Cross-Coupling Reactions Enabled by Well-Defined Ag(III) Compounds: Main Focus on Aromatic Fluorination and Trifluoromethylation

: Ag III compounds are considered strong oxidizers of difficult handling. Accordingly, the involvement of Ag catalysts in cross-coupling via 2 e (cid:0) redox sequences is frequently discarded. Nevertheless, organosilver(III) compounds have been authenticated using tetradentate macro-cycles or per fluorinated groups as supporting ligands, and since 2014, first examples of cross-coupling enabled by Ag I /Ag III redox cycles saw light. This review collects the most relevant contributions to this field, with main focus on aromatic fluorination/ per fluoroalkylation and the identification of Ag III key intermediates. Pertinent comparison between the activity of Ag III R F compounds in aryl-F and aryl-CF 3 couplings vs. the one shown by its Cu III R F and Au III R F congeners is herein disclosed, thus providing a more profound picture on the scope of these transformations and the pathways commonly associated to C (cid:0) R F bond formations enabled by coinage metals.


Introduction
Perfluorinated motifs such as fluorine itself or the trifluoromethyl group are ubiquitous in medicinal chemistry. [1] As a result, organofluorine compounds have found relevant applications in pharmaceutical and agrochemical industry, and ca. 20 % of drugs and over 50 % of agrochemicals contain at least one fluorine atom in their structure ( Figure 1A). [2] Most popular industrial methods to install a trifluoromethyl group or a fluorine atom in an aromatic scaffold are the wellestablished Swarts-Simons and Balz-Schiemann processes, respectively. [3,4] While economically viable and extensively used nowadays, these methods bring along major environmental drawbacks owing to: i) the requirement of harsh conditions; ii) their low yielding nature, limited selectivity or reproducibility; iii) functional group incompatibility, and iv) plausible production of chlorofluorocarbon gases (CFCs), responsible of the ozonosphere depletion. An elegant alternative to build aryl-R F bonds is exemplified by cross-coupling reactions, [5] which only requires catalytic amounts of a metal catalyst to grow molecular complexity with impressive selectivity. Nevertheless, for different reasons (low nucleophilicity of solvated fluoride, remarkable MÀ CF 3 bond strength,…), the CÀ R F bond formation was long believed as an unfeasible transformation. [6,7] This adverse panorama drastically changed since the breakthrough discovery by Grushin and Marshall in 2006, [8] who reported the benzotrifluoride elimination from [Pd II (Ph)(CF 3 )(Xantphos)] in quantitative yield upon thermal treatment ( Figure 1B), thus proving the possibility to build aryl-CF 3 bonds through Pd 0 /Pd II redox cycles. Shortly after, Amii [9,10] and Buchwald [11] reported the first catalytic approaches to trifluoromethylation and fluorination of aryl halides taking place through Cu I /Cu III [9,10] and Pd 0 /Pd II [11] redox cycles.
An attractive alternative rendering the aryl-R F coupling feasible relies on the preparation of high valent organometallics benefiting from the capacity of perfluorinated ligands to stabilize unusually high oxidation states (see, for instance, Figure 1C). Although isolatable, these high valent aryl-M-R F species are considerably more prone to get reduced, thus facilitating the aryl-R F bond formation. Within this context, high valent copper is currently acquiring a star role in crosscoupling reactions, and quite strikingly, fully authenticated organocopper(III) species proved trifluoromethylating compe-tent for a large panel of organic synthons via Cu III /Cu I or Cu III /Cu II /Cu I redox sequences. [12,13] Going down the coinage metals group, the use of silver salts as an additive in synthesis and catalysis is well documented, typically playing the role of halide scavenger (Figure 2A), [14] chemical oxidant ( Figure 2B) [15] or transmetallating agent ( Figure 2C). [16,17] Nevertheless, despite its close proximity to Cu and Pd in the periodic table, Ag ability to mediate cross-coupling has long been neglected. [18] Most likely, this is due to the widely preconceived, yet uncertain, ideas about Ag, namely: i) its incapacity to undergo 2e À redox processes and predominant radical-like behaviour; and ii) the highly oxidizing nature of high valent silver (Ag II /Ag III ). [19] Conversely, the number of isolatable Ag III compounds stabilized by macrocyclic or monodentate anionic ligands has increased considerably, thus awakening a renewed interest in  In October 2014, Dr. Nebra was appointed a CNRS tenured scientist at LHFA (Toulouse) and he now develops independent research dealing with the discovery of unprecedented high-valent organometallics [mainly Ni(IV), Ag(III) and Cu(III)] with special focus on fluorination and trifluoromethylation reactions. He has published 40 articles (h index = 24), and recently got the "2020 ICT Award" and the "2021 GEQOÀ RSEQ Award" to Young Researchers.
cross-coupling reactions mediated by silver. This critical essay covers genuine examples of arene functionalization enabled by spectroscopically identified organosilver(III) species, mainly focusing on fluorination and trifluoromethylation reactions along with the pathway by which those transformations took place.

The Rise of Cross-Coupling Reactions via Ag I /Ag III Redox Cycles
To our knowledge, first investigations on silver mediated cross-coupling reactions dates back to almost 25 years ago when rare CÀ C and CÀ O bond forming reactions were described by Omura using AgClO 4 in stoichiometric amounts. [20] Catalytic cross-couplings attracted significantly more attention since the publication of the first catalytic protocols for Sonogashira coupling in 2005 by Wang and Li (Figure 3 top), [21] followed right after by the discovery of Ullmann-type reactions by Chakraborty and co-workers [22] (Figure 3 bottom). These two works paved the way to deeply explore the silver applicability in cross coupling reactions and ignited a quite prolific area of investigation. Nevertheless, precise mechanistic investigations were lacking and scarce input on the reaction pathway and the nature of the involved aryl-Ag II or aryl-Ag III intermediates was provided in these seminal contributions.

Pioneering C(sp 2 )À C and C(sp 2 )-Heteroatom Couplings Mediated by Well-Defined Ag(III) Compounds
First spectroscopic observations supporting the capacity of organosilver(III) compounds to undergo aryl-heteroatom coupling via reductive elimination (R.E.) step were provided by Latos-Grazyński and co-workers. [23] To meet success, the authors used carbaporphyrinoids to encapsulate the Ag III thus ensuring the square planarity of the resulting macrocyclic aryl-Ag III platform 1, a key feature in the stabilization of highly oxidized silver. [24] With 1 in hand, they studied the pyridination of the aromatic ring (Figure 4 top), [23a] as well as other aryl-N, aryl-O and aryl-P bond formations. [23b-e] While the presence of Ag III intermediates was initially inferred on the basis of the achieved regioselectivity and the known stabilization of Ag III by corroles and carbaporphyrinoids, [25] the authors synthesized different aryl-Ag III complexes (2-3) at a later stage, [26] and proved unequivocally their ability to build aryl-N and aryl-P bonds with yields ranging from 45 % to 95 % (Figure 4 bottom). [23,26] Quite strikingly, this elegant ligand design allowed the authors to isolate and fully characterize the carboporphirin-Ag III derivative 3. Most remarkable, these studies provided crucial insights on the ability of Ag III complexes to create aryl-heteroatom bonds via R.E. step from Ag III , as indicated by the concomitant formation of Ag I species and the observed regioselectivity, unlikely for radical pathways.
A breakthrough discovery was accomplished by Ribas and co-workers who deeply explored the capacity of silver compounds to perform cross-coupling reactions, and thus, massive efforts were dedicated to thoroughly investigate the oxidative addition (O.A.) and the R.E. steps occurring at the metal centre. [27] In 2014, they succeeded in achieving the first aryl-X O.A. at silver(I) precursors (X = Cl, Br, I), thereby  accessing to the well-defined [aryl-Ag III ] 2 + complex of type 5-H ( Figure 5, top). 5-H was reached upon reaction of Ag I ClO 4 (2 equiv.) with the brominated macrocycle 4-H, and the Ag Ito-Ag III oxidation was driven by AgBr precipitation. This dicationic macrocyclic aryl-Ag III platform 5-R, which is conveniently stabilized by the aryl containing triaza macrocycles 4-H and 4-Me, was isolated in good yields and completely characterized by multinuclear NMR, HRMS and X-ray analysis. The square planar geometry in 5-H was confirmed by X-ray diffraction showing singularly short AgÀ C bond length of 1.974 Å, being in agreement with the previously observed data for other carboporphirin-Ag III systems. [25] Clear indication of the high oxidation state of silver in 5-H was provided by the diagnostic 109 Ag NMR chemical shift of 2127 ppm, similar to previously reported Ag IIIcompounds. [28] The reactivity of the isolated aryl-Ag III platform 5-H towards an array of carbon and heteroatom-based nucleophiles was then screened, thus illustrating the ability of Ag III to accomplish aryl-C and aryl-heteroatom bond forming reactions in excellent yields (89-100 %) under mild conditions ( Figure 5, bottom).
Ribas' group investigated the catalytic application of such complexes as well, and found out that Ag I OTf catalyzes the aryl-Br bond breaking/aryl-O bond forming sequence by using 20 mol% of catalyst loading, excess of nucleophile (20 equiv.), and triphenylphosphine co-catalyst (20 mol%). [27] A classical three steps mechanism is proposed involving an initial aryl halide O.A. to Ag I leading to the aryl-Ag III complex 5-H, the following nucleophile coordination to the metal centre, and lastly, the R.E. step to build the aryl-heteroatom bond with concomitant regeneration of Ag I catalyst. Although this catalytic system provided moderate TON (4), this contribution represents the first clear evidence of silver capacity to perform 2e À redox cycles under catalytic turnover (see Figure 6). Alternative pathways involving single electron transfer (SET) or radical behavior were discarded performing cyclic voltammetry and DFT calculations. Despite this entailed a turning point in the understanding of silver redox chemistry, cross-coupling events taking place through spectroscopically proven Ag I /Ag III redox cycles remains scarce and matter of important investigations.
Indeed, Ribas and Roithová [29] pursued their investigations to enable well controlled aryl-C and aryl-heteroatom bond formations catalyzed by silver while profiting from the template effect imposed by the aminoquinoline fragment (Scheme 1). By using this elegant substrate design strategy, a large variety of primary amines, phenols and α-carbonyls revealed suitable nucleophiles under basic conditions (CsF or t BuOK) and prolonged warming up to 100°C in DMSO. Although these conditions prevented the identification of the assumed aryl-Ag III intermediates of type 8, the aryl-N bond formation generally affords higher yields (30-85 %) compared to those obtained for the macrocyclic scaffolds. Nevertheless, regarding the scope of the aryl-halogen coupling, the reaction failed for the challenging fluorination, while the analogous chlorinated and brominated scaffolds were reached in high yields (95 % and 74 %, respectively). The feasibility of the Ag I / Ag III catalytic loop was supported by independent experiments, which also discarded the possible interference by contamination with other metals through ICP-MS analysis (especially palladium and copper).
Interestingly, in absence of external nucleophile, the orthomethylated aryl iodide of type 7 reacts with Ag I OTf leading to intramolecular cyclization yielding the 1,10-phenanthrolin-2(1H)-one scaffold 13. In operando mechanistic investigation through high-resolution mass spectrometry (HRMS) and helium tagging infrared photodissociation (IRPD) spectroscopy allowed the authors to identify two plausible reaction intermediates. A first ion of m/z 495 was attributed to a product arising from substrate coordination to Ag I prior to O.A. step, and a second ion of m/z 408 was assigned to the cyclized Ag I compound 11 that is generated via C(sp 2 )À H bond activation and subsequent CÀ C coupling. With this data, the authors attributed this unprecedented reactivity to the transient (yet elusive) aryl-Ag III intermediate 8 that evolves following two distinct pathways, either via C-heteroatom bond

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formation (path a), or alternatively, through the C(sp 2 )À H bond breaking/aryl-aryl bond forming sequence via intermediate formation of the HRMS/IRPD identified species 11 and ensuing proton shuttle to build the 1,10-phenanthrolin-2(1H)-one 13 (path b). Two years later Alves and co-workers [30] reported the catalytic aryl-Se bond formation starting from diaryl diselenides (14) and aryl boronic acids using AgNO 3 (10 mol%) as a catalyst. The reaction proceeds upon heating (100°C) in 1,4dioxane at air. Inspection of catalytic intermediates through HRMS analysis of the reaction crude, coupled to reaction monitoring by 77 Se NMR that displayed a new signal resonating at 382.6 ppm, pointed to in situ formation of the Ag III À Se complex [(PhSe) 2 Ag III ]NO 3 (16 in Scheme 2). Although 16 was not fully characterized nor isolated, its sole presence in the reaction mixture prompted the authors to claim that the aryl-Se bond is forged upon reaction of the Ag III À Se species 16 and the arylboron derivative. The precise mechanism by which 16 gave rise to the desired diaryl diselenides of type 15 remains unknown/speculative.

Aromatic Fluorination Enabled by High-Valent Silver
The transition metal promoted CÀ X bond activation is a versatile synthetic tool in the synthesis of molecules with high added value. A classical and highly efficient entry to the Cheteroatom bond formation from readily accessible organic halides and nucleophiles is the long-know Ullmann-type crosscoupling generally induced by Cu-complexes. [31] First mechanistic insight on the plausible involvement of organosilver(III) compounds in aryl-F bond formation was provided by X. Ribas and colleagues in 2014. [27] During the course of their studies on aryl-heteroatom bond forming reactions promoted by coinage metals, they succeeded to cleave aryl-X bonds (X = Cl, Br, I) thereby accessing to the welldefined [Ag III (aryl)] 2 + complex of type 5-R (R = H, Me; see Scheme 3 below). As commented above, these dicationic complexes 5-R were isolated in good yields and were completely characterized by multinuclear NMR, HRMS and X-ray analysis. The fluorination of intermediate 5-R was inefficient using Bu 4 NF as fluorine-source (only 39 % of fluorinated ligand was produced with R being H). Yield was Scheme 1. Ag-catalyzed aryl-Nu bond formation driven by strategically designed aminoquinoline templates (path a) and intramolecular cyclization in absence of external nucleophile (path b). S denotes a coordination vacancy or a CH 3 CN ligand.

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considerably increased by mixing the brominated pre-ligand and 2 equiv. of AgF in acetonitrile. After 24 h at 40°C, complete aryl-F bond formation was achieved (with R being Me). The high-valent Ag III F-intermediates could not be detected, and fluorination reaction occurs exclusively under stoichiometric conditions. However, the identification of the coupling-competent aryl-Ag III species 5-R in aromatic fluorinations shows promise for future development of catalytic aryl-F coupling involving aryl-Ag III -F entities. The Ag III -mediated arene fluorination of triaza-macrocycles is reminiscent of the Ullmann-type coupling catalyzed by [Cu I (CH 3 CN) 4 ][OTf] also developed by the same research team. [32] Despite all efforts invested in this coupling process since its discovery, [31] the real nature of the copper intermediates engaged in this transformation still represents an active debate forum. Once again, Ribas' group benefitted from an elegant ligand design strategy and succeeded in the isolation of the unprecedented [Cu III (aryl)X] + key-intermediates of type 17 represented in Figure 7. [32] 17 was fully characterized by multinuclear NMR, UV-visible spectroscopy, cyclic voltammetry, and X-Ray diffraction on single crystals. [32] These Cu IIIintermediates of type 17 were found to promote aryl-halide

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bond formation, including the challenging synthesis of fluorinated arenes. [32] Unfortunately, the fluorido-Cu III intermediate [Cu III (aryl)F] + could not be isolated. Nevertheless, the in situ formation of 18 by halide exchange from 17 using AgF seems to be feasible, thus being convincingly proposed as the resting state Cu III species under catalytic conditions and leading to the fast aryl-F reductive elimination, also leading to the recovery of Cu I -catalyst. Compared to its silver variant, this method provides obvious advantages in terms of synthetic utility, namely: i) the halogen exchange reaction displays remarkable catalytic turnover (TON up to 20); ii) it affords nearly quantitative yields with independence of the substitution pattern of the amino-groups; and iii) it represents a rare example of a copper catalyst enabling aryl-Cl bond cleavage via 2e À redox events, thus allowing efficient fluorination of the chlorinated triaza-macrocycle. Further mechanistic insights were provided by G. Liu et al. during the Cu I -catalyzed pyridine-assisted fluorination of aromatic bromides. [33] According to XANES/EXAFS analysis and author's interpretation, mainly Cu I and small amounts of Cu II are present in the reaction media when using iodobenzene as organic substrate. However, introduction of N-donor directing groups (such as pyridines) increase the electron richness around the Cu-precursor, allowing easy oxidation into high-valent [Cu III (aryl)X] species, thus accelerating the reaction rate and revealing the feasibility of a Cu I /Cu III redox scenario.
Similar approach has been used to perform catalytic fluorination mediated by gold. In the only example following a Au I /Au III redox pathway, the authors took advantage from the ability of different gold(I) compounds to insert into the Chalogen bond and subsequently perform the aryl-F bond in presence of AgF, driven by AgX precipitation (Scheme 4). [34] Mechanistic and theoretical studies, together with the previous isolation of the analogous fluorinating competent aryl-Cu III species, suggest that the reaction may proceed through 2e À redox cycles involving the participation of an aryl-Au III intermediate. In particular, HRMS analysis on systems involving stabilizing ligands (PMe 3 and NHC carbenes) led to the detection of Au III species, while experiments in presence of mercury ruled out the participation of colloidal gold(0) nanoparticles. Nevertheless, the isolation and characterization of any aryl-Au III resulted to be out of reach and the authors couldn't definitely rule out alternative reaction pathways.
All the above presented approaches to aromatic fluorination are related to the classic Ullmann-type cross-coupling reactions. However, other alternatives involving silver promoters and fluorine-based oxidants are conceivable. Indeed, oxidative fluorinations of simple arenes were sparingly explored back in 1980 by Zweig, Fischer and Lancaster using Ag II F 2 in hexanes as an oxidant and a fluorine source, concomitantly releasing Ag I F. [35] It took three decades until more straightforward methods were found to fluorinate aryl-boron derivatives, [36] aryl silanes [37] or aryl stannanes [38] using milder oxidants such as N-fluoropyridinium salts or Selectfluor®. This elegant alternative was exploited at the turn of 2010 by Ritter and co-workers, who applied silver salts to prompt the electrophilic fluorodestannylation of arenes by using overstoichiometric amounts of AgOTf (2 equiv.) and fluorinating agent, Selectfluor® (1.2 equiv.) (Scheme 5). [38] Under optimized conditions (i. e. stirring at room temperature for 20 min in an acetone solution), this simple and scalable method led to efficient C(sp 2 )À F bond formation for a large variety of substrates displaying multiple functionalities, including representative examples of late-stage C(sp 2 )À F functionalization. Nevertheless, in addition to the high toxicity of organotin reagents, this approach lacks selectivity and 10-20 % of protodestannylation is reached. According to the observed regioselectivity and mechanistic studies merging the isolation of the low valent bimetallics 19 a and 20 a together with their very distinct activity (45 % vs. 86 %, respectively), the authors proposed that the C(sp 2 )À F bond forging occurs via reductive elimination step from an unidentified Ag II -based bimetallic intermediate. In the upcoming years, they extended this methodology to more benign and readily available aryl boronic acids [36] and aryl silanes. [37] In the former case, [36] a large panel of (hetero)aryl boron surrogates displaying excellent functional group tolerance was efficiently fluorinated through a two-step procedure without the observation of unwanted protodeborylation (Scheme 5 top left). It's worth mentioning that this procedure stands for the first practical fluorination of aryl boronic acids allowing the scale up to grams. Mechanistically, the boron-to-Ag I aryl-group transfer takes place in first term in presence of NaOH (1 equiv.) and MeOH, while the C(sp 2 )À F coupling requires complete substitution of MeOH by acetone before adding the oxidant (F-TEDA-BF 4 , 1.05 equiv.), thus precluding the unwanted C(sp 2 )À OMe bond formation.
These conditions proved efficient as well for the oxidative fluorination of alkenyl boronic acids with complete stereoselectivity. This fact, together with the forging of C(sp 2 )À OMe and C(sp 2 )À OH coupled products in presence of residual MeOH or moisture, argues in favor of a concerted reductive elimination pathway from a bimetallic [Ag II ]À Ag II À F intermediate 21 that may alternatively undergo C(sp 2 )À O coupling

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by easy ligand exchange and subsequent R.E. step. To circumvent the need of a two-step procedure, Ritter's group developed an operationally simpler method for the electrophilic fluorination of aryl silanes using same oxidant (2 equiv.) upon heating (90°C) in acetone (Scheme 6 bottom left). [37] On this occasion, the simultaneous use of Ag 2 O (2 equiv.) and BaO (1.1 equiv.) results key to accomplish efficient fluorination limiting the formation of hydrodesilylated product to values below 5 %, while the addition of 2,6-lutidine (1 equiv.) precluded double fluorination on the arene. These conditions led to the fluorination of an ample family of (hetero)aryl-Si(OEt) 3 derivatives either bearing electron rich or electron withdrawing substituents, although slightly higher yields were reached for the latter ones. Application of this technology to 18 F radiolabelling of aryl-BNeop esters and aryl stannanes has been reported by Gouverneur and co-workers (Scheme 6 right), who isolated clinically relevant radiotracers such as [ 18 F]-6-fluoro-L-DOPA that are easily accessible from 22 by thermal treatment in presence of HI. [39] As a follow-up to these stoichiometric contributions, Ritter [40] reported a Ag I -catalyzed method for late-stage fluorination of aryl stannanes, impressively broadening the

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reaction scope compared to their seminal work. [38] This appealing transformation requires the heat (65-90°C) of acetone solutions containing variable loadings of Ag 2 O or AgOTf (5-20 mol%), over-stoichiometric amounts of Select-fluor® (1.5-2.0 equiv.), and NaOTf (1.0-2.0 equiv.) leading to the isolation of the fluoroarene in moderate to excellent yields (Figure 8, top). The unwanted protodestannylation reaction was inhibited by adding MeOH (5 equiv.) to the reaction media, resulting particularly useful when using 5 mol% of Ag 2 O as a catalyst. Examples of late-stage functionalization were illustrated and efficient fluorination of pharmaceutically relevant structural motifs such as Taxol, Ezetimibe or Strychnine was accomplished with yields ranging from 60 % to 90 %.
In this latest report, [40] based on the mechanistic clues previously obtained along with the new data gathered, the authors proposed a catalytic cycle for silver. First, the Sn-to-Ag I aryl-group transfer to afford the aryl-Ag I intermediate 19/ 20 occurs, followed by the 2e À oxidation with F-TEDA-PF 6 yielding a bimetallic Ag II À Ag II À F species 21 that builds the C(sp 2 )À F bond through R.E. step and restores the Ag I -catalyst (Figure 8, bottom). The main reason supporting the bimetallic pathway lies in their stoichiometric investigations showing the absolute need of 2 equiv. of Ag I precursor to reach nearly quantitative yields of fluoroarene, whilst the use of half an equivalent of Ag I salt only conducted to ca. 50 % conversion. Competing radical pathway was definitely ruled out through radical trap experiments using butylated hydroxytoluene (BHT), but unfortunately, no high-valent silver intermediate was trapped nor observed. An alternative path involving an initial Ag I -to-Ag II oxidation enabled by the oxidant, followed by the formation of a Ag III À F via disproportionation reaction from the bimetallic Ag II À Ag II À F (or similar) species 21, cannot be fully discarded. Indeed, the same strategy (this is the combination of Ag-catalyst and F-based oxidants) was employed few years later by Chaozong Li and co-workers, who reported the AgNO 3 catalyzed oxidative fluorination of carboxylic acids, [41] alkylboranes [42] and other (pro)aliphatic substrates [43,44] by using Selectfluor® as an oxidant and fluorine source in aqueous media (see Figure 9A and Figure 9B below). Although these transformations are beyond the scope of this review since they only focus the formation of C(sp 3 )À F bonds, the authors propose an intriguing Ag I /Ag III /Ag II catalytic cycle combining 2e À and 1e À redox transitions based on the redox potentials of the Ag I /Ag II couple and Selectfluor® ( Figure 9C). Accordingly, the authors suggest the preferred Ag I -to-Ag III oxidation initial step instead of the formation of Ag II intermediates (i. e. Ritter's proposal). A similar mechanistic scenario was later proposed by Zhao and co-workers for the C(sp 2 )À H bond fluorination of 2-aminopyrimidines 28 using over-stoichiometric Ag 2 CO 3 (2 equiv.) and Selectfluor® (1.2 equiv.) ( Figure 9D) under mild heat (70°C). [45] Radical scavenger experiments using TEMPO pointed to the involvement of * CF 3 radicals, and absence of reactivity was observed when using dialkylamino substituents. Built on these experiments, the initial formation of a Ag III À F intermediate Int-III was proposed, followed by its homolysis yielding the radical Int-IV and Ag II À F species that subsequently react one another to build the desired fluoroarene 29. [45] In 2013 Fier and Hartwig [46] reported the C(sp 2 )À H fluorination of pyridines and diazines using AgF 2 as fluorinating reagent. Despite the significant importance of achieving the ortho-selective fluorination of challenging pyridinyl substrates, little mechanistic insight is provided for the transformation. [46] Nevertheless, a Chichibabin-like reaction mechanism is tentatively proposed for the C(sp 2 )À H ortho fluorination involving the initial formation of the py-Ag II derivative 30 and subsequent Ag II to Ag I reduction step (Scheme 7). Interestingly, the heteroaryl fluorides obtained by this methodology can undergo nucleophilic aromatic substitution allowing the late-stage functionalization of medicinally relevant pyridines with a large variety of nucleophiles such as alkoxides, thiolates, amides or cyanide. [47]

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In spite of the experimentally proven feasibility of oxidative fluorination mediated by silver fluorides in high oxidation state, [36][37][38][39][40][41][42][43][44][45][46][47] the lack of mechanistic consensus partially arises from the limited knowledge on the actual species enabling the C(sp 2 )À F coupling event. In fact, the only work dealing with a precise mechanistic investigation for the oxidative fluorination of aryl rings mediated by high valent coinage metals has been reported by J. F. Hartwig and co-workers, who achieved the stoichiometric coupling of arylboronic esters and [Me 3 PyÀ F][PF 6 ] promoted by ( t BuCN) 2 Cu I OTf (2 equiv.) in presence of AgF (Figure 10 top). [48] Interestingly, the equimolar mixture of Cu-precursor and

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tion step to produce the corresponding aryl-Cu III -F intermediate. Conversely, 31 reacted with p-fluorophenylpinacolborate and AgF at 50°C to build a Cu III F 2 species 32, which subsequently underwent product liberation. The 19 F NMRobservation of the key-intermediate 32, along with its gradual consumption accompanied by the simultaneous aryl-F and FÀ BPin bond creations allowed the authors to identify the transmetalation step as the rate determining step. This fact gives an idea about the high propensity of high-valent aryl-Cu III -F species to induce the aryl-F R.E. step.
Although not strictly dealing with aromatic fluorination, the only crystalline Cu III À F was recently discovered by Zhang and co-workers. [49a] Taking advantage of an elegant ligand design, the pincer-type coordination of a dianionic pyridine based ligand allowed the isolation and complete characterization of a Cu III À F (35) that enables the fluorination of C(sp 3 )À H bonds (Figure 11 top). To meet success, they first accomplished the isolation of the parent Cu II À F species 34 (Figure 11 top), which was subsequently oxidized by treatment with [NAr 3 ]PF 6 at À 80°C, thereby obtaining the corresponding Cu III À F 35. In spite of its thermal instability, 35 was characterized by 1 H NMR analysis, UV-vis and Sc-XRD. In this first contribution, [49a] the proficiency of 35 in stoichiometric C(sp 3 )À H fluorination was demonstrated for a small array of substrates (7 examples; Figure 11 top), whilst a later contribution by the same group proved 35 to be catalytically competent for the electrochemical fluorination of aliphatic CÀ H bonds (Figure 11 bottom). [49b] This represents the first undeniable evidence for the involvement of Cu III À F species in catalytic fluorination.
The lack of well-defined Ag III À F compounds is in sharp contrast to the emerging chemistry of Au III À F derivatives as well. [50] In this sense, proof of concept for the efficiency of cationic Au III À F species in the fluorination of alkyl-group fragments was established by Mankad and Toste back in 2012, [51] when they succeeded in the preparation of the Au III difluoride 37 by formal F 2 -addition to (IPr)Au I (R) complexes of the type 36 using XeF 2 simultaneously as an oxidant and a source of fluoride ligands (see Scheme 8 below). In several cases (R = CH 2 CH 2 t Bu, cyclopropyl, neo-pentyl and CH 2 SiMe 3 ), the in situ formed Au III F 2 derivatives 37 were observed by 19 F NMR before fluoride dissociation to yield the cationic species 38, which is equilibrated with its dimeric form [38] 2 , as unequivocally demonstrated by crystallographic Figure 11. Two-step synthesis of the unique Cu III À F compound 35 known to date (top), and its activity in C(sp 3 )À H bond fluorination under stoichiometric (top) or electrocatalytic (bottom) conditions. Scheme 8. Au I -to-Au III oxidation using XeF 2 to reach the Au III difluoride 37 and fluorination of alkyl-group fragments via fluoride dissociation and subsequent C(sp 3 )À F reductive elimination from the elusive Au III À F intermediate 38.

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means. [51] Nevertheless, 38 undergoes alkylic fluorination at room temperature, although the resulting yield drastically fluctuates depending on the substitution pattern of the R group owing to plausible β-H elimination or carbocation-like rearrangements to build olefins or distinct fluoroalkane regioisomers, respectively. Kinetic and stereochemical analyses, coupled to DFT studies, suggested the concerted C(sp 3 )À F reductive elimination to occur from cationic 38, which is built via fluoride dissociation from the neutral Au III F 2 platform 37.
In spite of the flourishing interest on organometallic M III À F compounds (M equal to Cu or Au), the isolation and characterization of a Ag III À F remained elusive until 2020,  , Br), was formed. [53] Opposed to the extremely aggressive behavior of AgF 3 or [AgF 4 ] À , [54] which are considered amongst the most powerful known oxidizers, 41 seems to be easier to handle, although it becomes easily hydrolysed to form [PPh 4 ][Ag III (CF 3 ) 3 (OH)], thus requiring the use of quartz vessel and its handling and stocking at low temperature. Most remarkably, the ability of the Ag III À F complex 41 to undergo the trifluoromethylation of alkyl and aryl thiols was demonstrated, and the intermediacy of the Ag III -thiolate [Ag III (CF 3 ) 3 (SR)] À (42) was unequivocally assessed by MS spectrometry and 19 F NMR spectroscopy (Figure 12 bottom). [52] 41 represents the first well-defined Ag III species enabling the perfluoroalkylation of nucleophiles, with the SÀ CF 3 coupling event taking place in good yield (83-99 %) under mild heat (45°C) but coproducing [Ag I (CF 3 ) 2 ] À and fluoroform (HCF 3 ). Fluoroform release might be indica-tive of the involvement of * CF 3 radicals vs. the more attractive/ convenient 2e À R.E. step.

Aromatic Trifluoromethylation Enabled by High-Valent Silver
The aromatic trifluoromethylation mediated by transition metals constitutes one of the most challenging transformations among all known cross-coupling reactions. This is simultaneously due to the difficult aryl-CF 3 R.E. from a well-defined aryl-M-CF 3 fragment, [6] and the ubiquity of benzotrifluorides in both pharmaceutical and agrochemical markets. [1,2] In spite to the copper proficiency in promoting aryl-CF 3 bond formation, [55] and the suitability of palladium catalysts [56] to accomplish such a rewarding transformation, parent silver congeners have been scarcely investigated for this purpose given the assumed silver propensity to undergo 1e À redox sequences vs. Ag I /Ag III redox cycles. [57] Nevertheless, in 2011, the ability of silver compounds to enable aromatic trifluoromethylation was discovered by Sanford and coworkers, [58] who reported the stoichiometric C(sp 2 )À H bond trifluoromethylation of electron rich arenes mediated by AgOTf, Ruppert-Prakash reagent and KF (Scheme 9). The reaction requires over-stoichiometric amounts of AgOTf, and involves the * CF 3 radical release from in situ formed Ag I CF 3 , that is sequestered by the (hetero)arene giving rise to the desired benzotrifluoride in moderate to excellent yields.
First catalytic versions of this transformation via * CF 3 radical generation were reported shortly after by Greaney [59] and Zhang [60] combining either AgF or Ag 2 CO 3 , an oxidant [PhI(OAc) 2 or K 2 S 2 O 8 ], and a different trifluoromethylating agent (CF 3 SiMe 3 or CF 3 CO 2 H) with similar outcome (see below in Figure 13A and Figure 13B, respectively). Interestingly, variants of Greaney's method allowed Hafner and Brase to develop the ortho-selective C(sp 2 )À H bond trifluorometh-

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ylation of arenes bearing triazenes ( Figure 13C), [61] while C(sp 2 )À H bond trifluoromethylation of mesitylene and 2methyltiophene was achieved by Qing and co-workers by employing fluoroform-derived "ligandless" Ag I CF 3 (Figure 13D). [62] The very popular Langlois' reagent (CF 3 SO 2 Na) was also employed and proved useful to accomplish the regioselective trifluoromethylation of imidazoheterocycles in good yields, as demonstrated by Hajra and co-workers when using AgNO 3 and t BuOOH in catalytic amounts ( Figure 13E). [63] Despite the practicality of some of these methods, they all rely on the addition of * CF 3 radicals (presumably earned from Ag I CF 3 species) to arenes, and limited (if any) mechanistic information was disclosed regarding the actual nature of the AgCF 3 species arising from the oxidizing media (Scheme 9 and Figure 13). Different approaches to build benzotrifluorides were equally explored without involvement of * CF 3 radicals, and efficient synthetic routes were independently found by Hu [64] and Lee [65] for the functionalization of in situ forged arynes. The aryne intermediates Int-V and Int-VII are built either from 2-trimethylsilylphenyl triflates of the type 43 and CsF ( Figure 14A), [64] or the tetra-alkyne derivative 44 via intramolecular cyclotrimerization ( Figure 14B). [65] In the former case, the aryne moiety is functionalized twice upon addition of Scheme 9. Pioneering work for the aromatic trifluoromethylation enabled by AgCF 3 entities through * CF 3 radical generation (Sanford).

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iodoalkynes, whilst adventitious water plays the role of electrophile in the latter example. A distinct alternative was reported by Wang and coworkers [66] taking place by reacting the aryldiazonium salts 45, available from anilines via diazotization reaction, and freshly prepared Ag I CF 3 ( Figure 14C). Most remarkably, in addition to the outstanding substrate scope shown by this method, the authors pointed to the key participation of aryl-Ag III -CF 3 intermediates of type 46, hypothetically reachable upon the 2e À oxidation of Ag I CF 3 by the aryldiazonium salt. Nonetheless, this mechanistic scenario remains speculative and no spectroscopic support was provided for the Ag I /Ag III redox behavior.
First clear insight for the foreseeable Ag III /Ag I R.E. step forging CÀ CF 3 bonds was provided by Eujen and co-workers back in 1997, [28a] when they discovered a practical entry to Ag III species 47, 48 and 49 only stabilized by trifluoromethyl and cyanide ligands (Scheme 10). In this work, the authors noticed the facile decomposition of the Ag III anions [Ag III -(CN) 3 (CF 3 )] À (48) and [cis-Ag III (CN) 2 (CF 3 ) 2 ] À (cis-47) in DMF solutions affording trifluoroacetonitrile, while its parent compounds [trans-Ag III (CN) 2 (CF 3 ) 2 ] À (trans-47) and [Ag III -(CF 3 ) 3 CN] À (49) revealed remarkably more stable and required heating up to 50°C and 80°C, respectively. This study clearly indicates the suitability of trifluoromethyl ligands to support unusually high oxidation states in late transition metal compounds.
Nevertheless, it took about two decades until a first study proving the ability of organosilver(III) species to effect aryl-CF 3 bond forming reactions saw light, when Shen [67] and Nebra [68] simultaneously reported the trifluoromethylation of arylboron surrogates using the neutral complex Ag III -(CF 3 ) 3 (phen) (50) as a trifluoromethylating agent. Taking advantage from the significant stabilization provided by fluorinated arenes upon coordination to transition metals and the reluctance of the resulting species to R.E., Shen [67] and coworkers designed an audacious strategy to isolate the first aryl-Ag III (CF 3 ) 3 platform (52 a-e ) by using ortho-fluorinated arylboronic pinacol esters 51 a-e (Scheme 11). Thus, the ensuing σaryl-Ag III compounds 52 a-e were prepared in modest yield via boron-to-Ag III aryl-group transfer between the phen-Ag III derivative 50 and 51 a-e in presence of Cs 2 CO 3 . Once isolated and fully authenticated (including by Sc-XRD), 52 a-e underwent aromatic trifluoromethylation upon warming up to 85°C in chloroform. Profound mechanistic studies for the forging of benzotrifluorides from the isolated 52 a-e were carried out combining precise kinetics and Hammett plot analyses, radical or SET trap experiments, EPR monitoring and DFT computations. Taken together, this study undeniably argued in favour of a concerted R.E. pathway from the σ-aryl-Ag III Scheme 10. NCÀ CF 3 bond formation mediated by Ag III reported by Eujen.

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platform 52 a-e via the three-membered transition state TS-I depicted in Scheme 11. Shen's approach to aromatic trifluoromethylation is strongly inspired in the oxidative trifluoromethylation of arylboronic acids and derivatives occurring through Cu I /Cu III redox scenario. [69] Indeed, the same group [69] described analogous work using Grushin's complex, [12b] Cu III (CF 3 ) 3 (bpy) (53), to accomplish the two-step trifluoromethylation of (2,3,5,6-tetrafluorophenyl)-BPin derivatives 51 f-k involving the intermediacy of the isolatable [aryl-Cu III (CF 3 ) 3 ] À platform 55 f-k . Heated to 95°C in 1,2-dichloroethane, the σ-aryl-Cu III compounds 55 f-k produced the corresponding benzotrifluorides in excellent yields (82-99 %) (Scheme 12, right approach). In similar fashion to Ag III , in-depth mechanistic study confirmed the concerted R.E. step via TS-II. Although both methodologies require the isolation of the key σ-aryl-M III intermediate, the acquired global yields for the two-step trifluoromethylation are significantly higher for the Ag III promoter as a consequence of a more efficient boron-to-M III aryl transfer, and easier aryl-CF 3 coupling. In a later work, Shen and co-workers extended the scope of this method to alkyl-BPin analogues, even if previous formation of Li[alkyl-B( n Bu)Pin] becomes mandatory for the boron-to-Cu III alkylgroup transmetallation to proceed. [70] An alternative for the Cu III -mediated trifluoromethylation of arylboronic acids was discovered in 2016 by Zhang and Bie,[71a] who employed the Grushin's homologue Cu III -(CF 3 ) 3 (phen) (54 in Scheme 12, left approach) or reminiscent Cu III (CF 3 ) 3 (L) compounds [71b-d] as trifluoromethylating sources, and pure oxygen as an oxidant. [71a] The requirement of O 2 (instead inert atmosphere) seems to indicate the need of reoxidizing the CuCF 3 entities arising from the aryl-CF 3 coupling event. [71a] The authors tentatively proposed the initial forging of [Cu III (CF 3 ) 2 (aryl)(phen)] and subsequent R.E. step, which is in sharp contrast to the boron-to-Cu III aryl-group transfer found by Shen [69] under very close transmetallating conditions, leading instead to anionic σ-aryl-Cu III compounds 55 f-k . Anyhow, little information regarding the actual Cu III species mediating the aryl-CF 3 coupling is available, and the global reaction pathway remains uncertain.
Our group has recently investigated the chemistry of Ag III CF 3 species and found a safe and efficient entry to the long-known homoleptic anion [Ag III (CF 3 ) 4 ] À (57) starting from Ag I CF 3 and CF 3 SiMe 3 using ambient air as a mild oxidant (Figure 15 top). [68] With 57 in hand in multigram scale, its conversion to the neutral compounds Ag III -(CF 3 ) 3 (phen) (50) and Ag III (CF 3 ) 3 (bpy) (58) in high yield was achieved upon heating in acidic media (HOAc), and the neutral Ag III (CF 3 ) 3 (N^N) 50 and 58 were isolated and conveniently authenticated, including crystallographically. The neutral Ag III compounds 50 and 58 emerged as excellent promoters for the trifluoromethylation of arylboron surrogates in aqueous media, and a large array (ca. 50 substrates) of benzotrifluorides were attained using the phen-Ag III complex Scheme 12. Two-step trifluoromethylation of arylboronic esters enabled by Grushin's complex 53 taking place via initial formation of isolatable [aryl-Cu III (CF 3 ) 3 ] À intermediates 55 f-k and subsequent reductive elimination step involving TS-II (right approach, Shen). Trifluoromethylation of arylboronic acids using the phen-Cu III compound 54 and oxygen as an oxidant (left approach, Zhang). 50 as trifluoromethylating agent in presence of base (Cs 2 CO 3 ) and under mild heat (60°C) (Figure 15 bottom). Interestingly, the σ-aryl-Ag III compound Cs[Ag III (CF 3 ) 3 (4-NO 2 C 6 H 4 )] (52 l ) was isolated in 73 % yield (and fully authenticated) after smooth transmetallation reaction between the bpy-Ag III 58 and the corresponding aryl-BPin 51 l at 15°C. Heated to 60°C, 52 l released 4-nitrobenzotrifluoride with concomitant formation of Cs[Ag I (CF 3 ) 2 ], thus suggesting a concerted R.E. pathway during the aryl-CF 3 bond formation, and additional support for the 2e À vs. radical pathway was provided by radical clock experiments.
While Shen's work [67] is limited in scope and exclusively deals with ortho-fluorinated arylboronic esters, this aqueous methodology [68] allows for the trifluoromethylation of more than 30 arylboron surrogates in excellent yields (> 80 %), requiring lower temperatures and taking place in a single step, thereby avoiding the absolute need for the intermediate isolation of the aryl-Ag III platform 52.

Electronic Structure of High Valent Ag(III) Compounds and Inverted Ligand Field
This recently introduced concept, i. e. inverted ligand field (ILF), is referred to those metal complexes exhibiting an inverted electronic structure opposed to the classical model ( Figure 16 left). [72] In other words, the inverted model refers to those complexes no longer having frontier molecular orbitals (MO) mainly constituted by metallic atomic orbitals (AO), but by the ligand ones (Figure 16 right). Accordingly, the MO mainly contributed by metallic AO are buried in energy and their disposition for a given geometry is inverted to the expected order. [72] Moving along the transition series from early to late transition metals, a progressive stabilization of d orbitals occurs, then turning more nucleophilic. At some point, this bonding situation is maximized and the ligand orbitals become higher in energy than metallic ones, and thereby this inverted electronic arrangement results more likely.
Although the cationic nickel complex [(np 3 )Ni(SnPh 3 )] + (np 3 equal to N(CH 2 CH 2 PPh 2 ) 3 ) [73] stands for the first ever reported compound displaying ILF and additional reports [74] describing late transition metals with ILF saw light in between, with no doubt, the most famous case example is represented by the formally Cu III homoleptic anion [Cu(CF 3 ) 4 ] À . [75][76][77][78] As soon as in 1993, [76] Snyder found a nuclear charge of Cu close to + 1, and attributed this fact to the presence of an ILF configuration, implying the presence of a reduced Cu I metal centre, an oxidized CF 3 + ligand, and a mostly ionic bond. Lately, many articles have proven the atomic charge close to + 1 in [Cu(CF 3 ) 4 ] À , [77] although proposing a covalent bonding character. This interesting and never-ending debate about the appropriate assignment of the Cu oxidation state in [Cu-(CF 3 ) 4 ] À has recently been expanded to other formally Cu III compounds, [79] and considerable efforts are being paid to prove (or disprove) the presence of an ILF in those intriguing species. [78] Indeed, a recent comparative study shows that the full series of anions [M(CF 3 ) 4 ] À (M = Cu, Ag, Au) present an analogous ILF electronic structure ( Figure 17A). [80] The main difference along the series is the observed HOMO-LUMO GAP, which is considerably larger for Au vs. Cu and Ag, a

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common signature in transition metal chemistry with direct impact on the relative stability of the compounds going down the group. This study allowed to demonstrate experimentally this peculiar electronic structure through reactivity via thermal and photochemical activation. In all cases, the observed patterns perfectly match the predicted MO diagram, and clear evidence for covalency was provided according to the observed MÀ CF 3 bond homolysis. In line with this bonding depiction, all homoleptic anions [M(CF 3 ) 4 ] À proved trifluoromethylating competent via radical pathway to afford benzotrifluorides. The similar behaviour of the anions [M(CF 3 ) 4 ] À extends the debate around their actual oxidation state, and ILF considerations may apply to the whole coinage metal series in formally oxidation state + III. [80] Recently, the same group used this ILF phenomenon to rationalize the failure of Au III species to act as hydrogen-bonding acceptor. [81] Even though Grochala had proven high covalent bonding and notorious stabilization of the metallic AO vs. the ones of fluorides in high valent Ag species back in 2003 (representative example 62 is shown in Figure 17B left), [82] no heteroleptic Ag III compounds having ILF were identified until 2018, when Menjón reported the Ag III platform [PPh 4 ][Ag III (CF 3 ) 3 X] (X equal to F, Cl, Br, I, CN, N 3 ) ( Figure 17B middle). [83] They all exhibit analogous ILF electronic structure with the frontier orbitals mainly constituted by ligand AO. These moderately stable complexes underwent two decomposition patterns: i) a main one leading to the loss of two trifluoromethyl ligands; and ii) the concerted reductive elimination of CF 3 À X bonds from the Ag III À X anions, this secondary process being only observed for the most polarizing halides (Br, I). This situation provokes a decreasing stability with the heaviest halides, although the Ag III À X bond seems to be intrinsically stable in all cases. This key observation supports the feasibility of the challenging O.A. elementary step of organic halides to Ag I centre within the context of a purely Ag I /Ag III catalytic cycle, at least from a purely thermodynamic point of view.
In addition, the five coordinated dianionic compound [Ag III (CF 3 ) 2 Br 3 ] 2À (67) displaying ILF configuration and exhibiting an unprecedented trigonal bipyramidal geometry (TBP-5; Figure 17B right), was reported by Menjón and coworkers. [53] Exotic 67 is reachable from [PPh 4 ][trans-Ag III -(CF 3 ) 2 X 2 ] (X = Cl, Br) upon addition of a third halide ligand. This work, jointly to the tendency of the neutral platform Ag III (CF 3 ) 3 S (68; S = py, CH 3 CN, AsPh 3 ) to accommodate an apical fifth ligand, confirms certain degree of electrophilicity at Ag III centre ( Figure 17C). [84] Overall, these observations point to general Inverted Ligand Field configurations in Ag III Chemistry and the plausible expansion in coordination number, at least when dealing with formally Ag III R F compounds that are stabilized by (per)fluorinated ligands.

Outlook and Conclusions
Along this essay, we have examined the current State of Art in cross coupling reactions mediated by high-valent silver species. Over the last years (since 2014), a number of reports have proven Ag to undergo 2e À processes building CÀ C and Cheteroatom bonds same way its neighbouring atoms (Cu, Au, Pd) currently do. This recent discovery changes the erroneously preconceived ideas about Ag redox chemistry, a classic paradigm that made people only consider this metal to exclusively operate through 1e À transitions. In fact, contrary to the typically accepted behaviour of Ag III as aggressive oxidizing agents, several Ag III intermediates have been isolated so far and fully authenticated. Whenever possible, Ag III activity in fluorination and trifluoromethylation was compared to the one of Cu III and Au III species. Strikingly, in case of oxidative fluorination and trifluoromethylation reactions (i. e. Chan-Evans-Lam (CEL) coupling), better yields and broader substrate scope were provided by the organosilver(III) species vs. the analogous organocopper(III) compounds. This is in line with recent observations made by O'Hair, Ogle and Koszinowski, who examined the R.E. step from tetraorganylargentate(III) complexes [Ag III (R)(CH 3 ) 3 ] À through ESI-MS and DFT calculations pointing to a higher Ag III capacity to undergo cross-coupling [85] vs. the one shown by parent [Cu III (R)(CH 3 ) 3 ] À species. [86] Nevertheless, Ag III enabled cross-couplings are mainly restricted to the use of macrocyclic or perfluorinated ligands (R F = F, CF 3 ). This might be ascribed to the ability of these ligands to induce an inverted ligand field configuration thus stabilizing the high oxidation state through "non-innocent" ligand contributions. As a result, the vast majority of cases deals with the formation of CÀ F and CÀ CF 3 bonds.
As a matter of fact, Ag should no longer be considered as a simple spectator in catalysis but an active role player. Nonetheless, much effort is yet to come in order to expand Ag I /Ag III redox reactivity, and to clarify the different pathways by which these unprecedented transformations actually occur.