CF3-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

“The extraordinary instability of such an “ion” accounts for many of the peculiarities of organic reactions” – Franck C. Whitmore (1932). This statement from Whitmore came in a period where carbocations began to be considered as intermediates in reactions. Ninety years later, pointing at the strong knowledge acquired from the contributions of famous organic chemists, carbocations are very well known reaction intermediates. Among them, destabilized carbocations – carbocations substituted with electron-withdrawing groups – are, however, still predestined to be transient species and sometimes considered as exotic ones. Among them, the CF3-substituted carbocations, frequently suggested to be involved in synthetic transformations but rarely considered as affordable intermediates for synthetic purposes, have long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations.


Introduction
Carbocations are pivotal intermediates in organic chemistry, and carbocation-based synthetic chemistry continues to be a vital part of industrial and academic chemistry [1]. A countless number of carbocations have been generated and studied [2,3], and many famous organic chemists strongly participated in their development. Carbocations that are especially intriguing are the destabilized ones that have been elegantly reviewed over the past years by Gassman, Tidwell, and Creary [4][5][6]. The so-called electron-deficient carbocations, i.e., carbocations substituted with electron-withdrawing groups, drive original reactions, and the most important one among these cations is probably the α-(trifluoromethyl) carbocation. Many efforts are currently devoted to develop methods allowing the efficient insertion of fluorine atoms or fluorinated groups into organic molecules [7][8][9][10][11][12]. The increasing demand for fluorinated scaffolds, due to the striking beneficial effects generally resulting from the introduction of these fluorinated motifs [13], also participated in this development. These fluorine effects are nowadays remarkably established in many domains, including medicinal, organic, and organometallic chemistry, catalysis, chemical biology, and material sciences [14][15][16][17]. In this context, deciphering the impact that can be exerted by the trifluoromethyl group on a cation and the associated consequences when facing the challenge of developing innovative synthetic methods are the subjects of this review.

Review
Quantitative parameters accounting for the electron-donating or -withdrawing ability of substituents are of major importance in synthetic organic chemistry. The Hammett constant σ for a variety of substituents [18,19] and improved values, known as σ + , furnished by Brown et al. [20,21] -some of which are listed in Table 1 for selected substituents -were developed towards this aim. Following this classification, the CF 3 group is amongst the most electron-withdrawing substituents, with a σ p + value of +0.612 for the para-position. However, as noted by Reynolds et al. [22,23], "the electronic effect of a substituent depends to a certain extent upon the elec-tron demand in the system to which it is attached". Thus, despite the strong intrinsic electron-withdrawing character, the trifluoromethyl group was shown to modestly act as a π-electron donor when substituting a carbenium ion. Ab initio calculations were performed to account for the π-electron-donating ability of several substituents conjugated with carbocations ( Table 2). It is noteworthy that amongst the several substituents studied, the CF 3 group exhibits the lowest π-electron-donation ability in each investigated carbenium series, reflecting, as one could expect, the very poor stabilizing power by π-electron donation. A trend exists in the magnitude of the parameter according to the nature of the carbenium ions, which is in line with the carbenium ion stability (alkyl < allylic < benzylic). Thus, an increased π-electron transfer is present in the leaststabilized alkylcarbenium ions, in which a higher electronic contribution from neighboring substituents is required. Detailed ab initio studies have been focused on the stability of the CF 3 CH 2 + cation and provide pieces of thoughts on the origins of the stabilizing interactions in α-(trifluoromethyl)carbenium ions. The optimization of the geometry for CF 3 CH 2 + at the STO-3G level led to an energy minimum, in which one of the fluorine atoms is significantly closer to the positive carbon center (Figure 1, top, θ = 101°) [24]. However, exactly the same structural distortion was calculated for the ethyl cation. Furthermore, the very small π-electron density calculated in the 2pC orbital of CF 3 CH 2 + (0.04 electrons) led the authors to conclude that "there is no hyperconjugative stabilization by the CF 3 group". The presence of this attractive interaction should, how-ever, not be discarded. Indeed, the quantitative PMO analysis at the 6-31G* level allowed, by calculating fragment orbitals (FO), the identification of the nature of this attractive interaction [25]. The latter arose from a homoconjugation interaction (−5.3 kcal⋅mol −1 ) of one fluorine lone pair (πnF FO) with the empty 2pC orbital of the cationic carbon center (Figure 1, top). A second stabilizing interaction was also found and came from hyperconjugation of the CF 3 substituent, involving interactions between the empty 2pC orbital with the πCF 3 FO (−5.2 kcal⋅mol −1 ). In 2018, spectroscopic evidence for the generation of the first observable fluoronium ion 1 by Letcka et al., which can be seen as a strong nF→2pC interaction (Wiberg bond order of 0.53 for each C-F bond), gave additional credit to these calculations (Figure 1, bottom) [26][27][28]. The thermochemical data can also provide information on the effect of the CF 3 group on the stability of the carbenium ions. Calculations of the isodesmic reactions (1), (2), and (3) demonstrate the overall destabilizing effect of CF 3 compared to H or CH 3 when directly attached to a carbenium ion (i.e., α position, Scheme 1) [5,29]. Even an oxonium ion appears to be significantly destabilized by the presence of the CF 3 group. These data globally suggest, as one could expect, an electronic destabilizing effect of the CF 3 group when attached closely to a carbenium ion. However, any strong nF→2pC interaction might also influence the overall stability of any system. Any perspectives toward CF 3 -containing carbocation-based synthesis must take this trend into account, especially studies on the specific α-(trifluoromethyl)carbenium ions. This review aims to systematically relate the reported work in this field. For each part, a focus on a series of α-(trifluoromethyl)carbenium ions differing in its chemical environment will be scrutinized. The chapter will summarize kinetic studies and concomitant theoretical investigations on the cations formation and stability data as well as synthetic perspectives offered by the studied carbenium ions. Any discussion of the results coming from the ionization of perfluorinated substrates will not be addressed in this review [30][31][32][33].
Aryl-substituted trifluoromethylated carbenium ions α-(Trifluoromethyl)-substituted carbenium ions: At the dawn of their outstanding studies on carbocation chemistry, Olah et al. empirically demonstrated that despite exhibiting the highest Pauling electronegativity, the fluorine atoms, when directly linked to a carbenium ion, can be engaged in significant resonance electron donation (Scheme 2) [34]. While stabilizing the positively charged carbon center via lone pair conjugation, the electron density at the fluorine atom decreases, and this phenomenon is shown by a large downfield shift in the 19 F NMR spectrum of 8 compared to the neutral precursor 7. Following these studies on the evaluation of fluorine atom(s) substitution on cation behavior, Olah et al. then investigated the expected destabilizing effect resulting from the presence of fluorine atoms close to a carbenium ion [35]. Thus, Olah et al. envisioned the possibility to generate α-(trifluoromethyl)carbenium ions, and this achievement led to the first direct observation of these species using low-temperature NMR experiments in situ [35]. In this study, the authors furnished spectroscopic evidence for the complete ionization of several α-(trifluoromethyl) alcohol precursors 9a-c in a superacidic FSO 3 H-SbF 5 -SO 2 medium. They also brought experimental 19 F NMR variation values up to Δδ = +24.8 ppm (Scheme 3).
This suggests a partial stabilization of the cationic center by hyperconjugation and/or fluorine lone pair interaction, resulting in a certain degree of a positive charge of one fluorine atom. Interestingly, at least one phenyl substituent was required to allow the ionization of the starting alcohols into the corresponding carbenium ions. When the aromatic substituent was absent or upon installation of an additional CF 3 group, only the corresponding protonated alcohols 10d-g were observed.
Olah et al. also reported the 13 C NMR chemical shifts for carbenium ion 10c upon ionization of the alcohol precursor 9c in a superacid (Scheme 4) [36]. A large downfield shift was observed predominantly at the benzylic position (Δδ 13C = 110.1 ppm), with minor impacts at the ortho-and para-positions (Δδ 13C ≈ 20 ppm) relative to the starting alcohol 9c [37]. These variations are fully consistent with the presence of a positive charge located at the benzylic position, with only partial stabilization of the cationic center by the phenyl groups.
carbenium ions 12a-d from the corresponding carbinols 11a-d (Scheme 5) [38]. Tidwell et al. explored the influence of a CF 3 group on the solvolysis reaction of various benzylic sulfonate derivatives [39,40]. They found a linear free-energy relationship between the solvolysis rate of sulfonate 13f in different solvents compared to the one of 2-adamantyl tosylate, the latter being known to undergo solvolysis via the formation of a carbenium ion. Hence, the formation of a highly destabilized α-(trifluoromethyl)carbenium ion 14f OTs was established as the ratelimiting step in the solvolysis reactions of 13f (Scheme 6). Furthermore, the authors determined a k CH3 /k CD3 ratio of 1.54, highlighting an isotopic effect consistent with a solvolysis mechanism involving a carbenium ion (k CH3 /k CD3 = 1.48 for 2-methyl-2-adamantyl tosylate). Also, k H /k CF3 = 2⋅10 5 was established, illustrating the retarding α-CF 3 effect in the production of a carbenium ion [41]. In the solvolysis reaction of 13f, a mixture of the major product 15f, resulting from solvent substitution, and the minor elimination product 16f was observed. Further, 14 C labeling experiments on 13f confirmed that the formation of the ion pair 14f OTs was a reversible process [42]. Scheme 6: Illustration of the ion pair solvolysis mechanism for sulfonate 13f. YOH = solvent.
Later, Liu et al. explored the solvolysis of aryl derivatives 13a-i to highlight the importance of the nature of the aromatic substituent on the solvolysis rate ( Figure 2) [43]. As anticipated, a faster rate was observed for electron-donating groups, while electron-withdrawing groups slowed the process down. Plotting the Hammett-Brown correlation, established as log(k) = f(σ + ), gave a linear dependence of the rate with the σ + parameters of the aryl substituents, with a behavior in agreement with the transient formation of a carbenium ion. The slope of the straight line, ρ + = −7.46, reflects the very high electron demand induced by the CF 3 group. Remarkably, they found that CF 3 deactivates to such an extent that benzylic tosylate 13f was approximately 10 times less reactive than benzylic tosylate 17 (Figure 2, top). Similarly to the previous study, the Grunwald-Winstein plot [44] gave a linear free-energy relationship between the solvolysis rate for derivatives 13f or 13g and the solvent polarity parameter Y OTs [45]. The solvent participation in the solvolysis of these tertiary benzylic tosylates was thus defined as "unimportant" by the authors.
Gassman and Harrington successfully measured the solvolysis kinetics of CF 3 -substituted allylic triflates 18 and 19, showing a significant solvolysis retardation with CF 3 -substituted substrates ( Figure 3) [46]. These results are in accordance with an earlier study that revealed that 20 was unreactive in acetone/ H 2 O 70:30, even over a period of 35 days at 50 °C [47]. Encouraged by these preliminary results, Tidwell et al. envisioned the possibility to study the solvolysis reaction of secondary benzylic sulfonates [48]. In tertiary benzylic sulfonates [39,43], a linear free-energy relationship between the solvolysis rate for the secondary benzylic tosylates 21 ( Figure 4) and Y OTs was obtained. Similarly, the nature of the aromatic substituent influenced the solvolysis rate, with an observed acceleration for substrates adorned with electron donor substituents and a deceleration for those carrying electron-withdrawing substituents. The Hammett-Brown correlation gave a straight line, with ρ + = −10.1 (80% EtOH, 25 °C), a significantly greater magnitude than for the tertiary derivatives (−7.46), in agreement with the transient formation of a more destabilized carbenium ion (i.e., a secondary carbenium ion). They also noticed that the greatest magnitude of ρ + was obtained in the most nucleophilic and less ionizing solvents, in agreement with an increased electron demand on the aromatic substituent in a poorly ionizing solvent. This also suggests that the positive charge is delocalized to a higher extent on the aromatic substituent for the secondary tosylates than for the tertiary ones. These data support the hypothesis that the transient formation of a carbenium ion is the rate-limiting step and the absence of significant solvent par- ticipation in the latter. Richard also conducted extensive studies on the impact of the nature of the leaving group (I, Br, OSO 2 R, etc.) and on the aryl substituents (NMe 2 , OMe, SMe, etc.) in the derivatives 21, substituted with a secondary CF 3 group in the benzylic position, and reported similar conclusions [49,50]. A different behavior emerged from triflate derivatives 22 (Figure 5a). In addition to their enhanced reactivity (k Tf /k Ts = 2 × 10 4 ), a nonlinear free-energy relationship between the solvolysis rate and Y OTs was obtained, suggesting an important solvent participation in these cases. Further investigations on 22f showed deuterium isotope effects in agreement with the transient formation of a carbenium ion. A solvent dependence of the k H /k D ratio was also noticed, with the higher ratios being obtained in the most ionizing and less nucleophilic solvents (i.e., 1.34 ± 0.07 in HFIP vs 1.21 ± 0.01 in 80% EtOH). The subsequent solvolysis of enantioenriched triflate (R)-(−)-22f evidenced that in a poorly ionizing solvent, such as AcOH, solvol-ysis occurred with 41% inversion (and 59% racemization, i.e., product 23f was obtained with an enantiomeric ratio of ca. 70:30 in favor of the (S)-enantiomer), while complete racemization was observed in more ionizing TFA or HFIP as the solvent (Figure 5b) [48]. These observations are in agreement with a process generating a carbenium ion in highly ionizing solvents (TFA, HFIP, etc.) for the tosylates derivatives, and with the concomitant formation of a contact ion pair 25f OTf favoring the S N 2 process in less ionizing solvents (Figure 5c). Recent studies conducted by Moran et al. support the ionization via a S N 1 process for trifluoromethylcarbinol derivatives related to 22 under TfOH-HFIP activation [51].
Tidwell et al. investigated CF 3 -containing naphthyl-and anthracenylsulfonate derivatives 26 and 29 [52]. They reported that while the solvolysis of 26 afforded the expected compounds 27 and 28, that of 29 exclusively gave the ring-substituted products 30-32 (Scheme 7). A Grunwald-Winstein plot gave linear dependences of the solvolysis rate against Y OTs in both cases, suggesting that the formation of the carbenium ions was the rate-limiting step. Thus, the formation of products 30-32 is best explained by a complete charge delocalization from an α-(trifluoromethyl)carbenium ion to anthracenylcarbenium ion 33, with subsequent trapping of 33 by the solvent. The solvolysis of the bisarylated α-CF 3 -substituted tosylates bearing electron-withdrawing substituents was investigated by Liu and Kuo [53]. The Hammett-Brown correlation considering derivatives 34 ( Figure 6) gave a linear free-energy correlation with ρ + = −3.98, which is approximately half the value of those previously reported for the benzylic α-CF 3 -substituted tosylate derivatives 13 substituted by a methyl group ( Figure 2) [43,48]. The presence of the additional phenyl group, in addition to the CF 3 group, was suggested to induce a lower ρ + value. This could be explained in terms of a twisted electronpoor aryl ring, which was not in the plane of the carbenium ion for stereoelectronic reasons. The cation is thus stabilized by the additional phenyl ring in 35 ( Figure 6).  Early interest in bisarylated α-CF 3 -substituted alcohols was shown by Cohen and Kaluszyner [55,56] and by Streitwieser et al. [57]. The cyclodehydration of 9c occurs in polyphosphoric acid to afford fluorene 37 (Scheme 8) [57]. A mechanistic proposal invoking the initial generation of the α-(trifluoromethyl)carbenium ion 10c↔10c' was mentioned by the authors [55,56]. Related studies on diphenyl derivative 9c in a mixture of H 2 SO 4 and chloroform also showed the formation of fluorene derivative 37 in 25% yield [58]. Exploiting this impact of the trifluoromethyl substituent in the cationic Nazarov electrocyclization, the synthesis of CF 3 -substituted indenes 39a-c from the α-(trifluoromethyl)allyl-substituted benzyl alcohols 38a-c in strong acids has been reported (Scheme 9) [59]. The significant rate retardation observed upon the addition of further CF 3 groups, illustrated by the need for harsh reaction conditions, strongly supports the formation of delocalized α-(trifluoromethyl)carbenium ions 40a-c.
Vasilyev et al. also investigated this Nazarov electrocyclization for the synthesis of indene derivatives. Thus, a variety of indenes 42 could be readily obtained from α-(trifluoromethyl)allyl-substituted benzyl alcohols 41a or the corresponding silyl ethers 41b upon the reaction in a dichloromethane solution of sulfuric acid or triflic acid [60,61]. The authors also reported that indenes 42 could undergo a subsequent Friedel-Crafts alkylation when 41b was reacted in the presence of an external aromatic partner Ar'H in pure triflic acid. Thus, a variety of α-(trifluoromethyl) silyl ethers 41b was converted into the corresponding indanes 43 in low to high yields [62]. The trans-isomers were generally obtained as the major product (Scheme 10).

Bis[α-(trifluoromethyl)]-substituted carbenium ions:
More destabilized bis(trifluoromethyl)-substituted carbenium ions have also been suggested to exist as reaction intermediates. During their investigations on the reactivity of sulfuranes under acidic conditions, Martin et al. reported that sulfurane 44 reacts with triflic acid to provide alcohol 9g and sultine 46, according to 1 H and 19 F NMR assignments, and triflate 45f, which was isolated after basic workup of the reaction (59% yield) [63]. Hence, protonation of 44 led to dialkoxysulfonium triflate 47 along with the release of alcohol 9g. The subsequent formation of the excellent sultine leaving group 46 (assumed to be as good of a leaving group as N 2 ) [63] is the driving force for the decomposition of 47, generating collaterally bis(trifluoromethyl)substituted carbenium ion intermediate 48f OTf . Finally, triflate 45f is formed after ion pair recombination (Scheme 11). Similar experiments conducted with 18 O-labeled 44 confirmed the proposed mechanism, including the transient formation of 48f OTf .
The solvolysis of triflate 45f was explored next [63]. Heating 45f in water or methanol resulted in the expected solvolyzed  Substrate 51, bearing a tert-butyl group in the para-position, was also submitted to solvolysis in labeled H 2 18 O, generating the labeled benzylic alcohol 18 O-52 (Scheme 13). The solvol-ysis of 51 was found to be much faster than that of 45f by at least a factor of 10, encouraging the authors to suggest "a transition state resembling 48f in the rate-limiting step".
Sulfurane 53, bearing OC(CF 3 ) 3 groups, was also treated with triflic acid, affording dialkylsulfonium species 54 in 91% yield along with perfluoro-tert-butyl alcohol (Scheme 14) [63]. No further decomposition was observed in this case, suggesting that the especially challenging perfluoro-tert-butylcarbenium ion 55 cannot be generated. Highly deactivated bis(trifluoromethyl)-substituted carbenium ions and their precursors were also explored in detail by Tidwell et al. [64][65][66] and Richard et al. [67] in solvolysis studies of di(trifluoromethyl)-substituted tosylates 56 in comparison to the monosubstituted analogue 21f ( Figure 8). A linear free-energy relationship was found upon plotting the solvolysis rate against Y OTs and ρ + = −10.7 (TFA) for the Hammett-Brown correlation. The linear dependence of the rate on the solvent ionizing power, in addition to the strong effect of the substituents on the reactivity, are in agreement with the conclusions of Martin et al. [63] as they strongly support the formation of a bis(trifluoromethyl)-substituted carbenium ion 48. Surprisingly, a relatively low kinetic effect (k H /k CF3 = 54, in TFA) was observed by comparing the solvolysis rate of tosylates 21f and 56f. For p-OMe derivatives 21a and 56a, k H /k CF3 = 2.5 (HFIP) was obtained. These ratios are very small compared to typical k H /k CF3 ratios in the 10 4 -10 7 range [39][40][41]43,48,68]. Thus, while introducing one CF 3 group dramatically alters the reactivity, an additional CF 3 group does not seem to significantly impact the reactivity any further. The hypothesis of a ground-state strain release to explain this behavior was discarded as an analysis of the structures of 56f, 13f, and 21f by X-ray diffraction crystallography revealed similar bond angle distortions [64,65].

α-(Trifluoromethyl)heteroarylcarbenium ions
The presence of a strong electron-donating substituent could compensate the extreme deactivating power of the CF 3 group, favoring a further exploitation for synthetic purposes. In this context, Tidwell and Kwong-Chip compared the solvolysis of N-methylpyrrole 58 to 59 ( Figure 9) [70]. A very similar rate was determined for 58 and 59, with k CF3 = 4.40 × 10 −4 s −1 and k H = 1.84 × 10 −2 s −1 , respectively, providing a rate ratio of k H /k CF3 = 41.8. Plotting the solvolysis rate of 58 against Y OTs led to a linear free-energy relationship supporting the rate-limiting formation of a carbenium ion 60. The small k H /k CF3 ratio suggests here that the positive charge is highly delocalized in the pyrrole ring and should be regarded as a pyrrolium ion 60' rather than an α-(trifluoromethyl)carbenium ion 60 (Scheme 16). Similarly, trifluoromethyl-substituted indolium ions were invoked as intermediates in the recently reported galliumcatalyzed synthesis of unsymmetrical CF 3 -substituted 3,3'-and 3,6'-bis(indolyl)methanes from trifluoromethylated 3-indolylmethanols [71]. Alcohol 61 reacts with indole 62 to provide a product 63 or 64, depending on the temperature (Scheme 17). Mechanistic investigations were then undertaken by in situ lowtemperature NMR experiments, allowing the observation of thiophenium ions 77 Me -Cl and 77 Me -Br (Scheme 21). 19 F NMR analysis showed significant downfield shifts for the signal of the CF 3 group compared to the neutral precursors, characteristic of α-(trifluoromethyl)carbenium ions. However, and as ex-pected, the 13 C NMR spectra showed considerable downfield shifts for the carbon atoms C2 and C6, suggesting a highly delocalized positive charge in the heteroaromatic ring as depicted below.

α-(Trifluoromethyl)allylcarbenium ions
In 1976, Poulter et al. exploited the powerful electron-withdrawing effect of the CF 3 group to elucidate the prenyltransferase-catalyzed condensation mechanism [74,75]. The authors envisioned that substituting a methyl group in isopentenyl pyrophosphate (IPP) by a CF 3 group (Scheme 22, 79→78) should greatly reduce the reaction rate in the case of an ionization-condensation-elimination mechanism, while a small acceleration should be observed in the case of a displacement-elimination mechanism.
Promising results were first obtained during investigations conducted on CF 3 -substituted derivatives in S N 1-and S N 2-mechanism-based reactions (Scheme 23). A profound retardation effect for the solvolysis of 81 in acetone-H 2 O (S N 1) with k CH3 /k CF3 = 5.4 × 10 5 was observed, while 85 promoted the Finkelstein reaction (S N 2) about 11 times faster than 84 (k CH3 / k CF3 = 8.9 × 10 −2 , Scheme 23). This is the result of a destabilized cationic intermediate in the first case and a stabilized negatively charged transition state in the second.
When 78 was incubated in the presence of IPP and the enzyme prenyltransferase, a rate of 5.1 × 10 −4 nmol⋅min −1 ⋅mg −1 was measured for the condensation reaction (Scheme 24), which is to be compared to a value of 7.4 × 10 2 nmol⋅min −1 ⋅mg −1 observed for the condensation involving IPP and geranyl pyrophosphate (GPP). 78 was 1.5 × 10 6 times less reactive than geranyl pyrophosphate, allowing to conclude that the condensation mechanism involving prenyltransferase as a catalyst occurs via an ionization-condensation-elimination sequence.
As suggested by the aforementioned studies, α-(trifluoromethyl)-substituted allylic carbenium ions could exist in solution. The solvolysis of CF 3 -substituted allyl sulfonates was thus The reactivity of analogous monotrifluoromethyl-substituted allyl derivatives 94, bearing an aryl group in the vinylic position was also explored (Scheme 26). Trifluoroethanolysis of secondary triflate 94 gave a mixture of (Z)-95 and (E)-95 in a combined 70% yield, with an E/Z ratio of 17:83-8:92, depending on the nature of the aryl substituent (p-OMe or p-Cl, respectively). It is worth noting that the formation of S N 2 product 96 was not observed. Similar observations have been reported by Langlois et al. [77]. In order to get some insights into the mechanism, derivative 96 was synthesized and subjected to solvolysis. However, this compound was found to be stable under the reaction conditions [52]. When primary triflate 97 was subjected to solvolysis, the expected product (Z)-95 was obtained, and the rate was 50-100 times faster than when starting from 94. The Hammett-Brown correlation gave a poor dependence of the rate on the nature of the aryl substituent, and thus suggesting that the aryl group does not participate in the positive-charge stabilization. Finally, the Grunwald-Winstein plot gave a linear free-energy relationship between the rate and Y OTs , supporting the formation of a carbenium ion. From these observations, the authors concluded that 94 dissociates into an ion pair 98 in the rate-limiting step, in which the delocalized positive charge is highly concentrated in the γ-CF 3 position (see 98'), which is the electronically and sterically privileged position for the solvent approach, to subsequently give 95 (Scheme 27). Prakash et al. also investigated the formation of α-(trifluoromethyl)allylcarbenium ions from alcohol precursors in a superacid [78]. When allylic alcohol 99 was ionized with SbF 5 in SO 2 ClF at −78 °C, the corresponding α-(trifluoromethyl)allylcarbenium ion 100 was formed. The carbons atoms C1 and C2 exhibited very different chemical shifts, δ C1 = 157 ppm and δ C2 = 290 ppm, which are to be compared to the nontrifluoromethylated analogue (δ C1 = 206 ppm and δ C2 = 251.8 ppm). The authors suggested that "the positive charge is more unevenly localized in the cation" 100, with the resonance form 100'' contributing significantly more than 100' (Scheme 28). This unsymmetrical delocalized structure in carbenium compound 100 was also confirmed by DFT calculations at the B3LYP/6-31G* level, with a C2-C3 bond considerably shorter than the C1-C2 bond, with d C2 -C3 = 1.359 Å and d C1 -C2 = 1.427 Å.  [79,80]. It was also suggested that the resonance form 103' has a nonnegligible contribution as this α-(trifluoromethyl)allylcarbenium ion could be trapped by some electron rich arenes (i.e., xylene, cumene, etc.). The products 104 further react to afford indanes 105 after hydroarylation. A closely related study on dibrominated allylic α-(trifluoromethyl) alcohols also invoked the transient formation of allylic carbenium ions, such as 103 [81].

α-(Trifluoromethyl)alkynylcarbenium ions
It has been reported that the complex of Co 2 (CO) 6 and propargyl alcohols allows the facile generation of the corresponding propargylium ions (Nicholas reaction) in a relatively strong acidic medium (i.e., TFA, BF 3 ⋅Et 2 O, etc.). These cobaltcluster-stabilized propargylium ions exhibit a surprisingly high thermodynamic stability, comparable to that of triarylmethylcarbenium ions and are readily observable by NMR spectroscopy or isolable as salts with relatively weakly coordinating anions (BF 4 − , PF 6 − , etc.) [82]. In this context, Gruselle et al.
exploited the strong stabilization provided by Co-Co and Co-Mo bimetallic clusters to generate α-(trifluoromethyl)propargylium ions (Scheme 30). While the tertiary carbenium ion 108 was isolable as a solid [83,84], the tertiary carbenium ion 109 and the secondary derivatives 112a-c and 113a,b afforded oils. The secondary derivatives were much more sensitive in spite of the use of electron-rich Co-Mo clusters and could only be characterized by NMR and IR spectroscopy [85]. Upon ionization, the change in the electronic density is directly reflected by the downfield shift of the 19 F NMR chemical shift of the CF 3 group but also by a CO shift to a higher frequency. As a Heteroatom-substituted α-(trifluoromethyl)carbenium ions The stabilization of carbenium ions through oxygen lone pair back-donation [35] is a common feature in organic synthesis Scheme 33: Formation of α-(trifluoromethyl)propargylium ions from CF 3 -substituted propargyl alcohols. [88][89][90]. In this context, Olah, Pittman, et al. investigated the protonation of a variety of trifluoromethyl ketones in a superacid [35,91]. Trifluoromethyl ketone protonation was observed by NMR spectroscopy at −60 °C in a superacidic FSO 3 H-SbF 5 -SO 2 solution (Scheme 34).
Oxygen-stabilized α-(trifluoromethyl)carbenium ions (oxocarbenium ions) have been exploited for chemical synthesis [92][93][94]. Ketone 143a and ketoxime 143b undergo Friedel-Crafts Klumpp et al. explored the reactivity of CF 3 -substituted superelectrophiles (defined as multiply charged cationic electrophiles [101]) generated in superacid media [102]. Hence, when trifluoroacetyl pyridine 156 was treated with benzene in triflic acid, alcohol derivative 157 was obtained. In a superacid, 156 generates a dication 158 in which the electrophilicity is en-hanced through a strong charge repulsion (Scheme 39). This dication reacts with benzene to provide pyridinium-oxonium dication 159 in solution. Further arylation does not occur spontaneously, which was evident because alcohol 157 was isolated at the end of the reaction. Upon heating at 60 °C, the second arylation takes place, presumably via the formation of dicationic superelectrophile 160. Again, due to charge repulsions as well as due to the strong electron-withdrawing effect of the CF 3 group, the positive charge adjacent to the CF 3 group is highly delocalized within the phenyl ring, and arylation occurs regioselectively at the para-position, affording biaryl species 161.
Using this strategy, several trifluoromethyl ketones 162 and alcohols 163 bearing heteroaryl substituents (i.e., benzothiazole, quinoline, isoquinoline, benzimidazole, or imidazole) prone to be protonated were elegantly converted into the corresponding alcohols 163 and biphenyl compounds 161 in high yield (Scheme 40, top). The reaction of CF 3 -substituted 1,3-diketones 165a-d in TfOH was also deeply investigated by Klumpp et al. [101]. The syn-indanes 166a-d could cleanly be generated after successive well-defined arylation reactions via 167 (Scheme 40, bottom). Moreover, the CF 3 group was found to be essential in this reaction as 2,4-pentanedione did not react with benzene under similar conditions.
The use of acetal derivatives in place of ketones as precursors of oxygen-stabilized α-(trifluoromethyl)carbenium ions was also investigated. For instance, the readily available hemiacetal 168 was shown to react with benzene in the presence of a Lewis acid or H 2 SO 4 to form compounds 169-172 in various amounts, depending on the acid used (Scheme 41) [103]. It is assumed Scheme 40: Reactivity of α-CF 3 -substituted heteroaromatic ketones and alcohols as well as 1,3-diketones.
that an oxygen-stabilized α-(trifluoromethyl)carbenium ion is involved. It was shown that 168 could also react with (hetero)arenes [104,105] and alkenes [106] under Lewis acid activation but also with electron-rich arenes under thermal activation [107][108][109].  [112]. Mixing hemiacetal 175, arylaniline 176, and indole derivatives 149 in the presence of a catalytic amount of the moderately acidic (S)-TRIP (pK a = 3-4 in DMSO [113,114]) in dichloromethane afforded the chiral α-(trifluoromethyl)aminoaryl derivatives 177 in an excellent yield and enantiomeric excess (Scheme 42). The authors proposed that hemiacetal 175 and amine 176 react under the reaction conditions to give an imine in the first step, which is protonated by (S)-TRIP to generate the corresponding chiral CF 3 -substituted iminium ion. The latter subsequently reacts via the most accessible Re-face with indole 149 to afford the resulting Friedel-Crafts product 177. Worthy of note is the fact that the reaction works equally well with a CHF 2 -containing hemiacetal.
Nitrogen-stabilized α-(trifluoromethyl)carbenium ions have also been extensively investigated. Under electrochemical conditions, trifluoromethylated iminium ions 182 were successfully generated by Fuchigami et al. [115]. Starting from tertiary amines 178a-c, the corresponding hemiaminal ethers 179a-c were obtained (Scheme 43). The reaction is highly regioselective as no methoxylation of 178a and 178b was observed on the nontrifluoromethylated alkyl substituent (Me or Et). Hence, although amines 178a-c are more difficult to oxidize than their nonfluorinated analogues (E ox (PhNMe 2 ) = +0.71 V (SCE)), the radical cation 180 is formed under the reaction conditions, and deprotonation at the methylene unit near the CF 3 group is highly favored because of the higher acidity, accounting for the observed high regioselectivity. In addition, the transient stabi- Lewis acid activation of trifluoromethylated hemiaminal ethers has also been studied by Fuchigami et al. [115,116]. For instance, when 179b is treated with a slight excess of TiCl 4 in dichloromethane, iminium ion 182b can be trapped by TMSCN to furnish α-(trifluoromethyl)-α-aminonitrile 183 in 40% yield. The iminium was also successfully trapped by a silyl enol ether, affording a mixture of ketone 184 and heterocycle 185 (Scheme 44).
Langlois, Billard, and Blond reported on the Mannich-type reaction between silylated trifluoromethylated hemiaminal derivatives 189 [120] and enolizable ketones 188 [121]. The intermediate formation of trifluoromethylated iminium ion 192 by Lewis acid activation was suggested by the authors (Scheme 46). The resulting CF 3 -substituted β-amino ketones 190 could then be efficiently transformed in a one-pot procedure into the corresponding CF 3 -substituted enones 191 upon Brønsted acid treatment.
Langlois and Billard then exploited the reactivity of the trifluoromethylated iminium ion 192 and extended the scope of the reaction to a larger panel of nucleophiles, including alcohols, amines, aromatic and vinyl derivatives, as well as silylated nucleophiles (Scheme 47) [122].
Brigaud and Huguenot also suggested the formation of a trifluoromethylated iminium ion 187 during the course of their studies on a Strecker-type reaction [123]. Starting from tri- Viehe et al. also contributed by developing the chloroalkylamino reagent 199, bearing a geminal CF 3 group, which proved to be a valuable synthon for the introduction of the CF 3 group into molecules [125]. Thus, 199 exhibits a high reactivity towards many functionalities, as depicted below (Scheme 49). Interestingly, 200 and 201 are sufficiently stable to be synthesized, presumably due to electron delocalization (guanidinium ions).
The related thioacetal 204a was also studied and reacts with benzene upon treatment with strong Lewis acids (best with Scheme 48: Strecker reaction involving the trifluoromethylated iminium ion 187. AlCl 3 ) [139]. In this case, the only product formed in the course of the reaction was 205, isolated in 83% yield (Scheme 50). The proposed cationic intermediate in this reaction is a sulfur-stabilized α-(trifluoromethyl)carbenium ion 206 (an α-(trifluoromethyl)-substituted sulfonium cation).
Analogous to thioacetals 204a, chloroalkylthio derivatives 207a-c, bearing an adjacent CF 3 group, were also investigated [140]. It appeared that a sulfur-stabilized α-(trifluoromethyl)carbenium ion 208 can be generated from 207a by chloride abstraction following Lewis acid activation (e.g., SnCl 4 or ZnCl 2 ), opening an avenue for this cation to react with various nucleophiles (Scheme 51). Such a cation can also be trapped intramolecularly by a phenyl moiety; however, the length of the appended alkyl chain appeared to be of the utmost importance in this transformation.
Analogous to their work on the nitrogen counterparts (vide supra), Fuchigami et al. were successful in the electrochemical production of sulfur-stabilized α-(trifluoromethyl)carbenium ions [139,141]. Thereby, they converted sulfides 213a-h into thioacetals 204a-h (Scheme 52). It is worth to note that the presence of an aromatic substituent on the sulfur atom is essential for the sulfides to react. Also, lengthening the perfluoroalkyl chain from CF 3 to C 2 F 5 or C 3 F 7 resulted in a significant drop in the yield. Interestingly, while the electrochemical acetoxylation of 213a furnished 204a in an excellent yield of 93%, the Pummerer rearrangement of sulfoxide 214 under harsh conditions turned out to be less efficient, affording 204f in only 42% yield.
This reaction is thought to proceed stepwise via a first oxidative electron transfer, followed by deprotonation, a second oxidative electron transfer, and methoxylation or acetoxylation, respectively (Scheme 53). The driving force in this reaction is assumed to be the deprotonation of radical cation 215, a highly destabilized species due to the presence of the strongly electronwithdrawing CF 3 substituent, which leads to radical 216, synergistically stabilized by the electron-withdrawing CF 3 group and the electron donor sulfur atom through a captodative effect. Further oxidative electron transfer produces α-(trifluoromethyl)substituted sulfonium ion 206, leading to 204a,f after reacting with the solvent.  [142] 217a in a superacid by in situ NMR spectroscopy (Scheme 54) [143]. The remarkable characteristic of this strategy was the installation of a CF 3 group in the α-position of the N 2 moiety. This strategy relies on the high electron-withdrawing effect of the CF 3 group, which greatly destabilizes nearby positive charges. As a result, the dissociation rate for the generation of molecular nitrogen was considerably reduced, allowing the observation of the diazonium ion at a low temperature. However, warming the diazonium solution up to −20 °C resulted in a vigorous evolution of N 2 gas along with the clean formation of the resulting fluorosulfonate 219, with no direct observation of the α-(trifluoromethyl)carbenium ion. Further studies were conducted by Lenoir and Dahn to shed light on the mechanism of the solvolysis of CF 3 -substituted diazoalkane derivatives (Figure 10a) [144]. They measured an inverse kinetic isotope effect of k H /k D = 0.25 for the solvolysis of 217a in dioxane/H 2 O 60:40 in the presence of HClO 4 (3 ≤ pH ≤ 4) and mentioned that this low value is "typical of a preequilibrium protonation reaction" and the rate-limiting solvolysis of diazonium ion 218a (Figure 10b, in blue). Furthermore, the addition of a strong nucleophile dramatically increased the rate. The authors thus concluded that these observations are pieces of evidence for an A2 bimolecular process, which is also in agreement with the preferred decomposition pathway of other deactivated diazoalkanes (i.e., diazoacetate, k H /k D = 0.34) [145,146]. Extending the investigations to diazo compound 217b led to a different conclusion as a "normal" isotope effect of k H /k D = 1.67 was obtained in this case. Diderich found a comparable ratio of k H /k D = 2.13 for diazo compound 217c [147]. In these latter cases, the solvolysis of diazoalkanes 217b and 217c is supported by an A-S E 2 mechanism including a rate-limiting proton transfer (Figure 10b, in green) as the solvolysis rate approximately corresponds to the transfer rate of a proton (or deuteron). The difference in the reactivity between 217a and 217b,c would thus be due to the easier protonation of 217b,c compared to 217a, in a similar way as to how one can expect secondary carbanions to be more basic than primaries. Studies on CF 3 -substituted diazonium ions were next conducted by Kirmse and Gassen to determine the solvolysis mechanism [148]. They found that upon deamination of 221 using a solution of sodium nitrite in aqueous perchloric acid at pH 3.5, a 60:40 mixture of the elimination product 224 and alcohols 222 and 223 was obtained in a 95% overall yield. These alcohols result from either solvolysis (223, 40.3%) or rearrangement (222, 59.7%, reaction (1) in Scheme 55). Further investigations on the stereochemical aspects leading to product 223 showed that when enantioenriched amine (S)-221 (94% ee) was subjected to deamination, product (R)-223 was obtained, with an inverted configuration and an eroded enantiomeric purity of 65% ee (reaction (2) in Scheme 55). The authors thus concluded that the formation of (R)-223 from (S)-221 occurred by a nucleophilic substitution mechanism, with 70% inversion. Since the racemization via a diazo↔diazonium equilibrium was excluded due to negligible 2 D incorporation (i.e., <1%) when D 2 O was used, the 30% racemization noted in the process would account for the transient formation of a trifluoromethylsubstituted carbenium ion. ). This is a strong evidence for the transient formation of a carbenium ion as the isotope effect for the 1,2-H-shift is known to be very small in carbenium ions. It has been indeed previously demonstrated that a 1,2-H-shift isotope effect of k H /k D = 1.2-1.3 was obtained starting from 2-butyldiazonium ion 225, which is known to decay via a carbenium ion [149,150].
In the absence of the CF 3 group, 225-d 2 decays in a mixture of alkenes and alcohols. By taking only the alcohol mixture into account, alcohol 227-d 2 was considered to have been obtained via a nucleophilic substitution mechanism (88%) with 25% inversion and 226-d 2 via rearrangement (12%, Scheme 57). This contrasts with the previous results obtained for 218d, which lead to 40.3% of the nucleophilic-substitution product 223 with 70% inversion and 59.7% of rearranged 222 when This would be consistent with a less labile C-N bond in 218d and the formation of the extremely reactive α-(trifluoromethyl)carbenium ion 228 that is therefore more prone to undergo rearrangements to generate the more stabilized β-(trifluoromethyl)carbenium ion 229 (Scheme 58).  The β-and γ-CF 3 effects on the carbenium ions were also investigated by the same authors by systematically comparing the reactivity of a selected series of CF 3 -containing and analogous nonfluorinated diazonium ions toward solvolysis. The diazonium ion 234 led exclusively to alcohol 222, with the absence of any detectable rearranged products, while the CF 3free analogous species 225 underwent 12% rearrangement (reaction (1)  Even though the direct observation of α-(trifluoromethyl)carbenium ions was not the purpose of this study, it successfully brought a better understanding on the effect of a CF 3 group close to a positive charge.

Hypothetical formation of CF 3 -containing alkylcarbenium ions by activation of alcohol derivatives:
The solvolysis reaction of alkyl tosylates has attracted the attention of many chemists, and successive studies revealed that hydrogen or methyl shifts were effective and most prominent in strongly acidic solvents, such as HSO 3  stabilization by hyperconjugation, followed by 1,2-H-shift [155].
The solvolysis study on aliphatic trifluoromethyl tosylate derivatives in strong acids was conducted following theoretical studies [156,157]. While 248 and 252 showed a solvolysis rate comparable to that of 253 in 85-100% H 2 SO 4 , derivative 249 underwent solvolysis at a significantly slower rate ( Figure 11). This counterintuitive behavior was not considered to be in line with the intermediary formation of a carbenium ion, as β-(trifluoromethyl)carbenium ion 254 generated from 249 is expected to be more stable than α-(trifluoromethyl)carbenium ion 2 generated from 252. collected by Tidwell and Koshy [39] on benzylic α-(trifluoromethyl)-substituted tosylate derivatives (see section on α-(trifluoromethyl)-substituted carbenium ions), presumably due to the presence of a stabilizing phenyl moiety in the latter case. Analogous investigations on triflate derivatives were realized by Tidwell et al. [41]. Triflates are more reactive than tosylates -as illustrated by k Tf /k Ts = 7 × 10 4 for the elimination reactions of 259 and 260 -and were thus of interest in the context of solvolysis studies. The solvolysis of 260 in various solvents led to the sole formation of the elimination product, and no nucleophilic substitution of the triflate by the solvent was observed. Similar results were also reported previously by the authors for 259 (Scheme 65) [39]. Interestingly, no dependence of the elimination rate on the ionizing power of the solvents was observed, suggesting that the formation of an ion pair (either intimate or solvent-separated) was not the limiting step. However, the faster rate obtained in the most nucleophilic solvents implies that the solvent is involved in the rate-limiting step. Kinetic isotope effects in the elimination reactions of 260, 260-d 3 , and 260-d 6 were found to be k 260 /k 260-d3 = 1.78 and k 260 /k 260-d6 = 3.80. The effect of the solvents and added salts on the rate proved that the medium (solvent and salt) is involved in the rate-limiting step. Furthermore, the values obtained for the secondary isotope effect agreed with the elimination as the ratelimiting step and strongly support the hypothesis that the latter occurred from an intimate ion pair.
Starting from 261, no elimination product could be formed during the solvolysis reaction, and a 1,2-methyl shift occurred to generate 262 after solvent trapping, as reported by Roberts and Hall (Scheme 66) [158]. Kinetic studies revealed a linear free-energy relationship between the rate of the solvolysis against the Y OTf values. The isolated product 262 as well as the kinetic data strongly support the formation of the β-(trifluoromethyl)carbenium ion 263 in the rate-limiting step with considerable neighboring group participation, characteristic of a k Δ pathway. Bonnet-Delpon et al. successfully took advantage of the intramolecular stabilization of a cation induced by the presence of a CF 3 group to develop a method to access 1-(trifluoromethyl)tetralins [159]. For instance, upon the solvolysis of systems such as 264 in TFA/TFAA, the cyclized products 265 were obtained. Furthermore, it is known that the nontrifluoromethylated tosylate analogue undergoes the same cyclization via a k Δ process rather than a k c process [160]. The authors thus proposed that the aryl ring stabilizes the cation concomitantly after the elimination of the triflate anion to form the transition state 266 in the solvolysis reaction of derivatives 264. The same cyclization reaction occurred when derivatives such as 267 were solvolyzed in TFA/H 2 SO 4 , affording 268 (Scheme 67). However, while the nature of the aryl substituent R 1 had a negligible effect on the rate, the latter had a convincing dependence on the nature of the substituent R 2 . For benzylic systems 267, the authors proposed a k c pathway involving the formation of the more stable benzylic α-(trifluoromethyl)carbenium ion 269, with a subsequent cyclization reaction. Gassman and Doherty suggested that the introduction of a strongly electron-withdrawing group in the α-position of a positively charged carbon center could magnify the neighboring group participation so as to compensate for the increased electron deficiency at the incipient cationic center [4,161]. Using this strategy, Tilley et al. reported the first synthesis of strained CF 3 -substituted bicyclo[1.1.0]butane 271a via γ-silyl elimination of α-(trifluoromethyl)cyclobutyl tosylate 270a (Scheme 68) [162]. The reaction was proposed to occur via neighboringgroup participation of the silicon-based group, through homohyperconjugative stabilization of the pC orbital of the incipient α-R F -substituted carbenium ion by a percaudal (back lobe) par-ticipation of the σC-Si orbital (272, Scheme 68). Importantly, the initial W-conformation in the starting material 270a,b was mandatory to allow a sufficient orbital overlap as the U-conformation (endo-sickle-like isomer) failed to react within the reaction time (≈12 h). In 272, the positive charge is thus significantly delocalized at the silicon center, allowing a facile nucleophilic displacement at the silicon atom by a solvent molecule to afford 271a,b. The CF 3 moiety strongly affects the stability in 271a, which was found to be stable "indefinitely" when stored under an inert atmosphere at a low temperature and did not suffer from polymerization. Further investigations by Tilley et al. were conducted in order to enlarge the scope of the above-mentioned 1,3-silyl elimination of α-(trifluoromethyl) tosylate, which was restricted so far to cyclobutyl derivatives, and a variety of linear or cyclic α-(trifluoromethyl)-γ-silyl sulfonates was targeted (Scheme 69) [163,164]. While the solvolysis was readily performed with tosylate-like leaving groups in the case of aromatic substituents being present, as in 273a-h, or in the cyclic systems 274a,b, a better leaving group, such as triflate, was generally required for alkyl derivatives 275a-d.
Interestingly, CF 3 -substituted cyclopropanes 281 could be obtained from linear derivative 280 but also from cyclic 279 (cis-279 or trans-279) via an alternative mechanism. The proposed mechanism for the conversion of 279 into 281 invokes an alkyl shift, leading to the generation of a carbenium ion 283, stabilized by the β-effect of silicon (via the transition state 282), and further β-silyl elimination affords product 281 (Scheme 70). In addition, trans-279 reacted approximately 12 times faster than cis-279, and thus suggesting a neighboring-group participation via the σC-Si orbital in the proposed transition state 282. Very recently, Creary reported a study on the generation of CF 3 -subtituted γ-silylcarbenium ions via a cyclopropylcarbinyl rearrangement [164]. When cyclopropylcarbinylcarbenium ion 284 is generated, this species is in an equilibrium with the homoallylcarbenium and cyclobutylcarbenium ions 285 and 286 (Scheme 71) [164].
Creary investigated the solvolysis of CF 3 -substituted cyclopropylcarbinyl triflate 287a and obtained a mixture of bicyclobutane 271a and unrearranged solvent-substitution product 289a in 71% and 29% yield, respectively (Scheme 72) [164]. This result was in stark contrast with those obtained with Phand H-substituted analogues 287b and 287c because the main products of the reactions in the latter cases were cyclobutanes 290b and 290c. As mentioned previously, this is the result of an enhanced neighboring-group participation induced by the presence of the CF 3 group in 287a. A stronger percaudal stabilization is thus present in carbenium intermediate 272a, which leads mainly to 271a by solvent-assisted γ-silyl elimination.
Creary then considered the diastereomers of 287a-c, namely 291a-c. While 291b led to the same product 290b, the isomer 290a and unsubstituted 290c exhibited a different reactivity as they did not form the rearranged cyclobutane derivatives 290a and 290c (Scheme 73) [164]. It was mentioned that for isomers 291a-c, the conformation of the corresponding cyclobutylcarbenium ions 293a-c after the rearrangement would not allow the percaudal participation of the TMS group. Nevertheless, in the presence of a stabilizing group, such as a phenyl group, carbenium ion 293b is sufficiently stable and can undergo ring inversion to furnish carbenium ion 272b, stabilized by the TMS group, which finally gives 290b. On the other hand, in the presence of a CF 3 group or a H atom, 291a and 291c strongly suffer from the absence of this stabilization and are mainly converted to the unrearranged products 294a and 294c.  [165]. Hence, this demonstrated that the C-F activation of the CF 3 moiety to generate a difluoroallylcarbenium ion 295 was favored over the formation of a secondary α-CF 3 -substituted species 300 or a primary aliphatic β-(trifluoromethyl)carbenium ion 254. Indeed, no evidence for the protonation of TFP was obtained, highlighting once more the extraordinary electron-withdrawing and deactivating potential of the CF 3 moiety. It is worthy of note that the installation of an aryl group, however, makes the protonation of α-(trifluoromethyl)styrene derivatives possible, even though a retardation of the rate of 10 4 -10 7 has been measured due to the presence of the CF 3 group [68]. To overcome the difficulty to generate trifluoromethyl-substituted alkylcarbenium ions after the activation of trifluoromethyl-substituted alkenes, the stabilization by a neighboring group could be envisaged. In the enantioselective gem-difluorination of styrenes catalyzed by hypervalent iodoarene species, Jacobsen et al. elegantly exploited the stabilizing effect of an aromatic ring through skeletal rearrangement via a phenonium ion intermediate [166]. Recently, Gilmour et al. synthesized highly fluorinated scaffolds using this strategy (Scheme 76) [167]. The widely accepted mechanism for this transformation involves a first fluoroiodination of an olefin 301a-c to give 303a-c, followed by an anchimerically assisted iodonium elimination to generate the phenonium ions 304a-c and a subsequent regioselective fluoride addition to furnish compounds 305a-c (Scheme 76) [168]. In this example, the phenonium species 304a-c can be regarded as a "hidden" α-(trifluoromethyl)carbenium ion 306a-c, in which the fluorine atom in the α position stabilizes the cation by lone pair back-donation (see 306'a-c), favoring the whole process. vestigated the reactivity of CF 3 -substituted pentyne 307. The solvolysis of 307 in TFA and CF 3 CO 2 Na led to cyclobutanone 308 and alcohol 309. The isolation of 308 suggests the transient formation of β-(trifluoromethyl)vinyl cation 310. However, no trace of a cyclopropyl ketone 311 was observed, indicating that this route is prohibited as it requires the generation of a more destabilized α-(trifluoromethyl)vinyl cation 312 of higher energy (Scheme 77).
The photochemical formation of α-(trifluoromethyl)vinylcarbenium ions has also been suggested by Lodder et al. (Scheme 78) [170]. UV irradiation of vinyl compound 313 led to the formation of acetylene product 315, which is suggested to be formed via β-H-elimination from an open α-(trifluoro-methyl)vinylcarbenium ion 314. A kinetic isotope effect study gave a k H /k D = 1.22 ratio, which is in perfect agreement with β-secondary isotope effect values for reactions proceeding through a car-benium ion. The observation of product 317 strongly supports this cationic mechanism, as it is not unlikely that carbenium ion 314 undergoes a 1,2-fluorine shift (although such a rearrangement has not been experimentally demonstrated so far) to generate the more stable difluorinated allyl cation 316, which leads to 317 after internal return. Noteworthy, it has been calculated that such a vinyl cation 314 is 42.1 kcal⋅mol −1 higher in energy than the corresponding CH 3 -substituted analogues.
Nonclassical α-(trifluoromethyl)carbenium ions The very existence of nonclassical carbocations (3 centers, 2π-electrons) has been the subject of debate for decades. The 2-norbornyl cation became the most emblematic example, and its structure has been proposed either as two carbenium ions, 318a and 318b, in a rapid equilibrium or as a symmetrical cation 318c, displaying a nonclassical pentacoordinated carbon atom ( Figure 12) [171][172][173]. Krossing et al. eventually put an end to this debate by achieving the crystal growth and crystal structure determination of the 2-norbornyl cation, the structure of which was unequivocally assigned as 318c [174]. In 1984, as part of their investigations on carbocation stabilization by neighboring group participation, Gassman and Hall brought evidence for the nonclassical model using a strategy involving a progressive destabilization of the resulting cation by the introduction of CF 3 groups in the norbornene derivatives 319-321 ( Figure 13) [175]. They found a cumulative effect of the CF 3 groups on the solvolysis rate, with a 10 6 -fold decelerating effect upon the introduction of each CF 3 unit. The authors concluded that "the fact that each CF 3 group decreases the rate of ionization by 10 6 provides overwhelming evidence that the interactions of the double bond […] with the incipient carbocation involve symmetrical (nonclassical) transition states 322, rather than pairs of rapidly equilibrating (classical) cations".
2-Adamantyl tosylate is one of the main references to describe the S N 1 mechanism in which the carbenium character is maxi- mized. For this reason, Prakash, Tidwell, et al. tried to reach the highest k H /k CF3 ratio by exploring 2-adamantyl-2-trifluoromethyl tosylate (323), which was expected to exhibit a profound reluctance to generate a carbenium ion [176]. Ironically, the solvolysis of 323 in several solvents led to an average ratio of k H /k CF3 = 2.0, the smallest ratio ever obtained to date. The explanation for this unprecedented high reactivity for an α-(trifluoromethyl)alkyl tosylate partly lies in the structure of the major solvolysis product 324 (Scheme 79). Monitoring of the reaction by NMR spectroscopy allowed the observation of intermediate 327, which was suggested to result from a successive ion pair formation, rearrangement, and internal return. It was then observed that 327 was progressively converted into 324 at a rate 3 times slower than when it was produced from 323. From these observations, the authors concluded that the high reactivity of 323 was attributed to the σ-donation from the C3-C4 bond, allowing the positive charge to also be shared in the β-position of the CF 3 group via intermediate 326. Furthermore, the presence of a ground-state strain of approximately 6.5 kcal⋅mol −1 due to the presence of the CF 3 group was established in 323, and the relief of this intrinsic strain in the transition state would act as an additional driving force and accelerate this reaction.
The solvolysis of cyclopropyl-substituted α-(trifluoromethyl) tosylate 328 was investigated by Meyer and Hanack, who reported a high tendency of 328 for rearrangements [177]. Hence, the hydrolysis of 328 led to 329 and to a mixture of the rearranged products 330-332 (Scheme 80). Suspecting that 330 and 331 were obtained from the solvent trapping of the rearranged carbenium ions 336 and 337, respectively (Scheme 81), the cyclobutyl tosylate 333 and the cyclopropyl tosylate 334 were also solvolyzed ( Table 3). Interestingly, while 328 yielded 3.5% of the direct solvent-substituted product 329, 333, and 334 yielded 25% of 330 and 92% of 331, respectively, as a result of the lower tendency to rearrange, due to the higher ion stability. This suggests that 329 generates a highly reactive α-(trifluoromethyl)carbenium ion 335 upon solvolysis, which rapidly either rearranges via an alkyl shift to the β-(trifluoromethyl)carbenium ion 336 to give 330, or to the γ-(trifluoromethyl)car- benium ion 338 via σ C-C bond donation (i.e., a homoaromatic species), which is trapped at the primary carbon atom, similar as in norbornyl derivatives, to give 332. Also, 336 can further rearrange by alkyl shift to give the γ-(trifluoromethyl)carbenium ion 337, which leads to 331. What is striking from these observations is the effect of the CF 3 group on a positive charge nearby, as it continuously moves the latter from the α-to β-or eventually from the β-to the γ-position. Kinetic studies conducted by Roberts also support the formation of carbenium ion 335 as the rate-limiting step [178].

Conclusion
Destabilized carbocations exhibit structural and electronic features that reduce their lifetimes. CF 3 -substituted carbocations are probably the cations that have long been regarded as the worst possible intermediates to be generated in an organic transformation, and therefore were deeply studied as exotic species. The study of CF 3 -substituted carbocations has therefore produced valuable contributions to understand their implications in synthetic transformations. Through these efforts, which are the subjects of this review, great perspectives in modern synthetic chemistry are expected as a result of the exploitation of these underestimated cationic intermediates.