Hydrogenation of Naturally-Derived Nepetalactone as a Topical Insect Repellent

Abstract

Dihydronepetalactone (DHN) is a safe and effective topical insect repellent,(5,6,8) comparable in efficacy to that of N,N-diethyl-m-toluamide (DEET). The latter is the most commonly used active ingredient, found in many commercial insect repellents for a broad range of biting insects. DHN can be produced by hydrogenating nepetalactone (NL), which is the primary ingredient of the essential oil obtained from the renewably sourced catmint plant, Nepeta cataria. Optimizing the hydrogenation reaction to produce DHN from catmint oil is a key economic driver for the process. Prior to the study described here, Six Sigma methodologies were used to select palladium on carbon (5% Pd/C) as the catalyst of choice. The hydrogenation step was studied as a function of critical process variables and the composition of the oil. As described in this article, a robust, two-step hydrogenation process was developed to maximize the yield of the desired DHNs from treated catmint oil. It was observed that the composition of the catmint oil, vis-à-vis, the relative amounts of trans–cis and cis–trans-nepetalactone isomers, had a major impact on the activity and selectivity of the catalyst. This study also focused on minimizing the formation of a less desirable byproduct, puleganic acid. On the basis of the process variables tested in this study, temperature was found to have a strong effect on the activity and selectivity of the catalyst. Higher pressure enhanced the activity of the catalyst but it did not significantly impact the formation of undesired byproducts, such as puleganic and nepetalic acids. Spiking experiments with suspected catalyst poisons, such as dimethyl sulfide, dimethyl sulfoxide, nepetalic acid, and puleganic acid were also performed to study catalyst deactivation. Sulfur was identified as the main factor for the catalyst deactivation. Possible reaction mechanisms for the formation of less desirable puleganic and nepetalic acids have been suggested.