Stereoelectronic Effects and Conformation

A related stereoelectronic effect with particular relevance to fluoroaliphatic compounds is the gauche effect [38]. Contrary to expectations based solely on the steric repulsion of fluorine, 1,2-difluorocthanc prefers the gauche rather than antiparallel alignment of the fluorine substituents, by 0.5-0.9 kcal mol [39]. The same is observed for related compounds in which one fluorine atom is replaced 

The cis effect can also determine the stereochemistry of enzymatic reactions. The most prominent example is the metabolism of toxic fluoroacetate in the Krebs 

One impressive example of the systematic use of stereoelectronic effects to design biologically relevant molecules is a hyperstable collagen mimic [50] which owes its unusual stability mostly to the gauche effect induced by fluorine. 

When hydroxy was exchanged with fluorine, which cannot act as a hydrogen bridge donor, the stability of the triple helix was found to be dramatically increased. For the 30-mer (I ro-X/x-Gly), as model compound replacement of Xxx by Hyp 

The gauche effect exerted by fluorine (or by the hydroxy group in natural Hyp) and the electron-withdrawing amide group stabilize a conformation of the pyrrolidine ring which favors the triple-helical arrangement. In addition, the inductive effect of fluorine stabilizes the trans isomer of Flp, which is prerequisite for helix formation. 

---