Fluorine in fragrances: exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones

The CF₂ group is incorporated into specific positions within the lactone ring of the natural musk lactone, (12R)-(+)-12-methyl-13-tridecanolide, a constituent of Angelica root oil, Angelica archangelica L. The approach is taken as it was anticipated that CF₂ groups would dictate corner locations in the macrocycle and limit the conformational space available to the lactone. Three fluorine containing lactones are prepared by organic synthesis. One (8) has CF₂ groups located at the C-6 and C-9 positions, another (9) with CF₂ groups at the C-5 and C-9 positions, and a third (10) with a CF₂ group at C-8. Two of the fluorine containing lactones (8 and 10) were sufficiently crystalline to obtain X-ray crystal structures which revealed that the CF₂ groups do adopt corner locations. All three lactones were subject to computational analysis at the B3LYP-D3/6-311+G** level to assess the relative energies of different conformers. In all cases, the global minima and most of the lowest energy minima have squared /rectangular geometries and located the CF₂ groups at the corners. The lowest energy structures for 8 and 10 closely approximated the observed X-ray structures, suggesting good convergence of theory and experiment in determining relevant low energy conformations. All three compounds retained a pleasant odour suggesting the rings retained sufficient conformational flexibility to access relevant olfactory conformations.