Inductive effects, fluorine-substitution

Because of its strongly negative inductive effect, fluorine substitution tends to dramatically increase the acidity of organic acids [24, 25] (Table 1.5). For example, the acidity of trifluoroacetic acid (pK = 0.52) is four orders of magnitude higher than that of acetic acid (pK = 4.76). Even very tveak acids, for example tert-bu-tanol (pKa = 19.0), are converted by fluorination into moderately strong acids ((CF3)3C0H, pK, = 5.4). 

A one-pot titanium-catalyzed tandem sulfoxidation-kinetic resolution process was developed by Chan using TBHP as the oxidant This process combines asymmetric sulfoxidation (at 0°C) and kinetic resolution (at room temperature). Excellent enantiomeric excesses (up to >99.9%) and moderate to high chemical yields of sulfoxides were obtained [270] (Scheme 14.113). The effect of fluorine substitution at the backbone of BINOL on the catalytic activity in titanium-catalyzed sulfide oxidation with TBHP or cumyl hydrc en peroxide (CHP) was studied by Yudin [271]. Introduction of fluorines into the BINOL scaffold was found to increase the electrophilic character of the Lewis acidic titanium center of the catalyst The most intriguing difference between the FsBINOL and BINOL systems is the reversal in the sense of chiral induction upon fluorine substitution. A steroid-derived BINOL ligand has also been used for the same reaction [272]. 

Substitution of fluorine into an organic molecule results in enhanced chemical stabiUty. The resulting chemical reactivity of adjacent functional groups is drastically altered due to the large inductive effect of fluorine. These effects become more pronounced as the degree of fluorine substitution is increased, especially on the same carbon atom. This effect demonstrates a maximum in fluorocarbons and their derivatives. 

The 1,3-dipolar cycloadditions offluonnatedallenes provide a rich and varied chemistry Allenes, such as 1,1-difluoroallene and fluoroallene, that have fluorine substitution on only one of their two cumulated double bonds are very reactive toward 1,3-dipoles Such activation derives from the electron attracting inductive and hyperconjugative effects of the allylic fluorine substituent(s) that give nse to a considerable lowering of the energy of the LUMO of the C(2)-C(3) n bond [27]... 

From this series of calculations it is noted that the gas-phase reactivity of TFDO is substantially greater than that of DMDO. This rate difference has been ascribed largely to the inductive effect of the CF3 group. Fluoro-substituted dioxiranes have also played a unique role in the chiral epoxidation of alkenes. Houk and coworkers96 have identified a novel stereoelectronic effect that increases the rate of epoxidation when the fluorine substituent is anti to the oxygen of the developing C=0 group in the TS for epoxidation. 

Unsaturated fluorinated compounds are fundamentally different from those of hydrocarbon chemistry. Whereas conventional alkenes are electron rich at the double bond, fluoroal-kenes suffer from a deficiency of electrons due to the negative inductive effect. Therefore, fluoroalkenes react smoothly in a very typical way with oxygen, sulfur, nitrogen and carbon nucleophiles.31 Usually, the reaction path of the addition or addition-elimination reaction goes through an intermediate carbanion. The reaction conditions decide whether the product is saturated or unsaturated and if vinylic or allylic substitution is required. Highly branched fluoroalkenes, obtained from the fluoride-initiated ionic oligomerization of tetrafluoroethene or hexafluoropropene, are different and more complex in their reactions and reactivities. 

Dixon and Smart71 examined a series of fluorine-substituted phosphonium ylides. Fluorine stabilizes carbanions via an inductive effect, favouring pyramidal carbanions. Dixon and Smart argued that the first substitution of F on the ylidic carbon (H3P=CHF) causes the carbon to become very pyramidal (the sum of the angles at C is 338.5°), which reduces the potential overlap of the anionic orbital with any P orbitals. The leads to the long P—C distance of 1.723 A. The second F substitution (H3P=CF2) actually breaks the P—C bond and the system is best described as a weak interaction of phosphine with CF2. Trifluoromethyl groups act to stabilize the anions via hyperconjugation. This leads to a planar ylidic carbon in H3P=C(CF3)2. 

A plethora of substituted pentafluorobenzenes has been utilized in substitution reactions and the substitution pattern of the products has been thoroughly investigated.120 In most cases the inductive effect of the attached fluorine atoms is stronger than a possible mesomeric effect... 

The effect of monofluorination on alkene or aromatic reactivity toward electrophiles is more difficult to predict Although a-fluonne stabilizes a carbocation relative to hydrogen, its opposing inductive effect makes olefins and aromatics more electron deficient. Fluorine therefore is activating only for electrophilic reactions with very late transition states where its resonance stabilization is maximized The faster rate of addition of trifluoroacetic acid and sulfuric acid to 2-fluoropropene vs propene is an example [775,116], but cases of such enhanced fluoroalkene reactivity in solution are quite rare [127] By contrast, there are many examples where the ortho-para-dueeting fluorine substituent is also activating in electrophilic aromatic substitutions [128]... 

In general, fluorine substitution has exactly the impact upon proton chemical shifts that one would expect from a substituent of its high electronegativity. That is, its effect is largely inductive in nature. Schemes 2.7 and 2.8 provide a comparison of the relative effect of fluorine substituents as compared with those of other halogens and oxygen, which is closest in electronegativity to fluorine. 

The electron withdrawing inductive effects of the fluorine substituents render the carboxonium ion 3 more electrophilic than carboxonium ion 2, and consequently it reacts with benzene. Thus, the electrophilic reactivity of the carbonyl group can be greatly enhanced by Brpnsted or Lewis acid solvation and by substitution with electron withdrawing groups. 

A great deal of basicity data is available on substituted chlorophosphazenes. None has hitherto been published on fluoro-phosphazenes. A priori, one surmises a greater electron-withdrawing inductive effect for fluorine, which oould be compensated for by the greater potential of fluorine to back-donate by a mesomsric effect. Data is new compared on structurally related chloro- and... 

Treatment with base (NaH can be used) now converts the OH group into an alkoxide and it does the next aromatic nucleophilic substitution. In this reaction we are attacking the position metato the ketone so we cannot put the negative charge on the oxygen atom. The remaining three fluorines must stabilize it by the inductive effect we described earlier. 

We have also employed ETS to study the effect of fluorine substitution on the ir orbitals of benzene and ethylene (10). Here we briefly discuss the results for the fluoroethylenes. Fluorine substitution is known to cause only small shifts in tv ionization potentials (IP) of unsaturated hydrocarbons (1 1). For example, the vertical iv IP s of ethylene and perfluoroethylene agree to within 0.1 eV. The reason that has been most often forwarded to explain this is that the electron withdrawing inductive effect, which stabilizes the occupied orbitals, is nearly cancelled by the destabilizing resonance mixing of the fluorine p orbitals with the ir orbitals of the ethylenic double bond. 

Inductive effects of ortho substituents are important in governing the acidity of a C-H bond in substituted benzenes [106], and a variety of data indicate that the acidifying influence of fluorine falls off in the order ortho meta > para this is illustrated by Table 4.13 [107]. 

The effect of substituting fluorine for hydrogen in the methylene halides is to increase the rate of carbanion formation and presumably to stabilize the carbanion and decrease the pK. The effect of fluorine substitution on the acidity of other carbon acids is not so clear. In some cases fluorine substitution leads to a smaller increase in rate than expected from the inductive effect and in other cases results in a decrease in the rate of carbanion formation and an increase in pK values. The results shown in Table 6 were obtained for the rate coefficient (k) for methoxide ion catalysed carbanion formation per hydrogen atom by following the appearance of the MeOH absorbance in the IR spectrum when the esters were allowed to exchange in MeOD [167]. The acidity of the nitro-paraffins in Table 7 is mostly increased by chlorine substitution (p/T... 

The effect of fluorine, chlorine, or bromine as a substituent is unique in that the ring is deactivated, but the entering electrophile is directed to the ortho and para positions. This can be explained by an unusual competition between resonance and inductive effects. In the starting material, halogen-substituted benzenes are deactivated more strongly by the inductive effect than they are activated by the resonance effect. However, in the intermediate carbocation, halogens stabilize the positive charge by resonance more than they destabilize it by the inductive effect. 

Addition of flourine to H-mordenite enhanced considerably the acid strength of this catalyst but decreased the ratio of Brpnsted to Lewis acidity (167). Using IR spectroscopy of adsorbed pyridine, X-Ray diffraction, catalytic activity tests for cumene cracking, and microcalorimetric measurements of ammonia adsorption, it was shown that some of the acidic hydroxyl groups were substituted with fluorine and that the inductive effect of fluorine increased the acid strength of the remaining hydroxyl groups. 

In the case of difluorobenzenes, the reaction scheme is similar to the above-discussed one for monofluorobenzene oxidation. The regioselectivity of the reaction is governed by the cooperative mesomeric and inductive effects of two fluorine atoms and the product distribution lends further support for the mechanism of electrophilic substitution. 

---