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Electrophilic aromatic substitution in eutectic-type

Cite this: DOI: 10.1039/d4su00051j
mixtures: from an old concept to new sustainable
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horizons
Tatiana Martı́,†a Xavier Marset, †*a Celia Guillem,b Diego J. Ramón a

and Gabriela Guillena *a

The Friedel–Crafts reaction is present in many fields of chemistry, being especially relevant in industrial
applications, where it is one of the key methodologies to transform raw materials into functionalized
aromatic products. During the last few years, the industry has been compelled to modify the conditions
applied in its processes owing to the demand for more environmentally conscious and safe production
techniques. In this review, some alternatives to conventional solvents, such as the use of deep eutectic
Received 30th January 2024
Accepted 20th March 2024
solvents (DESs) as new reaction media with compatible catalysts, commonly used in Friedel–Crafts
reactions are reported. These new conditions represent a major step towards sustainability in
DOI: 10.1039/d4su00051j
comparison to traditional methods, which employ stoichiometric amounts of Lewis acids and organic
rsc.li/rscsus volatile solvents as reaction media.

Sustainability spotlight
Electrophilic aromatic substitution is one of the most relevant organic transformations in the chemical industry that generally take place at the initial steps of
any synthetic route. However, traditional methods to perform these reactions involve the use of stoichiometric amounts of strong acids or/and transitions
metals, as well as dangerous petrol-derived volatile organic solvents as reaction media. In addition, an aqueous work-up is needed to neutralize the mixture,
generating more by-products and contaminated water. This review covers the use of novel eutectic-type mixtures, which greatly reduce the environmental impact
of these procedures (goal 12, sustainable consumption and production) by employing bio-renewable components (goal 13, climate action) and recyclable
catalytic systems. The generated waste is thus reduced, and water contamination minimized (goal 14, life below water). Also, the future challenges of this process
are highlighted.

These protocols rely on the use of volatile organic solvents

Introduction (VOCs) in combination with strong Lewis or Brønsted acids,
While undertaking any organic chemistry course, one of the requiring an extra step of neutralization once the reaction is
rst reactions that students learn is electrophilic aromatic completed. Thus, the number of steps and, therefore, reagents
substitution. This transformation is one of the oldest C–C bond- are increased, generating salts as by-products that should be
forming reactions, which dates back to 1877,1 and is concep- treated as waste, thus leading to unacceptable values of the E-
tually simple enough to start understanding organic chemistry.2 factor of the product.5 Therefore, modern approaches should
In a nutshell, SE(Ar), which stands for substitution of electro- improve the E-factor of the processes by designing procedures
philic arenium, is a bi-molecular reaction in which an aromatic that generate less waste.
ring reacts with an electrophile via a Wheland intermediate to Recently, some efforts have been made to improve this
generate a new C–C bond aer proton elimination (Scheme 1).3 aspect. In this sense, the use of ionic liquids (ILs) was proposed
Although this reaction has been known for almost 150 years as an alternative to VOCs as reaction media.6 Over the years, ILs
and has found many applications in industrial processes, new have been found to offer some interesting properties, but they
advancements are still being proposed.4 The classical protocols,
using stoichiometric amounts of strong acids and halogenated
solvents, are far away from the current sustainability standards.

a
Departamento de Quı́mica Orgánica, Instituto de Sı́ntesis Orgánica (ISO), Facultad de
Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain. E-mail: xavier.
marset@ua.es; gabriela.guillena@ua.es
b
Kongsberg Discovery Spain, Partida Atalayes 20, Villajoyosa, 03570 Alicante, Spain
† These authors contributed equally to this work. Scheme 1 General scheme of a SE(Ar) reaction.

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are now excluded as a green alternative to VOC solvents as they

tend to be toxic,7,8 and their synthesis generates loads of waste
and uses non-renewable feedstocks. In contrast, deep eutectic
solvents (DESs) were proposed as alternative sustainable solvent
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systems, which maintain most of the advantages of ILs while Scheme 2 First Friedel–Crafts alkylation yielding eutectic mixtures.
greatly improving their sustainability aspects and decreasing
their manufacturing costs.9 Although it was not until the
beginning of this decade that deep eutectic solvents became
and benzene in the presence of aluminium chloride provided
popular in the scientic community as organic reaction media,
a mixture of anthracene and diphenylmethane (Scheme 2).19
the formation of eutectic mixtures has been known for decades.
When this condensation was extended to other benzene deriv-
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DESs are mixtures of two or more components with enthalpic-

atives, it was found that o-xylylene dibromide and toluene
driven negative deviation from thermodynamic ideality.10
reacted to afford a mixture of several compounds. The reaction
Although a myriad of mixtures have been described over the last
began with the formation of hydrobromic acid and 9,10-dihy-
decade11 and their toxicological properties must be individually
droanthracene, which aer the loss of 2 protons led to 3,40 -
addressed,12 in general these mixtures are formed from readily
dimethyldiphenylmethane as well as 2,6- and 2,7-dimethylan-
available and/or (bio)renewable components. Their preparation
thracenes. This reaction proceeded without the need of
typically involves only the mixing of components with slight
solvents, but the authors observed the formation of an eutectic
heating or grinding, without using any additional solvents, with
mixture coming from the mixture of the generated products,
the E-factor being zero and the atom economy 100%.
which was suggested to be one of the driving forces of the
There are ve types of DES described in the literature,13 with
reaction.
types I, II and IV containing metal halides in their structure.
These metallic salts can catalyse certain reactions while being
part of a recyclable solvent system. On the other hand, type III Synthesis of bis(indolyl)methanes
and V DESs are formed by mixtures of organic HBD (hydrogen
More recently, eutectic-type mixtures, and more specically
bond donor group) and HBA (hydrogen bond acceptor group),
DESs, have been proposed as reaction media in which Friedel–
containing salts in their structure (type III) or only non-ionic
Cras alkylations can be performed. One of the most studied
compounds (type V). Over the last years, DESs have found
examples in this sense is the synthesis of bis(indolyl)methane
many applications in organic synthesis,14 being used as inno-
through an electrophilic substitution reaction of electron-rich
cent reaction media in transition-metal catalysed processes,15 or
indole derivatives with several aldehydes.
as catalysts/promoters of certain reactions,16 as well as in
In 2012, an interesting variety of aromatic, heterocyclic and
organocatalysis.17 However, even if a number of reports of
aliphatic aldehydes, as well as simple ketones, were tested using
increasingly complex transformation are being reported in
0.1 mL of DES choline chloride and tin chloride mixture in a 1 :
these solvents, traditional reactivities are also explored in DESs.
2 ratio at room temperature in the presence of 0.3 mL of poly-
Although the nature of some DES, specially acidic ones,18 would
ethylene glycol (PEG) (Scheme 3a).20 Thus, the DES was used as
apparently be ideal to perform SEAr transformations, their
a catalyst and co-solvent, with PEG being a co-solvent of the
implementation in this type of processes has been scarcely
process. This method offers reaction yields similar to the ones
explored and is mainly applied to highly activated aromatic
reported with MeCN employing Zr-based catalysts21 or molec-
substrates. In this review, we aim to highlight the possibilities
ular iodine,22 among others, with the advantage of being
offered by these green and sustainable media to perform this
a recyclable catalytic system. Regarding the DES, it contains
transformation and also to show the limitations encountered
a metal halide with Lewis acidity character fullling a double
during their application.
role, as it acts as a component of the deep eutectic mixture but
also as a catalyst for the reaction. Therefore, the corresponding
Friedel–Crafts alkylation bis(indolyl)methane products were obtained in good to excel-
lent yields. Furthermore, the scope of the reaction was extended
The direct alkylation of aromatic compounds is a straightfor- to many commercial indole derivatives, getting the desired
ward way to produce substituted aromatic molecules which are products in excellent yields.
the starting materials not only of pharmaceuticals and mate-
rials but also of surfactant components.

Early examples of Friedel–Cras alkylation

Although the possible application of DES as media to several
organic reactions was demonstrated in the rst decade of the
20th century, there is an early report of a Friedel–Cras alkyl-
ation process where the formation of eutectic mixtures is shown
to be crucial for the success of the process. This example dates Scheme 3 Condensation of aldehydes and indoles using DES type I (a)
back to 1960 when the reaction between o-xylylene dibromide and type III (b).

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Scheme 4 Friedel–Crafts alkylation of indoles in choline chloride :

urea (1 : 2). Scheme 5 Alkylation of benzene using 1-decene in GaCl3-based
liquid coordination complexes.
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A couple of years later, the same reaction was described

using choline chloride : urea (1 : 2) as the solvent at 80 °C for 4 obtained aer mixing a donor molecule, such as amides,
hours (Scheme 3b) without the need of an additional acid to act amines, phosphines or thioureas, with an excess of an anhy-
as a catalyst for this transformation.23 Therefore, comparing drous metal halide [commonly Al(III) or Ga(III)].27
both processes, the use of a type I DES in the rst described Full conversions of 1-decene were achieved using tiny
process was replaced by a type III in the second, which trans- amounts of these LCC catalysts (0.25–2.00 mol% per mol of
lates into the substitution of a metal halide component by urea, olen) at room temperature, with the excess of benzene being the
an inexpensive and biodegradable organic component. In this solvent of the reaction (Scheme 5).28 Nonetheless, there is room
sense, the reaction was more efficient from a sustainable point for improvement in terms of selectivity towards 2-phenyldecane
of view, although part of the catalytic efficiency of the previous (up to 47%), which is the most biodegradable isomer. This fact
mixture was lost. In this case, different aromatic and alkenyl can be explained through a competition between the direct
substituted aldehydes were reacted with unsubstituted indole to attack of the arene on the generated carbocation on 1-decene and
test the scope of the reaction. Aer product isolation through a previous carbocation migration on to the most stable isomer.
extraction with an organic solvent, the desired products were Regarding the donor ligands tested to afford these LCC catalysts,
obtained in good to excellent yields. However, the aromatic dimethylacetamide, urea, trioctylphosphine oxide and 1-ethyl-3-
substitution was ineffective when applied to aliphatic alde- methylimidazolium chloride were employed, all of them
hydes, probably due to an aldol-type reaction competition. offering yields from 83 to 91%. These excellent yields are
Likewise, the use of ketones as electrophiles did not take place remarkable since the aromatic substrate is not activated towards
with the starting material being recovered unreacted. the electrophilic substitution and the catalytic LCC loading is
The same DES was used lately for the C-3 functionalization of rather low, being one of the rare examples of this transformation
indoles with electron-decient carbonyl compounds such as using DES applied to non-rich aromatic rings.
isatins. The achieved 3-substituted-3-hydroxyoxindoles are
interesting compounds in the eld of pharmaceutical and
natural products. The scope of the reaction was extended not Synthesis of 1,1-diarylalkanes
only to different isatins substituted in the benzene ring but also Very recently, the use of a DES composed of iron(III) chloride
to N-substituted isatins that reacted with substituted indoles at hexahydrate and glycerol (DES type IV) as a solvent and catalyst
room temperature (Scheme 4).24 All the tested starting materials has been reported for a wide variety of Friedel–Cras alkyl-
were well tolerated regardless of the fact of being decorated with ations.29 This strategy is compatible with benzylating reagents
different functional groups, proving the robustness of the such as styrenes, alcohols, acetates, ethers and chlorides, leading
method by leading to several 3-hydroxy-3-indolylindolin-2-ones to 1,1-diarylalkanes in good yields even when arenes bearing
in excellent yields. deactivating groups were used as nucleophiles (Scheme 6). In this
case, an excess of the nucleophilic arene was employed, allowing
Synthesis of monoalkylbenzenes in most cases the formation of two different liquid phases, which
were separated without the need of using any external work-up
The SE(Ar) can also take place between olens and arenes. When
solvent, and the product could be puried by distillation. In
this reaction is performed under controlled conditions, linear
this way, no VOC solvents were employed during the whole
monoalkyl arenes can be synthetized. In this sense, monoalkyl
process and the generation of waste was minimized.
benzenes containing chains with 10 to 14 carbons are valuable
intermediates for the synthesis of anionic detergents.25,26 These
compounds are obtained through a Friedel–Cras alkylation
reaction with benzene and alpha olens such as 1-decene.
Several GaCl3-based liquid coordination complexes (LCC) were
tested as catalysts, with benzene being used as the starting
material but also as the solvent of the reaction.
These liquid coordination complexes are liquid Lewis acids
formed by anionic, cationic and neutral coordination
complexes. These media, similar in structure to a DES, are Scheme 6 FeCl3/glycerol promoted synthesis of diarylalkanes.

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Synthesis of triarylmethanes example before at 70 °C (Scheme 9).34 The use of water as the
solvent, however, did not yield any product, while employing
In contrast to the previous sections, there are certain occasions in
neat ZnCl2 instead of the corresponding eutectic mixture
which the polyarylation led to the desired reaction product. An
provoked a three times decrease in the reaction yield. In this
interesting methodology to obtain triarylmethanes and diary-
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instance, a versatile scope of the reaction was examined through

lalkanes (quite important scaffolds in medicinal30,31 and materials
the test of different b-nitrostyrenes substituted by electron-donor
chemistry32) is through an electrophilic aromatic substitution
and -withdrawing groups as well as distinct N,N-alkyl and aryl
such as Friedel–Cras alkylation of arenes with aldehydes. For
instance, an electron-rich arene such as 1,2,4-trimethoxybenzene aniline derivatives. Good to excellent yields were obtained in all
was alkylated with several aromatic aldehydes decorated with cases except for the N-phenylaniline, whose corresponding
product was formed in only 46% yield, probably due to its lower
electron-withdrawing and -donating groups using choline chlo-
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nucleophilicity. Excellent regioselectivity was denoted for these

ride : zinc chloride (1 : 2) as the solvent and catalyst of the reaction
conditions as ortho or N-alkylation products were observed just
(Scheme 7).33 In addition, aliphatic aldehydes were also compat-
in trace amounts, while the most activated and less sterically
ible with these reaction conditions, affording the corresponding
hindered para-position was mainly alkylated and isolated. It is
diarylalkanes in good to excellent yields.
worth noting that in this case the DES is employed in a catalytic
The scope of this reaction was later expanded under the same
mild conditions for the synthesis of other triarylmethanes. In amount. Therefore, the role of the eutectic mixture is only as
this case, the alkylation of different arenes was performed using a reaction promoter and not as a solvent, which further decreases
the generated waste by employing neat conditions.
benzaldehyde as the coupling partner (Scheme 8).33 However, the
lower nucleophilicity and electron density on the aromatic ring
compared with the previous example notably decreased the yield Multicomponent reactions
of the reaction in some examples, which could be overcome by Multicomponent reactions have also been described in this
increasing the reaction time. eld as in the case of the domino Henry–Friedel–Cras alkyl-
ation process of aldehydes, nitromethane and N-substituted
Arylation of b-nitrostyrene derivatives anilines using choline chloride : zinc chloride (1 : 1) described
below (Scheme 10).35 The versatility of the reaction was
Changing the electrophile to b-nitrostyrene derivatives allows the explored, with benzaldehydes containing electron-withdrawing
synthesis of interesting compounds. The arylation of b-nitro- and -donating groups providing the corresponding products
styrenes with highly nucleophilic mono- and dialkyl anilines has in good yields. Heterocyclic aldehydes were also tolerated,
been carried out using 10 mol% of the same DES as in the except for the case of 4-pyridine carboxaldehyde being the ex-
pected product not detected probably due to the lower electron
density of the pyridine ring. It is worth mentioning that the
reaction was tested by the same authors using VOC solvents
such as EtOH, MeCN or DMSO, as well as using water and ZnCl2
as additives, not leading to the formation of the desired product
or affording only marginal yields.
Besides, secondary, and tertiary anilines showed moderate to
Scheme 7 Friedel–Crafts alkylation of electron-rich arene with alde- good yields and regioselectivity as only para-alkylated products
hydes using choline chloride : zinc chloride (1 : 2). were obtained.

Scheme 8 Friedel–Crafts alkylation of benzaldehyde with nucleo-

Scheme 10 One pot domino Henry–Friedel–Crafts alkylation medi-
philes using choline chloride : zinc chloride (1 : 2).
ated by choline chloride : zinc chloride (1 : 1).

Scheme 9 Friedel–Crafts alkylation of several nitroalkenes with N,N- Scheme 11 Alkylation of phenol with tert-butyl alcohol using choline
dialkyl anilines using choline chloride : zinc chloride (1 : 2). bisulfate : p-toluenesulfonic acid (1 : 1).

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Scheme 14 Friedel–Crafts acylation of several aromatic compounds

using choline chloride : zinc chloride (1 : 3).
Scheme 12 Preparation of triarylmethane compounds using DES type
I (a) and type IV (b).

reaction and also the conventional solvents by these eutectic

mixtures, thereby increasing the sustainability of the process.
One of the rst Friedel–Cras acylations using a deep
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eutectic solvent as a reaction medium was described in 2016.

The acylation of aromatic compounds has been reported using
propionic and benzoic anhydrides as acylating reagents. The
eutectic mixture formed by choline chloride and zinc chloride
in 1 : 3 molar ratio (35 mol%) was used as a catalyst under
Scheme 13 Preparation of triarylmethane compounds using different microwave irradiation (Scheme 14).40
DES.
To expand the applicability of this methodology, the scope of
the reaction was developed comprising 28 examples varying the
acylating reagent used, temperature (100–140 °C) and the
The alkylation of phenol with tert-butyl alcohol to synthesise reaction time (5–20 min) but also a great amount of different
tert-butyl phenols has been described using choline bisulfate aromatic compounds was tested. Aromatic compounds con-
and p-toluenesulfonic acid mixture in a 1 : 1 molar ratio taining electron-donating groups such as methoxy substituents
(Scheme 11).36 Milder reaction conditions were needed to carry were benzoylated in good to excellent yields. Even though
out this alkylation, with the reaction taking place only at 30 °C, longer reaction time and higher temperatures compared with
to give a high conversion ratio of tert-butyl alcohol, most the previous example were needed, alkyl-substituted benzenes
probably due to the high acidic activity of the solvent. also reacted in good yields. Furthermore, thioanisole was ben-
This kind of process is also described in patents as the one zoylated in excellent yield. However, the application of this
shown in Scheme 12. The preparation method for triaryl- reaction condition to non-activated substrates was not tested.
methane compounds through a Friedel–Cras alkylation using In addition, the regioselective Friedel–Cras propionylation
the DES formed by benzyltrimethylammonium chloride : zinc at position 3 of several electron-rich heteroaromatic scaffolds
chloride (1.5 : 1) was developed (Scheme 12a).37 Different such as pyrrole, benzofurane or indoles decorated with both
electron-rich aromatic compounds and a variety of diary- electron-withdrawing and electron-donating groups was
lcarbinols were tested, obtaining the desired products in high possible under these conditions with good to excellent yields,
selectivity and reaction yield. The same conditions were re- even without the need of NH protection.
ported when using the DES formed by ethylene glycol : zinc The acylation of electron-rich arenes using carboxylic acids is
chloride (2 : 1).38 an interesting approach since water is the only by-product of the
Another process in which the eutectic mixture formed by reaction, increasing the eco-scale values. This process has been
ZnCl2 and ethylene glycol has been used as both a co-solvent reported by using the combination of the same deep eutectic
and catalyst is the multicomponent synthesis of tetrahy- solvent as in the previous example with the ionic liquid [AMIm]
droquinolines.39 This reaction involves a [4 + 2] cycloaddition OTf (1-allyl-3-methylimidazolium triuoromethanesulfonate)
between N-arylimines and electron-rich olens through a Lewis (Scheme 15).41
acid catalyst, i.e., zinc chloride (Scheme 13). Regarding the scope of this reaction, the benzoylation of
In addition, the reaction can be performed under microwave anisole and thioanisole gave mainly the p-substituted product
irradiation, fullling another green chemistry principle related in moderate yield. Acylation of electron-rich arenes afforded the
to the design of reactions for increased energy efficiency, as well corresponding products in moderate to good yields with high
as the ones related to the use of DES, which are safer solvents selectivity. Naphthalene derivatives were also tolerated in
and auxiliaries, and the use of renewable feedstocks.

Friedel–Crafts acylation
Likewise, deep eutectic solvents have been used for the Friedel–
Cras acylation of interesting compounds. As mentioned
before, these green solvents play a dual role as acid catalysts and Scheme 15 Friedel–Crafts acylation of different arenes with carbox-
solvents. This fact has allowed the substitution of the tradi- ylic acids using a binary mixture formed by ChCl : ZnCl2 (1 : 3) and
tional moisture-sensitive Lewis acids used in this type of [AMIm]OTf.

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moderate yields. Furthermore, uorene and biphenyl were

benzoylated in moderate yields at the 3-position and p-position,
respectively.
In addition, the acylation of indole was carried out in
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moderate yield with high selectivity for the 3-position. Oxygen- Scheme 18 Friedel–Crafts acylation using choline chloride : pyrrole
containing heterocycles such as benzofuran gave mixtures of (3 : 7) combined with praseodymium triflate.
2- and 3- benzoylated products. Note that in all cases the yield
and selectivity were determined by GC using naphthalene as an
internal standard.
Another example of F–C acylation was reported in 2017 when
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the acylation of 1,2,4-trimethoxybenzene using choline chlo-

ride : zinc chloride (1 : 2) was carried out at 70 °C (Scheme 16).42
Several electrophilic reagents were tested, obtaining the desired
product in moderate to good yields, except for a couple of cases
in which the yield was quite lower. Scheme 19 Friedel–Crafts acylation of phenols using zinc chloride :
The reaction between benzoyl chloride and the aforemen- acetic acid (1 : 2).
tioned substrate showed a higher yield under these conditions
(85%). Regarding linear acyl chloride, it was demonstrated that
the yield obtained decreased with increasing the chain length. An interesting alternative to the traditional Lewis acids
Concurrently, other acid chlorides besides acyl chloride commonly used in Friedel–Cras acylation is metal triates.
produced a notable decrease in the yield to 33%. Predictably, These compounds are greener than traditional ones. Further-
anhydrides showed less reactivity than acyl halides and even more, metal triates present high Lewis acidity and elevated
some anhydrides such as succinic anhydride did lead to the tolerance to water, which makes them suitable for their use in
desired product. Finally, p-toluenesulfonyl chloride reacted organic solvent media but also aqueous media.
with the substrate, obtaining the target product in 56%, prob- Very recently, an acylation reaction of different electron-rich
ably due to the important steric hindrance but also the weak- arenes has been reported using praseodymium triate as
ened electron-withdrawing ability. a catalyst and a mixture of choline chloride and pyrrole in a 3 : 7
The acylation of several arenes with benzoyl chloride molar ratio as a solvent. The reaction took place using 1
matching the conditions used in the previous case was reported equivalent of benzoic anhydride as the acylating reagent at 100 °
by the same authors (Scheme 17).42 The scope of the reaction C under microwave conditions (Scheme 18).43
denoted that the product yields were affected by electron- The synthesis of ve aromatic ketones was developed using
donating ability but also by the steric hindrance of the arenes. these optimized conditions. Different arenes with electron-
Unsurprisingly, the best results were obtained when using donating substituents such as methoxy- or methyl-groups
arenes with strong electron-donating substituents, increasing were tested, obtaining the desired products in good yields for
the yield when substituents directing to ortho and para posi- all cases.
tions are present at the aromatic ring. Nevertheless, the target The Friedel–Cras acylation of substituted phenols was
products were not obtained when reacting aromatic freshly reported using the eutectic mixture formed by zinc
compounds with weakly activating electron-donating substitu- chloride : acetic acid in a 1 : 2 molar ratio under mild conditions
ents but neither with electron-withdrawing groups. (Scheme 19).44 The scope of the reaction includes several phenol
derivatives such as catechol, resorcinol, hydroquinone and
phloroglucinol. The desired products were obtained in all cases
in excellent yields, apart from the case of phenol. In this occa-
sion, aer 180 minutes of reaction, a mixture composed of the
unreacted phenol, phenyl ester and hydroxyl-aryl ketone prod-
ucts was observed probably due to the lower electron density on
the benzene ring.
Scheme 16 Friedel–Crafts acylation of 1,2,4-trimethoxybenzene with
different acylating reagents using choline chloride : zinc chloride (1 : 2). Assessment of green metrics
In this review, the use of alternative eutectic-based solvents has
been described. Most of these solvents full a dual role, acting
as reaction media and catalysts at the same time, and greatly
improving the sustainability of the methods over traditional
approaches thanks to the use of less toxic, safer to use (non-
volatile, non-ammable) and in some cases biorenewable
Scheme 17 Friedel–Crafts acylation of different arenes with benzoyl solvent systems. In addition to these qualitative improvements,
chloride using choline chloride : zinc chloride (1 : 2). other quantitative parameters can be analysed. Table 1

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Table 1 Summary of reactions and green metrics

Entry Reaction Yields DES employed/DES-type Starting materials E-Factor Atom economy

1 Scheme 3a 64–97% ChCl : SnCl2 (1 : 2)/type I PhCHO, indole 67.1 94.7

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2 Scheme 3b 77–99% ChCl : urea (1 : 2)/type III 4-Anisaldehyde, indole 35.7 95.1
3 Scheme 4 85–94% ChCl : urea (1 : 2)/type III 1-Methylisatin, indole 48.0 99.9
4 Scheme 6 9–99% FeCl3$6H2O : glycerol (3 : 1)/type IV 4-Chlorostyrene, o-xylene 8.7 94.3
5 Scheme 7 61–94% ChCl : ZnCl2 (1 : 2)/type I PhCHO, 1,3,6-trimethoxybenzene 203.7 95.2
6 Scheme 9 46–93% ChCl : ZnCl2 (1 : 2)/type I Nitrostyrene, Me2NPh 110.2 99.9
7 Scheme 10 30–83% ChCl : ZnCl2 (1 : 2)/type I PhCHO, MeNO2, Me2NPh 4249.8 93.7
8 Scheme 11 85–99% ChHSO3 : p-TsOH (1 : 1)/type III t
BuOH, PhOH —a 98.9
9 Scheme 13 92% ZnCl2 : EG (1 : 4)/type IV p-Nitroaniline, PhCHO, trans-anethol —a 95.4
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10 Scheme 14 64–94% ChCl : ZnCl2 (1 : 3)/type I Anisole, benzoic anhydride 269.0 63.4
11 Scheme 15 31–89% ChCl : ZnCl2 (1 : 3)/type I Trimethylbenzene, PhCO2H 217.6 92.5
12 Scheme 16 33–85% ChCl : ZnCl2 (1 : 2)/type I Trimethoxybenzene, PhCOCl 44.2 88.1
13 Scheme 18 73–92% ChCl : pyrrole (3 : 7)/type III Anisole, benzoic anhydride 166.7 63.4
14 Scheme 19 92–99% ZnCl2 : AcOH (1 : 2)/type IV Phloroglucinol, AcOH 38.0 133.2b
a b
E-Factor not included due to a certain lack of information in the original source. Acetic acid was part of the solvent and therefore was not
included in the atom economy calculation.

summarizes some of the most important aspects of the previ- Conclusions

ously discussed transformations and adds the E-factor and
atom economy values. In general, the atom economy of this The pursuit of more sustainable procedures has impregnated
kind of reaction is very high, since most of the atoms contained every aspect of synthetic chemistry, not only when developing
in the starting materials can be found in the nal products. ground-breaking transformations, but also revisiting some of
Thus, the Friedel–Cras approach is highly desirable from the the most important traditional transformations, as is the Frie-
sustainability point of view. However, atom economy does not del–Cras reaction. In this sense, eutectic-type mixtures proved
consider some other parameters such as work-up solvents or to be efficient alternatives to traditional reaction media, ful-
purication methods. For this reason, E-factor has been also lling in some cases a double role as solvents and catalysts.
included in Table 1. In general, most of the presented results Thus, the safety of these processes is improved while reducing
show E-factor values within which can be expected for ne the generated waste, with some of these processes being already
chemicals or pharmaceutical products, although some of them patented and used on an industrial scale.
show high values mainly due to the use of excess work-up However, loads of effort is still needed to unravel the full
solvents. The case of entry 4 is particularly interesting, in potential of these mixtures. Although in general good yields are
which a very low E-value is obtained thanks to the thoroughly reported in this review, the substrates are mostly limited to
designed process in which no additional work-up solvents are electron-rich arenes. Inactivated aromatic rings have shown
required. This type of approach should be used as inspiration to limited or null reactivity so far, and novel strategies employing
develop more sustainable processes in the future by considering less sustainable media still have to be adapted to eutectic
every aspect of the reaction, including work-up processes. mixtures. Thus, further research is still needed to achieve better
Another conclusion that can be drawn from Table 1 is the yields without compromising the sustainable aspect.
preference to use type 1 DESs for these transformations. Type 1 In addition, eutectic mixtures containing a component with
DESs present a metal halide in their structure combined with a strong Lewis acid character have proven to act as an efficient
a quaternary ammonium salt (entries 1, 5–7, and 10–12). The catalyst for this kind of transformation. However, only a few
presence of these metal salts endows the solvent with a Lewis archetypical DES-like mixtures have been tested. A systematic
acid character, promoting the use of the DES as a catalyst. study testing several mixtures with different Lewis acid
Similarly, type IV DESs contain a metal halide in combination components and their catalytic ability is still missing, and it
with a hydrogen bond donor molecule, like glycerol (entry 4) or could pave the way for further research.
ethylene glycol (entry 13). These solvents have been less Finally, these eutectic mixtures can act as innocent solvents
explored so far but offer some of the best results and should be or even catalysts, but the use of some DES components as
taken into account in the future when designing a new reaction electrophiles has not been explored in this type of trans-
process. Finally, type III DESs do not contain any metal salt in formation. If this strategy is followed, an excess of the electro-
their structure (entries 2, 3, 8 and 13), and are still able to philic reagent will be used, as it would be part of the solvent
promote the desired transformations with or without the mixture, but due to the recycling capability of these solvents, no
addition of an additional catalyst. In this sense, type III DESs additional waste would be produced while the efficiency of the
can be seen as the less toxic mixtures, but the high efficiency reaction is maximised.
and the possibility to be recycled of types I, II and IV make them In conclusion, eutectic-type mixtures have been found to be
also interesting to be used. efficient solvents and catalysts to perform Friedel–Cras

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transformations while improving the sustainability of the 14 F. M. Perna, P. Vitale and V. Capriati, in Deep Eutectic
process. However, more research should be conducted to make Solvents, 2019, pp. 111–134, DOI: 10.1002/
these methods achieve the highest standards. 9783527818488.ch7.
15 X. Marset and G. Guillena, Molecules, 2022, 27, 8445.
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

16 S. E. Hooshmand, S. Kumar, I. Bahadur, T. Singh and

Author contributions R. S. Varma, J. Mol. Liq., 2023, 371, 121013.
T. M. and X. M. processed the data and wrote the original dra. 17 D. A. Alonso, S.-J. Burlingham, R. Chinchilla, G. Guillena,
D. J. R.; C. G.; and G. G. obtained the resources needed for this D. J. Ramón and M. Tiecco, Eur. J. Org Chem., 2021, 2021,
research and reviewed the manuscript. 4065–4071.
18 H. Qin, X. Hu, J. Wang, H. Cheng, L. Chen and Z. Qi, Green
Open Access Article. Published on 21 March 2024. Downloaded on 4/20/2024 2:49:41 AM.

Energy Environ., 2020, 5, 8–21.

Conflicts of interest 19 K. Sisido, U. YôKo, T. Nakamura and H. Nozaki, J. Org.
Chem., 1961, 26, 1368–1371.
There are no conicts to declare.
20 N. Azizi and Z. Manocheri, Res. Chem. Intermed., 2012, 38,
1495–1500.
Acknowledgements 21 Z.-H. Zhang, L. Yin and Y.-M. Wang, Synthesis, 2005, 2005,
1949–1954.
This research has been made possible with the nancial 22 B. P. Bandgar and K. A. Shaikh, Tetrahedron Lett., 2003, 44,
support received from the University of Alicante (VIGROB- 1959–1961.
316FI) and the Spanish Ministerio de Ciencia e Innovación 23 S. Handy and N. M. Westbrook, Tetrahedron Lett., 2014, 55,
(PID2021-127332NB-I00). T. M. thanks to the University of Ali- 4969–4971.
cante for a fellowship (UAIND21-11C). 24 A. Kumar, R. D. Shukla, D. Yadav and L. P. Gupta, RSC Adv.,
2015, 5, 52062–52065.
Notes and references 25 J. A. Kocal, B. V. Vora and T. Imai, Appl. Catal., A, 2001, 221,
295–301.
1 C. Friedel and J.-M. Cras, C. R. Chim., 1877, 84, 1392–1395. 26 A. Shokri and S. Karimi, Russ. J. Appl. Chem., 2021, 94, 1546–
2 J. J. Li, in Name Reactions: A Collection of Detailed Reaction 1559.
Mechanisms, ed. J. J. Li, Springer Berlin Heidelberg, Berlin, 27 J. M. Hogg, F. Coleman, A. Ferrer-Ugalde, M. P. Atkins and
Heidelberg, 2006, pp. 240–242, DOI: 10.1007/3-540-30031- M. Swadźba-Kwaśny, Green Chem., 2015, 17, 1831–1841.
7_107. 28 K. Matuszek, A. Chrobok, J. M. Hogg, F. Coleman and
3 R. Valiulin, in Organic Chemistry: 100 Must-Know M. Swadźba-Kwaśny, Green Chem., 2015, 17, 4255–4262.
Mechanisms, De Gruyter, Berlin, Boston, 2020, pp. 92–93, 29 A. Presa Soto, M. Ramos-Martı́n and J. Garcı́a-Álvarez,
DOI: 10.1515/9783110608373-039. ChemRxiv, 2024, preprint, DOI: 10.26434/chemrxiv-2024-
4 A. H. Mohamed and N. Masurier, Org. Chem. Front., 2023, 10, pvzsr.
1847–1866. 30 A. V. Cheltsov, M. Aoyagi, A. Aleshin, E. C.-W. Yu,
5 R. A. Sheldon, Green Chem., 2017, 19, 18–43. T. Gilliland, D. Zhai, A. A. Bobkov, J. C. Reed,
6 G. I. Borodkin and V. G. Shubin, Russ. J. Org. Chem., 2006, 42, R. C. Liddington and R. Abagyan, J. Med. Chem., 2010, 53,
1745–1770. 3899–3906.
7 K. S. Egorova and V. P. Ananikov, ChemSusChem, 2014, 7, 31 S. Mondal and G. Panda, RSC Adv., 2014, 4, 28317–28358.
336–360. 32 Y.-Q. Xu, J.-M. Lu, N.-J. Li, F. Yan, X.-W. Xia and Q.-F. Xu, Eur.
8 T. P. T. Pham, C.-W. Cho and Y.-S. Yun, Water Res., 2010, 44, Polym. J., 2008, 44, 2404–2411.
352–372. 33 A. Wang, P. Xing, X. Zheng, H. Cao, G. Yang and X. Zheng,
9 D. A. Alonso, A. Baeza, R. Chinchilla, G. Guillena, I. M. Pastor RSC Adv., 2015, 5, 59022–59026.
and D. J. Ramón, Eur. J. Org Chem., 2016, 2016, 612–632. 34 M. A. Ranjbari, H. Tavakol and M. Manoukian, Res. Chem.
10 D. O. Abranches and J. A. P. Coutinho, Annu. Rev. Chem. Intermed., 2021, 47, 709–721.
Biomol. Eng., 2023, 14, 141–163. 35 Z. Hu, G. Jiang, Z. Zhu, B. Gong, Z. Xie and Z. Le, Chin. J. Org.
11 B. B. Hansen, S. Spittle, B. Chen, D. Poe, Y. Zhang, Chem., 2021, 41, 325–332.
J. M. Klein, A. Horton, L. Adhikari, T. Zelovich, 36 J. Xiong, D. Zhang, G. Yang and Z. Zhang, Ind. Eng. Chem.
B. W. Doherty, B. Gurkan, E. J. Maginn, A. Ragauskas, Res., 2021, 60, 13204–13213.
M. Dadmun, T. A. Zawodzinski, G. A. Baker, 37 A. Wang, P. Xing and X. Zheng, China Pat.,
M. E. Tuckerman, R. F. Savinell and J. R. Sangoro, Chem. CN201510582680A, 2015.
Rev., 2021, 121, 1232–1285. 38 A. Wang, P. Xing and X. Zheng, China Pat., CN105237362A,
12 J. Torregrosa-Crespo, X. Marset, G. Guillena, D. J. Ramón 2016.
and R. M. Martı́nez-Espinosa, Sci. Total Environ., 2020, 704, 39 W. J. Quintero, M. C. Ávila and C. Ochoa-Puentes, J. Chem.
135382. Educ., 2023, 100, 4763–4771.
13 D. O. Abranches and J. A. P. Coutinho, Curr. Opin. Green 40 P. H. Tran, H. T. Nguyen, P. E. Hansen and T. N. Le, RSC Adv.,
Sustainable Chem., 2022, 35, 100612. 2016, 6, 37031–37038.

RSC Sustainability © 2024 The Author(s). Published by the Royal Society of Chemistry
 View Article Online

Critical Review RSC Sustainability

41 H. T. Nguyen, N. Le, Y. Kawazoe, N.-N. Pham-Tran and 43 M.-T. T. Nguyen, N. Le, H. T. Nguyen, T. D. V. Luong,
P. H. Tran, ChemistrySelect, 2022, 7, e202103708. V. K. T. Nguyen, Y. Kawazoe, P. H. Tran and N.-N. Pham-
42 X. Jin, A. Wang, H. Cao, S. Zhang, L. Wang, X. Zheng and Tran, ACS Omega, 2023, 8, 271–278.
X. Zheng, Res. Chem. Intermed., 2018, 44, 5521–5530. 44 F. Tamaddon and H. Rashidi, Res. Chem. Intermed., 2023, 49,
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

3589–3603.
Open Access Article. Published on 21 March 2024. Downloaded on 4/20/2024 2:49:41 AM.

© 2024 The Author(s). Published by the Royal Society of Chemistry RSC Sustainability