Abstract View

Objective: Electric cigarettes are gaining popularity due to their appealing flavors. Menthol is one of the most common and popular flavors. Previous studies have shown that menthol affects lung and cardiovascular functions^1,2. To evaluate the biodistribution and health effect of different optical isomers of menthol we aim to synthesize ¹⁴C-labeled menthol. Traditionally, menthol has been synthesized by using high pressure hydrogenation techniques or using gaseous reactant applying higher pressure. These conditions and any current industrial methods are not easily translated to small scale research laboratory production of ¹⁴C-labeled menthol. Here we investigate the synthesis of menthol via in situ hydrogenation of thymol under atmospheric pressure and optimization of the reaction conditions.  

Methods: Menthol was synthesized from thymol in two steps. Thymol was hydrogenated by using potassium formate in presence of Pd/C in water to produce menthone followed by reduction of menthone using sodium borohydride (2 eq.) in methanol (Scheme 1). The hydrogenation reaction of thymol was optimized by changing different parameters like time, temperature, mol% of catalyst, and the amount of potassium formate. Conversion of thymol to menthone and menthone to menthol were confirmed by GC-MS and NMR analysis.

Results: We have successfully synthesized menthol from thymol by in situ hydrogenation under atmospheric pressure with more than 99.99 % conversion of thymol to menthone. Reaction time, temperature, catalyst, and HCOOK amount affect the hydrogenation process. The optimized conditions were: reaction time of 7 h, reaction temperature of 80 ^oC, catalyst (10 wt% Pd/C) concentration of 5 mol%, and 6 equivalents of potassium formate. The reduction of menthone to menthol proceeded with quantitative yield.

Conclusions: Following the above-mentioned optimized conditions, we can easily synthesize ¹⁴C-labeled menthol from commercially available [¹⁴C]thymol with high radiochemical yield. Currently, we are optimizing the separation method for different optical isomers of menthol.

References:

1         Wang, Q., Lucas, J. H., Pang, C., Zhao, R. & Rahman, I. Tobacco and menthol flavored nicotine-free electronic cigarettes induced inflammation and dysregulated repair in lung fibroblast and epithelium. Respiratory Research 25 (2024). https://doi.org/10.1186/s12931-023-02537-9

2         Ramalingam, A. R. et al. Acute and Persistent Cardiovascular Effects of Menthol E‐Cigarettes in Mice. Journal of the American Heart Association 14 (2025). https://doi.org/10.1161/jaha.124.037420

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