ChemCatChem - 2022 - Muthuvel

Review
ChemCatChem doi.org/10.1002/cctc.202101579
www.chemcatchem.org
C F Bond Activation and Functionalizations Enabled by

Metal-free NHCs and Their Metal Complexes
Karthick Muthuvel[a] and Thirumanavelan Gandhi*[a]
Dedicated to Prof. D. Gajapathy on the occasion of his 75th birthday
ChemCatChem 2022, 14, e202101579 (1 of 15) © 2022 Wiley-VCH GmbH

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Review
The activation and functionalization of C F bonds in various is relatively scarce. NHCs based catalytic C F activation stands
fluoroorganics were found to be a daunting task owing to their out owing to its easy accessibility, stability, and facile reactivity.
innate inertness. Harnessing the C F bonds will alleviate the Metal-NHCs were exploited in hydrodefluorination, C C, and
toxicity and environmental issues posed by them, and provide C B coupling reactions. Additionally, R M(F)(NHC), an oxida-
new pathways to access value-added products. Although tive-addition intermediate that was conveniently isolated allows
several strategies have been employed such as metal com- to decode catalytic C F functionalization pathways. This minire-
plexes, Brønsted acids, Lewis acids, and photocatalyst to view provides the prominence of NHC and metal-NHC in the
activate the C F bonds, however, the use of NHC or Metal-NHC area of catalytic C F bond functionalization.
1. Introduction N-wingtips. Besides, saturation on the ring and the type of the
carbenes too play a vital role in its reactivity.[33–37] More
Fluoroorganics are favorable compounds in plastics, refriger- relevantly, NHCs are considered as a potential alternative to
ants, agrochemicals, pharmaceuticals, and electronic devices as phosphine-based systems and they are proven to be very
they are known for their robustness[1–4] This uncommon high effective in cleaving the C F bonds. Metal-NHCs react stoichio-
thermal and chemical stability is complemented by the small metrically with fluoroarenes to form aryl-metal-fluoride com-
size and high electronegativity possessed by fluorine atom.[5–8] plexes I as an isolable intermediate. Most likely, aryl-metal-
And thus, the cleavage of the C F in fluoroorganics is fluoride complexes were generated either by oxidative addition
challenging as the bond dissociation energy of them is more or by the nucleophilic attack. These developments enlightened
than 130 kcal/mol.[9] However, these intricate C F bond clea- the mechanistic pathways and guided the correct choice of
vages are feasible both in presence of metal and metal-free metal and NHC counterparts. Catalytically, the inclusion of
conditions. Thus, these routes will mitigate the environmental hydrogen sources to aryl-metal-fluorides completes hydrode-
hazards (CFCs) and address the bioaccumulation of fluorinated fluorination process II whereas organometallic reagents result
pharmaceuticals.[10] in cross-coupled products III. Likewise, catalytically aryl-metal-
Interestingly, the activation of the C F bonds gives access fluoride complexes react with aryl halides and boronic esters to
to partially fluorinated building blocks from easily available give homocoupled III and borylated products IV respectively.
perfluorinated chemicals resulting in value-added products.[2,11] More impressively, this intriguing C F bond cleavage happens
In other words, replacement of fluorine atom in C F bond with elegantly with the intervention of NHC as a coupling partner.
other functionality involving C O, C S, C N, C P, C B, C Si, Both mono V and double VI C F bond activations were
and C-halogen bond formation will make fluoroorganics more accomplished. Distinctively, fluoroalkenes display C F bond
amenable and useful.[12,13] To complement these functionalities, cleavage revealing this addition-elimination capability alongside
concomitant formation of thermodynamic sinks such as HF, its leaving-group tendency resulting in rearranged coupled
R3SiF, or BF4 were observed. Generally, cleavage of the C F product VII (Figure 1).
was effected by using metal complexes[14,15] (metallocenes,[1,16–20]
metal-phosphines,[7,21–26] metal-carbonyls,[4,6,23] metal-NHCs,[27,28]
and rare earth metals[29,30]), strong Brønsted acids (such as
hydrogen halides), strong Lewis acids[31] (such as aluminum,[3,9]
boron, carbocation, and silylation compounds[15,32]) and
photocatalysis.[9] In the case of metal complexes, both stoichio-
metric and catalytic conversions were achieved, where the
former transformation assisted in understanding the key steps
involved in the catalytic cycle. It has been understood that
NHCs are versatile moieties exhibiting interesting reactivity,
which acts as organocatalysts as well as metal-NHC catalysts.
NHCs are significantly stronger donors than commonly used
tertiary phosphines which can be substantiated by Tolman
electronic parameters (TEP). NHC exhibits improved stability to
air, moisture, and is facile to oxidative-addition reactions. NHCs
impart high stability to metals at higher oxidation states
whereas phosphines are prone to form phosphines oxides.
Advantageously, NHC’s electronic and steric can be easily
manipulated by changing the substituents on its backbone and
[a] K. Muthuvel, Dr. T. Gandhi

Department of Chemistry, School of Advanced Sciences
Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
E-mail: velan.g@vit.ac.in Figure 1. C F activation and functionalization by metal and metal-free NHC.

Review
2. C-F activation by metal NHC (stoichiometric

and isolated intermediates)
The activation of the C F bond was primarily effected by the

mediation of a transition metal catalyst, where oxidative-
addition is the primary step that paves the way for various
organic transformations such as hydrodefluorination (HDF),
Scheme 1. Ni F formation by C F activation.
Kumada and Suzuki-Miyaura reaction. The investigation of the
isolated intermediates, especially NHC M-F species signifies the
reactivity of the metal catalyst and reaction pathways. Further-
more, these studies facilities the design and development of
new M-NHC for C F activation and functionalization. Although
Ni-NHCs and Ni-Phosphines were known and well-studied for
the catalytic C C coupling via C F activation, studies on the
reaction intermediates are sparse. In 2005, Radius and his
coworkers have elegantly shown the activation of C F in
hexafluorobenzene 2 with dimeric complex [Ni2(iPr2Im)4(COD)] 1.
The highlight of this reaction is that C F activation occurred
smoothly and was completed in one hour to give the trans
product [Ni(iPr2Im)2(F)(C6F5)] 3 a, in contrast to the Ni-phosphine
catalysts which took a long time (Scheme 1).[38] In 2008, the
same group reported a detailed mechanistic investigation to
understand the role of ligand and reaction temperature. The
activation of the C F bond in different fluoro aromatics was
carried with 1 and [Ni(iPr2Im)2(η2 C2H4)] 4. Interestingly, from
the viewpoint of 1, 2 b, and 2 g–j underwent site- selective (C4)
C F activation para to the functional group whereas 2 c–f did
not show any clear trend in the activation process
(Scheme 2).[14] Later reacting 5 with 4, a temperature-sensitive
C F site-selective activation was observed. At 30 °C, an
exclusive C4 C F activated intermediate 3 l was observed, when
the same reaction was carried out at room temperature, a Scheme 2. C-F activation in different fluoroarenes
mixture of 3 l and 3 m was formed by C F activation at C4 and
C2 positions respectively. Similarly, 6 gets activated to give 3 j
and 3 k at C1 and C2 positions respectively at 20 °C. Like 1, 4
reacted with 2 to yield 3 a (Scheme 3). The unusual o-C F adducts and ligand assisted step which has a lower energy state
selectivity may be due to the binding of N atom of C5F5N to the than the corresponding oxidative-addition intermediate. Be-
Ni(0) by the nucleophilicity of the {Ni(iPr2Im)2} 4 fragment. sides, additional factors like radical mechanism and dinuclear
However, theoretical studies by Johnson with analogous Ni(0)- adduct were also not ruled out for this unusual o-C F activated
phosphine system suggested the involvement of π-bound product.[39,40] To further explore the C F bond activation in the
Thirumanavelan Gandhi studied chemistry at Karthick Muthuvel was born in Vikramam,

the Muthurangam Govt Arts College, Vellore Tamil Nadu, India. He has completed his
(1997–1999) and received his Ph. D in 2005 Bachelor’s at The American College and Mas-
from the Indian Institute of Science, Bengaluru ter’s degree (chemistry) at Thiagarajar college
under the supervision of Prof. Balaji R. (2013–2015), Madurai. He worked as a project
Jagirdar. He pursued his postdoctoral studies assistant under Dr. Gouriprasanna Roy at Shiv
(2006-2008) at The Johns Hopkins University, Nadar University, Greater Noida, UP. Currently,
Baltimore with Prof. Kenneth D. Karlin. He he is pursuing his Ph.D. under the supervision
served as a senior scientist in Cookson India of Dr. G. Thirumanavelan at VIT, Vellore, India.
Research Centre (Alent plc), Bengaluru (2009- His research work focuses on the synthesis of
2010). He started his academic career at new NHC carbene complexes and the utiliza-
Vellore Institute Technology, Vellore in 2011 tion of acyl imidazolium salts as an acylating
wherein currently he is an Associate Professor. source.
His research interest focused on the develop-
ment of metal-NHC catalysts and sustainable
synthetic methodologies.

Review
Scheme 4. Dual para C F activation with C1 and C4.
Scheme 3. C2 and C4 activation at varying temperatures.
isolated 3 a and 3 i, the same group treated these complexes

with 0.5 equiv. of 1 at above 60 °C resulted in an interesting
consecutive C F bond activation to give 7 a and 7 b (Scheme 4).
Usually, such dinuclear metal complexes possessing tetrafluor-
ophenyl and octafluorobiphenyl bridging ligands are prepared
by the reaction of the dilithiated fluoroarene with a suitable
metal. Unfortunately, 7 a and 7 b did not participate in further
C F bond activation when 1 was introduced in excess at
elevated temperatures[41] Lately, the same group explored
similar chemistries with [Ni(Mes2Im)2] (Mes2Im = 1,3-dimesityl-
imidazolin-2-ylidene) 9 a which efficiently activates the C F
bond in polyfluorinated arenes to give a series of nickel
fluoroaryl fluoride complexes 9 c–h (Scheme 5). Additionally, a
comparative study of 9 a, with 9 b ([Ni(iPr2Im)2], (Ni(0)-NHC
bearing a sterically less demanding iPr) on C F activation was Scheme 5. C F activation by Ni(Mes2Im)2 with different fluoroarenes.
performed to get the insights on its reactions pathway.

Experimentally, the redox potential of 9 a with 2 does not
match, and thus electron transfer route is overruled. Insightfully, luene, and decafluorobiphenyl form stable mononuclear species
the DFT calculations reveal that the C F activation process at 78 °C with a series of cobalt precursors. For instance, the
proceeds through the NHC-assisted pathway for both 9 a and reaction of 10 a with 2 leads to mononuclear complex 10 b at
9 b. However, mechanistically 9 a proceeds via fluorine atom 78 °C which on warming to 60 °C results in a stable dinuclear
abstraction and phenyl radical formation, whereas 9 b favors species 10 c. Eventually, cobalt(II) fluoroaryl 10 d and the side
concerted oxidative addition.[42] Very recently, Radius and co- product 10 e were isolated. The final step seems to demand
workers turned their focus from Ni to Co, i. e., the C F activation substantial activation energy as heating up to 100 °C is
at NHC cobalt half-sandwich complexes of the type necessary to achieve insertion of 10 a into the C F bond to
[CpCo(NHC)(olefin)] 10 a. Hexafluorobenzene, octafluoroto-

Review
form the 10 d. This overall reaction is a one-electron oxidative compounds catalyzed by iron(ll)fluoride complex bearing bulky
addition starting from 10 a to 10 d and 10 e (Scheme 6).[43] β-diketiminate ligand.[46] In 2002, Fort and co-workers hinted at
dehalogenation of fluorobenzene catalyzed by Ni(0)/IMes·HCl/i-
PrONa combination to yield benzene (yield = 45 %), and sodium
3. Organic transformations-catalytic process isopropoxide as the source of hydrogen[47]. Later, in 2009
Whittlesey and co-workers investigated the metal-NHC (precata-
3.1. Hydrodefluorination (HDF) lyst) for the catalytic HDF. The N-aryl substituted N-heterocyclic
carbene complexes Ru(NHC)(PPh3)2(CO)(H)2 11 a–d promotes
With the known passive nature of the C F bonds in fluoroar- the catalytic hydrodefluorination (HDF) of aromatic fluorocar-
enes, the hydrodefluorination (HDF) method helps to remove bons in the presence of alkyl silanes to give perfluoroarenes
the more stable C F bond and replace it with C H. Besides, along with coordinatively unsaturated species Ru-
HDF will mitigate the problem posed by chlorofluorocarbons (NHC)(PPh3)(CO)HF 11 e–h. However, they witnessed that 11 b
(greenhouse gases). Milstein and co-workers were the first to (R = IMes) failed to replace phosphine ligands completely.
tame the C F bonds, and they reported rhodium-phosphine Interestingly, in this HDF chemistry, the highly regioselective
catalyzed F/H exchange with hydrosilanes.[44,45] Later, Holland 1,2-partially fluorinated products starting from C6F5H 12 were
group demonstrated the HDF of perfluorinated aromatic observed, which is in contrast with the previous reports by both
Milstein and Holland showed 1,4-products (Scheme 7).[48] In
2011, the same group revealed the mechanistic pathways and
DFT calculation for the regioselective 1,2-partially fluorinated
products. Based on the DFT calculations, the catalytic cycle of
hydrodefluorination (HDF) of 12 to 1,2,3,4-C6F4H2 13 by 11 a,d is
depicted in (Scheme 8). The nucleophilic attack of a Ru hydride
ligand on the fluoroarene ring supports the unusual ortho-
regioselectivity that was observed experimentally.[49] Comple-
mentary to this work, in 2013, they unveiled a complete DFT
study on 11 b, which supports (i) a concerted process with Ru–
H/C F exchange occurring in a single step; and (ii) a stepwise
pathway in which the rate-determining transition state involves
removal of HF and formation of a Ru-σ-fluoroaryl complex
(Scheme 8). Besides, the nature of the metal coordination
environment, and more specifically, the NHC ligand was found
Scheme 6. Co F formation and C F activation by Co-NHC.
Scheme 7. Whittlesey’s HDF by Ru(NHC)(PPh3)2(CO)H2. Scheme 8. Mechanism for nucleophilic hydride attack.

Review
to play a pivotal role in promoting the HDF reaction as well as

the regioselectivity (Scheme 9).[50] In 2015, they disclosed even
more reactive mixed carbene-phosphine complex 16 [Ru-
(IEt2Me2)2(PPh3)2(H)2] (IEt2Me2 = 1,3-diethyl-4,5-dimethylimidazol-
2-ylidene). This unusual reactivity arises owing to the trans-
arrangement of the two hydride ligands (H Ru–H geometry)
which imparts greater nucleophilicity at the ruthenium center
which generates multiple HDF products, i. e., up to monofluor-
obenzene 17 (Scheme 10). [51][52] Earlier, Radius group had
shown the stoichiometric C F bond activation of fluoroarenes
using 1 and isolated the intermediate complexes. Later, they
used such Ni-NHCs for the catalytic HDF reactions. Effectively, 1
catalytically activates the C F bonds of fluoroarenes and
exchanges with hydrogen from hydrosilanes to yield 19. With
the experimental findings, the following pathways for the
catalytic HDF are identified. Initially, C F activation of the
polyfluoroarene proceeds via oxidative addition, then H/F
exchange was achieved by the addition of hydrosilanes. p-
Scheme 9. Site-selective dehydrofluorination. Perfluorotolyl nickel hydride complex formed undergoes reduc-
tive-elimination to an intermediate bearing η2-C, C-coordinated
arene ligand, and the subsequent ligand exchange with the
higher fluorinated polyfluoroarene leads to the expulsion of
lesser fluorinated polyfluoroarenes thereby continuing the
catalytic cycle (Scheme 11).[53] Tuning the [(IMes)AuH] 21 for
direct HDF of fluoroarenes are quite challenging due to its low
reactivity. However, in 2012, Zhang and co-workers demon-
strated the effective catalytic HDF by introducing the DMAP,
which promotes the C F bond activation by unusual π–π
interaction. They inferred neither oxidative-addition nor nucleo-
philic attack of the C F bond was involved during this Au-NHC
Scheme 10. Consecutive dehydrofluorination Ru(IEt2Me2)2(PPh3)2(H)2 catalyzed HDF reaction. The participation of DMAP π–π
interaction was supported by UV vis spectral titrations, 1H
NMR spectroscopic studies, and DFT calculations. The reduced
activation barriers in the presence of DMAP (31.6 kcal/mol) than
that in its absence (40.8 kcal/mol) during this reaction show the
involvement of π–π interaction. Moreover, 1H and 19F-NMR
studies show that this π–π interaction promotes the hydrogen
transfer from [(NHC)AuH] 21 to the pyridyl N atom of 21 a,
resulting in the C F bond cleavage in 21 b (Scheme 12).[54] In
this array of works, in 2013 Peris and co-workers employed a
different approach by harnessing the catalytic cooperative
effect contributed by heterodinuclear-NHC based complexes 25
in HDF reactions. The role of palladium and ruthenium metal
bound to the single NHC ligand was studied, where the former
activates the C F bond and later reduces substrates via catalytic
transfer hydrogenation under mild reaction conditions. Their
control studies reveal that the heterobimetallic complex is
catalytically efficient than the mixture of the related homodime-
tallic complexes of ruthenium and palladium. Interestingly, 25 is
an effective HDF catalyst both for aromatic and aliphatic
carbon-fluorine bonds. The amount of base (NaOtBu) plays a
crucial role in HDF of 4-fluorobenzotrifluoride, which is reduced
to two different products in the presence of four equivalents of
base. Sequentially, the aromatic C F bond is reduced first,
followed by a reduction of the CF3 group. However, with one
equivalent of base only the aromatic C F bond was reduced
Scheme 11. Mechanism of oxidative addition. (Scheme 13).[55]

Review
ocyclobutyl complex 28 b in the presence of a Lewis acid

(Me3SiOTf). The formation of 28 b is by migration of a fluoroalkyl
to a reactive carbon center, which is unstable, culminated in
perfluorocyclobutene. However, the reaction of 28 a with
CF3COOH leads to stable ring-functionalized products 28 c and
perfluorocyclobutene 29 (Scheme 14).[56]
3.3. Fluorine transfer by defluorination
A typical C F activation proceeds via the oxidative addition at

the metal center, and it is unfamiliar to witness this process
held away from the metal center. In the recent past, the fluorine
transfer reaction has attained greater importance concerning
the impact of organofluorines on the environment. Ogiwara
and co-workers developed a fluorine transfer reaction from
benzoyl fluoride to acid anhydrides using Pd-phosphine
catalysis.[57] In 2020, Saunders and co-workers reported a
fluorine transfer from a perfluorinated Rh-NHC complex 30 a to
organic electrophiles, representatively toluoyl chloride 31 and
Scheme 12. Dehydrofluorination by Au-NHC. acetic anhydride to form a monodefluorinated bimetallic rhoda-
cycle 30 b and acyl fluorides 32. The formation of 30 a involved
nucleophilic attack of a perfluorinated aryl by a strong
nucleophile generated from the deprotonation of Cp*, and this
rendered the C F bond unusually electron-rich. This facilitates
perfluorinated ligand in 30 a to transfer fluorine to organic
electrophiles. The computational studies complement the
unusual electron-rich C F bond present in perfluorinated ligand
units in 30 a (Scheme 15).[58]
3.4. Kumada type cross-coupling reactions
Aryl fluorides are infamous substrates for being non-participant

in cross-coupling reactions. To make them participate, a high
electron-rich metal center, i. e., low-valent metals with electron-
donating ligands, sterically hindered ligands, and strong M F
bond-forming metal is required. Strategically, in 2001, Herr-
mann group used the catalytic combination of [Ni(acac)2]
(acac = acetylacetonate) and the imidazolium salt 1 bearing
Dipp (Dipp = 2’,6’diisopropylpheny) to involve the aryl fluorides
23 to couple with aryl Grignard reagent (strong Mg F) to form
Scheme 13. Dehydrofluorination by catalytic cooperative effect.
3.2. Defluorination in metallacycle
In 2015, Baker and his team demonstrated the facile Csp3 F and
Ni CF bond activation in low-coordinate pseudo-three-coordi-
nate nickelacycle (NHC Ni) 28 a, which leads to novel perfluor- Scheme 14. Defluorination in metallacycle.

Review
biaryls 34 a–l (Scheme 16).[59] In the same line, in 2006, Radius

and co- workers revealed that 1 can catalyze Kumada-type
cross-coupling reactions, i. e., the reaction of perfluorotoluene
with 2.5 equiv. of para-tolyl magnesium bromide, however,
biaryls were isolated in poor yields.[60] Similarly, in 2014, Li and
co-workers too observed cross-coupled products in poor yield,
and it was due to the formation of biphenyls (homocoupling
product of phenylmagnesium bromide).[61,62] In 2012, Deng and
co-workers applied the similar strategy as Hermann, but with
the environmentally benign catalytic system, [Fe-NHC]2,
[(IPr2Me2)Fe(μ2-NDipp)2Fe-(IPr2Me2)] (IPr2Me2: 2,5-diisopropyl-3,4-
dimethylimidazol-1-ylidene; Dipp: 2,6-diisopropylphenyl). Inter-
estingly, 35 is effective in cross-coupling aryl fluorides 23 with
alkyl Grignard reagents in good yields, and this is the first
example of a Fe-catalyzed C F bond functionalization in an
NHC environment (Scheme 17).[63]
Scheme 15. Fluorine transfer defluorination.

3.5. Suzuki-Miyaura type cross-coupling
Subjecting C F bonds for Suzuki-Miyaura cross-coupling will

pave the way to generate biaryl derivatives from the chemically
inert fluoroarenes. In 2005, Robins showed that such coupling is
possible by reacting 6-fluoropurine nucleosides 37 with arylbor-
onic acids. This reaction proceeds with 10 mol% 38 in the
presence of 10 mol% Ni(COD)2 to yield various examples of 6-
arylpurine coupled products 39 a–f (Scheme 18).[64] In the
following year, Radius and his co-workers reported usage of
exemplar precatalyst 1 (2 mol%) for the Suzuki-Miyaura cou-
pling, where perfluorinated arenes couples with arylboronic
acid. Subjecting octafluorotoluene and perfluorobiphenyl to
cross-coupling is the highlight of this methodology
(Scheme 19).[60] Ohashi and co-workers briefly showed the 1
catalyzed Suzuki-Miyaura cross-coupling reactions of octafluor-
otoluene, hexafluorobenzene, and fluorobenzene with 4-meth-
oxyphenyl neopentylglycolato boronate ester (Bneop) to give
Scheme 16. Kumada type cross-coupling by aryl-Grignards.
Scheme 17. Kumada type cross-coupling by alkyl-Grignards. Scheme 18. Suzuki-Miyaura cross-coupling to form 6-arylpurine.

Review
3.6. Hiyama and Negishi type cross-coupling
Radius further scrutinized his complex 1 for other cross-

coupling reactions and observed that this catalyst is very
efficient in Hiyama and not with Negishi type cross-coupling.
Hiyama cross-coupling reactions were realized by reacting
ArSi(OMe)3 and ArSi(OEt)3 with fluoroarene to give biaryls in fair
and good yields. Interestingly, when the additive NMe4F was
used alkoxy transfer from PhSi(OR)3 to the perfluoroarene
occurs to yield ArF-OR 42 via the formation of a C O bond
(Scheme 21). However, Negishi cross-coupling with ZnR2 (R=Me,
Et) gave the expected product with a very low yield. This is due
to the formation of nickel alkyl complexes trans-[Ni-
(iPr2Im)2(alkyl)(ArF)] (alkyl=Me, Et) 43, which do not undergo
controlled reductive elimination even at high temperature
(Scheme 22).[67]
Scheme 19. Suzuki-Miyaura cross-coupling with boronic acids.
3.7. Defluoroborylation
the corresponding biaryls of 87 %, 35 %, and 20 %, The synthesis of arylboronic esters is of great importance in
respectively.[65] However, in 2016 Radius exemplified the organic synthetic chemistry as they are widely used in Suzuki-
versatility of 1 in Suzuki-Miyaura cross-coupling of fluoroarenes
with various aryl boronates. Among various aryl boronates,
ethyleneglycolato (aryl-Beg) and neopentylglycol (aryl-Bneop)
esters were the most efficient. The additive CsF is best for this
coupling reaction (Scheme 20).[66]
Scheme 21. Hiyama cross-coupling reaction.
Scheme 20. Suzuki-Miyaura cross-coupling with boronic esters. Scheme 22. Negishi type cross-coupling reaction.

Review
Miyaura cross-coupling. Utilization of C F bond in fluoroareanes elegantly used Ni0 complex (CAAC)2Ni 46 for catalytic homocou-
for borylation is scarce. Previously, in 2015, Martin and Hosoya pling of aryl fluorides to form biaryls (Scheme 24).[71]
independently reported borylation of monofluoroarenes with a
catalytic amount of Ni0/PCy3.[68,69] Radius studied his precatalyst
1 for defluoroborylation, but it decomposed in the presence of
diboron esters at high temperatures. Alternatively, when the
4. C F bond activation by N-heterocyclic
catalytic amount of [Ni(IMes)2] complex 9 a was used in place of carbene and their isoelectronic
1, C F borylation of fluoroaromatic compounds was successful. analogs-stoichiometric reaction
The borylation of fluoroarenes containing different degrees of
fluorination was achieved in moderate to good yields, even 4.1. Fluoroarenes
diborylation products were observed (Scheme 23).[70]
Electron deficient arenes are likely to undergo nucleophilic
aromatic substitution (SNAr) reaction, a unique class where the
3.8. Reductive homocoupling C F bond activation can be achieved a little easier compara-
tively. NHCs are notable organics that act as spectator ligands
Substituting one σ-donating quaternary carbon atom in place in organometallics and catalysis, In contemporary Kuhn and
of a π-donating N atom in the NHCs forms a new set of unusual Arduengo harnessed the electron-rich carbon center in NHCs to
carbene, cyclic (alkyl)(amino)carbene (CAAC) with the increased activate and functionalize C F bond in pentafluoropyridine and
nucleophilic and electrophilic properties. In 2014, Roesky group C H bonds in acetylene & acetonitrile respectively.[72] The
breakthrough work by Kuhn and co-workers in 1998, describes
the C F activation of pentafluoropyridine 6 by tetraalkylimida-
zol-2-ylidenes 48 & 49 at low temperatures (Scheme 25).[73]
After a decade, the same group reported the C F activation
of hexafluorobenzene using 49 in the presence of boron
trifluoride diethyl etherate to give 1,3-diisopropyl-4,5-dimethyl-
2-(perfluorophenyl)imidazolium tetrafluoroborate 52 a. 2,2’-(per-
fluoro-1,4-phenylene)bis(1,3-diisopropyl-4,5 dimeth-
ylimidazolium)bis(tetrafluoroborate) 53 was formed when 49
and 2 are taken in the ratio of 2 : 1 in BF3 · Et2O solution
(Scheme 26). Likewise, 49 reacts with perfluorobenzonitrile, 1,3-
dicyano-2,4,5,6-tetrafluorobenzene, and 2,4,6-trifluoro-1,3,5-tria-
zin in the presence of BF3·Et2O to give C F functionalized
product 2, 2-(4-cyano-2,3,5,6-tetrafluorophenyl)-1,3-diisopropyl-
4,5-dimethylimidazolium tetrafluoroborate 52 b, 2-(2,4-dicyano-
2,5,6-trifluorophenyl)-1,3-diisopropyl-4,5-dimethylimidazolium
tetrafluoroborate 52 c, and 2-(4,6-difluoro-1,3,5-triazin-2-yl)-1,3-
diisopropyl-4,5- dimethylimidazolium tetrafluoroborate 52 d
respectively (Scheme 27).[74]
In 2015, Bertrand and co-workers used Et2CAACs 54 to
activate para-C F bond in pentafluoropyridine 5 to give 55.
Independently, Et2CAACs and pyridine are redox-active species,
further, they studied their properties by conjugating them
together (Scheme 28).[75] In the following year, Turner reacted
Me2
CAACs 56 with hexafluorobenzene 2 and pentafluoroben-
Scheme 23. Borylation by C F activation.
zene 12 to give double C F activated products 57 a and 58,
which possess two chiral centers and were isolated as a racemic
Scheme 24. C F reductive homocoupling. Scheme 25. C F activation by tetraalkylimidazol-2-ylidenes.

Review
Scheme 29. C F double activation by Me2CAACs.
example where 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-

ylidene (IPr, 59) accommodated two molecules of octafluoroto-
luene 18 at C2 and C4 position to give 60 a via C F bond
activation. This acts as an interesting precursor to prepare
abnormal (aNHC) metal complexes (Scheme 30).[77]
In 2017, Radius and co-workers, inspired by Roesky group[71]
Scheme 26. C F double activation by tetraalkylimidazol-2-ylidenes.
have chosen Me2CAACs 56 to activate C F bond in a series of
fluoroarenes to give Me2CAAC(F)(ArF) products 61 a–d. Addition-
ally, when the excess of Me2CAAC was reacted with C6F6 2 and
C12F10 8, a consecutive C F activation bond was accomplished
to give 57 a and 57 b (Scheme 31). Furthermore, the weak C F
bond in the 61 a–d was easily cleaved heterolytically, thereby
showing its potential as a mild fluoride source or fluoride
transfer reagent (Scheme 32).[78] In 2017, Chaplin and co-work-
ers demonstrated the activation of the C F bond in hexafluor-
obenzene 2 and octafluorotoluene 18 using bioxaline- derived
NHC IBioxMe4 63 in the presence of fluorinated solvents.
Interestingly, 63 with 2 leads to syn-64 b and anti-64 c via
double C F activation, whereas with 18, a single C F activated
product 64 a is noticed. The liberated fluoride ions from
fluoroarenes are responsible for the oxazoline ring-opening
process resulting in zwitterionic imidazoliumolates
(Scheme 33).[79] In 2019, Sen and co-workers observed the C F
activation in 2 when it is reacted with saturated NHC (SIPr) 65.
This reaction was driven by the deprotonation from the
backbone of 65 at C4 position which leads to the formation of
Scheme 27. C F activation with different fluoroarenes.
mesoionic compound 66 a and the release of HF. The
elimination of HF was confirmed by adding one more
equivalent of 65, which forms imidazolium salt 66 b with HF2
as the counter anion (Scheme 34).[80] Later in the same year,
when they treat hexafluorobenzene 2 with two equivalents of
65 in the presence of BF3·Et2O, within 15 minutes they observed
double C F activated dicationic salt compound 67 a with two
Scheme 28. C F activation by Et2CAACs.
mixture. Even when a large excess of hexafluorobenzene was

taken, double C F activated products were only noticed and
this is due to polarisation towards the second C F activation
(Scheme 29).[76] In 2016, Lee and co-workers reported a unique Scheme 30. Unusual C F activation to form aNHC.

Review
Scheme 34. Formation of mesoionic NHC.
ray analysis (Scheme 35).[81] Very recently, Sen group reported

the triple C-F activation by 1,3-bis-(2,6-diisopropylphenyl)-
imidazol-2-ylidene (IPr, 59), where functionalization of all three
carbons in the imidazole 60 b of the 59 by C5F5N 5 and further
extended his work to report the selective C F activation over
the C-H bond in CHF4N 15. Sen group also theoretically
Scheme 31. Mono and double C F activation by Me2CAACs.
calculated the ~G for the triple C F activation and character-
ized the complex by single X-ray spectroscopy (Scheme 36).[82]
4.2. Fluoroalkenes
Unlike, fluoroarenes, fluoroalkenes exhibits unique reactivity as

they are prone to undergo nucleophilic substitution of fluorine
by an addition-elimination process. This is due to the electron-
Scheme 32. Fluorine atom abstraction by Lewis acid. withdrawing inductive effect shown by fluorine, the repulsive
interaction between the fluorine lone pairs of electrons & π-
electrons, and the considerable leaving group ability of
fluorine.[83] In 2016, Baker group harnessed the nucleophilic
nature of the NHC to react with various electrophilic fluoroal-
kenes to give NHC-fluoroalkene compounds. Before this work,
Ogoshi and Arduengo reported the synthesis of such NHC-
Scheme 33. Mono and double C F activation by NHC IBioxMe4.
BF4 molecules as the counter anions. Then 67 a was reduced

with Li leading to the formation of Thiele’s hydrocarbon with
tetrafluorophenylene linker 67 c. Interestingly, the formation of
6 7c is achieved in a single step, when Mg is used as a reducing
agent. Both 67 a and 67 c were characterized by single-crystal X- Scheme 35. Formation of Thiele’s hydrocarbon by C F activation.

Review
Scheme 38. Nucleophilic substitution at Cα polyfluoroalkenyl imidazolium

Scheme 36. C F activation in three carbons of imidazole. salts.
fluoroalkenes but accompanied by poor yields and longer

reaction time.[65,84]
Baker’s group addressed these issues and extended the
scope of the reaction. Additionally, they have compared the
NHC-fluoroalkene compounds with Breslow intermediate which
arises out of NHC and aldehyde. When BF3 · Et2O was treated
with NHC-fluoroalkenes 71, selective abstraction of fluoride ions
takes place to form polyfluoroalkenyl imidazolium salts 72 in
high yields (Scheme 37). With polyfluoroalkenyl imidazolium
salts in hand, they explored the formation of Cα and Cβ
substituted products via C F activation by reacting with
corresponding nucleophiles. For instance, 68 reacts with
nucleophiles 4-(dimethylamino)-pyridine (DMAP) and 1-meth-
ylimidazole to give Cα products 69 a and 69 b respectively
without the release of HF (Scheme 38). Later, when they react
nitrogen-, oxygen- and sulfur-based nucleophiles with 68 a/b,
regio- and chemoselective Cβ substituted products 73 a–f were
observed with the release of fluoride salts (Scheme 39).[85,86]
Scheme 39. Nucleophilic substitution at Cβ polyfluoroalkenyl imidazolium
salts.
5. Organocatalysis
In 2017, Yang and Zhong reported the NHC-catalyzed [4 + 2]

cycloaddition of γ-fluoroenals 75 with isatins 74 to provide
biologically active 3’-spirocyclic oxindoles 77 with excellent
enantioselectivity. Initially, nucleophilic addition of the chiral
NHC 76 with γ-fluoroenals results in conjugated Breslow
intermediate and then transforms to vinyl enolate via C F
cleavage. Eventually, [4 + 2] cycloaddition with isatin leads to
the desired product (Scheme 40).[87]
6. Summary
In this minireview, we attempted to highlight the key aspects of

various methodologies involving NHCs to utilize the inert C F
Scheme 37. C F activation to form polyfluoroalkenyl imidazolium salts. bonds to generate more value-added products. A significant

Review
Conflict of Interest
The authors declare no conflict of interest.
Keywords: cross-coupling · fluorine · homogeneous catalysis ·

N-heterocyclic carbenes · organocatalysis
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Review

C F Bond Activation and Functionalizations Enabled by

ChemCatChem 2022, 14, e202101579 (1 of 15) © 2022 Wiley-VCH GmbH

[a] K. Muthuvel, Dr. T. Gandhi

ChemCatChem 2022, 14, e202101579 (2 of 15) © 2022 Wiley-VCH GmbH

2. C-F activation by metal NHC (stoichiometric

The activation of the C F bond was primarily effected by the

Thirumanavelan Gandhi studied chemistry at Karthick Muthuvel was born in Vikramam,

ChemCatChem 2022, 14, e202101579 (3 of 15) © 2022 Wiley-VCH GmbH

Scheme 4. Dual para C F activation with C1 and C4.

Scheme 3. C2 and C4 activation at varying temperatures.

isolated 3 a and 3 i, the same group treated these complexes

performed to get the insights on its reactions pathway.

ChemCatChem 2022, 14, e202101579 (4 of 15) © 2022 Wiley-VCH GmbH

Scheme 6. Co F formation and C F activation by Co-NHC.

ChemCatChem 2022, 14, e202101579 (5 of 15) © 2022 Wiley-VCH GmbH

to play a pivotal role in promoting the HDF reaction as well as

ChemCatChem 2022, 14, e202101579 (6 of 15) © 2022 Wiley-VCH GmbH

ocyclobutyl complex 28 b in the presence of a Lewis acid

3.3. Fluorine transfer by defluorination

A typical C F activation proceeds via the oxidative addition at

3.4. Kumada type cross-coupling reactions

Aryl fluorides are infamous substrates for being non-participant

Scheme 13. Dehydrofluorination by catalytic cooperative effect.

3.2. Defluorination in metallacycle

ChemCatChem 2022, 14, e202101579 (7 of 15) © 2022 Wiley-VCH GmbH

biaryls 34 a–l (Scheme 16).[59] In the same line, in 2006, Radius

Scheme 15. Fluorine transfer defluorination.

Subjecting C F bonds for Suzuki-Miyaura cross-coupling will

Scheme 16. Kumada type cross-coupling by aryl-Grignards.

ChemCatChem 2022, 14, e202101579 (8 of 15) © 2022 Wiley-VCH GmbH

3.6. Hiyama and Negishi type cross-coupling

Radius further scrutinized his complex 1 for other cross-

Scheme 21. Hiyama cross-coupling reaction.

ChemCatChem 2022, 14, e202101579 (9 of 15) © 2022 Wiley-VCH GmbH

Scheme 24. C F reductive homocoupling. Scheme 25. C F activation by tetraalkylimidazol-2-ylidenes.

ChemCatChem 2022, 14, e202101579 (10 of 15) © 2022 Wiley-VCH GmbH

Scheme 29. C F double activation by Me2CAACs.

example where 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-

Scheme 28. C F activation by Et2CAACs.

mixture. Even when a large excess of hexafluorobenzene was

ChemCatChem 2022, 14, e202101579 (11 of 15) © 2022 Wiley-VCH GmbH

Scheme 34. Formation of mesoionic NHC.

ray analysis (Scheme 35).[81] Very recently, Sen group reported

Unlike, fluoroarenes, fluoroalkenes exhibits unique reactivity as

Scheme 33. Mono and double C F activation by NHC IBioxMe4.

BF4 molecules as the counter anions. Then 67 a was reduced

ChemCatChem 2022, 14, e202101579 (12 of 15) © 2022 Wiley-VCH GmbH

Scheme 38. Nucleophilic substitution at Cα polyfluoroalkenyl imidazolium

fluoroalkenes but accompanied by poor yields and longer

In 2017, Yang and Zhong reported the NHC-catalyzed [4 + 2]

In this minireview, we attempted to highlight the key aspects of

ChemCatChem 2022, 14, e202101579 (13 of 15) © 2022 Wiley-VCH GmbH

The authors declare no conflict of interest.

Keywords: cross-coupling · fluorine · homogeneous catalysis ·

[1] O. Eisenstein, J. Milani, R. N. Perutz, Chem. Rev. 2017, 117, 8710–8753.

ChemCatChem 2022, 14, e202101579 (14 of 15) © 2022 Wiley-VCH GmbH

ChemCatChem 2022, 14, e202101579 (15 of 15) © 2022 Wiley-VCH GmbH

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