Fluorine in fragrances: exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactonesElectronic supplementary information (ESI) available. CCDC 1427901-1427903. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ob02023a. For access to research data and metadata see DOI: 10.17630/f6dc25c1-c693-4c59-a164-3ccce6e7ef15

• 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
• Published: 15.12.2015
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob02023a

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. The synthesis of a series of selectively fluorinated musk lactones is reported with CF 2 groups at various locations to bias conformation the ring.