Polyfluoroalkylation is a reaction of introducing a polyfluoroalkyl group directly into an organic substrate [16–18]. This group of reactions can in turn be divided by reaction mechanism. While polyfluoroalkyl groups may vary, most of the scientific attention and developments concern the introduction of the CF3group , although in recent years difluoromethylation with a CF2H group has seen a resurgence of interest .
In nucleophilic trifluoromethylation, the active particle is a CF3–anion . This anion itself is very unstable, and rapidly decomposes into fluoride anion and difluorocarbene [53,54] (see Scheme2.8).
Scheme 2.8 Representative reactions with nucleophilic trifluoromethylation reagents
The trifluoromethyl anion can be stabilized by pulling the electron density from the carbon atom. This can be achieved by metal coordination (e.g., copper) , or by form-ingσ-bonds with lead or silicon. The Ruppert-Prakash reagent is based on the latter principle (see Figure2.3). This reagent was first synthesized in 1984 [52,56,57]. The advantage of this compound is its resistance to water and acidic conditions. Ruppert-Prakash reagent requires an initiator, for which TBAF is usually resorted to . Other initiators include CsF, DMSO, K2CO3, LiOAc, or KOt-Bu [57,58]. Examples of reactions involving this reagent are shown in Scheme2.8.
Another widespread nucleophilic trifluoromethylating agent is a common fluoro-form (CHF3), used in combination with a strong base (such as KOt-Bu). This reagent exhibits high reactivity with carbonyl compounds in dimethylformamide .
In this type of reaction, the active trifluoromethyl donor group carries a positive charge (e.g., CF3+) [13,50]. The first reagent enabling electrophilic trifluoromethylation, diaryl
(trifluoromethyl)sulfonium salt (Ar2S+CF3SbF6–) was created by Lev Yagupolski in 1984, as a result of the interaction of aryl trifluoromethyl sulfoxide with SF3+SbF6-, which was accompanied by a reaction with an electron-enriched arene . Yagupolski reagent was used for trifluoromethylation of thiophenolate. The whole class of compounds de-rived from above-mentioned reagent is also referred to as Yagupolski reagents (see Fig-ure2.3). The generalized limits of their application [13,50,60] are shown in Scheme2.9 (black arrows were used for color-coding).
Scheme 2.9 Representative selection of electrophilic trifluoromethylation reactions with the most common reagents. Electrophilic reagents are color-coded along with the scope of their application. Arrows for trans-formation matching the name color imply that this reagent can be used for such transforation. Color codes are: black – Yagupolski reagents;blue–Umemotoreagents;green–Tognireagents.
A whole group of Umemoto reagents, developed in 1990, are commercially avail-able and well-known tools for trifluoromethylation, the action of which is based on the same principle to Yagupolski’s [59–61](see Figure2.3). For this type of compounds, sul-fur can be replaced by oxygen, selenium or tellurium. Among the substrates studied
in the trifluoromethylation reaction with Umemoto reagents are pyridine, aniline, tri-phenylphosphine and the lithium salt of phenylacetylene. The main reactions using Umemoto reagents [50,60,61] are shown in Scheme2.9(blue arrows were used for color-coding).
Another type of CF3+ donors includes reagents based on hypervalent iodine (III).
These reagents are commonly referred to as Togni reagents (see Figure2.3) [62–65].
Thiols, alcohols, phosphines, arenes and heterocyclic compounds [63,64], inactivated olefins  and unsaturated carboxylic acids  are commonly targeted as substrates for trifluoromethylation with Togni reagents [50,63] (representative scope is depicted in Scheme2.9, green arrows were used for color-coding).
In radical trifluoromethylation, as the name might suggest, the active particle is a free radical trifluoromethyl group [13,67,68].
O CF3 O
CF3 F3C S
OAg O F3C
X = Cl, Br, I
O 1) LDA 2) BEt3, CF3I
O CF3 T, or hν, or H2O2 tBuOOH, Cu(OTf)
T, or hν TiO2,
X = NH, S, O
Scheme 2.10 A generalized depiction of pathways of generating the trifluoromethyl radical (top part), and selection of its most common applications (bottom part)
Speaking of trifluoromethyl radical, the fluorine atom acts not only as an electron-acceptor, which exhibits an inductive effect, but also as a weak donor, due to the interac-tion of an unpaired fluorine electron pair with the singly-occupied HOMO of the central radical. Like its methyl analog, the trifluoromethyl radical has a pyramidal structure, but a large inversion barrier for the latter differentiates it from the former, thus making
fluoromethyl species more electrophilic and very reactive. For example, in the reaction with styrene, the trifluoromethyl radical proceeds 440 times faster than with the methyl radical .
Reagents such as bromotrifluoromethane (CF3Br) and other haloform compounds were used for this type of reactions, but in response to the requirements of the Montreal Protocol, alternative substances had to be sought, among which trifluoroiodomethane (CF3I) is the most common [68,69]. Among more specific reagents is a mixture of tri-fluoromethyl iodide and triethylborane. Other reagents that produce the tritri-fluoromethyl radical include Langlois reagent (sodium trifluoromethanesulfinate, see Figure2.3) and bis-trifluoroacetyl peroxide. Generalization of approaches used to generate trifluoro-methyl radical and its most common applications is depicted is Scheme2.10.
A 1949 article  described the photochemical reaction of iodotrifluoromethane with ethylene to produce 3-iodo-1,1,1-trifluoropropane. Reagents such as iodo- and bromotrifluoromethane (via thermal or photochemical initiation), silver trifluoroacet-ate together with titanium oxide (photochemical initiation), as well as a mixture of so-dium trifluoromethanesulfinate, copper (II) triflate and tert-butyl hydroperoxide were used for direct trifluoromethylation of arenes  (see Scheme2.10).
The last sub-group of trifluoroalkylation reactions are the metal-mediated reactions.
They are based on in situ formation of complexes between transition metals and CF3 species.
In reactions of addition between aromatic compounds and metal-trifluoromethyl complexes, the latter usually contains copper, less often palladium and nickel . The first such reaction was carried out in 1968 by McLaughlin and Thrower .
H CF3 CuCl, tBuOK
[ CuCF3 ]
N CF3 DMF
X = I, Br H
Scheme 2.11 Generalized depiction of copper-mediated trifluoromethylation reactions
In 1969, it was modified by Kobayashi and Kumadaki, and consisted of the interac-tion between iodobenzene and iodotrifluoromethane, using copper powder in dimethyl-formamide at 150◦C, resulted in the formation of trifluoromethylbenzene [72,73]. An intermediate in reactions of this type is the perfluoromethyl-metal complex.
The reaction with the Pd(OAc)2catalyst was described in 1982 by Kitazume et al., using zinc powder, and the main intermediate was CF3ZnI associated with the active catalyst – Pd (0) . Subsequently, the conditions for this reaction were improved by using copper for mediation of trifluoromethyl species (see Scheme2.11).
The first reaction of this type with a copper catalyst was described in 2009 by Oishi et al., and is based on the interaction of iodoarene, trifluoromethylsilane, copper iodide, and 1,10-phenanthroline . Variations of this reaction are based on the use of an-other trifluoromethyl donor, potassium trifluoromethyl trimethoxyborate , the use of arylated boronic acids , trifluoromethyl sulfonium salts  or trifluoromethyl copper (I) phenanthroline complex . Generalized approaches and scope of copper-mediated trifluoromethylation are depicted in Scheme2.11.
In our attempt to systematize and cover the main approaches to polyfluoroalkylation, attention was drawn to trifluoromethylation, as this is the most researched and im-plemented moiety. One might bring up the question – what about introducing other (poly)fluorinated species (e.g., CHF2, CF2H, C2F5, etc.)? As going in-depth for each and every group is well beyond the scope of this chapter, we will try to answer this question very briefly.
Overall, approaches to introducing other polyfluoroalkyl groups are similar to tri-fluoromethyl group, same mechanisms and strategies are being tested and optimized, even reagents are often similar (except for variation in fluorine content), but the extent to which it is successfully achieved is largely dependent on the desired group.
Selective introduction of monofluoromethyl group (CH2F), although still actively developing in the last decade (group of Hu has been particularly active in this area), still remains the most challenging of the series . Fluoromethylene halides (CH2FX), monofluoromethyl analogs of Yagupolski and Langlois reagents, and many more ana-logs of already established trifluoromethylation techniques have been developed .
Despite all the progress, most of the reagents are effective in transferring CH2F only to heteroatoms (nitrogen, oxygen, sulfur), while forming C-C bond directly with CH2F moi-ety still remains a challenge [13,80].
In the case of difluoromethyl group, relatively higher stability of CF2H moiety fa-cilitated development of its direct introduction to substrates . The vast majority of these methods are based on electrophilic and radical approaches. While CHF2I is a conventional reagent for such a goal, a great contribution was done by Baran and co-workers, who developed zinc difluoromethanesulfinate (Zn(SO2CF2H)2, also known as DFMS)  to achieve direct difluoromethylation of (het)aryl compounds. Other not-able examples include CF2H-analog of Ruppert-Prakash reagent (developed by Zhu et al., and used for copper-mediated C-H oxidative difluoromethylation of heterocycles) , difluoroacetic acid with radical precursors via transition metal catalysis , and using a CF2H-analog of Langlois reagent for difluoromethylation of heterocycles via
ganic photoredox catalysis .
Lastly, trifluoroethylation and polyperfluoroalkylation can be achieved mainly by electrophilic and nucleophilic methods, using reagents with a fluorine-containing moi-ety of interest, in a fashion analogous to trifluoromethylation . As a notable example, an interesting approach of introducing tetrafluoroethylene  and pentafluoroethyl-ene  moieties utilizing bis(alkylthio)carbenium salts  was developed in the group of Röschenthaler. When used in combination with desulfurative fluorination treatment, these salts can be used as "masked" electrophilic polyfluoroalkylation reagents [85,86].