Apr 22 2016
A team of researchers at The Scripps Research Institute (TSRI) have discovered a novel and optimized way to attain a chemical reaction that is used a lot in the pharmaceutical, flavor, and fragrance industries.
Scripps Research Institute chemists Phil Baran (left) and Evan Horn pose in front of an electric car, whose principles of sustainable transport pertain to the sustainable chemistry in the Baran lab's new electrochemical allylic oxidation reaction, which eliminates toxic chemicals from a widely employed chemical process. (Photo credit: Image courtesy of The Scripps Research Institute.)
Conventional techniques of “allylic oxidation” generally apply toxic and/or expensive reagents, such as ruthenium, chromium, or selenium. This prevents the reaction from being scaled to industrial level, like in the case of manufacturing of pharmaceuticals.
Conversley, The TSRI team’s unique technique is easily scalable as it utilizes economical safe chemicals, coupled with conventional electrochemistry.
Turns out one of the best reagents you can buy is sitting in your wall socket.
Phil Baran, Professor of Chemistry, TSRI
The team partnered with pharmaceutical chemists at Bristol-Myers Squibb and China-based Asymchem Life Science, and demonstrated the importance of the unique method by using it to make over 40 in-demand compounds in a cost-effective, clean and scalable manner, compared to the earlier techniques.
The scope of the reaction is just phenomenal, it’s super easy to do, and the overall improvement in environmental sustainability is dramatic.
Phil Baran, Professor of Chemistry, TSRI
The research findings were published April 20, 2016, in the Nature journal.
Just a Little Oxygen
Allylic oxidation reactions fundamentally connect oxygen to carbon inside a cluster of atoms known as an allyl group, which is a basic feature of organic molecules. A drastic change can be witnessed upon adding one oxygen atom to the properties of the whole molecule. Therefore, allylic oxidation is utilized in chemistry to either enhance the properties of a current compound or to facilitate the synthesis of a compound otherwise available from plants only.
Since most of the earlier known allylic oxidation reactions use reagents that are either costly or toxic, or both, they have been used mostly in small-scale applications as the toxic waste load is easily controllable.
Some years back, Baran worked out of his laboratory to discover an economical and environmentally friendly process to conduct allylic oxidations in order for it to be used on a larger scale. They found a very obscure electrochemistry-based technique in a 1985 book published by Japanese researchers. Although this technique offered too low a yield to be of any difference on its own, it provided direction to a better technique as it did not need number of tricky reagents used in other allylic oxidations.
Current from a Simple Battery
After elaborate experimentation, Baran and his team, including co-lead authors Research Associate Evan J. Horn and graduate student Brandon R. Rosen, created a novel electrochemistry-based technique where all of the reagents and other system details are fairly simple, economical, and environmentally friendly.
The electrodes used to transmit current via the reaction vessel are composed of vitreous carbon and do not cost much. The oxygen source is not a pure gas as that could trigger an explosion or fire at industrial scales. Instead, a commonly available liquid oxidant, tert-butyl hydroperoxide was chosen.
The base and solvent are pyridine and acetone, which are readily available in chemistry labs and are cheap. The electrochemical mediator, which aids in eliminating hydrogen atoms from the original molecules to provide room for oxygen, is obtained in a single step from a non-toxic, economical and extensively available flame retardant. The electric current is managed by a potentiostat, which can be managed by a laptop. The current is supplied by a simple battery.
You could use a lantern battery or even a car battery if you wanted.
Phil Baran, Professor of Chemistry, TSRI
At first, Baran and his colleagues showcased the novel technique using allylic oxidations to alter many compounds of interest to Bristol-Myers Squibb (BMS), which has an ongoing research partnership with the Baran laboratory.
The TSRI team, along with Baran, showcased the technique on over 12 compounds widely referred to as terpenes, which are sought widely by chemists in the pharma industry.
Among other things we used the method to make some terpene natural products. A few of these related to medicinal chemistry, but we also made some compounds that are important for the flavor and fragrance industry—stuff that smells real nice.
Evan J. Horn, Research Associate, TSRI
One reaction produced a difficult to create nootkatone, which is a natural compound that helps to provide flavor to grapefruits and could be a safe insecticide.
Striking Improvements
In most of these experiments, the novel technique’s benefit over earlier techniques offered better yields, safer and economical reagents.
For one oxidation, the prior method required a chromium reagent in a 15 to one ratio with the compound to be oxidized, yet we were able to accomplish the same transformation with electricity and a cheap, safe, industrial oxidant and no chromium.
Brandon R. Rosen, Graduate Student, TSRI
Chemists at Asymchem Life Science, a process-oriented contract research organization with a lot of interest in electrochemistry, conducted one demonstration reaction at a medium, 100-gram scale and established its robustness and simplicity by just using a bucket bought from the hardware-store as their reaction vessel.
Doing that with a traditional chromium or ruthenium reagent would have generated far too much toxic waste.
Phil Baran, Professor of Chemistry, TSRI
Going forward, Baran and his team at TSRI will be exploring probable fragrance- and flavor-related applications using this method. They will also be partnering with BMS and Asymchem to create electrochemistry-based techniques for reactions beyond allylic oxidation.
Our hope, is that 10 years from now, at companies like BMS medicinal chemists and process chemists will routinely employ electrochemistry—and will all have potentiostats at their hoods, next to their stirring plates.
Phil Baran, Professor of Chemistry, TSRI
The paper, “Scalable, Sustainable Electrochemical Allylic C–H Oxidation,” was also co-authored by Yong Chen and Jiaze Tang from Asymchem; and Ke Chen and Martin D. Eastgate from Bristol-Myers Squibb.
The National Institute of General Medical Sciences (GM-097444), Asymchem and Bristol-Myers Squibb provided funding for the research.