Fluorine, effect nucleophilic substitution

As mentioned in the introduction, partially fluorinated compounds are highly useful, however methods for their synthesis are strictly limited in many cases. For example, nucleophilic substitution occurs with difficulty at the position a to a trifluoromethyl group due to its strong electron-withdrawing effect, although sulfur and selenium nucleophiles undergo such a substitution rather efficiently (Scheme 6.1). 

The activating effect of the azide makes the fluorine labile, so that there is a risk of excess azide incorporation when attempting preparation by nucleophilic substitution of bromofluorocarboxylates, giving more explosive products than anticipated. 

Fluorination in the electrophilic 2-, 4-, and 6-positions is effected by substitutions of other halides, and this is normally performed by nucleophilic displacement with fluoride ion <1994HC(52)1>. Hydrofluoric acid can also be used, and in the case of 2,4-dichloro-5-trichloromethylpyrimidine 111, replacement of all five chlorine atoms occurred, to give 2,4-difluoro-5-trifluoromethylpyrimidine 112, which was subsequently hydrolyzed to give 5-tri-fluoromethyluracil 113 <1996JFC(77)93>. 

A carbocation is strongly stabilized by an X substituent (Figure 7.1a) through a -type interaction which also involves partial delocalization of the nonbonded electron pair of X to the formally electron-deficient center. At the same time, the LUMO is elevated, reducing the reactivity of the electron-deficient center toward attack by nucleophiles. The effects of substitution are cumulative. Thus, the more X -type substituents there are, the more thermodynamically stable is the cation and the less reactive it is as a Lewis acid. As an extreme example, guanidinium ion, which may be written as [C(NH2)3]+, is stable in water. Species of the type [— ( ) ]1 are common intermediates in acyl hydrolysis reactions. Even cations stabilized by fluorine have been reported and recently studied theoretically [127]. 

Treatment of o/rfo-hydroxymethyl-jljl-difluorostyrcncs 135 with sodium hydride effects an intramolecular nucleophilic substitution of a vinylic fluorine by the hydroxyl group to furnish 3-fluoro-l//-isochromenes (Equation 65) <2001BCJ971>. 

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. 

The destabilization of sp -bound fluorine by p-jt repulsion activates fluorinated aromatic compounds totvard nucleophilic attack and subsequent substitution. The susceptibility of the carbon center toward nucleophiles is also enhanced by the negative inductive (—T) effect of fluorine. In particular, if the aromatic compound is also activated by —M electron-withdrawing substituents, for example a nitro or cyano group, in the ortho or para positions the fluorine is easily replaced by a variety of nucleophiles even under very mild conditions via a resonance stabilized Meisenheimer complex (Scheme 2.39). The ease of nucleophilic halogen replacement - F > Cl > Br > I - is in the opposite order to that for aliphatic nucleophilic substitution. 

A more convenient approach to the exchange of hydroxy groups by fluorine is one-step activation-substitution - the alcohol is treated with a sufficiently electron-deficient, fluorine-containing reagent which condenses with it, with liberation of a fluoride ion. This ion, in turn, effects nucleophilic replacement of the now present leaving group. Stereochemically, this process results in clean inversion at the carbon center. 

If equimolar quantities of tetramethylammonium fluoride and a threefold excess of Me3SiCF3 or its homologues are used the perfluoroalkyltrimethyl silane acts as an effective source of nucleophilic perfluoroalkyl equivalents for nucleophilic substitution of aliphatic triflates [90] (Scheme 2.136). This method enables the simple synthesis of partially fluorinated alkane structures which are of interest in the chemistry of liquid crystals and other functional materials. 

Similarly, the fluoromethanes have F—C bonds that shorten128 as the number of fluorines increases from one in 2.87 to four in 2.90, and the number of generalised anomeric effects accumulates. The bond-strengthening represented by these bond-shortenings contributes to the reduced reactivity towards nucleophilic substitution seen in polyhalogenated alkanes. 

FIGURE 8.5 Effects of fluorine on nucleophilic aromatic substitution processes. 

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