Molecular Design Exploiting a Fluorine gauche Effect as a Stereoelectronic Trigger

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.

Can acyclic conformational control be achieved via a sulfur–fluorine gauche effect?

“…This approach to molecular design has found widespread application in catalysis, 5 bioactive molecule design, 6 material science 7 and agrochemistry. 8 In the majority of cases, the substituent (X) is a Period 2 atom, typically oxygen or nitrogen.…”

Chemistry without Bo(a)rders

“…[13,14] Furthermore, we were able to extend this principal to chiral DMAP analogues, showing that by invoking the fluorine gauche effect we could predictably control molecular space, by hindering rotation around the only rotatable sp 3 -sp 3 bond. [15] This design approach was verified by X-ray analysis as well as computational methods, where a clear preference for the gauche conformation (φNCCF ≈ 60°) was apparent. With the goal of exploiting the similar fluorineammonium ion gauche effect, a configurationally defined fluorine was installed at the C9 carbinol center of cinchona alkaloids (Figure 7, right).…”

Deconstructing Covalent Organocatalysis

“…This has led to the X-ray crystal structure analysis of numerous primary catalytic species and model systems (e.g., [12][13][14][15][16][17], including cinchonium salts, [55] acyl pyridinium salts (16), [56] and protonated analogues thereof. [57] Thegiven intermediate may be important for effective catalysis,f unction as ab ridge en route to asecondary catalytic species,orsimply be as pectator or catalyst reservoir.T od elineate its role in catalysis,asynergistic mechanistic approach is essential but this first requires the preparation and isolation of the species of interest. Thestudy of reactive intermediates remains av ibrant yet challenging aspect of physical organic chemistry.…”