Issue Date: March 13, 2017
Electrosynthesis gives organic chemists more power
When it comes to electrochemistry, the first thing that pops into mind probably isn’t C–H activation or arene cross-coupling reactions. You might think of batteries and solar cells, or industrial processes such as electroplating and the electrolytic production of metals such as aluminum. Others might think of cyclic voltammetry, a technique used to study the chemical properties of compounds and reaction mechanisms.
But for plain old organic chemistry, like those arene cross-couplings, electrochemistry isn’t common in research or used widely on a preparative scale. The century-old chlor-alkali electrolysis process to prepare chlorine and sodium hydroxide from sodium chloride solution is one exception. And emerging more recently have been clean energy electrocatalytic reactions such as splitting water to make hydrogen and reducing carbon dioxide to make simple hydrocarbons.
Today’s chemists have been simply reluctant to adopt electrosynthesis, believing the technology is too cumbersome or expensive. Yet as a growing cadre of researchers is showing, the benefits of the technology can no longer be overlooked.
“Synthetic chemists have long viewed electrochemistry as an area where a few people do interesting reactions that are difficult for everyone else to repeat,” says Kevin D. Moeller of Washington University in St. Louis. “That view is changing: The field is undergoing a dramatic uptick in popularity at the present, which for those of us who have been advancing the technique for a while now is really exciting.”
“There is a real resurgence of electrosynthesis,” adds Siegfried R. Waldvogel of Johannes Gutenberg University Mainz. “The invasion of more synthetically oriented scientists is propelling the area dramatically.”
Synthetic organic reactions are fundamentally about adding and subtracting electrons to and from target molecules. Researchers achieve electron pushing typically through the power of an acid, base, or metal catalyst, accompanied by the activity of a cocatalyst or oxidizing and reducing agents to complete the circuit, so to speak, allowing the catalyst to be recycled.
In recent years, improvements in photocatalysis, in which light interacting with a catalyst helps drive the electron-transfer process, have further boosted organic synthesis. Electrosynthesis is offering a similar boost, except it’s a pair of electrodes controlling electron flow in the reaction vessel instead of a lightbulb. Electrochemical synthesis shares some of the same perceived barriers to adoption as photocatalysis, but both approaches present the benefit for chemists to do more with less.
Electric current, when used as a surrogate reagent, offers researchers the ability to avoid toxic or dangerous oxidizing or reducing reagents, protecting groups, and catalysts typically used in organic synthesis. Moreover, reducing or eliminating heating and cooling of reaction vessels can cut energy consumption. Another plus is the ability to selectively target functional groups in a molecule during a reaction based on their different redox potentials, which is useful in diversifying intermediates and final products.
Those advantages play right into the hands of the modern synthetic organic chemist, who is faced with the challenge of creating increasingly complex molecules in a greener, more sustainable, safer, and more cost-effective manner over current reagent-based approaches.
Waldvogel’s group, for example, in collaboration with researchers at Evonik Industries, last year created a metal-free, oxidant-free one-step electrochemical protocol for cross-coupling phenols to make symmetrical and nonsymmetrical biaryl diols (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201604321 and 10.1002/anie.201605865). The researchers just expanded the approach to aniline-aniline cross-couplings to form 2,2´-diaminobiaryls (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201612613).
Overall, the scalable “power-to-chemicals approach” is important for making specialty, value-added products, Waldvogel notes, including drug candidates, agrochemicals, flavors and fragrances, catalyst ligands, and molecules for materials science. And going beyond standard batch processes, Waldvogel’s team is developing continuous electrochemical processes using microflow reactors, which can further increase efficiency and reduce waste.
“This stuff is extraordinary,” Waldvogel exclaims. “These findings bring oxidative cross-coupling to the next level. Electrosynthesis represents a disruptive technology and will be a game changer for industry .”
In another example, Jun-ichi Yoshida and coworkers at Kyoto University have been helping advance electrosynthesis with a series of arene functionalization reactions. Yoshida’s team carried out electrochemical oxidation of toluene derivatives to form benzyl cations that accumulate in solution, what Yoshida refers to as a “cation pool.” Reactions with subsequently added nucleophiles give the desired benzylic C−H/aromatic C−H cross-coupling products. The Kyoto researchers have used this approach to make a variety of compounds, including a precursor of TP27, an inhibitor of protein tyrosine phosphatases. PTPases, as they are called, are regulators of cell growth and metabolism associated with conditions such as diabetes (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b05273).
Taking another approach, Shannon S. Stahl’s group at the University of Wisconsin, Madison, has been working toward developing more efficient electrochemical oxidation of biomass-derived alcohols. TEMPO (2,2,6,6-tetramethyl-1-piperidine N-oxyl) is an effective catalyst for such oxidations, but it requires running reaction cells at high electrode potentials. Stahl’s group found that copper bipyridine and TEMPO work as cooperative partners for the two-electron oxidation of alcohols to make ketones and aldehydes. The dual electrocatalyst oxidations run at a fivefold faster rateand operate at an electrode potential a half-volt lower than that used for the TEMPO-only process (Nature 2016, DOI: 10.1038/nature18008).
“This is incredibly impactful research—the reemergence of electrochemistry deserves our attention,” says Phil S. Baran of Scripps Research Institute California. Getting the attention of reluctant chemists isn’t going to be easy, however, as Baran along with Evan J. Horn and Brandon R. Rosen in his group point out in a recent perspective article (ACS Cent. Sci. 2016, DOI: 10.1021/acscentsci.6b00091).
In their experience, the Scripps researchers find a number of electrosynthesis “fears” must be overcome. These include investing in equipment. The barrier to investment becomes higher, they note, when chemists discover that a standard instrument for preparative electrolysis doesn’t exist and that many of the recent electrosynthesis success stories reported in the literature relied on home-built rather than commercially available equipment.
Adding to that fear, the Scripps researchers point out, is trying to understand the complex reaction setup, from the potentiostat to the endless number of variables encountered, such as deciding what type of reaction cell, electrode, or electrolyte to use for a given reaction. Plus, a common misconception is that only aqueous solvents can be used, when many organic solvents do work. Another misconception is that product separation is difficult.
Baran’s group became involved with electrosynthesis out of necessity, he says, when his team was attempting to prepare the dimeric natural product dixiamycin B. After extensive screening, the researchers couldn’t find a chemical oxidizing reagent capable of forging the N–N bond needed to couple the two monomer units in the final reaction step. Only after exhaustive evaluations did they begin to consider an electrochemical oxidation.
Rosen, Baran, and their coworkers found a plausible method, assembled the needed equipment, and then dialed in the oxidation parameters to accomplish what no chemical reagent could. The achievement demonstrated “the power of electrochemistry in organic synthesis, particularly in complex settings that require exquisite chemoselectivity,” Baran notes.
Baran’s group now turns more often to electrosynthesis. For example, the researchers were looking for a practical chemical method for direct allylic C–H oxidations to make enone and allylic alcohol derivatives as intermediates for preparing terpene natural products. Typical approaches involve chromium or selenium reagents and palladium or rhodium catalysts, which are unsuitable in an industrial process, because of their toxicity or their cost.
Horn, Rosen, Baran, and their colleagues, working in collaboration with chemists at Bristol-Myers Squibb, found an inexpensive N-hydroxyphthalimide catalyst that undergoes electrode oxidation to form an oxygen-centered radical that leads to the oxidation products. The researchers tested it by converting valencene to nootkatone, the major flavor compound in grapefruit. Process chemists subsequently used the approach to convert dehydroepiandrosterone derivatives to enones on a 100-g scale, eliminating the need for 80 g of a chromium reagent and the need to remove chromium-based contaminants from the product (Nature 2016, DOI: 10.1038/nature17431).
“Electrochemistry holds great promise for organic chemistry in terms of incredible efficiency and unique reactivity,” Baran says. “But in order for it to really catch on, it will need to penetrate the most populated market of practicing organic chemists: Those in industry.”
That barrier also appears vulnerable to falling. “We are motivated by electrochemistry’s ability to precisely control the flow of electrons in a redox process and its potential to access novel mechanisms,” says Jeremy Starr, an associate research fellow at Pfizer whose group has been advocating organic electrosynthesis for several years. This power is amply illustrated, Starr notes, by the stories Baran and others are laying out, “which really capture the excitement of this field with some of the most inspiring examples of what currently can be done.”
An especially important and perhaps underappreciated application for organic electrochemistry is in late-stage functionalization of drug lead compounds, Starr points out. His team has been using electrosynthesis to introduce oxygen or fluorine, or for making new C–C bonds, in small samples of complex molecules. At the other end of the spectrum, electrochemical oxidations, reductions, and cross-coupling reactions can offer synthetic and cost efficiencies for scale-up by sparing the use of stoichiometric quantities of reactants, he says.
“Like photoredox chemistry, I think the popularity of organic electrochemistry will grow as the perception of a high barrier to entry falls away, as inexpensive and easy-to-use power supplies and analytical tools become available, and as the relative ease of controlling and scaling the reactions becomes more broadly appreciated in the synthesis community,” Starr observes.
Besides pushing to develop new electrochemically enabled reactions, the research groups leading the way are also pushing to develop instrumentation specifically for the organic synthesis community, in some cases collaborating with lab equipment companies. The goal for these new products is to offer what Baran calls “out-of-the-box” instrumentation, or what Waldvogel says is equipment “like a utility truck, not a high-end Ferrari.” Waldvogel has already helped launch IKA’s lab-scale continuous-flow electrosynthesis system, called Electrasyn Flow. Baran hints that a product codeveloped in his lab will be unveiled later this year.
For Washington University’s Moeller, his group has been working for close to 30 years to make organic electrosynthesis more accessible. Moeller’s team was one of the first to show that electrochemistry can be used to couple two nucleophilic reagents, opening up a new set of reaction pathways. The researchers have used these reactions along with electrochemical amide oxidations to synthesize a range of complex molecules. Many of these reactions can be driven by sunlight using solar cells or by other simple power sources, Moeller says, “providing evidence that anyone can do this.”
To demonstrate, Moeller and his coworkers attached small photovoltaic cells normally used to power toy cars and boats or 6-V lantern batteries to the electrodes in their reaction flasks. Using these setups, they reproduced the yields of electrochemical reactions they originally ran with a conventional power supply. With Moeller’s guidance, Jeffrey Aubé’s group, then at the University of Kansas and now at the University of North Carolina, Chapel Hill, has shown how a repurposed cell phone charger can serve as a power supply and mechanical pencil leads can replace carbon electrodes. The researchers reported how that simplified equipment could be used for the C–H oxidation of polycyclic lactams in late-stage functionalizations (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201504775).
“Over the period of many years, a series of dedicated scientists has explored electrochemical methods in ways that both illustrate their potential and define the experimental parameters needed to more fully capitalize on them,” Moeller says. “Now with increasing pressure on the synthetic community to run more sustainable reactions, we have the opportunity to fully capitalize on this potential to enable a broad scope of synthetic transformations. No longer is electrochemistry the realm of specialists, and that change could not be more welcome.”
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