Ultrasound-assisted synthesis and stereoselectivity analysis of para-menthane-3,8-diol from citronellal via the Prins reaction.

para-Menthane-3,8-diol (PMD) is a widely used bio-based insect repellent. However, its conventional synthesis is limited by protracted reaction times. Herein, we report an ultrasound-assisted Prins cyclization of citronellal, a monoterpenoid aldehyde, to PMD under 20 kHz irradiation. Using pure citronellal, ultrasound irradiation at 40% amplitude (∼48 µm) afforded PMD with 98% GC-FID purity within 2 h, compared with 87% PMD obtained after 10 h under conventional heating. Even at 100% amplitude (∼120 µm), the reaction proceeded within 10 min while maintaining a high PMD content of approximately 93%. For lemon eucalyptus (Eucalyptus citriodora) oil, ultrasound irradiation at 40-60% amplitude (∼48-72 µm) reduced reaction times from 15 h to 0.5-2.0 h while providing PMD contents comparable to those obtained by conventional heating. Notably, crystallization from the natural oil feedstock increased the cis-isomer content to 90%, compared with 65% obtained from pure citronellal. The observed cis stereoselectivity is proposed to arise from steric effects associated with the 3-methyl substituent of citronellal during intramolecular cyclization. Density functional theory calculations qualitatively support the proposed stereoselective mechanism. These findings provide an efficient approach for the synthesis and purification of PMD while offering mechanistic insights into stereochemical control in Prins cyclization reactions.