Fluorination steric effects

Dolbier Jr., W. R. Palmer, K. W. Effect of terminal flnorine substitution on the Cope rearrangement boat versus chair transition state. Evidence for a very significant fluorine steric effect, J. Am. Chem. Soc. 1993,115,9349-9350. 

Cobalt trifluoride fluorination corresponds to the electron-transfer mechanism via a radical cation. RF groups attached to the ring enhance the stability of intermediate dienes and monoenes. Perfluoroalkyl pyridines, pyrazines, and pyrimidines were successfully fluorinated but pyridazines eliminated nitrogen. The lack of certain dienes was attributed to the difference in stability of FC=C and RFC=C and steric effects [81JCS(P1)2059]. 

GL 1] [R 1] [R 3[ [P la-d[ A ratio of ortho-, meta- and para-isomers for mono-fluorinated toluene amounting to 5 1 3 was found for the falling film micro reactor and the micro bubble column at a temperature of -16 °C (3, 38]. This is in accordance with an electrophilic substitution pathway. The relatively high amoimt of ortho-isomers is due to the small size of the fluorine moiety as the ortho position is amenable to steric effects. 

The addition reaction of allylsilane to acetaldehyde with BF3 as the Lewis acid has been modeled computationally.95 The lowest-energy TSs found, which are shown in Figure 9.2, were of the synclinal type, with dihedral angles near 60°. Although the structures are acyclic, there is an apparent electrostatic attraction between the fluorine and the silicon that imparts some cyclic character to the TS. Both anti and syn structures were of comparable energy for the model. However, steric effects that arise by replacement of hydrogen on silicon with methyl are likely to favor the anti TS. 

The best carbonyl components for these reactions are highly electrophilic compounds such as glyocylate, pyruvate, and oxomalonate esters, as well as chlorinated and fluorinated aldehydes. Most synthetic applications of the carbonyl-ene reaction utilize Lewis acids. Although such reactions may be stepwise in character, the stereochemical outcome is often consistent with a cyclic TS. It was found, for example, that steric effects of trimethylsilyl groups provide a strong stereochemical influence.28... 

Figure 6. Effect of using a special near-neighbor fluorine-fluorine excluded volume to account for the steric effects of the phenyl ring. This serves the same purpose as dyad weights which discriminate against certain sterically forbidden conformations.

This chapter aims to summarize our efforts to investigate the effects of fluorinated amino acid substitutes on the interactions with natural protein environments. In addition to a rather specific example concerning the interactions of small peptides with a proteolytic enzyme, we present a simple polypeptide model that aids for a systematic investigation of the interaction pattern of amino acids that differ in side chain length as well as fluorine content within both a hydrophobic and hydrophilic protein environment. Amino acid side chain fluoiination highly affects polypeptide folding due to steric effects, polarization, and fluorous interactions. 

In the previous chapter we described a systematic study of the interactions of small model peptides with a rather specific enzyme. In our attempt to systematize the effects of fluorinated amino acids on peptide and protein interactions we have established a model system that lays the foundation for a more general approach. How do the steric effects and the degree of fluorination as well as the polarity of fluoroalkyl amino acid side chains affect the folding of proteins and the strength of peptide-protein interactions In order to answer this central question we choose a very common folding motive, the a-helical coiled coil. 

Whereas the van der Waals radius of the fluorine atom is the smallest one after that of hydrogen, its volume is actually closer to that of oxygen (Table 1.16). Note that if the volume is an intrinsic property, steric effects are dependent on the observed phenomena. They frequently appear in dynamic processes. This allows comparison of steric parameters of various groups, fluorinated or not. These parameters show that the CF3 group is at least as bulky as an isopropyl or isobutyl group (Table 1.17). These data are confirmed by the values of the rotation, or of inversion barriers, of fluorinated diphenyl-type compounds (Figure 1.6). 

In the case of insertion toward fluorine (41), there is an even greater amount of positive-positive charge repulsion between the ortho and ipso carbons than in the transition state and this effect is responsible, in part, for a higher activation barrier for insertion toward F to form 41 than away from fluorine to form 40. Therefore, the origin of the pronounced influence of ortho,ortho-difluoro substitution on the lifetime of singlet arylnitrene and the increased activation energy of its cyclization is the result of combination of the steric effect and the extraordinary electronegativity of fluorine atom. 

Understanding the steric effects of fluorination can often be quite confounding. For example, fluorine and oxygen have almost the same van der Waals radius44 45 (see Table 6). 

End-to end dimers of 210 incorporating a fluorinated spacer segment (compound 211) form only a nematic and two different types of SmA phases, one with bilayer structure, the other an interdigitated one. This phase transition was attributed to a change of the molecular conformation from folded (bent), stabilized by segregation of the RF-segments (SmA(HT)), to linear, favored by reduced conformational mobility and steric effects (SmA(LT)) [368]. 

A single fluorine substituent at C-5 (as in radical 13) leads to a significant, 11-fold decrease in rate constant. This decrease no doubt derives largely from the steric effect which would be expected from any substituent at the 5-position. A methyl substituent, for example, gives rise to a 45-fold decrease in cyclization rate [164]. Interestingly, whereas the presence of a 5-methyl substituent causes endo-cyclization to become preferred (63%), the cyclization of 5-fluoro-5-hexenyl radical remains exo-specific within our NMR analytical methodology ( 4%). 

Table 11 shows very little variation in the orientation of the addition of trihalogenomethyl radicals to vinyl fluoride, but for vinylidene fluoride there is a 4.5-fold increase in the orientation ratio (kjkj across the table. This change in orientation does not follow polarity and suggests that steric effects may be having some effect. The rates relative to ethylene for the three fluorine-containing radicals are very similar. 

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