Brugia Malayi - Clark Science Center - Smith College

Methyl Transfer of Oxygen Nucleophiles in Organic Synthesis
Yuan Ji and Jessica Sweeney
Methylation is widely used in organic chemistry to synthesize molecules including polymers and pharmaceuticals. Common
substrates to synthesize are phenols, carboxylic acids, and aliphatic alcohols. The goal of our research is to find safer and costeffective
reagents to perform methylation. Currently, the most common methods of methylation involve hazardous and highly
toxic chemicals such as diazomethane. Diazomethane is explosive and must be synthesized using specialized glassware due to its
instability. Exposure to current methylating agents has caused several deaths since 2008. 1
In our research, we methylated benzoic acid and phenol using dimethyl carbonate as a safe-alternative to diazomethane.
We ran over one-hundred reactions this summer to determine the best conditions. Most reactions were run on a 25 mg scale.
Various bases were screened with equivalents ranging from 1 to 0.1. We also screened a range of catalysts, solvents, and varied the
temperature and duration at which these reactions were run.
Data obtained from screening were quantified using a gas chromatograph-mass spectrometer. By running samples containing
known concentrations of our product along with an internal standard, we were able to construct standard curves that correlate GC
signal integration with concentration of product.
We established the best conditions for methylating benzoic acid were using catalytic amounts of potassium carbonate (0.2 eq.)
at 90 o C for 72 hours. This reaction was run on a 100 mg scale. The product was isolated and an 81% yield was obtained. Another
set of reactions were run using trimethyl orthoacetate in placement of dimethyl carbonate as the methylating agent.
Similar to the methylation of benzoic acid with dimethyl carbonate, starting conditions for methylation with orthoacetate
included a catalyst, methylating agent, and starting material. We have had success with catalytic amounts of metal halides at a
temperature of 90 o C (73%). Lastly, methylation of phenol was also researched.
Much like the benzoic acid methylation, various bases, catalysts, and solvents were screened. Thus far, the best conditions for
methylation of phenol with dimethyl carbonate include catalytic amounts of 1,2-dimethylimidazole and extreme heat (~150 o C);
these conditions gave a 74% yield. During the semester we hope to establish mild conditions for the methylation of benzoic
acid with orthoacetate and the methylation of phenol by continuing to screen more catalysts, bases, and temperatures. After a
successful ten weeks over 170 reactions were run and quantified. (Supported by the Howard Hughes Medical Institute)
Advisor: David Gorin
References:
1.
Shieh, W.-C.; Dell, S.; Repic, O. “Nucleophilic catalysis with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) for the esterification of carboxylic acids with dimethyl
carbonate.” Journal of Organic Chemistry 2002, 67, 2188-2191. b)Rekha, V. V.; Ramani, M. V.; Ratnamala, A.; Rupakalpana, V.; Subaraju, G. V.; Satyanarayana, C.; Rao,
C. S. “A simple, efficient, green, cost effective and chemoselective process for the esterification of carboxylic acids.” Organic Process Research and Development
2009, 13, 769-773. c) Carafa, M.; Mesto, E.; Quaranta, E. “DBU-Promoted Nucleophilic Activation of Carbonic Acid Diesters.” European Journal of Organic
Chemistry 2011, 2458-2465.
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