Fluorine in fragrances: exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones
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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.
Corr , M J , Cormanich , R , von Hahmann , C , Buehl , M , Cordes , D B , Slawin , A M Z & O'Hagan , D 2016 , ' Fluorine in fragrances: exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones ' Organic & Biomolecular Chemistry , vol 14 , no. 1 , pp. 211-219 . DOI: 10.1039/C5OB02023A
Organic & Biomolecular Chemistry
Copyright 2016 the Authors. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (http://creativecommons.org/licenses/by/3.0/).
DescriptionThe authors thank EPSRC for a grant. CNvH also thanks the Fluorine Division of the American Chemical Society for a Moissan Summer Undergraduate Fellowship. RAC thank FAPESP for a fellowship (#2015/00975-7).
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