Molecular design exploiting a fluorine gauche effect as a stereoelectronic trigger

Rey, Y. P., Zimmer, L. E., Sparr, C., Tanzer, E.-M., Schweizer, W. B., Senn, H. M. , Lakhdar, S. and Gilmour, R. (2014) Molecular design exploiting a fluorine gauche effect as a stereoelectronic trigger. European Journal of Organic Chemistry, 2014(6), pp. 1202-1211. (doi: 10.1002/ejoc.201301730)

Abstract

Acyclic conformational control often relies on destabilising noncovalent interactions to give rise to predictable conformer populations. Pertinent examples of such strategies include allylic strain (A1,2 and A1,3) and syn-pentane interactions. However, the incorporation of fluorine vicinal to an electron-withdrawing group (F–Cβ–Cα–X) can lead to predictable conformations as a consequence of stabilising hyperconjugative and/or electrostatic interactions. Herein, we describe the application of a fluorine gauche effect to predictably control torsional rotation in a class of fluorinated 4-(dimethylamino)pyridine (DMAP) analogues. Intramolecularisation, such as protonation or acylation, generates an electropositive nitrogen centre vicinal to the fluorine atom at a molecular hinge (F–Cβ–Cα–N+); this is the only rotatable sp3–sp3 bond. In so doing, this “substrate binding” triggers a conformational change akin to the induced fit process inherent to enzymatic systems. Herein, we validate this design approach to control molecular space. A number of X-ray structures are documented that display this gauche preference (φNCCF ≈ 60°). Preliminary catalysis experiments are disclosed together with a kinetic and reactivity analysis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Senn, Dr Hans
• Authors: Rey, Y. P., Zimmer, L. E., Sparr, C., Tanzer, E.-M., Schweizer, W. B., Senn, H. M., Lakhdar, S., and Gilmour, R.
• Subjects: Q Science > QD Chemistry
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: European Journal of Organic Chemistry
• Publisher: Wiley - V C H Verlag GmbH & Co. KGaA
• ISSN: 1434193X
• ISSN (Online): 1099-0690