribution is to figure out how best to go about doing chemistry in water.”
One way to do organic chemistry in water is to directly mimic nature. The human body is packed with enzymes. These proteins act as biological catalysts that speed up chemical reactions, and they work in an aqueous environment. Evolution has been fine-tuning enzymes for a very long time, says Dörte Rother, a biochemical engineer at RWTH Aachen University. So why not hijack enzymes to synthesize valuable compounds for you?
Cells are like tiny water balloons. Biocatalysis naturally lends itself to doing reactions in water because enzymes are produced in water-filled cells, Rother says. But to run reactions that are not specific to biology, scientists separate the enzymes and use them under different reaction conditions. The first step is finding an enzyme that makes a molecule similar to a desired molecule, Rother says. Through enzyme engineering, scientists can tune enzymes to make specific organic molecules not found in nature.
“The catalyst itself is really green,” Rother says. Because enzymes are designed to work in our bodies, they operate at a neutral pH value and don’t require the high temperatures and pressures often needed to activate catalysts for organic reactions. Enzymes are environmentally benign in other ways too. “They don’t produce toxic waste,” Rother says. “If you want to get rid of them at the end, you simply heat them. Then they are dead, and you can throw them away.”
The catch is that biocatalysts tend to have a yield problem. Enzymes don’t typically make large amounts of compounds; they make only what they need to fulfill their biological function. That’s not ideal for industry, which strives to efficiently make large amounts of a compound, Rother says. And the answer to this challenge, counterintuitively, is putting enzymes in organic solvents.
Enzymatic biocatalysis reactions tend to give higher yields in organic solvents. And according to Rother’s analysis, using organic solvents creates less organic waste than running the same reactions in water. Industry typically aims to use enzymes to make nonnatural compounds, such as drug molecules. These compounds tend to be very insoluble in water. As a result, researchers have to use large amounts of organic solvents to separate their products from the enzymes, Rother says, negating the benefits of using water in the first place.
Overall, running biocatalysis reactions in green organic solvents is more environmentally friendly, she says, because scientists can get higher yields that don’t need as much workup and purification. This conclusion might surprise people, Rother says. “But you need to consider the complete process to look at the environmental factor,” she says, even if water is the solvent.
If using enzymes for biocatalysis is considered working with nature, then running organic reactions in water might be considered working against nature. But there are several ways chemists can coax organic molecules to react in water. Researchers separate these methods into various types but disagree on how many types there are. For simplicity’s sake, this article presents three basic types: in water, on water, and with water.
In water basically means putting the compounds in water with no additives. For this method to work, the compounds have to be soluble in water, and the reactions happen in the water itself, says Fabrice Gallou, a scientist at the pharmaceutical company Novartis. Chemists tend to start with what they know, he says. And that means dissolving compounds in solution to react. Chemists like to put compounds in solution so they can analyze and control things, but that’s an issue when the compound isn’t very soluble in solvents, he says. One way to help reluctant organic molecules go into an aqueous solution is to change the pH of the water.
The pH of neutral water is 7. Tweaking it up or down can greatly affect reagents’ solubility, says Dan Bailey, a sustainability scientist at Takeda Pharmaceuticals. Imagine the organic compound a chemist is trying to dissolve contains a carboxylic acid group, he says. Adding a base to this aqueous mixture will pull off a hydrogen ion, leaving a negative charge on the compound. A charged species is much more likely to go into the polar water solution than a neutral one, Bailey says. So in some cases, “you can get full dissolution of organic reaction components in water without really using any sort of surfactant or other solubilizing additive,” he says.
The important word there is some. Manipulating the pH works only in cases in which the molecule has built-in ionizable groups, Bailey says. That’s not the case for a high percentage of molecules, especially ones used in the pharmaceutical industry, Gallou says. Drugs have to contain very specific functional groups in exact places to be effective against a target in the body. Often, the required functional groups turn the compounds into “brick dust,” Gallou says, organic chemistry slang for something that’s hopelessly insoluble, especially in water. Pharmaceutical compounds that can work in pure water are “exceptional things,” Gallou says.
Instead of fighting against the chemical unwillingness of organic molecules to dissolve in water, some chemists take advantage of this feature. On water refers to reactions that occur at the interface—where the organic blobs touch the water blobs. The compounds are clearly not soluble in water, Lipshutz says. “They usually sit on the surface in a neat state,” he says.
Researchers have found that these types of reactions have an unexpected boost: some chemical reactions run faster at the water-organic interface than they do in traditional organic solvents. This hydrophobic effect was first proposed by organic chemist Ronald Breslow, says C. J. Li, an organic chemist at McGill University. This reaction acceleration comes down to organic compounds forming blobs in water, he says. Water molecules form hydrogen bonds with one another, which pushes the organic molecules away, Li says.
“The organic molecules are squeezed together. And that internal pressure is extremely high,” he says. High enough that even though the mixing occurs at room temperature and pressure, the reactions inside the organic blobs go faster than they would otherwise. Breslow found that on-water conditions accelerate the Diels-Alder reaction by as much as 700 times (J. Am. Chem. Soc. 1980, DOI: 10.1021/ja00546a048).
K. Barry Sharpless later developed the on water term and examined the effect in depth by showing that several other uni- and bimolecular reactions also get higher yields or faster reaction times than those performed in an organic solvent (Angew. Chem., Int. Ed. 2005, DOI: 10.1002/anie.200462883). Many scientists have also shown this reaction boost since then, and now the phenomenon is accepted as a given, Li says.
But one of the downsides of on-water reactions is that they are limited to the surface of the aqueous-organic divide. To address this limitation, chemists have had to come up with crafty ways to increase the organic-water surface area.
To figure out how to make organic compounds and water mix better, chemists need to once again look to the early days, Lipshutz says. Scientists don’t know the exact recipe for the primordial soup that gave rise to RNA, but they do know that it wasn’t straight-up H2O. “Clearly the water wasn’t pristine. What was in the water that enabled chemistry to happen?” Lipshutz asks.
Adding another component, such as a surfactant, to help the water and organic layers mix is at the heart of with-water chemistry. Surfactants are molecules that have a hydrophilic, or water-loving, part connected to a lipophilic part, the greasy end of the molecule. “When you add surfactants to water, they self-assemble into structures known as micelles,” Takeda’s Bailey says. Micelles are essentially little bubbles in which the surfactant molecules line up such that the hydrophilic parts are pointing out toward the water and the hydrophobic parts face the inside. The idea is that these micelle bubbles act as sort of nanoreactors. The approach is known as micellar catalysis.
When chemists add oily organic molecules to mixtures with micelles, the compounds wiggle into the greasy spaces at the centers. “They come together and react, and then they can migrate back out into the surrounding water,” Bailey says. “Because you have higher effective concentrations of reaction components inside these micelles, you tend to get faster reaction rates.”
Micellar catalysis is one of the most active areas in with-water research, at least in part because Lipshutz has showed that it can be so successful. After the UC Santa Barbara EH&S specialist told Lipshutz about his waste output, the organic chemist threw all his synthetic efforts into finding ways to use water as a solvent.
In 2008, Lipshutz published his first research on micellar catalysis by showing it can work with olefin cross-metathesis reactions, which are typically performed in an organic solvent such as dichloromethane (Org. Lett. 2008, DOI: 10.1021/ol800028x). Since then he’s ticked off a number of other common synthesis reactions, including 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).
Lipshutz has also produced an army of chemists doing further research in micellar catalysis. Former postdoctoral researcher Sachin Handa, now at the University of Louisville, stuck with the field, studying the application of micellar chemistry to Buchwald-Hartwig aminations (ACS Catal. 2019, DOI: 10.1021/acscatal.9b02622), carbanion intermediates (ACS Catal. 2020, DOI: 10.1021/acscatal.0c01196), and click chemistry (ChemSusChem 2022, DOI: 10.1002/cssc.202201826).
In addition, Lipshutz’s group has teamed up with Gallou at Novartis to develop a biodegradable surfactant, derived from vitamin E and polysarcosine, called Savie (J. Am. Chem. Soc. 2023, DOI: 10.1021/jacs.2c13444).
Wilfried Braje, a chemist at the pharmaceutical company AbbVie, has done work in a similar vein, using a benign cellulose derivative as a surfactant. Hydroxypropyl methyl cellulose is often used in drugs and foods, including some kinds of ketchup. But instead of forming micelles, it makes structures with lipophilic pockets.
There is still work to be done to scale up these types of reactions for industry, Braje says. One problem is changing solubility over the course of the reaction, he says. The compound can sometimes come crashing out of solution, forming a blobby gumball around the stir bar.
“The reaction still works,” he says. But if this were to happen in a flow reactor that uses easily clogged tubes to deliver the solution to the next part of the reaction process, the entire operation might come to a screeching halt. “It’s not something that we could transfer to a large reactor,” Braje says.
Scaling up organic reactions in water to the volumes that industry requires is only one of the challenges. Doing chemistry in water “isn’t going to be a silver bullet that allows you to develop a sustainable process without putting in the work,” Takeda’s Bailey says. “We often tend to focus on the reaction portion of a process because that’s where our expertise as chemists lies.” Chemists need to look at the entire process, which includes purification and isolation of the target compounds.
“We need to make sure we’re driving reductions not only in the reaction portion of the process but in those downstream unit operations as well,” Bailey says.
Another challenge is the pushback some chemists give these techniques. “The first thing you hear is, ‘Things have been done this way for centuries, literally. Why should I change now?’ ” Novartis’s Gallou says. “By design, especially in pharma, we are very much risk averse. We don’t like the changes.” People weigh the pros and cons of a change very carefully, Gallou says. “You really need to have significant benefits to induce that change.”
In addition, it’s difficult to change production techniques that have already been established and cleared by regulatory authorities. “It’s not easy to change, even if technically we can demonstrate the change is beneficial,” Gallou says. There’s so much at stake when a company makes compounds in large amounts, including changing protocols and the lengthy filing process required by regulatory agencies.
The problem of organic-solvent waste won’t be solved just by switching all organic chemistry to water. “I don’t think there’s a one-size-fits-all approach to solving this green chemistry problem,” Lipshutz says. “I think we need lots of alternatives.”
Bailey agrees. “I don’t think there will be a future point where we’re using 100% chemistry-in-water processes. I think there’ll be a variety of strategies, but I think this will be an extremely important component of that strategy,” he says.
Whatever those are, Lipshutz says he hopes changes are made soon. “I look at kids and I wonder what the future has in store for them because we have finite resources on the planet. And the evidence is that we are consuming these resources at an enormous rate.”
When are chemists going to reach the point of inflection where people start doing more environmentally friendly reactions? “We’re not there yet,” Lipshutz says. Part of the answer depends on what the driving force for this change is going to be, he says. “Is it going to be climate change? Is it going to be regulatory? Is it going to be costs? Or all the above?”
Lipshutz laments the slow pace of progress. “But the discoveries are there to be made,” he says. When scientists see the possibilities in doing chemistry in water—both the challenges and the excitement of making discoveries—more people will jump in, he says. “Water is not our enemy,” Lipshutz says. “It’s actually our best friend.”