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TUTORIAL REVIEW

Cite this: Chem. Soc. Rev., 2020,
49, 1643

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Emerging unconventional organic solvents for
C–H bond and related functionalization reactions
Congjun Yu, a Jesus Sanjose-Orduna,
´
´
Monica H. Perez-Temprano*b
´
´

b

Frederic W. Patureau

*a and

Received 23rd August 2019

Solvent engineering is an increasingly essential topic in the chemical sciences. In this context, some
recently appeared unconventional solvents have shown their large potential in the field of C–H bond

DOI: 10.1039/c8cs00883c

functionalization reactions. This review aims not only at recognizing and classifying a short selection
of these emerging solvents, in particular halogenated ones, but also at providing a medium term

rsc.li/chem-soc-rev

perspective of the possibilities they will offer for synthetic method development.

Key learning points
(1) Much C–H bond functionalization reactivity can be gained by looking beyond conventional organic solvents.
(2) Key transitions states can be decisively controlled by carefully designed solvents.
(3) The field of unconventional solvent mediated C–H bond functionalization is still in its infancy.
(4) So far, interestingly, the majority of these unconventional solvents are (per-)halogenated (but this could evolve in the future).
(5) More unconventional solvent enabled C–H bond functionalization reactivity can be expected in the coming years, as well as new privileged organic solvents.

Introduction
The organic solvents in which chemical processes occur are rarely
a topic of discussion,1 and if so, often only on a very basic level.
In the past few years, however, incredible reaction discoveries
were enabled by new organic solvents, in particular halogenated
ones such as HFIP, trifluoroethanol, trichloroethanol, tetrachloroethylene and others, which were not usually employed in organic
synthetic methods before. Some of these new unconventional
solvents often have an ‘‘extra-ordinary’’ (out of the ordinary)
quality to them: the new reactions don’t or barely operate in
their absence. What makes them so special? How will this
change organic and organometallic synthesis, in particular for
direct C–H bond functionalization coupling reactions? This
tutorial review is focused on those new organic solvent effects
on C–H bond functionalization reactivity. It should be noted
that due to early reviews on one of these leading emerging
solvents: Hexafluoroisopropanol (HFIP),2–4 only the selected
(most recent) insights on that particular solvent will be covered.
Conversely, with HFIP no longer being the only unconventional
a

Institute for Organic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany. E-mail: Frederic.Patureau@rwth-aachen.de
b
¨sos Catalans 16,
Institute of Chemical Research of Catalonia (ICIQ), Avinguda dels Paı
43007 Tarragona, Spain. E-mail: mperez@iciq.es

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organic solvent on the shelf, a more inclusive overview on
this rising topic was increasingly needed. With this tutorial
review, we hope to support the key learning points mentioned
above and thereby encourage further research efforts in these
areas, in particular for applications in innovative (C–H bond
functionalization based) synthetic method development.
Moreover, by choice of the authors, ionic liquids, supercritical
CO2, or water are not covered in this selective tutorial review.
While some of the key learning points certainly apply to these
media as well, and while each of the latter media could justify
a review in its own right, the choice has been made to focus
priory on the emerging, often not yet fully recognized, unconventional organic solvent enabled C–H bond functionalization
reactivities.

Defining ‘‘unconventional organic
solvent’’
For the purpose of this tutorial review focused on direct C–H
bond functionalization, an unconventional (or not yet conventional) solvent may be defined as a seldom utilized organic
solvent with reactivity supporting properties that go beyond
solvents broadly considered as conventional. This expression is
meant to support the discussion and key learning points.

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HFIP and TFE: super polar, super H-bond
donors
Hexafluoroisopropanol (HFIP) is arguably the most popular
oxo-halogenated unconventional solvent at the moment for
C–H bond functionalization reactions, closely followed by trifluoroethanol (TFE).2–4 Therefore, of all the selected unconventional solvents covered in this review, HFIP and TFE already
benefit from (somewhat) deeper mechanistic understanding.
Their main features are a high polarity (for an organic solvent),
combining both a hydrophobic as well as a hydrophilic side, and
a mildly acidic OH group (pKa analogous to that of a phenol).
This is combined with excellent single H-bond donor properties,
a phenomenon enjoying growing consensus in the scientific
community to explain its extra-ordinary reactivity enabling
character.2–4 Interestingly, this is also associated with a very strong
shielding effect at the oxygen atom, easily measured in 17O NMR

Scheme 1

Congjun Yu was born in 1990 in
Shandong, China. He got his BSc
at Shanghai Normal University in
2013. After that, he studied at the
Shanghai Institute of Organic
Chemistry (SIOC), CAS, and
obtained his MSc in 2016 under
the supervision of Prof. Zhang.
Since January 2017, he joined
Prof. Patureau’s group now at
the
Institute
of
Organic
Chemistry of the RWTH Aachen
University, where he is pursuing
Congjun Yu
his PhD degree. He has been
focusing on developing novel strategies to achieve selective crossdehydrogenative coupling (CDC) reactions.

´
´
Jesus Sanjose-Orduna obtained
his BSc and MSc Degrees from
the University of Barcelona in
2014 and 2015, respectively. He
then joined the research group of
´
´
Monica H. Perez-Temprano at the
Institute of Chemical Research of
Catalonia (ICIQ), where he is
pursuing his PhD degree. During
his thesis, he has investigated the
intricacies of Cp*Co-catalyzed
C–H functionalization reactions,
not only to provide a comprehen´
´
Jesus Sanjose-Orduna
sive mechanistic picture of these
transformations but also to improve their efficiency based on
fundamental knowledge.

Frederic W. Patureau was born in
1982 in France. He got his BSc
(2003) and MSc (2005) at the
University of Paris-Sud Orsay.
He obtained his PhD degree in
the group of Prof. Reek at the
University of Amsterdam (UvA) in
2009. He was then a Humboldt
postdoctoral fellow in the group
of Prof. Glorius at the University
¨
¨
of Munster (WWU Munster). He
started his independent career as
a Junior-Professor at the TU
Frederic W. Patureau
Kaiserslautern University (2011–
2018). Since 2018, he is Professor at the Institute of Organic
Chemistry of the RWTH Aachen University. His research is focused
on investigating novel strategies for pragmatic cross-couplings and
other metal catalyzed reactions.

´
´
Monica
H.
Perez-Temprano
received her BSc (2005) and MSc
(2006) from the University of
Valladolid. She carried out her
PhD thesis (2011) under the
supervision of Prof. Espinet and
Prof. Casares at the University of
Valladolid. In 2012, she moved
to the University of Michigan to
work under the supervision of
Prof. Sanford. In 2015, she
began her independent career as
´
´
Monica H. Perez-Temprano Group Leader at the Institute of
Chemical Research of Catalonia
(ICIQ). Her research interests are focused on the rational design of
efficient and sustainable approaches for the synthesis of organic
molecules using fundamental organometallic chemistry.

1644 | Chem. Soc. Rev., 2020, 49, 1643--1652

17

O NMR of some conventional and unconventional solvents.5

spectroscopy, in comparison to the non-fluorinated analogues
(Scheme 1).5 All these properties ensure highly specific solvation
of transitions states, typically decreasing activation energies.
As mentioned above, different reviews have covered the
effect of perfluorinated alcohols on organic transformations.

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Tutorial Review

Therefore, this section will focus on a very selected number of
recent examples in the context of C–H functionalization reactions,
one of the cornerstones of modern synthetic chemistry.
In 2018, some of us revealed the beneficial effect of HFIP
in Cp*Co(III)-catalysed C–H functionalization reactions. Initially,
the authors observed that the addition of HFIP as additive
accelerated dramatically the C–H activation of N-(2-pyrimidylindole) by [Cp*Co(MeCN)3](BF4)2, from 24 h to 1 h (Scheme 2a).6
Driven by this extraordinary boosting effect, they next investigated
the global influence of HFIP in catalysis. They selected as benchmark transformations the reaction between N-(2-pyrimidylindole)
and diphenylacetylene, as coupling partner. Using these starting
materials, several literature precedents have described chemodivergent reactivity depending on the reaction conditions: hydroarylation vs. oxidative annulation (Scheme 2b).7,8 These reactivity
patterns represented an ideal test case for investigating the role
of HFIP since, a priori, it could play opposite effects. In both
cases, the authors discovered that the addition of HFIP enables
the use of milder conditions for obtaining the corresponding
product in almost quantitative yields, but presumably due to
different reasons. In the formation of the annulated product,

it seems that its high polarity is crucial for solubilizing the
salts present in the reaction mixture. On the other hand, in
the hydroarylation reaction, its role as proton source probably
facilitates the protodemetalation step of the catalytic cycle.
Over the past year, different literature precedents have shown
solvent-controlled C–H functionalization processes when using
HFIP and/or TFE. Miura and co-workers have demonstrated the
selective C–H alkenylation and alkylation of 2-pyridones with
acrylates, depending on the employed solvent (Scheme 3a).7
Using DMF, the authors observed the expected formation of the
C6-alkenylated product. In sharp contrast, HFIP promoted the
alkylation processes due to its capability to act as a proton source.
Loh and co-workers have reported selective Cp*Co-catalysed C–H
aminomethylation or hydroxymethylation of heteroarenes using
1,2-oxadetidine as coupling partner (Scheme 3b).8 The formation
of the aminomethylated product was favoured when using PhCF3
as solvent, while 2,2,2-trifluoroethanol (TFE) was the best choice for
developing the hydromethylation protocol. Interestingly, Rovis et al.
have reported an unexpected regiodivergent Cp*Ir(III)-catalysed
alkene diamination protocol (Scheme 3c).9 The authors observed
the formation of five- or six- membered ring lactams by the
employment of HFIP and TFE, respectively. They hypothesised that
the higher acidity of HFIP compared to TFE is the responsible of
the regioselectivity.
Apart from the mentioned examples, other research groups
have also shown during the last year the extraordinary capability
of TFE or HFIP to promote different C–H functionalization
processes using (Cp*)-based Group 9 (Co, Rh or Ir) precatalysts. Chang and co-workers have developed a synthetic
protocol for accessing g-lactams via C–H amidation, through a

Scheme 2 Beneficial effect of HFIP in Cp*Co-catalysed C–H functionalization reactions using alkynes as coupling partners.

Scheme 3 Chemoselective Cp*MIII-catalysed C–H functionalization
reactions using TFE and/or HFIP.

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Scheme 4 Synthesis of g-lactams via Cp*IrIII-catalysed C–H functionalization reactions.

Ir-carbonylnitrenoid intermediate, using a pre-catalyst supported by bidentate ligands (Scheme 4).10 In this particular
case, 2,2,2-trifluoroethanol exhibited a higher performance
than HFIP. This methodology featured a wide substrate scope,
good group tolerance and scalability.
These protic perfluorinated solvents have also been exploited
to develop novel stereoselective transformations (Scheme 5).
In this regard, Cramer et al. have disclosed the highly efficiency
of TFE in the enantioselective synthesis of cyclopentenylamines,
using a chiral CpxRhI(cod) pre-catalyst, in terms of yield and
enantioinduction (Scheme 5a).11 The authors proposed that the
strong ionizing ability of the perfluorinated alcohol favours
the generation of the active rhodium(III) species involved in the
C–H activation step. This is supported by the low conversions
observed in less polar solvents such as dichloromethane or
toluene. Following the same strategy, Cramer has recently developed the enantioselective synthesis of dihydroisoquinolones with
chiral cyclopentadienyl cobalt complexes (Scheme 5b).12 In this
case, the employment of HFIP as solvent improved the reactivity,
when compared to TFE.
Other research groups have taken advantage of HFIP to
engineer different C–C and C–heteroatom bond-forming reactions using other transition metals pre-catalysts, or even in
their absence. For example, Larrosa has described a Pd/Ag
protocol for the a-arylation of benzo[b]thiophenes.13 In the

Scheme 5

Stereoselective C–H functionalization reactions.

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Chem Soc Rev
context of early transition metals, Donohoe has exploited HFIP
unique properties, such as its high polarity and hydrogen
bonding capability, to promote the stereoselective synthesis
of oxygen-containing heterocycles by titanium complexes, using
allyl or benzyl alcohols as alkylating reagent (Scheme 6a).14
Preliminary mechanistic studies showed the formation of a
titanium species, containing two hexafluoroisopropoxy units,
which presumably are involved in the cyclization reaction.
Ritter and co-workers have reported a Fe-catalysed aromatic
C–H amination, using [MsO–NH3](OTf) as nitrogen source,
for the synthesis of unprotected anilines (Scheme 6b).15 The
versatility of this methodology is attributed to the use of HFIP.
The formation of a HFIP–triflate hydrogen bond, supported
experimentally, enhances the reactivity of [MsO–NH3](OTf) as
oxidant. Moreover, the presence of HFIP increases the electrophilicity of putative cationic radical species, making the addition
of the nitrogen source facile to more electron-poor arenes. The
same group has developed a metal-free late-stage C–O formation
protocol, using bis(methanesulfonyl)peroxide as terminal oxidant
and hexafluoroisopropanol as solvent (Scheme 6c).16 This example
is particularly remarkable since, a priori, O-centred radicals
generated from the peroxide could participate in the hydrogenatom abstraction from HFIP, hindering the desired reactivity.
HFIP has also been applied as solvent in the development of
photocatalytic C–H functionalization processes. In this context,
Chen and He have shown its extraordinary effect, compared to
CH2Cl2 or even TFE, in the remote Csp3–H heteroarylation of free
aliphatic alcohols using hypervalent iodine as oxidant under
irradiation (Scheme 7a).17
Leonori has described the regioselective amination of simple
arenes using alkyl amines as coupling partners (Scheme 7b).18

Scheme 6
by HFIP.

C–C and C–heteroatom bond-forming reactions promoted

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Table 1

Carboxylate-directed C–H allylation with vinyl acetate

Yield (%)

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Entry

Scheme 7

Photoredox C–H functionalizations.

Base (equiv.)

Solvent

a

b

1
2
3
4
5
6
7
8

K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3

NMP
1,4-Dioxane
toluene
EtOH
HFIP
AcOH
TFE
Trichloroethanol

18
5
Trace
28
15
—
60
60

3
—
—
Trace
13
—
5
Trace

Table 2

Scheme 8

meta-Selective C–H bond functionalizations by Maiti.19–22

The authors explored different reaction conditions, being HFIP
selected as the solvent of choice when activating weakly electronrich arenes. This solvent was also used in a parallel screening
approach for the late-stage functionalization of complex molecules relevant for drug discovery. Recently, HFIP was also utilized
in some other high profile synthetic methods, such as meta- and
para-selective C–H bond functionalizations by Sunoj and Maiti
(Scheme 8).19–22 Clearly, HFIP will remain a top unconventional
organic solvent on the shelf of synthetic method developers in
the years to come.

Trichloroethanol: the new HFIP? or a
completely uncharted territory?
In the wake of the unconventional reactivity enabled by HFIP,
Trichloroethanol has very recently appeared as a unique solvent
for organometallic catalysis and C–H bond functionalization
coupling reactions. This effect seems very different from the
previous paragraph on HFIP and trifluoroethanol, as trichloroethanol seems to outperform the former solvents in those new
synthetic methods. This could have something to do with intra
and inter-molecular H-bonding network differences, completely altering the stabilization of the various key transitions
states. These were mainly explored by the Gooßen group.23–25
They recently developed a series of carboxylate-directed C–H
allylations with vinyl acetates (Table 1), allyl amines (Table 2),
allyl alcohols or ethers (Table 3). In their condition optimizations,
trichloroethanol was always found to be the best solvent for the
reactions, especially compared with HFIP and TFE. Moreover, in
a very different transformation, Bonne and Rodriguez26 reported

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(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)

Carboxylate-directed C–H allylation with allyl amine

Entry

Additive (mol%)

Solvent

Yield (%)

1
2
3
4
5
6
7
8

—
—
—
—
—
—
—
CF3CO2H (30)

Toluene
Dioxane
MeOH
tert-Amyl alcohol
HFIP
TFE
Trichloroethanol
Trichloroethanol

Trace
Trace
8
Trace
47
30
52
80

Table 3

Carboxylate-directed C–H allylation with allyl alcohol

Yield (%)
Entry

Temp. (1C)

Solvent

a (E/Z)

b

1
2
3
4
5
6
7

60
60
60
60
60
60
50

Toluene
CH3CN
tert-Amyl alcohol
HFIP
TFE
Trichloroethanol
Trichloroethanol

13 (2.5 : 1)
8 (2 : 1)
16 (1.8 : 1)
27 (2 : 1)
68 (1.7 : 1)
80 (2 : 1)
89 (2 : 1)

6
3
—
—
—
—
—

an organocatalyzed enantioselective synthesis of aza-sevenmembered rings in which trichloroethanol performed as an
extra-ordinary solvent to achieve both high diastereoselectivity
and enantioselectivity (Table 4).
It can be reasonably assumed that the intra and inter-molecular
H-bonding networks greatly differ from trifluoroethanol, to HFIP,
to trichloroethanol, thus greatly affecting stabilizing interactions
with key transitions states. This is again well illustrated in
Scheme 1, wherein the shielding pattern of the oxygen atom

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Table 4

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Reaction developed by Bonne and Rodriguez groups

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Entry

Solvent

Time

Yield (%)

dr

ee

1
2
3
4
5
7

Toluene
DCM
CH3CN
EtOH
Trichloroethanol
Same (at À7 1C)

15 h
15 h
15 h
15 h
24 h
3 days

0
0
0
92
91
94

—
—
—
3:1
5:1
7:1

—
—
—
97
99
99

greatly differs from CF3 to CCl3, probably betraying significant
H-bonding differences. In other words, there seem to exist a great
margin of transition state and reactivity tuning, simply by structural design of the oxo-halogenated solvent. It is therefore reasonable to expect that HFIP and trichloroethanol mediated reactivity
will continue flourishing in the coming years. Moreover, the
discovery of other unconventional oxo-halogenated solvents can
be expected as well.

Tetrachloroethylene: p-acid effect,
‘‘Knochel Trick,’’ and enantioselective
supramolecular catalysis
Just as Trichloroethanol in the previous section, tetrachloroethylene (C2Cl4) is also not a very common solvent in synthetic
organic chemistry, not to mention in C–H bond functionalization reactions. It is nonetheless a cheap chemical commodity,
used notably for dry-cleaning, for industrial degreasing, and as
a synthetic precursor.27 However, as a perchlorinated solvent,
its solubilizing capacity is sometimes only moderate. It is
therefore often utilized in combination with other co-solvents.
Herein, we shall discuss only the most recent examples, in
particular those which are metal catalysed, and in which C2Cl4
plays an essential role. While the examples that we selected
are relatively few, and mechanistically not sufficiently investigated, the decisive role of C2Cl4 in those transformation may
have a profound impact on the field of synthetic method
development.
One the best leads to understand the effect of C2Cl4 is
probably the ‘‘Knochel trick.’’ In a pioneering and inspiring
1998 work, Knochel reported a Ni-catalysed C(sp3)–C(sp3) bond
forming cross coupling reaction.28 The overall reaction
(Scheme 9) runs under basic/reductive organo-zinc conditions.
The authors found that catalytic amounts of 3-trifluoromethylstyrene had a pronounced acceleration effect on the rate of the
reaction. Analogously structured trifuoromethyl-ketones were
also investigated, however none was found as efficient as the
3-trifluoromethylstyrene catalyst, considerably increasing the
efficiency of the reaction. In a second contribution in 1999,
Knochel clearly formulated the hypothesis along which the
electron-poor olefin would facilitate the rate limiting reductive

1648 | Chem. Soc. Rev., 2020, 49, 1643--1652

Scheme 9

The ‘‘Knochel trick,’’ 1998.

elimination step through transient p-acid coordination to the
active metal centre.29
The ‘‘Knochel trick’’ clearly suggests that when faced with a
rate limiting reductive elimination that will not yield, one can
simply use a p-acidic olefin additive or co-solvent. It has been
twenty years since Knochel formulated the concept, yet, in spite
of numerous cases wherein reductive elimination controls
and limits the rate and scope of the coupling reaction, many
of which concern C–H bond functionalization reactions, the
‘‘Knochel trick’’ has been only seldom utilized.30 Of course,
styrenes are rarely chemically inert additives. For instance, they
may insert in all sorts of metal–carbon bonds, they may trigger
undesired redox processes, they may even polymerize. What
this concept arguably needs is a somewhat cheaper and more
stable olefinic p-acid, perhaps, for example, tetrachloroethylene
(C2Cl4). Crystallographic proof of the ability of C2Cl4 to really
bind to transition metal catalysts is very scarce, although this
may be solely due to limited general interest in such organometallic motives. In 2014, Figueroa and co-authors reported a
beautiful crystal structure of a TCE–Pd0 complex (Scheme 10),
thereby demonstrating the affinity of TCE for low oxidation
state metal centres.31 Therein, the characteristic Pd–CCl2 distance:
2.042(3) Å, and the pronounced loss of planarity of the C2Cl4 ligand
suggest a relatively strong Z2 coordination mode. This

Scheme 10 Figueroa’s X-rayed TCE–Pd0 complex (2014), and general
concept (beneath).

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crystallographic data therefore confirms the validity of applying
‘‘Knochel’s trick’’ with C2Cl4 as additive/co-solvent.
Some of us have started doing so in 2013, in the Ru-catalysed
dehydrogenative C1–N dimerization of carbazoles,32 a system
that was revisited with a mechanistic investigation, in collaboration with the Maseras group, in 2018 (Scheme 11).33 Therein, C2Cl4
was found to be a superior co-solvent (chlorobenzene is utilized as
an additional co-solvent in order to improve solubility).
Moreover, the advanced DFT calculations of Maseras (as well
as our kinetic investigations) leave no doubt as to the rate
limiting character of the C1–N (cooperative polynuclear)
reductive elimination step. It is therefore not surprising that
C2Cl4 would be found a superior co-solvent for this process, by
analogy to Knochel’s system. Some of us were moreover able to
transpose this reactivity to a true hetero-coupling: the Ruthenium
catalysed cross dehydrogenative ortho N-carbazolation of diarylamines, in 2014.34 This remains at the moment the only direct
access to this motif in a single step (Scheme 12).
Interestingly, it should be mentioned that C2Cl4 was also
utilized as a privileged solvent in metal free (enantioselective)
coupling reactions. Recently for example, Papai and Takemoto
reported an asymmetric hetero-Michael addition of a,b-unsaturated
carboxylic acids under organo-catalytic conditions (N–H bond
functionalization, Scheme 13).35 Some of the best results in terms
of conversion and especially enantiomeric excess were obtained in
C2Cl4 as a solvent. The highly halogenated character of the solvent
possibly imposes a good compromise between dissolving capacity
and maximized H-bonding strength/efficiency between substrates
and supramolecular chiral catalyst – thus a very different mode of

Tutorial Review

Scheme 13 Asymmetric hetero-Michael addition of a,b-unsaturated
carboxylic acids under organo-catalytic conditions, 2018.

action than that of for example HFIP. In general, we suspect also
other beneficial effects of the C2Cl4 solvent, such as solvating/
stabilizing p-complexes with electron-rich substrates.
Overall, it can be said that the p-acid induced reductive
elimination strategy is a promising concept. We anticipate that
method developers with reductive elimination issues will
increasingly incorporate the ‘‘Knochel trick’’ in their optimization,
in particular with cheap co-solvents such as C2Cl4 or analogous.
This is an occurrence which we expect to increase in the field of
C–H bond functionalization, as the elementary steps before
reductive elimination (i.e. C–H bond activation) become increasingly facile with improved catalyst and ligands designs.

Beyond halides: the case of cumene:
oxidant activator, radical reservoir, and
‘‘Mukaiyama Trick’’ for C–H bond
functionalizations and cross
dehydrogenative couplings

Scheme 11 Ru catalysed cross dehydrogenative carbazolation of carbazoles (homo-coupling) under TCE, 2013–2018.

Scheme 12 Ru catalyzed cross dehydrogenative carbazolation of diarylamines (hetero-coupling) under TCE, 2014.

This journal is © The Royal Society of Chemistry 2020

As a last example, it is also possible to consider halide-free
unconventional solvents with reactivity enabling properties
that go beyond those of conventional organic solvents in C–H
bond functionalization/cross dehydrogenative coupling reactions.
Until recently, the use of cumene as a solvent has remained
anecdotic. Nevertheless, this cheap commodity solvent, also the
main component in Hock’s phenol synthesis process,36 has
allowed significant progress in some redox active chemical
transformations. Its main feature and difference from classical
aromatic solvents is its pronounced radical character. Indeed,
its tertiary position accommodates a rather persistent carbon
centred radical. The consequence of this specific feature is well
illustrated when comparing cumene to some classical solvents in
the direct oxidation of diarylmethane to benzophenones with O2,
under additive and catalyst free conditions (Scheme 14). Recently,
Ren and Wang found such a reaction to be feasible in cyclohexane,
nevertheless requiring 5 bars of dioxygen gas in order to
achieve high yields in this additive free process (Method A).37

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Scheme 14 Oxidation of diarylmethanes with O2 under additive free
conditions: the importance of the solvent, 2017–2019.

Moreover, interestingly, they found that methanol, acetonitrile, DMF,
and even toluene do not accommodate this reaction. Cumene
however, has been demonstrated by some of us to accommodate
this very same ultra-simple reaction at only 1 bar of dioxygen gas,
under otherwise similar reaction conditions (Method B).38
This effect is what Maes39 recently described as the
‘‘Mukaiyama trick.’’40 Its principle, which Mukaiyama did not
exemplify on cumene but rather on other components, relies on
the ability of cumene to readily activate dioxygen towards the
cumyl radical and other activated species such as the cumyl
hydroperoxide. The so called ‘‘Mukaiyama trick’’ is the concept
of intercepting this radical oxidation process in order to trigger
the oxidation of another species, such as the diarylamethane
substrate (Scheme 15), which would otherwise require harsher
and/or catalytic reaction conditions. Thus, the cumene solvent
is an organic activator of dioxygen, analogously to, for example,
Cupper salts/catalysts. This of course may come to the cost of
potential by-products (for example hydroxylated or dehydrogenated cumyl species), although not necessarily if the cumyl
radical only serves as radical chain propagator. This is what one
could call the ‘‘Radical Reservoir effect.’’
The first clear radical involvement of the cumene solvent, in a
cross dehydrogenative reaction in which it is not also the target

Chem Soc Rev
substrate, may be the additive free phenol phenothiazine coupling
reaction (2015, Scheme 15).41 In that reaction, the phenothiazine
substrate intercepts the oxidized cumyl intermediates to form a
persistent, EPR characterizable42 N-centred radical species, which
then triggers the C–N bond formation with phenols. Thus, the
cumene solvent allowed the first O2 mediated, additive and catalyst
free, intermolecular cross dehydrogenative amination reaction.
Cumene has therefore a reactivity enabling character,
especially under mildly oxidative conditions. A year later, in
2016, Zhou and Cai reported another cross dehydrogenative
amination reaction with cumene as solvent, together with a
copper salt (Scheme 16).43
In 2017, Bao reported a Palladium nanoparticle catalysed
cross dehydrogenative coupling of aldehydes with aryl pyrazoles,
wherein the pyrazole unit serves as coordinative directing
group (Scheme 17).44 Interestingly, the oxidizing driving force of
that reaction is an organic peroxide, with cumene as a solvent.
Unfortunately, this interesting contribution is not extensive on the
role of the solvent. However, a radical chain propagator role may
be suggested on the basis of comparison with other systems
discussed in the present review (i.e. Scheme 14).
Also in 2017, a particularly interesting case of Rh(II) catalysed
carbene insertion coupling reaction reported by Lu and Wang,45
demonstrated a clear superiority of cumene over any other tested
solvent (Table 5). This might suggest the involvement of radical
chains in that reaction, possibly stimulated by the cumene
solvent’s radical reservoir effect.
In 2018, some of us also reported a Copper catalysed
dehydrogenative aminomethylation of phenols, with a peroxide
as the oxidant and cumene as the solvent.46 There too, the
radical reservoir role of the cumene solvent might explain its
clear superiority compared to all other tested solvents (Scheme 18).
It was notably verified that the C–H benzylic position of the solvent
is important. Indeed, cumene (and toluene), were found to be
considerably superior solvents in this reaction compared to
benzene, or tBu-benzene. It should be noted that replacing cumene
with cumene-D12 did not have a measurable impact on the initial
rate of the reaction, making it difficult to obtain any experimental
kinetic evidence for the radical role of cumene. TEMPO, a classical
radical scavenger, does suppress the reaction. Moreover, the fact

Scheme 16

Scheme 15 The cumene/O2 mediated oxidative phenothiazination of
phenols, 2015.

1650 | Chem. Soc. Rev., 2020, 49, 1643--1652

Zhou and Cai’s reaction with cumene, 2016.

Scheme 17

Bao’s reaction with cumene, 2017.

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Table 5

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Condition optimization of Lu and Wang’s reaction with cumene

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Entry

Catalyst

Temp. (1C)

Time (h)

Solvent

Yield (%)

1
2
3
4
5
6
7
8
9
10
11
12

Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4

80
80
80
80
80
80
80
80
80
80
80
80

24
24
24
24
24
24
24
24
24
24
24
24

DCE
CHCl3
MeCN
1,4-Dioxane
DMF
Cyclohexane
Benzene
Toluene
Xylene
Chlorobenzene
Nitrobenzene
Cumene

60
38
24
41
NR
28
56
58
65
35
25
87

(‘‘Knochel Trick’’), among other properties. It is an excellent
co-solvent in systems in which a reductive elimination step
would be rate determining. HFIP is a very polar and excellent
H-bond donor. It is well suited to lower the energies of certain
polar transition states, or to increase chemo and/or enantio
selectivity by tuning the activation energy differences of various
mechanistic pathways. Its range of application is therefore
considerable, and is likely to increase in the coming years.
Trichloroethanol, a structural similar and cheaper solvent,
seems to possess completely different properties. Thus, the
discipline of emerging unconventional organic solvent enabled
C–H functionalization reactivity has started to flourish in the
past few months. We expect this field to considerably expand
in the coming years, in terms of number and versatility of
applications, in terms of number and design of unconventional
solvents on the shelf, and especially in terms of understanding
of their modes of actions, which remains largely insufficient at
this point. These are exciting times ahead!

Conflicts of interest
There are no conflicts to declare.

Acknowledgements
Scheme 18

Cu catalysed Aminomethylation of phenols in cumene, 2018.

that tBu-benzene is a significantly less competent solvent than
cumene leaves little doubt as to its probable radical role in this
cross dehydrogenative coupling reaction.
In summary, cumene seems to be a particularly well suited
solvent for oxidative transformations, or reactions involving
radical chain processes, or both. Its C-centred radical persistency
seems to be a key feature of this reactivity enabling character.
cumene being a very cheap solvent, its use in novel oxidative and/
or radical synthetic method development is expected to radically
increase in the coming years, in particular in aerobic and/or
peroxide containing systems.

Conclusions
In conclusion, we have presented a short selection of emerging solvents in the field of synthetic method development,
in particular for C–H bond functionalization reactions.47 Our
non-exhaustive short-list includes: HFIP, trifluoroethanol,
trichloroethanol, C2Cl4, and one emerging non-halogenated
unconventional solvent: cumene. For several of these solvents,
an understanding of some of the mode(s) of action is starting to
emerge. Cumene is a radical oxidant activator, a semi persistent
radical reservoir, and a ‘‘Mukaiyama Trick’’ reducer. Cumene is
therefore an excellent choice in systems in which oxidation or
redox processes are the limiting factor. Tetrachloroethylene is
a cheap and stable p-acid, a reductive elimination enabler

This journal is © The Royal Society of Chemistry 2020

F. W. P. acknowledges ERC project 716136: 2O2ACTIVATION,
and DFG project PA 2395/2-1 for financial support on this and
related topics. M. H. P.-T. thanks CERCA Programme/Generalitat de Catalunya and the Spanish Ministry of Economy, Industry and Competitiveness (MINECO: CTQ2016-79942-P, AIE/
FEDER, EU) for the financial support. COST action CA15106
(CHAOS – C–H Activation in Organic Synthesis) is also
acknowledged.

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