Development of pentafluoroethylation methods

Abstract

Compared to the smallest perfluoroalkyl group, i.e. trifluoromethyl (CF₃), the pentafluoroethyl group (C₂F₅) has rather been overlooked in terms of synthetic methods and applications in pharmaceuticals/agrochemicals. However, this situation has changed in the last decade or so where more reports have appeared in the literature describing the reagents and reactions that can allow the efficient preparation of C₂F₅-containing compounds. This review summarizes the methods of pentafluoroethylation for the period of ca. 2015–2025 organized by reagents including transition metal-based reagents, perfluoroalkyl silanes, gaseous reagents, hypervalent iodine, sulfonium ylide and sulfoximine reagents, and miscellaneous reagents. These methods have significantly advanced our access to structurally diverse pentafluoroethylated compounds and will have a major impact on their potential applications in medicinal chemistry as drug candidates and in organic synthesis as building blocks.

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Yihan Tang

Dr Yihan Tang received his PhD in Chemistry from The Chinese University of Hong Kong in 2025 under the supervision of Prof. Gavin Chit Tsui. He is currently a Research Professor in the Department of Chemistry at Chung-Ang University (South Korea), working with Prof. Eun Jin Cho. His research is focused on organofluorine chemistry and DFT-guided mechanistic studies of organic reactions.

Tao Dong

Dr Tao Dong received his PhD in Chemistry from The Chinese University of Hong Kong under the supervision of Prof. Gavin Chit Tsui. He is currently a postdoctoral fellow at The Chinese University of Hong Kong, Shenzhen (China), working with Prof. Tiow-Gan Ong. His research focuses on organofluorine chemistry and organometallic chemistry.

Gavin Chit Tsui

Prof. Gavin Chit Tsui received his PhD from the University of Toronto in Canada with Prof. Mark Lautens. During his PhD studies, he also worked with Prof. Tamio Hayashi at Kyoto University as a JSPS fellow. He then joined the research group of Prof. Benjamin List (Nobel laureate) at the Max-Planck-Institut für Kohlenforschung in Germany as a Humboldt postdoctoral fellow. Prof. Tsui was the recipient of the Humboldt-Bayer Postdoctoral Fellowship, Thieme Chemistry Journals Award and Asian Core Program Lectureship Awards (Thailand, Taiwan, Japan, Korea, Singapore). He started his independent career at the Chinese University of Hong Kong (CUHK) as an Assistant Professor. He was promoted to the rank of Associate Professor with tenure in 2022.

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1. Introduction

Method development for introducing perfluoroalkyl groups into organic molecules has become increasingly important,¹ owing to the desirable biological and chemophysical properties exhibited by perfluoroalkylated compounds which are prevalent in marketed drugs.² The smallest perfluoroalkyl group CF₃ has been shown to be crucial in drug discovery and its installation, i.e. trifluoromethylation, has been extensively studied and reached certain level of maturity.³ In contrast, the pentafluoroethyl group (C₂F₅), a homolog of CF₃, has been largely overlooked in the literature until recently. Although C₂F₅ belongs to the broader family of perfluoroalkyl groups, its installation is not simply an extension of the trifluoromethylation methodology. In practice, the limited availability and different reactivities of C₂F₅-containing reagents have made pentafluoroethylation a more specialized and less developed transformation. According to a SciFinder® search, during the period of 2000–2022, there were over 3000 references on the topic of “trifluoromethylation” versus less than 100 references on “pentafluoroethylation”. That being said, bioactive compounds containing the C₂F₅ group are well-documented including angiotensin II receptor antagonist DuP-532, antihypertensive potassium channel opener KC-515 and fulvestrant for treating breast cancer (Scheme 1).⁴ The number of pentafluoroethylated drug molecules, however, is significantly lower than that of the trifluoromethylated ones, despite some evidence pointing to the superior biological activities of the pentafluoroethylated congeners.⁵ Thus, new tools for pentafluoroethylation will have impact on the application of C₂F₅-containing compounds as therapeutic agents in the future.

Scheme 1 Bioactive compounds containing the C₂F₅ group.

Review articles containing pentafluoroethylation reactions are limited and often include various kinds of perfluoroalkylation reactions.⁶ However, in this review, we focus solely on the development of pentafluoroethylation methodology and related reagents in the past decade (ca. 2015–2025). The content is categorized by reagents: (1) transition metal-based reagents; (2) perfluoroalkyl silanes; (3) gaseous reagents; (4) hypervalent iodine, sulfonium ylide and sulfoximine reagents; and (5) miscellaneous reagents. The shorthand “C₂F₅” or “CF₂CF₃” for the pentafluoroethyl group is used interchangeably throughout this review.

2. Transition metal-mediated pentafluoroethylation

2.1 CuC₂F₅ reagent (as a solution in DMF) generated from pentafluoroethane (C₂F₅H)

Transition metals played an important part in pentafluoroethylation and copper was among the most used metals for this development. In 2013, Grushin's group disclosed a landmark report on the cupration of pentafluoroethane (C₂F₅H) for the preparation of a novel CuC₂F₅ reagent.⁷ Pentafluoroethane is an inexpensive and readily available gas that is used as a refrigerant and fire suppression agent. It is a potent greenhouse gas yet non-ozone depleting. Following their previous protocol for the preparation of CuCF₃ from fluoroform (CF₃H),⁸ Grushin and co-workers demonstrated that a “CuC₂F₅” species could be formed using CuCl, KO^tBu and pentafluoroethane in DMF (Scheme 2). The in situ generated [K(DMF)][(^tBuO)₂Cu] reacted with C₂F₅H smoothly at room temperature and atmospheric pressure to give “CuC₂F₅” quantitatively, which was structurally characterized to be [K(DMF)₂][(^tBuO)Cu(C₂F₅)] by X-ray crystallography. Surprisingly, only CF₃H and C₂F₅H could be cuprated, and other higher H-perfluoroalkanes were found to be unreactive under identical conditions.

Scheme 2 Cupration of pentafluoroethane to generate “CuC₂F₅”. {“CuC₂F₅” = [K(DMF)₂][(^tBuO)Cu(C₂F₅)]}.

Grushin's CuC₂F₅ complex was found to be much more thermally stable than the previous CuCF₃ complex derived from fluoroform. Its stability allowed efficient pentafluoroethylation of not only (hetero)aryl iodides but also less reactive bromides (Scheme 3). Moreover, the CuC₂F₅ reagent could also react with other types of substrates including benzylic/vinylic halides,⁹ arylboronic acids and terminal alkynes.

Scheme 3 Pentafluoroethylation of (hetero)aryl iodides/bromides using CuC₂F₅ generated from C₂F₅H.

Subsequently, Grushin and co-workers prepared four new well-defined L_nCu^IC₂F₅ complexes using the “ligandless” CuC₂F₅ generated from pentafluoroethane by adding ligands (L).¹⁰ These complexes, including [(Ph₃P)₂CuC₂F₅], [(bpy)CuC₂F₅], [(Ph₃P)Cu(phen)C₂F₅] and [(IPr*)CuC₂F₅], were structurally verified by X-ray crystallography. In particular, the [(Ph₃P)Cu(phen)C₂F₅] complex was shown to be an efficient pentafluoroethylating reagent for acid chlorides to synthesize pentafluoroethyl ketones (Scheme 4).

Scheme 4 Well-defined L_nCu^IC₂F₅ complexes and pentafluoroethylation of acid chlorides for the synthesis of pentafluoroethyl ketones using [(Ph₃P)Cu(phen)C₂F₅].

Since 2020, Tsui's group has investigated new reactivities of the CuC₂F₅ reagent generated from pentafluoroethane. Prior to their works, the majority of the applications of this reagent were in cross-coupling type pentafluoroethylation based on Cu(I) reaction pathways. Tsui and co-workers found that unactivated alkenes could be pentafluoroethylated with CuC₂F₅ under aerobic conditions to form novel allylic CF₂CF₃ compounds with excellent E-selectivity and functional group tolerance (Scheme 5).¹¹ The use of air, an ideal green oxidant, was the key to this reaction. The allylic CF₂CF₃ product could be further transformed to diverse pentafluoroethylated compounds through reactions at the double bond. Mechanistic studies strongly suggested the involvement of the C₂F₅ radical. Initially, Cu^IC₂F₅ is oxidized by molecular oxygen to Cu^IIC₂F₅, which undergoes Cu–C bond homolysis to release the C₂F₅ radical. Addition of the C₂F₅ radical to the alkene generates the carbon radical A. Intermediate A may combine with Cu(II) to form an alkyl–Cu(III) intermediate C, which undergoes β-hydride elimination to furnish the product. Alternatively, A may undergo single-electron oxidation by Cu(II) to afford carbocation B, followed by deprotonation under basic conditions to yield the same product. Thus, Tsui and co-workers have unlocked an unprecedented radical pathway of the CuC₂F₅ reagent generated from pentafluoroethane where CuC₂F₅ could act as a source of the C₂F₅ radical under air at room temperature.

Scheme 5 Pentafluoroethylation of unactivated alkenes using CuC₂F₅ generated from C₂F₅H to synthesize allylic C₂F₅ compounds.

Pyrrolidines and cyclopentanes are prevalent structural motifs in pharmaceuticals and natural products. Domino radical cyclization of 1,n-dienes represents a highly efficient and atom-economical strategy for constructing such five-membered hetero- and carbocycles. Building on the observation of the pentafluoroethyl radical from the CuC₂F₅ reagent under aerobic conditions, Tsui and co-workers subsequently developed a domino radical cyclization/bis(pentafluoroethylation) of 1,6-dienes to synthesize fluoroalkylated pyrrolidine and cyclopentane scaffolds containing two C₂F₅ units (Scheme 6).¹² The reactions proceeded smoothly at room temperature open to air affording the desired pyrrolidines (up to 7.7 : 1 d.r.) and cyclopentanes (up to 12 : 1 d.r.). Upon column chromatography, the major diastereomers could be isolated with d.r. >20 : 1. The relative cis configuration of the two –CH₂C₂F₅ groups was confirmed by X-ray crystallography. Overall, three bonds were formed and ten fluorine atoms were introduced in this transformation in one step.

Scheme 6 Domino radical cyclization/bis(pentafluoroethylation) of 1,6-dienes using CuC₂F₅ generated from C₂F₅H to construct pentafluoroethylated pyrrolidine and cyclopentane scaffolds.

Tsui's group also reported that when applying the CuC₂F₅ reagent to styrene derivatives, instead of unactivated alkenes, a variety of pentafluoroethylated products could be obtained depending on the substrates and conditions (Scheme 7).¹³ The chloropentafluoroethylated products predominated at 0 °C whereas bis-pentafluoroethylated dimers were favoured at 50 °C. Vinyl C₂F₅ products were obtained with substrates containing para amino groups at room temperature. Formyloxylated products were formed with substrates containing para methoxy groups at 0 °C. With α-methylstyrenes, hydroxypentafluoroethylated products were obtained using B₂Pin₂ as an additive.¹⁴ Overall, a single reagent allowed access to diverse pentafluoroethylated products from styrene derivatives.

Scheme 7 Divergent pentafluoroethylation of styrene derivatives using CuC₂F₅ generated from C₂F₅H.

Tsui and co-workers reported the gram-scale synthesis of TEMPO–C₂F₅ by capturing the C₂F₅ radical generated from the CuC₂F₅ reagent (Scheme 8).¹⁵ A series of TEMPO derivatives were employed to prepare novel pentafluoroethoxyamines which were well-characterized including X-ray structural analysis. An unexpected application of the TEMPO–C₂F₅ compound was found when it was heated in acetonitrile at 40 °C with alcohols. Trifluoroacetylation of alcohols occurred smoothly to afford the corresponding trifluoroacetates up to 94% yield. This transformation featured a broad substrate scope tolerating both alcohols and amines, and proceeded under mild and base-free conditions. Kinetic analyses revealed that both the thermal decomposition of TEMPO–C₂F₅ in MeCN and its reactions with nucleophiles followed first-order kinetics with respect to TEMPO–C₂F₅, whereas the latter processes exhibited zero-order dependence on the nucleophile concentration. These results, together with DFT calculations, support a mechanistic pathway involving N–O bond heterolysis through a Stieglitz-type rearrangement, forming a pentafluoroethoxy anion that undergoes α-fluoride elimination to generate trifluoroacetyl fluoride, which is subsequently trapped by nucleophiles. The computed energy profile further corroborated this mechanistic proposal and rationalized the solvent and substituent effects observed experimentally.

Scheme 8 Preparation of TEMPO–C₂F₅ using CuC₂F₅ generated from C₂F₅H and its applications in trifluoroacetylation of alcohols and amines.

Another useful application of the CuC₂F₅ reagent generated from C₂F₅H was in the synthesis of pentafluoroethylated heterocycles. Click chemistry, particularly the Cu-catalyzed azide–alkyne cycloaddition (CuAAC) for constructing 1,2,3-triazoles, represents one of the most powerful and reliable transformations in modern synthetic chemistry. Tsui and co-workers have described a copper-mediated interrupted click reaction that enabled the synthesis of 5-pentafluoroethyl-substituted 1,2,3-triazoles in a single step using the CuC₂F₅ reagent (Scheme 9).¹⁶ The reaction proceeded under mild conditions and exhibited a broad substrate scope compatible with both aryl and alkyl alkynes to deliver the desired triazoles in good to excellent yields. Moreover, this methodology was successfully applied to the synthesis of a 5-pentafluoroethyl analogue of the antiepileptic drug rufinamide, highlighting its potential in medicinal chemistry for precise incorporation of fluorinated motifs into bioactive frameworks.¹⁷

Scheme 9 Interrupted click reaction using CuC₂F₅ generated from C₂F₅H for the synthesis of pentafluoroethylated 1,2,3-triazoles.

2.2 Well-defined CuC₂F₅ complexes generated by other methods

Besides Grushin's CuC₂F₅ reagent derived from pentafluoroethane, other well-defined CuC₂F₅ complexes have also been described in the literature. In 2011, Daugulis et al. documented the synthesis of [K(DMPU)₃]⁺[(CF₂CF₃)CuCl]⁻ from CuCl, KF and TMSCF₃ in DMPU/THF in 14% yield, which was characterized by NMR spectroscopy and X-ray crystallography (Scheme 10a).¹⁸ This anionic complex was a temperature and moisture sensitive solid that decomposed at room temperature under argon over few hours. In 2012, Hartwig et al. reported the preparation of [(phen)CuC₂F₅] from [Cu(Mesityl)]₅, t-BuOH, 1,10-phenanthroline (phen) and TMSCF₂CF₃ in 78% yield (Scheme 10b).¹⁹

Scheme 10 Daugulis' (a) and Hartwig's (b) methods for preparing CuC₂F₅ complexes.

The [(phen)CuC₂F₅] complex was utilized for constructing C(sp²)–C₂F₅ bonds under mild cross-coupling conditions (Scheme 11). The combination of Ir-catalyzed C–H borylation with Cu-mediated pentafluoroethylation enabled the direct transformation of simple arenes into pentafluoroethylated arenes. It was demonstrated that the [(phen)CuC₂F₅] complex could undergo oxidative addition and reductive elimination analogous to [(phen)CuCF₃]. The same group further extended the cross-coupling to heteroaryl bromides.²⁰ Compared to [(phen)CuCF₃], these pentafluoroethylation reactions gave higher yields and broader substrate scope, tolerating both electron-rich and electron-deficient heterocycles. A later mechanistic investigation by the same group provided insights into the reactivity and electronic structure of the copper(I) pentafluoroethyl complexes.²¹ The study revealed that oxidative addition of aryl halides to copper(I) pentafluoroethyl complexes proceeds most efficiently with electron-poor ligands, showing an inverse relationship between ligand donor strength and reactivity. This counterintuitive trend was attributed to the higher electrophilicity and lower activation barrier of less electron-rich Cu(I) centres.

Scheme 11 Pentafluoroethylation of arenes and heteroaryl bromides using [(phen)CuC₂F₅].

Weng/Zhang and co-workers employed the copper(I) pentafluorocarboxylate complex [(phen)₂Cu][O₂CC₂F₅] for the decarboxylative pentafluoroethylation of vinyl bromides (Scheme 12).²² The E/Z configuration of the products corresponded to the starting alkenes.

Scheme 12 Pentafluoroethylation of vinyl bromides using [(phen)₂Cu][O₂CC₂F₅].

Sanford's group developed a NHC–copper(I) pentafluoroethyl complex (IPr)Cu^I–C₂F₅ for the pentafluoroethylation of aryl halides bearing ortho-directing groups (Scheme 13).²³ It was shown that pyridine, pyrazole, oxazoline, imine and ester directing groups could dramatically enhance the reactivity of aryl bromides/chlorides with this complex. Moreover, a catalytic version was also demonstrated using 20 mol% of (IPr)CuCl and TMSC₂F₅.

Scheme 13 Pentafluoroethylation of aryl bromides using (IPr)Cu^I–C₂F₅ enabled by directing groups.

In 2024, Tsui/Shen and co-workers reported the preparation of a bispentafluoroethylated organocuprate [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex (Scheme 14).²⁴ This complex was synthesized from TMSC₂F₅ (ultimately from HC₂F₅) on gram-scale as a stable white solid.

Scheme 14 Preparation of the [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex.

Using this copper complex, the authors were able to achieve an unprecedented decarboxylative pentafluoroethylation of readily available carboxylic acids under photocatalytic conditions (Scheme 15).

Scheme 15 Photocatalytic decarboxylative pentafluoroethylation using [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻.

Furthermore, the [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex exhibited a range of reactivities towards diazonium salts, organic halides, boronic esters, terminal alkynes and (hetero)arenes as a versatile pentafluoroethylating reagent (Scheme 16). Thus, a single reagent allowed the construction of C(sp³)-/C(sp²)-/C(sp)–CF₂CF₃ bonds.

Scheme 16 [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex as a versatile pentafluoroethylation reagent.

2.3 ZnC₂F₅ reagents

Besides CuC₂F₅ species, pentafluoroethylzinc reagents were also among the first to be prepared and characterized. In 2011, Daugulis' group reported the formation and structural confirmation (X-ray) of (DMPU)₂Zn(C₂F₅)₂ from TMP₂Zn and HC₂F₅ (Scheme 17a).¹⁸ Mikami's group subsequently reported the preparation of this reagent from C₂F₅I and used it for the pentafluoroethylation of aryl iodides with catalytic CuI.²⁵ Fan and co-workers employed (DMPU)₂Zn(C₂F₅)₂ in a Cu-catalyzed pentafluoroethylation of allyl phosphates for the construction of C(sp³)–C₂F₅ bonds (Scheme 17b).²⁶ The Cu(acac)₂/phenanthroline catalytic system promoted efficient coupling of allyl phosphates with (DMPU)₂Zn(C₂F₅)₂ to afford allyl C₂F₅ products in high yields and excellent regio- and stereoselectivities. Mechanistic studies supported the formation of the π-allyl–Cu(III) intermediate indicating transmetalation of Zn(C₂F₅)₂ to copper followed by oxidative addition and reductive elimination. Furthermore, the reaction conditions could be applied to the introduction of CF₂H, C₃F₇, C₄F₉ and C₆F₁₃ groups. Liu/Cao and co-workers developed a copper-catalyzed, chloroamide-directed benzylic C–H bond pentafluoroethylation using the (DMPU)₂Zn(C₂F₅)₂ reagent (Scheme 17c).²⁷ Mechanistic studies suggested the formation of benzylic radicals via intramolecular C–H bond activation, followed by copper-mediated transfer of the C₂F₅ group to the benzylic radicals. Zeng's group described a copper-catalyzed cross-coupling of propargyl gem-dichlorides with (DMPU)₂Zn(C₂F₅)₂ to synthesize chloro-substituted pentafluoroethyl allenes (Scheme 17d).²⁸ Mechanistic studies suggested transmetalation between Zn(C₂F₅)₂ and Cu(I) to form an active [Cu^IC₂F₅] species followed by a possible S_N2′ substitution.

Scheme 17 Preparation of the (DMPU)₂Zn(C₂F₅)₂ reagent (a) and its applications in pentafluoroethylation of allyl phosphates (b), benzylic C–H bonds (c) and propargyl gem-dichlorides (d).

2.4 Other metal–C₂F₅ complexes

Nickel and cobalt complexes have also been explored for metal-mediated pentafluoroethylation. Vicic's group reported the preparation of a solvated Ni^II(C₂F₅)₃ complex from [(dme)NiBr₂], TMSC₂F₅ and AgF in acetonitrile solvent in the presence of [NMe₄]Cl (Scheme 18a).²⁹ This Ni(II) complex could undergo single-electron oxidation to release the C₂F₅ radical enabling stoichiometric pentafluoroethylation of aryl diazonium salts under mild conditions. Khusnutdinova's group developed a photoactive cobalt(III) pentafluoroethyl complex with naphthyridine ligands, which could undergo visible-light-induced Co–C₂F₅ bond homolysis to generate the C₂F₅ radical (Scheme 18b).³⁰ This complex enabled stoichiometric and preliminary catalytic pentafluoroethylation (with Togni reagent) of electron-rich arenes and heteroarenes via C–H bond transformations.

Scheme 18 Pentafluoroethylation using Ni- (a) and Co–C₂F₅ (b) complexes.

Overall, transition metal-based reagents have provided one of the most established platforms for pentafluoroethylation. Well-defined metal–C₂F₅ complexes can offer predictable reactivity and broad applicability in C(sp)–C₂F₅, C(sp²)–C₂F₅ and C(sp³)–C₂F₅ bond formation. Thus, structurally diverse pentafluoroethylated products can be accessed. However, many of these methods still require pre-formation and stoichiometric use of organometallic C₂F₅ species. Their operational practicality may be limited by the reagent stability under air and moisture as well as functional group tolerability of the substrates.

3. Pentafluoroethylation using perfluoroalkyl silanes

3.1 Trifluoromethyl silanes

The Ruppert–Prakash reagent (TMSCF₃) is one of the most popular reagents for trifluoromethylation reactions.³¹ In 2018, Hu's group revealed a remarkable usage of TMSCF₃ in pentafluoroethylation.³² The so-called “C₁ to C₂” process relied on the formation of CuCF₃ from TMSCF₃ followed by spontaneous transformation into CuC₂F₅ (Scheme 19). By mixing CuCl, KF, and TMSCF₃ (1.5 : 1 : 1) in DMF at room temperature, CuC₂F₅ was formed in 75% yield with minimal formation of CuCF₃. Aryl iodides were efficiently pentafluoroethylated with the in situ generated CuC₂F₅. Three plausible pathways (a–c) for the formation of CuC₂F₅ from CuCF₃ were suggested by the authors. Path b was refuted due to the absence of tetrafluoroethylene (TFE) in the reaction system. Electron-rich alkenes, phenols and thiophenols were tolerated and did not afford difluoromethylation products, suggesting that free difluorocarbene species were not formed, thus path c was also not likely. Since metal–CF₃ complexes are known to be precursors of metal difluorocarbenes (M=CF₂), the authors argued that the Cu=CF₂ species could be formed as a possible intermediate for CuC₂F₅ (i.e. path a).

Scheme 19 The use of TMSCF₃ for pentafluoroethylation of aryl iodides via in situ generated CuC₂F₅.

The TMSCF₃-derived CuCF₂CF₃ was also successfully applied in the pentafluoroethylation of organoboronates and terminal alkynes under aerobic conditions by Hu and co-workers (Scheme 20).³³ The ligand 1,10-phenanthroline was found to be essential for the pentafluoroethylation of organoboronates but was not required for terminal alkynes. Aromatic and alkenyl organoboronates gave moderate to high yields while alkyl ones failed. A variety of aromatic terminal alkynes were converted to the corresponding pentafluoroethyl alkynes and alkyl substrates were also tolerated. An analogous approach for the generation of the “ligandless” CuC₂F₅ from TMSCF₃ was reported by Boutureira and co-workers.³⁴ The authors demonstrated pentafluoroethylation of unactivated C(sp²)–X bonds (X = I, Br) including late-stage introduction of the C₂F₅ group into glycals, nucleosides and nucleobases. Detailed and insightful studies such as ¹⁹F NMR and ESI-MS analyses were carried out to probe the nature of the reagent in solution. A pathway of insertion of [Cu=CF₂] to [Cu^ICF₃] was suggested for the formation of [Cu^IC₂F₅].

Scheme 20 Pentafluoroethylation of organoboronates and terminal alkynes under aerobic conditions using TMSCF₃-derived CuCF₂CF₃.

In 2017, Hu and co-workers realized that TMSCF₃ could serve as a source of tetrafluoroethylene (TFE) by dimerization of difluorocarbene generated in situ in a two-chamber system from TMSCF₃/NaI in THF.³⁵ The TFE could react with CsF, CuI and phen leading to the formation of (phen)CuC₂F₅ which facilitated pentafluoroethylation of iodoarenes. Later on, this method was applied to the efficient (5 min) pentafluoroethylation of arenediazonium salts in the Sandmeyer-type reaction by the same group (Scheme 21).³⁶ The in situ generated TFE was reacted with CuSCN and CsF to form the CuC₂F₅ reagent.

Scheme 21 Pentafluoroethylation of arenediazonium salts via in situ generated TFE from TMSCF₃/NaI.

3.2 Pentafluoroethyl silanes

Compared to TMSCF₃, the pentafluoroethyl silane TMSC₂F₅ is a more direct pentafluoroethylation reagent albeit at a higher cost from current commercial suppliers. Transition metal-catalyzed cross-coupling type pentafluoroethylation using R₃SiC₂F₅ has been described. In 2017, Sanford's group reported a palladium-catalyzed pentafluoroethylation of aryl bromides using TMSCF₂CF₃ (Scheme 22).³⁷ The reactivity of (P^tBu₃)Pd^II(Ph)(R_F) type complex was investigated through experimental and computational studies. DFT calculations showed that the α-fluoride elimination of the CF₂CF₃ derivative (ΔG^‡ = 34.7 kcal mol⁻¹) was less likely than the CF₃ derivative (ΔG^‡ = 20.8 kcal mol⁻¹). The P^tBu₃ ligand was crucial for the reaction and potassium fluoride was used as an activator.

Scheme 22 Palladium-catalyzed pentafluoroethylation of aryl bromides using TMSCF₂CF₃.

In the same year, Amii and co-workers reported a copper-catalyzed pentafluoroethylation of aryl iodides using potassium (pentafluoroethyl)trimethoxyborate (Scheme 23).³⁸ This reagent was prepared from TMSCF₂CF₃ and trimethylborate in the presence of potassium fluoride, which enabled the transformation under base-free conditions. Interestingly, one example of the pentafluoroethylation of 1-iodo-3-nitrobenzene using TMSCF₂CF₃ (56% ¹⁹F NMR yield) is mentioned in this paper.

Scheme 23 Copper-catalyzed pentafluoroethylation of aryl iodides using potassium (pentafluoroethyl)trimethoxyborate prepared from TMSCF₂CF₃.

The direct use of pentafluoroethyl silanes in the cross-coupling reactions would be more efficient and atom-economical. To this end, Tsui's group developed a protocol to use Et₃SiCF₂CF₃ in the Cu-catalyzed pentafluoroethylation of aryl and alkenyl halides (Scheme 24).³⁹ The reagent Et₃SiCF₂CF₃ was prepared on a 200 mmol scale from low-cost materials chlorotriethylsilane and pentafluoroethane. By using CuI/phen (1,10-phenanthroline) as the catalyst, KF as the activator and Et₃SiCF₂CF₃ as the reagent, aryl or alkenyl iodides were smoothly converted into pentafluoroethyl arenes and alkenes in good yields. This method featured broad substrate scope and excellent functional group compatibility, offering a simple and practical approach to access pentafluoroethylated compounds.

Scheme 24 Copper-catalyzed pentafluoroethylation of aryl/alkenyl iodides using Et₃SiC₂F₅.

MacMillan's group developed a metallaphotoredox pentafluoroethylation of organobromides in 2020.⁴⁰ This copper-catalyzed process allowed nucleophilic pentafluoroethylation of aryl, heteroaryl and even alkyl bromides using TMSC₂F₅ as a convenient nucleophile (Scheme 25). The key strategy in this reaction is a silyl radical-mediated halogen abstraction–radical capture (HARC) pathway, where the silyl radical abstracts the bromide to generate a carbon radical followed by combination of the pentafluoroethyl copper complex. This strategy circumvents the need for the substrates to undergo challenging Cu-mediated oxidative additions, thus significantly broadening the reaction scope to include alkyl substrates. This method provides a mild, general, and efficient approach to install perfluoroalkyl groups including CF₃, C₂F₅ and C₃F₇, which was also utilized in late-stage functionalization of drug analogues.

Scheme 25 Metallaphotoredox pentafluoroethylation of (hetero)aryl and alkyl bromides using TMSCF₂CF₃.

Wei/Shang/Wang and co-workers reported a copper-mediated photochemical late-stage pentafluoroethylation of arylthianthrenium salts using the in situ generated CuC₂F₅ from TMSC₂F₅ (Scheme 26).⁴¹ The reaction could be significantly accelerated by adding a catalytic amount of rac-BINAP, which completed in only 15 minutes. The same group also applied the reaction to aryl iodides, with the reactions being completed within one hour.⁴²

Scheme 26 Copper-mediated BINAP-accelerated pentafluoroethylation of arylthianthrenium salts and aryl iodides using TMSC₂F₅.

Expanding on the utility of transition metal-free perfluoroalkylation, Kuninobu/Kanai and co-workers developed a 2-position-selective C–H functionalization of quinolines using perfluoroalkyltrimethylsilanes (Scheme 27).⁴³ This catalyst-free protocol relied on the dual activation of the substrate and the silane reagent through an in situ generated hydrogen fluoride source (CF₃COOH and KHF₂) and the additive DMPU. While the study primarily focused on trifluoromethylation, the methodology was successfully extended to pentafluoroethylation, as demonstrated by the reaction of 6-methylquinoline with TMSC₂F₅ to furnish the corresponding 2-pentafluoroethylated product in 83% yield and excellent regioselectivity.

Scheme 27 2-Position selective pentafluoroethylation of the C–H bond of a quinoline derivative using TMSC₂F₅.

Cao's group reported a transition metal-free pentafluoroethylation of gem-difluoroalkenes (1,1-diaryl-2,2-difluoroethenes) using TMSC₂F₅ in the presence of TBAF (Scheme 28).⁴⁴ This simple protocol allowed the selective synthesis of both mono- and bis-pentafluoroethylated alkenes.

Scheme 28 Pentafluoroethylation of gem-difluoroalkenes using TMSC₂F₅.

Apart from carbon–C₂F₅ bond formations, pentafluoroethyl silanes have also been employed to construct heteroatom–C₂F₅ bonds. Qing's group reported a silver triflate (AgOTf)-mediated oxidative pentafluoroethylation of alkyl alcohols and phenols with TMSC₂F₅ (Scheme 29).⁴⁵ Selectfluor was used as a key oxidant. Various pentafluoroethyl ethers were obtained and the method could be extended to the oxidative heptafluoropropylation and ethoxycarbonyldifluoromethylation as well. The reaction presumably proceeds via Ag(I)CF₂CF₃ generated from AgOTf, KF and TMSC₂F₅, which may undergo oxidative addition to the O–H bond forming a Ag(III) species in the presence of an oxidant, and subsequent reductive elimination leads to the formation of the O–C₂F₅ bond in the pentafluoroethyl ether product.

Scheme 29 Silver-mediated oxidative pentafluoroethylation of alkyl alcohols and phenols for the synthesis of pentafluoroethyl ethers using TMSC₂F₅.

The same group developed a copper-mediated oxidative pentafluoroethylthiolation of aryl boronic acids, utilizing TMSC₂F₅ and elemental sulfur as the source of the pentafluoroethylthio group (Scheme 30).⁴⁶ This reaction employed 2-fluoropyridine as a ligand, enabling the transformation of aryl and heteroaryl boronic acids into the corresponding pentafluoroethyl sulfides.

Scheme 30 Copper-mediated oxidative pentafluoroethylthiolation of aryl boronic acids using TMSC₂F₅ and elemental sulfur.

Tsui and co-workers described a practical synthesis of pentafluoroethyl sulfides by using thiosulfonates as electrophiles and TMSC₂F₅ as a nucleophile (Scheme 31).⁴⁷ This method allowed access to both aryl and alkyl pentafluoroethyl sulfides in high yields. Moreover, pentafluoroethane could be employed directly in the presence of a base to react with thiosulfonate. Thus, challenging S–C₂F₅ bond formation was achieved in this simple protocol without the need for transition metals.

Scheme 31 Transition metal-free pentafluoroethylation of aryl and alkyl thiosulfonates for the synthesis of pentafluoroethyl sulfides using TMSC₂F₅.

Compared to pre-formed metal–C₂F₅ complexes, pentafluoroethyl silanes are generally more convenient and versatile C₂F₅ sources, particularly because they can be handled as bench-stable reagents and used in conjunction with transition metal and photoredox catalysis. On the other hand, the high cost and limited availability of some C₂F₅–silanes, together with the need for activators such as fluoride salts may hinder their applications.

4. Pentafluoroethylation using gaseous reagents

4.1 Pentafluoroethane (C₂F₅H)

The use of gaseous pentafluoroethane for generating well-defined CuC₂F₅ complexes and their applications in pentafluoroethylation reactions have been described above (cf. Section 2.1). There are also reports of using this gas directly to introduce C₂F₅ groups with or without transition metals. Daugulis and co-workers described the CuCl/phen-catalyzed pentafluoroethylation of 2-iodobenzoate with pentafluoroethane in the presence of TMP₂Zn and DMPU (Scheme 32a).¹⁸ The in situ formation of (C₂F₅)₂Zn(DMPU)₂ was proven to be crucial. Shibata and co-workers reported the use of pentafluoroethane as a nucleophile in addition reactions to aldehydes, ketones and esters (Scheme 32b).⁴⁸ The use of potassium bases with triglyme or tetraglyme as a solvent for the encapsulation of the K cation with glymes was the key to success.

Scheme 32 Pentafluoroethylation of an aryl iodide and carbonyl compounds using pentafluoroethane with or without transition metals.

4.2 Tetrafluoroethylene (TFE)

Ogoshi/Ohashi and co-workers have demonstrated that tetrafluoroethylene (TFE) could also be employed as a starting material for the preparation of pentafluoroethylated aromatic compounds (Scheme 33).⁴⁹ The reaction design relied on the fluorocupration of TFE with (phen)CuF and CsF to generate the active species (phen)Cu(C₂F₅) in situ, which was isolated and confirmed by X-ray crystallography. The key to suppressing the competing oligomerization of TFE was to refrain from stirring the reaction mixture.

Scheme 33 Cu-catalyzed pentafluoroethylation of aryl iodides using tetrafluoroethylene (TFE).

5. Pentafluoroethylation using hypervalent iodine, sulfonium ylide and sulfoximine reagents

5.1 Pentafluoroethyl hypervalent iodine reagents

The application of hypervalent iodine chemistry to perfluoroalkylation has significantly advanced the synthesis of perfluoroalkyl compounds. Following the success of the famous Togni reagents for electrophilic trifluoromethylation,⁵⁰ researchers began to design analogous pentafluoroethylating reagents including the early development of Yagupolskii and Umemoto's pentafluoroethyliodonium salts.⁵¹ In 2016, Shen's group reported an improved method for the preparation of pentafluoroethyl benziodoxole (BIX–C₂F₅) as an electrophilic pentafluoroethylating reagent (Scheme 34a).⁵² The BIX–C₂F₅ reagent was synthesized from BIX–F with TMSC₂F₅ in anhydrous CH₃CN at room temperature. It is a crystalline white solid and the structure was confirmed by X-ray crystallography. By using a weak base such as DBU or K₂CO₃, BIX–C₂F₅ could react with β-ketoesters in good yields. Moreover, copper-catalyzed pentafluoroethylation of (hetero)aryl boronic acids was also achieved using this reagent.

Scheme 34 Synthesis of the BIX–C₂F₅ reagent and its applications in copper-catalyzed pentafluoroethylation of (hetero)aryl boronic acids (a) and asymmetric pentafluoroethylation (b).

Later on, Vallribera/Granados and co-workers developed an asymmetric pentafluoroethylation using BIX–C₂F₅ (Scheme 34b).⁵³ The authors achieved the asymmetric α-pentafluoroethylation of alkyl 1-indanone-2-carboxylates using La(OTf)₃/(S,R)-indanyl-pybox as a chiral Lewis acid catalytic system. A quaternary α-pentafluoroethyl centre could be constructed with up to 89% ee. Chen's group also used BIX–C₂F₅ to accomplish the ring-opening pentafluoroethylation of cycloalkanols in a dual photoredox/copper-catalyzed protocol (one example).⁵⁴

Khaskin's group reported a “ligand-free” nickel-catalyzed pentafluoroethylation of (hetero)arenes using the pentafluoroethyl Togni reagent (Scheme 35a).⁵⁵ The [(MeCN)₂Ni^II(C₂F₅)₂] catalyst was prepared from TMSC₂F₅ and could efficiently functionalize (hetero)arene C–H bonds including natural products, drug analogues and peptides containing an aromatic unit. A radical mechanism was proposed based on preliminary studies. Subsequently, the same group described the synthesis of a cyclometalated (CH₃CN)₂Ni(C₄F₈) complex for C–H bond pentafluoroethylation including chemoselective modification of tryptophan residues demonstrating potential for late-stage peptide derivatization (Scheme 35b).⁵⁶

Scheme 35 Nickel-catalyzed pentafluoroethylation of (hetero)arenes using the C₂F₅–Togni reagent.

Hong/Choi and co-workers employed the C₂F₅–Togni reagent in a copper-catalyzed alkyne cyclization to synthesize pentafluoroethylated thiazoles (Scheme 36a).⁵⁷ The starting materials were aryl or alkyl-substituted thioureas containing a terminal alkyne. Liu/Li and co-workers described a copper-catalyzed radical cyanopentafluoroethylation of isocyanides using the same reagent (one example) (Scheme 36b).⁵⁸

Scheme 36 Copper-catalyzed alkyne cyclization and cyanopentafluoroethylation of isocyanides using the C₂F₅–Togni reagent.

5.2 Sulfur-based pentafluoroethylating reagents

Shen/Lu and co-workers developed pentafluoroethyl-substituted sulfonium ylides as electrophilic pentafluoroethylating reagents (Scheme 37).⁵⁹ They were prepared by the cross-coupling of phenyl pentafluoroethyl thioether with dimethyl diazomalonate using a rhodium catalyst. Efficient pentafluoroethylation of β-ketoesters, electron-rich heteroarenes and aryl iodides was achieved using these reagents.

Scheme 37 Preparation of pentafluoroethyl sulfonium ylides and application in copper-mediated pentafluoroethylation of aryl iodides.

Tsui/Magnier and co-workers developed a pentafluoroethyl sulfoximine reagent for the photocatalytic pentafluoroethylation-difunctionalization of styrene derivatives (Scheme 38a).⁶⁰ The reagent was prepared from a pentafluoroethyl sulfide which was synthesized according to a previously reported protocol.⁴⁷ Under mild photocatalytic conditions, the sulfoximine reagent could react with styrene derivatives tolerating various nucleophiles such as alcohol, water, thiol, carboxylic acid, amine and arene, leading to the difunctionalized pentafluoroethylated products (Scheme 38b). Moreover, the challenging C–H bond pentafluoroethylation of arenes was also achieved photocatalytically (Scheme 38c).

Scheme 38 Synthesis of a pentafluoroethyl sulfoximine reagent (a) and applications in photocatalytic pentafluoroethylation-difunctionalization of styrene derivatives (b) and C–H bond pentafluoroethylation of arenes (c).

The mechanism involves the release of the C₂F₅ radical from sulfoximine in the photoredox cycle, which then adds to styrene leading to the formation of a carbocation trapped by a nucleophile (Scheme 39). This pathway would be a more efficient and green method for the generation of the C₂F₅ radical compared to the copper-based methods (cf. Section 2.1).

Scheme 39 Proposed mechanism for the photocatalytic pentafluoroethylation-difunctionalization of styrene derivatives using the pentafluoroethyl sulfoximine reagent.

6. Miscellaneous pentafluoroethylating reagents

Pentafluoropropionic acid, pentafluoropropionic anhydride (PFPA), and pentafluoropropionate are readily available pentafluoroethylated compounds. The direct introduction of C₂F₅ groups into (hetero)aromatic rings using these reagents would be attractive. However, the oxidation of perfluoroalkylacetates is challenging due to their high redox potentials, which are beyond the accessible potential range of most photocatalysts. To address this issue, Stephenson and co-workers in 2016 developed a photoredox system using pyridine N-oxides as reagents for the decarboxylation of TFAA and PFPA as perfluoroalkyl sources (Scheme 40).⁶¹ This protocol operated under mild conditions and could be scaled up to even kilogram quantities in flow, demonstrating its practicality for preparative and industrial applications. The presence of EDA complexes was evidenced by visible absorption and characteristically linear relationship between their charge-transfer absorbance energy. Upon photoexcitation, these EDA complexes undergo electron transfer leading to the fragmentation of the acylated pyridine N-oxide to generate the C₂F₅ radical, which subsequently adds to electron-rich arenes followed by re-aromatization to give the pentafluoroethylated products. Su and co-workers later on discovered an acid-triggered reactivity umpolung of acetoxime esters, enabling direct generation of fluoroalkyl radicals from readily available fluoroalkyl anhydrides under visible light.⁶² This mechanistically distinct strategy eliminated the need for preformed N-oxide adducts and extended the scope to include electron-deficient (hetero)arenes and various fluoroalkyl groups.

Scheme 40 Photochemical pentafluoroethylation of (hetero)arenes using pyridine N-oxides and pentafluoropropionic anhydride (PFPA).

In addition to photo-induced pentafluoroethylation using PFPA, copper was also found to be an efficient catalyst. Sodeoka and co-worker reported a perfluoroalkylation of unactivated alkenes using acid anhydrides including PFPA (Scheme 41a).⁶³ In their reaction system, PFPA reacts with urea·H₂O₂ to generate a diacyl peroxide, which undergoes Cu^I-catalyzed decarboxylation to afford a pentafluoroethyl radical. The radical then adds to the unactivated alkene eventually leading to the desired pentafluoroethylated product. In their subsequent work, the authors extended this strategy to achieve Cu-mediated 1,2-bis-pentafluoroethylation of alkenes and alkynes (Scheme 41b).⁶⁴ Notably, the addition of the bpy ligand significantly improved the reaction yields.

Scheme 41 Copper-catalyzed/-mediated pentafluoroethylation of unactivated alkenes (a) and alkynes (b) using pentafluoropropionic anhydride (PFPA).

Pentafluoropropionate has been shown as an economical C₂F₅ source in the preparation of a pentafluoroethyl copper reagent. Mikami and co-workers employed ethyl pentafluoropropionate to obtain CuC₂F₅ in virtually quantitative yield (Scheme 42).⁶⁵ The CuC₂F₅ reagent prepared was successfully applied to the pentafluoroethylation of aryl bromides and aryl boronic acids.

Scheme 42 Copper-mediated pentafluoroethylation using ethyl pentafluoropropionate as the C₂F₅ source.

More recently, Nocera and co-workers developed an electrophotocatalytic perfluoroalkylation that directly generates perfluoroalkyl radicals from native perfluoroalkyl carboxylates via Ag(II)-mediated LMCT excitation under visible light (Scheme 43).⁶⁶ This preactivation-free and redox-economical strategy differed fundamentally from previous systems thus achieving radical formation without N-oxide adducts or acid-induced umpolung chemistry. Other perfluoroalkyl groups such as CF₃ and C₃F₇ could also be installed by this method.

Scheme 43 Electrophotocatalytic pentafluoroethylation by LMCT excitation of Ag(II) pentafluoroethyl carboxylates.

Weng and co-workers reported a catalyst-free [3+2] cycloaddition for the synthesis of pentafluoroethylated heterocycles (Scheme 44).⁶⁷ A standout feature of this methodology was the utilization of chloropentafluoroethane (R115), a regulated byproduct of refrigerant production, as the pentafluoroethyl source. The authors successfully converted R115 into pentafluoropropanal O-(2,4-dinitrophenyl) oxime, which served as a stable precursor for pentafluoropropanenitrile. Upon treatment with triethylamine, the nitrile could be generated at room temperature almost quantitatively. Under transition-metal-free conditions, the in situ generated pentafluoropropanenitrile acted as a highly reactive electrophile in [3+2] cycloaddition reactions. Various dipole classes were demonstrated affording the pentafluoroethylated heterocycles in moderate to good yields.

Scheme 44 Synthesis of pentafluoroethylated heterocycles via cycloaddition of pentafluoropropanenitrile derived from chloropentafluoroethane (R115).

7. Conclusion

In summary, the past decade has witnessed tremendous progress in the development of reagents and methods for the synthesis of pentafluoroethylated compounds. From earlier transition metal-based [MC₂F₅] reagents and the use of C₂F₅H gas to the latest silicon-, iodine- and sulfur-based pentafluoroethylating reagents, chemists now have a much more complete toolbox for preparing structurally diverse compounds containing the C₂F₅ groups. These efforts will certainly have an impact on the future applications of pentafluoroethylated molecules in drug discovery. Furthermore, the pentafluoroethyl group can serve as a synthetic handle for other emerging fluorinated motifs through C–F bond activation. Tsui and co-workers have demonstrated that pentafluoroethylated alkenes can serve as useful building blocks for synthesizing polyfluorinated alkenes containing a unique F- and CF₃-substituted sp²–carbon (Scheme 45).⁶⁸ Their methods adopted a “defluorinative functionalization” strategy,⁶⁹ including rhodium-catalyzed defluoroarylation,^68a copper-catalyzed defluoroborylation^68b and defluorosilylation,^68c and palladium-catalyzed defluorofunctionalization,^68d for constructing carbon–carbon and carbon–heteroatom bonds in the products. More importantly, the reactions exhibited excellent levels of stereoselectivities. Thus, future works in this direction can be pursued where one or more C–F bonds in the C₂F₅ group is activated and functionalized selectively resulting in novel fluorinated compounds.

Scheme 45 Transition metal-catalyzed stereoselective defluorinative functionalization of pentafluoroethylated alkenes.

Author contributions

Yihan Tang: conceptualization and writing – original draft. Tao Dong: conceptualization and writing – original draft. Gavin Chit Tsui: conceptualization, supervision, writing – review & editing, and funding acquisition.

Conflicts of interest

There are no conflicts to declare.

Data availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Acknowledgements

This work was supported by the Research Grants Council of Hong Kong (CUHK 14303823 and JLFS/P-404/24) and The Chinese University of Hong Kong (Strategic Seed Funding for Collaborative Research Scheme SSFCRS 2024–25). We also thank the State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences for support (2026PT0008).

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