Fluorine in fragrances: exploring the difluoromethylene (CF 2 ) group as a conformational constraint in macrocyclic musk lactones

• Published in: Organic & biomolecular chemistry Vol. 14; no. 1; pp. 211 - 219
• Main Authors: Corr, Michael J., Cormanich, Rodrigo A., von Hahmann, Cortney N., Bühl, Michael, Cordes, David B., Slawin, Alexandra M. Z., O'Hagan, David
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 07.01.2016
• Subjects: Chemistry; Chemistry, Organic; Crystallography, X-Ray; Fatty Acids, Monounsaturated - chemical synthesis; Fatty Acids, Monounsaturated - chemistry; Fluorine - chemistry; Hydrocarbons, Fluorinated - chemistry; Lactones - chemical synthesis; Lactones - chemistry; Macrocyclic Compounds - chemistry; Models, Molecular; Molecular Conformation; Perfume - chemistry; Physical Sciences; Quantum Theory; Science & Technology; CHEMISTRY; RING
• DOI: 10.1039/C5OB02023A
• ISSN: 1477-0520; 1477-0539

The CF 2 group is incorporated into specific positions within the lactone ring of the natural musk lactone, (12 R )-(+)-12-methyl-13-tridecanolide, a constituent of Angelica root oil, Angelica archangelica L. The approach is taken as it was anticipated that CF 2 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 CF 2 groups located at the C-6 and C-9 positions, another ( 9 ) with CF 2 groups at the C-5 and C-9 positions, and a third ( 10 ) with a CF 2 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 CF 2 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 CF 2 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.