February 21, 2022, a collaboration between researchers from the California Institute of Technology, Lin Research Group, and Merck & Co., Inc. led by Cornell, released a paper titled, “Electrochemically Driven Cross-Electrophile Coupling of Alkyl Halides.” This paper revealed their work regarding the usage of controlled electrochemistry(the science behind the chemical processes that cause electrons to move) to bond carbon with alkyl halides under co-authors Song Lin, the team lead, and Da-Gang Yu.
Halides are compounds with two parts. The first is a halogen atom, which is any one of the six elements in group 17 of the periodic table. The other is any element that is less electronegative than the halogen atom being used. Usually, the halides have to be activated by metals, however, their goal was to eliminate that need as the process created unwanted, highly-reactive byproducts. After experimenting and overcoming different challenges with bonding between carbon and the alkyl halides, the team then shifted focus to carbon-pyridine bonding.
Certain substances are very commonly found in pharmaceutical products, such as pyridines. Pyridine is a type of heterocycle, a compound whose molecules are arranged in a ring-like structure with at least one non-carbon molecule. They are commonly used in medicines to improve water solubility. C-H carboxylation utilizes the movement of electrons to carboxylate the molecule. Carboxylating pyridines could change the function of the molecule and allow it to bind to proteins, providing a greater variety of uses for it. It also provides a method of addressing and even harnessing the increasing CO2 levels in the atmosphere.
The team had two options with which they could approach their task: undivided and divided cell carboxylation. In chemistry, a cell is a group of resources or substances treated as a single entity (like organelles part of a biological cell) that transfers energy through electricity. Both of the methods require the anodes and cathodes to be present for the redox reactions, that are reactions in which electrons are either lost (oxidized) or earned (reduced). The anode is the electrode losing electrons, making it positive and the cathode is gaining electrons, making it negative. An anodic reaction is composed of an electron leaving the anode for the cathode, and a cathodic reaction follows the same line of reasoning. The two go hand-in-hand- where there is an anodic reaction there has to be a cathodic reaction. The difference between the divided versus undivided methods is that in an undivided cell the anode and cathode are in the same solution, however in divided cells they are separated by a porous barrier, through which only ions can travel. The team realized that simply by changing their electrochemical reactor, the cell, they were able to create two different products, both which can be utilized in the pharmaceutical world. By using an undivided cell, the process results in C4-carboxylation where the reactions involve carbon number four of the molecule(In organic molecules, the different carbon atoms in the molecule are differentiated by giving them numbers). However, the use of a divided cell resulted in C5-carboxylation which used carbon number five. This is because in each process, the team could attach their carbon to different parts of the pyridine, and if you recall from your biology class, a molecule’s structure determines its function or potential.
The paper’s co-author Song Lin expressed high hopes as he said, “This is the first time we discovered that by just simply changing the cell, what we call the electrochemical reactor, you completely change the product… [this] will allow us to continue to apply the same strategy to other molecules, not just pyridines, and maybe make other molecules in this selective but controlled fashion.” This has the potential to revolutionize pharmaceutical chemistry, with researchers possibly being able to create the molecules they need with a greater variety presented by different processes.
The process wasn’t seamless, however. The first big problem the team faced was that pyridine and carbon dioxide are not natural partners. Carbon dioxide is an inert gas, meaning it is usually non-reactive as due to the molecule’s structure, the positive charge of the carbon is being canceled out by the oxygen atoms while pyridine is a reactive molecule. The team utilized organic synthesis for this process, where “building blocks” are used to compose molecules from scratch. Another complication was that electrodes - the anodes and cathodes - can degrade over time, essentially putting a time crunch on the research and limiting the amount of product that could be made. This is a problem they had run into with their alkyl halides, which they solved by turning to Kimberly See, the paper’s co-author for the halides, at the California Institute of Technology. Her team recommended an additive that could stave off the degradation, enabling higher production rates which could turn out to be useful in pharmaceutical production.
The team now aims to continue their experimentation with the carboxylation of different molecules to potentially revolutionize the production of certain pharmaceutical compounds and even combat growing CO2 levels through their use of carbon. Their work has already provided numerous breakthroughs in the pharmaceutical world, whether it be eliminating the need for certain processes or amplifying the usefulness and efficiency of other substances. The Cornell-organized collaboration between the California Institute of Technology, Lin Research Group, and Merck & Co., Inc. will hopefully continue to produce results that may change the system dramatically.