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Natural Products

A natural mosquito repellent’s most active form found

Chemists synthesized the most potent diastereomer by controlling reaction conditions

by Charles Q. Choi, special to C&EN
September 23, 2021


A close-up shot of a mosquitor with broad black stripes alternating with thing white ones.
Credit: Shutterstock
Aedes albopictus—a species of mosquito that can carry Zika, chikungunya, and dengue—can be repelled using p-menthane-3,8-diol.

Found in lemon eucalyptus, p-menthane-3,8-diol (PMD) is one of the five chemicals recommended by the US Centers for Disease Control and Prevention as a mosquito repellent and the only natural one on the list. Now scientists have discovered that one form of PMD may prove to be nearly as effective against certain types of mosquitoes as the benchmark synthetic mosquito repellent, DEET, yet significantly less toxic to people (J. Agric. Food Chem. 2021, DOI: 10.1021/acs.jafc.1c03897).

Mosquitoes are the world’s deadliest animal, with mosquito-borne diseases killing more than 1 million people worldwide each year. DEET is commonly used to fend away the insects, but it can irritate the skin and can be neurotoxic. Natural alternatives such as cedar and lavender essential oils can ward off mosquitoes and are less toxic, but these substances often evaporate quickly, limiting their effectiveness. In contrast, PMD is longer lasting.

In nature, PMD can be found as a mix of four diastereomers—compounds that have the same molecular formula and linkages between atoms but different 3D shapes. Previous work suggested these four diastereomers were equally active against the mosquito Anopheles gambiae, the main vector for malaria in sub-Saharan Africa. That struck organic chemist Marc Lemaire of Claude Bernard University Lyon 1 and his colleagues as odd, since the smell of a molecule and its consequent effectiveness at repelling mosquitoes are closely related to its shape.

A reaction scheme showing how a colder reaction temperature causes the formation of 1R-(+)-cis-PMD from citronellal while a warmer reaction temperature produces 1R-(–)-trans-PMD.
Using lower reaction temperatures, chemists can predominantly produce the more active cis forms of p-menthane-3,8-diol.

To explore PMD’s effects on mosquitoes, the researchers in France collaborated with colleagues in Madagascar to test how well each of the four diastereomers repelled Aedes albopictus, a species that can spread diseases such as Zika, chikungunya, and dengue. All the diastereomers repelled mosquitoes to similar degrees when tested in a laboratory setup where there was almost no air circulation. But the results differed significantly when the compounds had the chance to vaporize and disperse, such as when applied to human skin. One diastereomer, (1R)-(+)-cis-PMD, was the clear winner for best repellent over time due to its lower evaporation rate—the duration of its repellent effect is “very similar to DEET,” Lemaire says.

Industrially, PMD is usually made from citronellal, which naturally occurs in citronella, rose, and geranium oils as well as in lemon eucalyptus. By controlling the temperature during synthesis, Lemaire and his team discovered they could influence which PMD diastereomers were predominantly made. Specifically, the more active cis forms of PMD are produced at lower reaction temperatures, a finding that could help in commercial production of the most effective PMD diastereomer, Lemaire notes.

The researchers also found that PMD repelled mosquitoes more effectively when tested on three women than on three men. One possibility is that female skin may release fewer mosquito attractants, such as carbon dioxide or lactic acid, so PMD can better mask these compounds. But “we really have to work on this point because it may be necessary to find specific repellents for the different types of skin,” Lemaire says.

Apurba Bhattacharjee, a computational medicinal chemist at Georgetown University who has investigated mosquito repellents and compounds against mosquito-borne diseases, notes that future work may want to investigate how climate and temperature change the effectiveness of these molecules. “Remember, these products should mostly be useful in tropical countries with high levels of humidity,” says Bhattacharjee, who did not take part in the study.

Lemaire and his colleagues now plan to “produce a blend of natural or almost natural chemicals with very high efficiency and long-duration effect—24 h could be optimal,” he says. They also are looking for molecules they can include in polymers to create protective materials such as nets and clothing.


This story was updated on Sept. 30, 2021, to correct the structure of R-citronellal. The molecule’s aldehyde group was drawn as an alcohol.


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