Electronic effect, fluorine

Comparing the potentials across each row, we can test the idea of additivity of ortAo-substituent effects for 2-fluoro, 6-chloro, and then 2-fluoro-6-chloro substitution. The definition of a = 0 changes across each row to permit easy visual addition of the potentials in the physically appropriate manner to assess the degree of additivity of ort/io-chlorine and ort/io-fluorine substituent effects. For o-fluorotoluene and 2-fluoro-6-chlorotoluene, a = 0 denotes the (minimum-energy) pseudo-trans conformation for o-chlorotoluene, a=0 denotes the pseudo-cis conformation. The notion of additivity has considerable merit in all three electronic states. 

The introduction of fluorine atoms in a molecule can be used to modify the processes and the rates of metabolism of the drug, in order to extend the plasma half-life or to avoid the formation of toxic metabolites. Because of the properties of fluorine atom, in particular its electronic effects, it may interact differently on the bio-transformation steps, according to the type of processes involved... 

Based on the known substrate specificity of a-chymotrypsin, phenylalanine has been chosen as the amino acid at the Pi position (P-nomenclature according to Schechter and Berger) [55]. The a-proton at Pi has been substituted either by methyl or trifluoromethyl. Substitutions beyond Pi contain trifluoromethyl alanine or aminoisobutyric acid. Therefore, each fluorosubstitution can be compared to its natural as well as fluorine-free a-substituted analog, thereby enabling differentiation of the steric and electronic effects. Scheme 2 summarizes the amino acids that have been used in this study. 

By far, 2-fluoro-2-deoxyfuranoses have been the most studied compounds. Indeed, at a structural level they are the closest analogues of 2-deoxynucleosides. Due to its electronic effect, the fluorine atom in the 2 position inhibits development of a positive charge on the anomeric carbon (which is responsible for the hydrolytic cleavage of nucleosides). In order to enhance the stability of 2-deoxynucleosides in acidic medium, and thus make oral administration of an antiviral compound easier, introduction of a fluorine atom in the 2 position is a commonly used strategy. The resulting protective effect toward proteolysis has been well demonstrated, as exemplified by the fluorinated analogues of ddl and ddA (cf. Chapter 3, Figure 3.13). However, the presence of this fluorine atoms often induces modifications in the antiviral properties of the molecule. ... 

The application of ESCA to the elaboration of chemical composition is well established in the case of fluorocarbon based systems for which the span in shift range for the Cu level is particularly favourable consequent upon the large electronic effect of replacing hydrogen by fluorine. In many cases comparable information may be derived from the more familiar spectroscopic techniques such as 1R and NMR one area in which ESCA comes into its own, however, is in the analysis of polymeric... 

Fluorine in organic compounds is associated with a set of electronic effects inductive and mesomeric, stabilizing and destabilizing, pulling or pushing electrons, which are convincingly... 

Hydrogenation of 2,2,2-trifluoroacetophenone and its derivatives with a mixture of trans-RuCl2[(S)-xylbinap][(S)-daipen] and (CH3)3COK in 2-propanol gives the S alcohols quantitatively with a high optical purity (Scheme 1,64) [258]. Unlike with many chiral borane reagents [264], the sense of enantioface discrimination is the same as in hydrogenation of acetophenone. The electronic effects of 4 -substituents on the enantioselectivity are small. These chiral fluorinated alcohols are useful as components of new functionalized materials [265]. 

Electronic effects. The high electronegativity of fluorine (4.0 as compared to 2.1 for H) often changes the electronic properties of the molecule, resulting in modified physical properties and chemical reactivity. 

This is contrary to the normal situation in that electron-withdrawing substituents lead to an upheld shift, and vice versa. Adcock and coworkers have shown, using compounds of the type 1,2 and 317,24, that this reverse effect results from the redistribution of a electrons in the C—F bond resulting from changes in the fluorine % electron density. Compounds such as 1,2 and 3 are such that the relationship between the fluorine and the substituent is well defined in terms of the distance and the number of intervening bonds. The fluorine-19 chemical shifts of compounds of the type 1 follow the correlation ... 

Thus the synthesis of heterocyclic compounds with one or more heteroatoms along with perfluoroalkyl groups is possible if the fluorinated molecule has a multiple bond and if an anionic center may be generated at the heteroatom or carbon atom of the functional group in intramolecular nucleophilic cyclization reactions. These new approaches point to the specific effect of fluorine atoms and to the important role of the electronic effects in... 

---