My research project this summer, titled “Examining the Wagner-Jauregg Reaction: Providing an Alternative to Morphine,” was designed to explore the possibility of synthesizing a molecule similar to morphine, but without the addictive qualities. Through my research, I looked at known chemical reactions that might provide a pathway to forming a morphine-like molecule and explored ways to change and increase the effectiveness of those reactions. My project built off of the research of several students that studied at St. Lawrence in the past, as well as Dr. Tartakoff’s own research. The work done on my research project was a small part of a larger research idea that has been ongoing and will likely be worked on for years to come, but the discoveries made through my research were essential contributions to the project’s continuation.
To conduct my research, I started by running a known variation of the Wagner-Jauregg reaction, which reacted 4-methoxystyrene with maleic anhydride, using a small amount dimethylaniline (DMA) to inhibit polymerization, and dimethyl sulfoxide (DMSO) as my reaction’s solvent. This allowed me to see how the process worked and practice setting up chemical reactions, as well as the purification process involved in order to get a clean 1H NMR spectrum to analyze. I then swapped out the maleic anhydride for a compound called N-methylmaleimide, which replaces one of the oxygen atoms in maleic anhydride with a nitrogen atom and adds an extra carbon atom. This seemingly small change, however, led to the formation of a new type of product formed from a chemical reaction known as an “ene” reaction, and appeared in a 2:1 ratio in comparison to the desired Wagner-Jauregg product. In order to try to shift the 2:1 product ratio towards the Wagner-Jauregg product, I changed variables such as reaction temperature, scale, and amount of N-methylmaleimide, but each change resulted in the same 2:1 ratio. I also substituted in N-phenylmaleimide in a series of reactions, which made a series of new products that were interesting but more difficult to purify.
After establishing the effectiveness of N-methylmaleimide as one of the starting materials in the reaction, I examined ways to change the other starting material (4-methoxystyrene) to make it more reactive. To do this, I synthesized compounds that differed from the 4-methoxystyrene by the addition of a different functional group, which is something that can drastically affect reactivity. These compounds included 1-methoxy-4-(1-methylethenyl)benzene and benzenemethanol, 4-methoxy-α-methylene-, 1-acetate. By examining the NMR spectra of the resulting reaction products, I was able to see which starting materials made more product. I also ran multiple different reactions at the same time, so that I could test them at regular intervals to examine which reactions were most efficient in terms of reaction time. I found that the 1-methoxy-4-(1-methylethenyl)benzene was more reactive than the 4-methoxystyrene, which will be important to consider in any future investigation further into improving reactivity.
After examining reactivity, I wanted to find ways to improve the purification process to fully characterize the products I was making. I had to adjust the method several times, sometimes from product to product, and eventually I found a combination of solvent washes and extraction techniques that purified most of the products at least some of the way. However, it was difficult to separate the Wagner-Jauregg and “ene” products from one another, since they have very similar solubilities. I was able to successfully isolate a small amount of the Wagner-Jauregg product from one of the reactions, which can be used for further testing in a future project and/or by another student and moves the project one step closer to synthesizing the core structure of a morphine molecule.