Carbocations fluorine substituents

Richard, J. P. Amyes, T. L. Bei, L. Stubblefield, V. The effect of beta-fluorine substituents on the rate and equilibrium-constants for the reactions of alpha-substituted 4-methoxybenzyl carbocations and on the reactivity of a simple quinone methide. J. Am. Chem. Soc. 1990, 112, 9513-9519. 

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]... 

Richard interprets these measurements as implying an increase in delocalization of charge and increase in double bond character at the benzylic carbon atom of the carbocation as the number of electron withdrawing fluorine substituents increases. This is consistent with a changing balance of contributions of the valence bond resonance forms 59 and 60. 

This modified charge distribution in the transition state leads to a mismatch between substituent effects on the rate of reaction and on the equilibrium constant. With respect to the fluorine substituents in Scheme 31, these decrease both the stability of the carbocation and the stability of the transition state. However, while there must be less carbocation character in the transition state than in the carbocation itself the positive charge is located to a greater degree on the benzylic carbon atom and therefore will be more sensitive to stabilization by substituents. If substituent effects at the a-carbon atom in the carbocation and in the transition state are then of comparable magnitude, there will be no net effect on the rate of reaction, as is observed. 

According to the rule formulated in [15], the combined a- and /1-effects (of fluorine substituents) imply that fluoroolefins will react with electrophiles so as to minimize the number of fluorines f to electron-deficient carbon in the transition state. In accordance with this rule, reaction of CH2=CF2 with HF starts as an attack of electrophile (H+) on the CH2 group of ethylene (Eq. 32, pathway A), since this process leads to carbocation 12 stabilized by two a-fluorines in contrast to the much less stable intermediate 13 containing two /1-fluorines and derived from the initial attack of H+ on the CF2 group of the olefin ... 

Solvolysis of allylic fluorides may be acid-catalysed [35] and the influence of fluorine substituents at different positions is interesting. Solvolysis of 5.15A occurs where fluorine at the 1-position is able to stabilise an attached carbocation but in the isomer 5.15B fluorine at the 2-position deactivates and solvolysis of 5.15B does not occur under conditions where 5.15A reacts (Figure 5.15). Similar hydrolysis of 1,2-diethoxytetrafluorocyclobutene leads to the well-known, very stable, squarate anion [36] (Figure 5.16a). 

Does a fluorine-substituent stabilize carbocation is an interesting question to be clarified in this section. In spite of the strong electron-withdrawing nature of a fluorine atom in molecules, the fluorine atom stabilizes a-carbocation by releasing its lone-pair electrons to the vacant p-orbital of the carbocation. However, it destabilizes (3-carbocation because of its strong electron-withdrawing nature (Scheme 1.53). 

The stabilization of the carbocation intermediate 35 by the isobutylidene group must be a driving force to promote the reaction. The striking feature in the cyclization is a remarkable acceleration effect by the fluorine substituent at the same carbon. The fluorine substituent gives an excellent rate of acceleration and product yield. In contrast, the SnCU-catalyzed cyclization of nonsubstituted polyolefin 34 (R = H) in hexane gives only 30% of the cyclized product in 20 min. 

However, Markovnikov s rule is not always hold true. For example, the reaction of CF CH = CH with HBr gives CFgCH2CH,Br rather than CF CHBrCH Here, the presence of electron-withdrawing fluorine substituents has a destabilisrng influence on the two possible intermediate carbocations. The destabilisingeffectwillbe greater for the more substituted carbocation since the carbocation is closer to the fluorine substituents and so the favoured carbocation is the least substituted one in this case. 

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]. 

Fluorination has a particularly profound effect on the additions of nucleophiles to per-fluorinated alkenes where the intermediate is anionic. Such processes are dramatically assisted by the strongly stabilizing influence of perfluoroalkyl groups substituted at the incipient anionic site.66 Similar to carbocations (see Section 1.4.), the effect of fluorination in such systems is often ambiguous when monofluorination is involved. a-Halogens generally stabilize anions in the order bromine > chlorine > fluorine, which is the exact opposite to the inductive electron-withdrawing order of the substituents. This effect reflects the importance of l7t-repulsion.67... 

Diethylaminosulfur trifluoride (DAST, Et2NSF3) a-cleaves cyclic ketoximes to give fluorinated carbonitriles,47 e.g. (27)—> (28). Two mechanisms are proposed, one for substrates with substituents that can stabilize an a-carbocation, and an iminium cation route for ketoximes without such groups. 

The difluorobenzyl cation (Figure 4.20) is stable under conditions in which the benzyl cation undergoes rapid polymerisation [57] and and NMR studies [58] have shown that, as the electron demand of the aromatic ring increases (i.e. R is electron-withdrawing), the TT(p-p) donation of fluorine to the carbocation centre also increases, leaving the electron density at relatively constant for a variety of aromatic substituents. 

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. 

The stability of fluorinated carbocations [1] is determined by a delicate equilibrium between inductive destabilization and mesomeric stabilization of the positive charge. a-Fluoro substituents stabilize the positively charged carbon by TT-donation... 

It is interesting to see completely different regiochemistries in nucleophilic and electrophilic reactions to 1,1-difluoroethene as a model. Scheme 1.55 shows a typical electronic effect of the fluorine atom as a substituent. Electrophiles mostly attack the (3-carbon of 1,1-difluoroethene generating a-difluorinated carbocations as intermediates in contrast to regioselective nucleophilic additions on the a-carbon of 1,1-difluoroethene generating (3-fluorocarbanions. 

Fluorine-stabilized carbocation chemistry was applied to the biomimetic cyclization of polyolefins by Johnson (Scheme 1.64) [18]. The rates and product yields in the cyclization are significantly controlled because of the electronic nature of the substituents attached in the middle carbon-carbon double bond of polyolefin 34. The isobuylidene substituent accelerates the reaction rate and also provides the desired cyclized product 36 in a good yield. 

---