Cyrene A Bio-Based Novel and Sustainable Solvent

Green Chemistry
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Cyrene: a bio-based novel and sustainable solvent

Cite this: Green Chem., 2022, 24,
for organic synthesis
Open Access Article. Published on 28 July 2022. Downloaded on 11/15/2023 11:00:27 AM.
6435
Naya A. Stini,†a,b Petros L. Gkizis †a,b and Christoforos G. Kokotos *a,b
Dihydrolevoclucosenone (Cyrene is its market name) is a biomass-derived solvent that can be produced
in only two steps from biomass, while being biodegradable, non-mutagenic and non-toxic. Its “green”
profile combined with its physical properties makes Cyrene a plausible substitute for a number of widely
Received 21st June 2022, used toxic organic solvents. The first attempt to assess Cyrene as a solvent dates back to 2014 and since
Accepted 28th July 2022
then, numerous research groups have opted for this promising alternative. Cyrene has successfully been
DOI: 10.1039/d2gc02332f employed as a solvent in materials chemistry, peptide chemistry, organic synthesis and many more
rsc.li/greenchem research fields, which are going to be discussed in the context of this review.
1. Introduction dimethyl formamide (DMF), N-methylpyrrolidone (NMP),

dimethyl sulfoxide (DMSO) or N,N-dimethylacetamide (DMAc),
Over the past few years, the increasing emphasis on green which are considered toxic organic solvents, both for the
chemistry has turned the interest of many scientists worldwide environment and human health.7 Lately, great effort has been
towards research fields, such as the development of green sol- devoted to replacing toxic and hazardous organic solvents with
vents and water-mediated or solvent-free reactions. This high novel easily-disposable solvents, minimizing the ecological
demand for environmentally friendly procedures to access pro- footprint.
ducts has increased the development of more sustainable pro-
cesses in the last few years.1 Furthermore, one of the major
issues faced by the chemical industry is the large amount of
waste generated by the chemical processes every day. The 2. General remarks
amount of waste is mainly associated with solvents, thus the Cyrene synthesis from biomass
replacement of widely used, but toxic organic solvents, by safer Dihydrolevoglucosenone or 6,8-dioxabicyclo[3.2.1] octanone is
and non-toxic alternatives is of great importance. The basic a cellulose-derived solvent, which can be synthesized in a two-
concern of a process chemist is to alter the employed reaction step process from biomass. The first step for its synthesis was
schemes, avoiding hazardous solvents or reagents, in order to reported back in 1973 by Broido and coworkers,8a who charac-
decrease the amount of waste produced. This idea is exception- terized correctly the chemical structure of levoglucosenone
ally conceptualized by Anastas and coworkers under the title (LGO), as a result of cellulose pyrolysis (Scheme 1). Although
of the Twelve Principles of Green Chemistry.2 Cyrene was synthesized before, the first structural characteriz-
In the context of this review, we intend to focus on a novel ation of the molecule was incorrect. Since then, a lot of effort
bio-based solvent, which is produced by Circa under the trade has been put in increasing the conversion of cellulose into
name Cyrene.3 There is a number of articles or reviews focused
on the earlier attempts at using Cyrene as a solvent4–6 and the
readers can divert their attention to these for some of the early
contributions. Our aim is to focus and discuss Cyrene-
mediated reactions that provide environmentally friendly solu-
tions. Cyrene is considered to be a potential alternative to
a
Laboratory of Organic Chemistry, Department of Chemistry, National and
Kapodistrian University of Athens, Panepistimiopolis 15771, Athens, Greece.
E-mail: [email protected]
b
Center of Excellence for Drug Design and Discovery, National and
Kapodistrian University of Athens, Panepistimiopolis 15771, Athens, Greece
† Denotes equal contribution. Scheme 1 Production of Cyrene from cellulose.
This journal is © The Royal Society of Chemistry 2022 Green Chem., 2022, 24, 6435–6449 | 6435
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LGO. Various methods have been developed concerning the Table 1 Physical properties of Cyrene versus other dipolar aprotic
pyrolysis of cellulose, mostly by investigating a wide range of solvents
acids to succeed in obtaining the highest yields.8 In 2011, the
Properties Cyrene NMP DMF DMSO DMAc
Circa group reported a thermal method which afforded LGO in
40% yield.9 The Circa group patented a method for the for- Boiling point 227 °C 202 °C 153 °C 189 °C 165 °C
Density [g ml−1] 1.25 1.03 0.948 1.100 0.937
mation of LGO, which involves the catalytic pyrolysis of
Solubility with water Miscible Miscible Miscible Miscible Miscible
biomass using phosphoric acid in sulfolane.9 Having in hand π* 0.93 0.90 0.88 1.00 0.85
the best results for producing the main precursor of dihydrole- δD [MPa] 18.8 18.0 17.4 18.4 16.8
δP[MPa] 10.6 12.3 13.7 16.4 11.5
voglucosenone, Circa initiated the industrial production of
δH [MPa] 6.9 7.2 11.3 10.2 10.2
this promising derivative under the trade name Cyrene,3 and
since then the interest in its use as a bio-based solvent has

been gradually increasing.
The second and final step involves the reduction of levo- Cyrene is very unstable toward strong acids and oxidizing or
glucosenone, by hydrogenation, to afford Cyrene (Scheme 1). reducing agents.6
In this context, various palladium catalysts have been widely Cyrene is a colorless viscous liquid with a high boiling
employed, such as Pd/Al2O3 10 or Pd/C;6,10 however, rhodium point (227 °C), which offers the possibility to mediate reac-
catalysts and zirconia-supported catalysts have been used as tions taking place in a wide range of temperatures. Cyrene’s
well.11 Moreover, a one-pot synthesis of Cyrene from levogluco- polarity profile was studied using DFT experiments, comple-
senone was suggested by Wang and coworkers,12 while in mented by the Kamlet–Abboud–Taft parameters that were also
2018, levoglucosenone was reduced to Cyrene using an alkene obtained (Table 1).5 The results showed that Cyrene has a
reductase.13 similar π* value to N-methylpyrrolidone (NMP), which verifies
its definition as an aprotic solvent. As far as the Hansen solu-
bility parameters (HSP) are concerned, Cyrene presents a
Properties of Cyrene similar dispersion term (δD) to DMSO, a polar term (δp)
Regarding its chemical structure, Cyrene is an optically active similar to DMAc and hydrogen bonding interactions (δH)
ketone composed of two fused rings, which form a cyclic similar to NMP.6 The density of Cyrene is 1.25 g mL−1 at
acetal (Scheme 1). The ring fusion results in a double anome- 293 K. Compared to NMP, DMF, DMSO or DMAc which are
ric effect, which stabilizes the existence of the cyclic acetal.5 In listed as hazardous (H360) by the Registration, Evaluation,
general, acetals are stable towards bases and nucleophiles and Authorization and Restriction of CHemicals (REACH),
Thessaloniki. In 2012, he was appointed as a postdoctoral fellow

at the Aristotle University of Thessaloniki in collaboration with
the University of Crete (ERC-Grant). In 2014, he was appointed as
a Technology Transfer Research Scientist at Pharmathen S.A.
Pharmaceuticals, Thessaloniki, Greece. In 2020, he joined the
group of Prof. Christoforos G. Kokotos at the National and
Kapodistrian University of Athens as a postdoctoral researcher.
His research interests focus on the development of photochemical
reactions for the formation of C–C bonds and their application in
the synthesis of pharmaceuticals and bioactive compounds.
Prof. Christoforos G. Kokotos was born in Athens, Greece (1981)
and studied Chemistry at the National and Kapodistrian
From left to right: Dr Petros L. Gkizis, Assoc. Professor University of Athens, Greece (2003). He completed his PhD studies
Christoforos G. Kokotos and Naya A. Stini at the University of Bristol, UK (2007) under the supervision of
Prof. Varinder Aggarwal. He then carried out postdoctoral work
Naya A. Stini is a MSc student at the Department of Chemistry, at Princeton University, USA in the group of Prof. David
National and Kapodistrian University of Athens, under the super- W. C. MacMillan. He was elected as a Lecturer of Organic
vision of Assoc. Professor Christoforos G. Kokotos. Naya studied Chemistry in the Department of Chemistry of the National and
Chemistry at the Department of Chemistry of the National and Kapodistrian University of Athens, Greece and promoted to
Kapodistrian University of Athens and graduated in 2021 with Assistant Professor (2016) and Associate Professor (2020). He was
honors. She then begun her MSc studies in the Kokotos group also elected as a Chemistry Europe Fellow in 2022 (class
and her research interests focus on Green Chemistry and 2020–2021). His research interests focus on asymmetric organoca-
Photochemistry. talysis, photocatalysis and green methodologies on oxidation reac-
Dr Petros L. Gkizis was born in Athens, Greece. He obtained his tions and their application in the synthesis of pharmaceuticals,
BSc and MSc degrees and PhD from the Aristotle University of bioactive molecules and high-added value chemicals.
6436 | Green Chem., 2022, 24, 6435–6449 This journal is © The Royal Society of Chemistry 2022
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Cyrene has no known toxicity issues.7 Thus, major pharma- Ray and coworkers reported the polymerization of Cyrene,
ceutical companies seek for an alternative reaction medium.7a aiming at bio-based polymers.20
Additionally, Cyrene is biodegradable, biorenewable, non-
mutagenic and non-reprotoxic (Table 1).7 Cyrene is also misci- Reactions where Cyrene fails to become a suitable solvent
ble with water, which appears to be a very interesting property,

Interestingly in most literature reports, researchers tend to
since the high miscibility in water facilitates Cyrene removal
present their successful results; however, non-successful
from reaction mixtures using liquid–liquid extraction. This
results have their own merit. For further reference, reactions
feature is extremely important, especially in industrial scale
where Cyrene is not a compatible solvent could be of high
reactions, since Cyrene can be easily removed from the reac-
interest. Even though Cyrene appears to be an excellent choice
tion mixture and upon water distillation, it can be easily
of solvent, as we are going to discuss later in this review
reused.
article, its reactivity that arises from its structure in some
cases narrows down its use. In 2018, Hunt and coworkers
reported that Cyrene had a very low performance when
3. Cyrene in organic chemistry employed in biocatalytic esterifications, although it was com-
Cyrene as a reactant or a reagent mented that neither DMF nor NMP were effective.21 Their
incompatibility with this reaction can be attributed to the fact
Since the interest in Cyrene began to rise, several research that polar solvents disrupt the water layer around the enzyme,
groups initially investigated its use in several benchmark reac- decreasing its activity.22 In 2017, Szekely and coworkers
tions. Based on its structure, Cyrene behaves as a ketone attempted to use Cyrene as the solvent in a diastereoselective
bearing two α-reactive positions. Thus, Cyrene was examined synthesis of 2,4,5-trisubstituted-2-imidazolines from benz-
as a reactant in various reactions, such as the Beckmann reac- aldehyde and ammonia.23 The results were far from success-
tion,14 the Claisen–Schmidt reaction with aldehydes,15 the ful, since no product was obtained. The high reactivity of
Bayer–Villiger oxidation16 and hydrogenation with various Cyrene when it is employed as the solvent may cause that
metals (Scheme 2).17 Additionally, its chiral chemical structure failure. Under no circumstances should we forget the nature of
was used for the preparation of chiral auxiliaries for Diels– Cyrene as a compound, which implies that in reactions, such
Alder reactions18a or sulfa-Michael reactions.18b Furthermore, as the Grignard reaction (Scheme 3A) or aldol reaction
in 2018, Mencer and coworkers reported the formation of exo- (Scheme 3B), it could not be used as the solvent, as it would
cyclic enones, upon condensation of Cyrene with aldehydes, react.
which could further react with another molecule of the carbo-
nyl compound, leading to a structure like 8,19 while in 2019, Cyrene as the reaction medium in cross-coupling reactions
As already stated, our main intention in this review is to high-
light the use of Cyrene as an alternative and eco-friendly
solvent. Furthermore, we intend to discuss the replacement of
dipolar aprotic solvents by Cyrene and its applications in
numerous reactions, such as cross-coupling reactions. The
latter was first reported by Sherwood and coworkers, who
Scheme 3 (A) Grignard reaction, (B) aldol condensation reaction of

Scheme 2 Examples of reactions where Cyrene was used as a reactant. Cyrene.
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briefly studied the efficiency of Cyrene in the Menschutkin leading to the desired alkynes in good to excellent yields.24
reaction4 and the fluorination nucleophilic substitution reac- Furthermore, aryl bromides were also employed, but the
tions,4 which are going to be discussed later in the context of obtained yields were significantly lower. A vast variety of
this review. alkynes were also employed to react with iodobenzene,
affording the desired product in excellent yields, as most of

Sonogashira reaction the reactions were quantitative. Finally, heteroaryl alkynes and
ortho-substituted aryl iodides were used, affording the desired
In 2016, Watson and coworkers were the first to attempt a Pd- products in good to excellent yields.
catalyzed cross coupling reaction using Cyrene as the solvent At the same time, a Cacchi-type reaction was reported with
(Table 2).24 In general, the Sonogashira reaction takes place in the use of ortho-amino or ortho-hydroxyaryl iodides (Scheme 4).24
a dipolar aprotic solvent, thus DMF is mostly used in this kind
The generated intermediate from the Sonogashira coupling

of reaction. The attempt to replace DMF posed some chal- reaction undergoes a 5-endo-dig cyclization, upon increasing
lenges, such as the need for a higher catalyst loading and/or the reaction temperature. The resulting substituted benzofur-
higher reaction temperatures.24 Furthermore, the authors in ans, indoles or aza-indoles constitute important classes of
this case experienced prolonged reaction times and lower molecules, widely used in biological and pharmaceutical
yields. They initiated their investigations using iodobenzene sciences. In both reported protocols, the reaction output using
(13) and phenylacetylene (14) as a model reaction to find the both Cyrene and DMF is similar, indicating that Cyrene can be
optimum reaction conditions (Table 2).24 The employed palla- an excellent alternative medium for the Sonogashira cross-
dium catalyst was [Pd(PPh3)Cl2] and CuI was used as the addi- coupling reaction.
tive. A variety of bases were tested, but only Et3N afforded the
desired product, whereas in the cases where K3PO4 and
Suzuki–Miyaura cross-coupling reaction
Cs2CO3 were employed, no product was obtained (Table 2,
entries 3 and 4 vs. 1, Table 1). In these cases, it was reported Watson and coworkers, in their effort to expand the use of
that the aldol reaction products of Cyrene, 11 and 12 Cyrene in palladium-catalyzed cross coupling reactions, exam-
(Scheme 3B), were formed. The authors examined the for- ined its use in a classical Suzuki–Miyaura coupling reaction
mation of the aldol condensation by-products using a variety (Table 3).25 In the literature, suitable solvents for the Suzuki–
of bases at different temperatures. All inorganic bases, apart Miyaura reaction are usually THF, DMF or 1,4-dioxane. In
from KOAc at 25 °C, resulted in the condensation products. As 2018, the authors investigated the use of Cyrene, for a more
far as organic bases were concerned, pyridine and DBU deli- environmentally friendly approach, affording similar reaction
vered the condensation product at every temperature that was yields.25 In their efforts to find the optimized conditions, the
tested, whereas DIPEA and Et3N led to the condensation authors employed 4-bromotoluene (19) and phenylboronic
product, only when the reaction was performed at 100 °C. acid (20) as a model cross coupling reaction (Table 3).25
Following their observations, the authors employed Et3N at Different bases were examined and Cs2CO3 outperformed all
room temperature to suppress the aldol condensation reaction others. The major drawback appeared to be the consistency of
of Cyrene.24 With the optimized conditions in hand, they the reaction. The formation of dimer 12 (resulted from the
investigated the scope of aryl iodides in the Sonogashira reac- aldol condensation of Cyrene) was not controllable, leading to
tion. Electron-deficient and electron-rich aryl iodides afforded different results each time. To overcome this problem, water
the desired product in excellent yields. meta- or ortho- was exploited as the co-solvent, facilitating the fluidity of the
Substituted aryl and heterocyclic iodides were also examined, reaction mixture.25 They further examined the co-solvent pro-
spect at different temperatures, and higher yields were
obtained when a significantly higher reaction temperature was
Table 2 Sonogashira reaction of 13 with 14 using Cyrene as the solvent used.
Having the optimized conditions in hand, different classes
of organoboron reagents were tested, as well as various organo-
boron nucleophiles and aryl electrophiles. Electron-rich and
electron-deficient aryl halides afforded great to excellent
results, as did all the organoboron nucleophiles that were
Temperature Base Reaction time Yield tested.25 An interesting finding by the authors was that the use
Entry Base (°C) equiv. (h) %
1 Et3N 20 3 5 100
2 Et3N 20 1.1 5 98
3 K3PO4 20 3 5 —
4 Cs2CO3 20 3 5 —
5 Et3N 30 1.1 1 96
All reactions were carried out with 13 (0.25 mmol), 14 (0.26 mmol), Pd
(PPh3)2Cl2 (2 mol%), CuI (4 mol%), base, Cyrene, temperature, various
reaction times, and N2. Scheme 4 Cacchi-type annulations of α-aminohydroxy iodoarenes.
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Table 3 Suzuki–Miyaura reaction of 19 with 20 using Cyrene as the

solvent
Entry Solvent H2O (equiv.) Temperature (°C) Yield (%)
1 Cyrene 5 20 82
2 Cyrene 5 30 —
3 Cyrene 1.8 mL 20 81
4 Cyrene 1.8 mL 30 80
5 Cyrene 1.8 mL 50 94
6 DMF 1.8 mL 50 98
7 THF 1.8 mL 50 92
8 1,4-Dioxane 1.8 mL 50 100
9 H2O 50 31
All reactions were carried out with 19 (0.25 mmol), 20 (0.25 mmol),
and Pd(dppf)Cl2·CH2Cl2 (4 mol%).
of a medium polarity solvent, such as 40% EtOAc in petroleum

ether, facilitated the purification of the products, since dimer
12 was removed via filtration as it precipitated easily. They also
continued by probing the synthesis of 4′-methyl-biphenyl-
carbonitrile (OTBN) 24, which is a key intermediate in the syn-
thesis of an angiotensin II receptor antagonist (Scheme 5).25
Thus, they applied the optimized reaction conditions in a
larger scale of four grams. The results were very promising,
since the obtained yield agreed with the expected yield in
smaller scales.
Scheme 6 Synthesis of the sinapate β–β’ dimer 26 using Cyrene as the
solvent and various products of ethyl sinapate dimerization.
Dimerization of sinapic esters
Among the most challenging tasks in organic synthesis is the
preparation of β–β′ dimers of sinapic acid derivatives. The
an enzyme (laccase from Trametes versicolor), whose high
major drawback in all the methodologies reported in the litera-
affinity with the dimers may explain the presence of oligomers.
ture is the formation of the β-O-4′ dimer. Having studied the
Another major issue was the formation of the rearrangement
β–β′ dimerization of sinapyl alcohol, Allais and coworkers con-
product, whose solution was not efficient by changing the
cluded that a lot of presented problems could be easily circum-
solvent. Thus, the authors decided to use a different enzyme,
vented by tuning the reaction parameters.26 Later in 2020, they
Horseradish Peroxidase, HRP (types II and IV), but no better
proposed a copper(I)-catalyzed dimerization process.27 Ethyl
results were attained. After several unsuccessful attempts, they
sinapate was chosen as the model compound and they applied
opted for mimicking the active site of the enzyme using
conditions that were found in previous work of sinapyl alcohol
copper(I) bromide, air (O2) and pyridine at 50 °C for 24 h.
dimerization. Instead of the desired product 26, a complicated
Under these conditions, the desired product was obtained
mixture comprising the desired dimer 26, the β-O-4′ dimer 27
with good selectivity. Later, they sought greener alternatives
and a dimer obtained by a rearrangement of the desired dimer
for the reaction, where Cyrene was found to be the most
ethyl sinapate 28, that did not react with other oligomers, was
efficient solvent for the reaction. Apart from greening the
obtained (Scheme 6). The method involved the utilization of
process, the use of Cyrene as the reaction medium led to a
decrease in the amount of pyridine used, since it did not play
the role of the solvent and it was just used only as the oxidiz-
ing agent. The optimized conditions were applied to several
sinapic esters with great results (Scheme 6). Longer aliphatic
chains reacted very well, as did bulkier substituted groups,
achieving high yields (87% to 91%). For purification, a simple
extraction with EtOAc and HCl was enough to obtain the pure
Scheme 5 Gram-scale synthesis of OTBN 24. product.
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C–H difluoromethylation reactions

In 2021, Quero and coworkers studied the difluoromethylation
of heteroarenes (29) or terminal alkynes (31) (Scheme 7).28
They used copper iodide (CuI) particles anchored onto boron
nitrate nanosheets (BNNs). Due to their unique properties,

Scheme 8 Synthesis of urea 35 in Cyrene.
BNNs have gained a lot of attention lately. The authors
anchored CuI nanoparticles and created a heterogenous cata-
lyst, with which they performed the fluoromethylation reac-
tion. They initiated their investigation using benzothiazole reaction time. Additionally, extensive work-up and purification
and TMSCF2H, as the fluorination source, using NMP as the procedures are required. Since DMF is considered as a proble-
solvent and various bases such as t-BuOK, Na2CO3, NaHCO3 matic solvent in industry, and additional work-up procedures
and KOH. Finally, the best results were obtained with the use increase the manufacturing cost, Cyrene was considered as an
of KOH in the presence of Cyrene as the solvent (Scheme 7).28 alternative solvent, eliminating these disadvantages. The inves-
The proposed mechanism for the reaction demands the exist- tigation began with a model reaction which involved phenyl-
ence of an oxidant, which oxidizes the substrate to produce isocyanate (33) and pyrrolidine (34) in Cyrene (Scheme 8).29 A
an intermediate able to undergo a reductive elimination simple optimization followed, whilst the major challenge was
and afford the final product. Simultaneously, the catalyst is the development of a purification protocol to minimize the by-
restored. They used 9,10-phenanthrequinone (PQ) as the products. To develop an industrial applicable protocol the
oxidant.28 Having the best conditions in hand, the authors authors suggested a simple work-up process using water and
researched the scope of substrates which may effectively react. dichloromethane for a liquid–liquid extraction process.
A wide range of substituted benzothiazoles were studied and However, in many cases, further purification was needed,
electron-richer benzothiazoles seemed to be more effective since in some cases Cyrene co-eluted with the product. The
than electron-deficient ones. They also examined the recovery authors in their effort to provide a greener reaction protocol
and recyclability of the catalyst. Upon reaction completion, the investigated alternative purification protocols to minimize the
catalyst was filtered and washed with ethyl acetate and water, amount of waste produced. They proceeded with trying
and dried at 65 °C. The catalyst was reused up to five times, different acid/base work-up procedures, but both Cyrene
concluding in an effective protocol with the use of biosustain- and the synthesized urea derivatives were decomposed.
able Cyrene as the solvent. The authors indicated that repla- Surprisingly, the addition of water to the reaction mixture
cing common solvents, such as NMP and DMF, with Cyrene facilitated the purification of the formed urea, up to the point
led to short reaction times and greater yields. Furthermore, that all Cyrene was removed from the product. The water
the reported protocol was applied successfully to a wide range addition for the removal of Cyrene also eliminated the use of
of substrates. non-green solvents, used in other methods. Having found the
optimum reaction conditions for both the reaction and the
Synthesis of ureas purification of the products, the authors tried to expand the
scope of the amines used, when they reacted with phenyl iso-
Having in mind the pivotal role of ureas in a variety of fields,
cyanate.29 Cyclic and aliphatic secondary amines led to the
in 2017, Camp and coworkers tried to synthesize ureas from
desired products in good to excellent yields. The authors also
amines and isocyanates using Cyrene, instead of DMF, as a
examined the effect of a substituent on the aryl ring of the iso-
greener approach (Scheme 8).29 The major drawback using
thiocyanate. It appears that electron-deficient aryl isocyanates
DMF in the synthesis of urea derivatives appears to be the long
gave better results than the electron-rich ones, which is attrib-
uted to the increased electrophilicity of the isothiocyanate
carbon. The position of the substituent also plays a crucial
role, since due to steric hindrance, ortho-substituted aryl iso-
thiocyanate derivatives led to significantly lower yields.
Overall, a greener alternative for the synthesis of ureas was pro-
posed and it was proven that Cyrene can possibly be used
industrially as a solvent, since its removal is possible, just by
treating the reaction with water.
Isothiocyanate synthesis
In 2021, Meier and coworkers, having underlined the impor-
tance of developing in situ procedures for the formation of iso-
thiocyanates (ITCs) due to their toxicity, suggested a method
Scheme 7 Difluoromethylation of heteroarenes (29) and terminal
alkynes (31) using Cyrene as the solvent. All reactions were performed
that minimizes the negative impact.30 In that work, the
with 29 or 31 (1.0 equiv.), TMSCF2H (2.0 equiv.), catalyst (10 mg), t-BuOK authors employed elemental sulfur as the sulfurization agent
(3 equiv.), and 9,10-phenanthrenequinone (PQ) (1.2 equiv.). to avoid the use of metal catalysts, widely used in other similar
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approaches. Knowing from the literature that amines could be

used as organocatalysts in reactions that had isothiocyanates
as isolable intermediates, they began their investigations by
employing tertiary amines as organocatalysts. The use of ter-
Scheme 9 General reaction process for the synthesis of

tiary amines to trap the intermediate is essential, since in the isothiocyanates.
presence of primary or secondary amines, the ITC intermedi-
ate is instantly converted into a thiourea (Table 4).30 Next,
optimization of the reaction conditions such as the tempera- isocyanide tested was successfully synthesized, with steric hin-
ture, solvent and stoichiometry was done. In addition, the drance not playing a significant role. Electron-withdrawing
optimization of the purification method was also done. With and -donating groups, when aromatic and benzyl isothiocya-
the optimum conditions in hand, a wide range of amines nates were synthesized, did not affect differently the reaction
reacted with a model isocyanide, n-dodecyl isocyanide (36) outcome. The only substrate that presented problems and did
(Table 4).30 Various bases were also tested, with 1,8-diazabicy- not react was a carboxylic acid salt, perhaps because of solubi-
clo(5.4.0)undec-7-ene (DBU) and triazabicyclodecene (TBD) lity difficulties.
leading to quantitative conversion, whereas 4-dimethyl-
aminopyridine (DMAP) and 1-methylimidazole (NMI) were not Amide and peptide synthesis
as efficient (entries 1–3 and 6, Table 4). Triethylamine (TEA)
and 1,4-diazabicyclo[2.2.2]octane (DABCO) also afforded HATU mediated amide coupling. Synthesis of amides is
remarkable results (entries 4 and 5, Table 4). With these becoming more and more popular, since the number of pep-
results, the amount of base needed was also investigated and tides, approved for drug use, is increasing rapidly. Usually for
DBU demonstrated great results, when used in a catalytic amide synthesis, coupling reagents, such as N-[(dimethyl-
amount, in just 4 hours (entries 11 and 12, Table 4). A temp- amino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methyl-
erature screening followed, and moderate temperatures were methanaminium hexafluorophosphate N-oxide (HATU)
decided to be used. Finally, they sought the best solvent for or (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-
the reaction among numerous green solvents to decrease the morpholino-carbenium hexafluorophosphate (COMU) are
environmental impact. Cyrene led to the quantitative for- employed using dipolar aprotic solvents, such as DMF and
mation of the desired product after two hours reaction time, NMP. As it is already established, Cyrene is a good alternative
while GVL and DMSO afforded 92% and 85% yield, respect- to these solvents, thus in 2018 Watson and coworkers, follow-
ively. This can be easily attributed to its ability to dissolve and ing their findings, examined Cyrene’s use for amide coupling
stabilize polysulfur chains. via HATU coupling, obtaining similar results.31 Initially, they
Finally, numerous isothiocyanates were synthesized to studied the reaction between p-toluic acid (41) and aniline (42)
assess the scope of the developed method (Scheme 9).30 Every in the presence of HATU as the coupling agent (Table 5).31 The
reaction was completed in just one hour; however, some incon-
sistencies were observed. Due to Cyrene’s high viscosity, the
Table 4 Base screening for the optimization of the reaction using
stirring rate plays an important role in the reaction outcome.
DMSO as the solvent Among all the tested bases, DIPEA was found to be the suitable
Table 5 Reaction optimization for the amide coupling in Cyrene
Base Reaction time Conversiona

Entry Amine equivalents (h) (%)
1 DMAP 1.00 2 38
2 NMI 1.00 2 38
3 DBU 1.00 2 99
4 DABCO 1.00 2 84 DIPEA Reaction time Stirring Conversiona
5 TEA 1.00 2 76 Entry equiv. (h) rate (%)
6 TBD 1.00 2 100
7 DBU 0.10 2 57 1 2 24 Variable 87
8 DBU 0.10 22 67 2 2 1 Variable 84
9 TBD 0.10 2 36 3 2 1 200 73
10 TBD 0.10 22 69 4 2 1 400 71
11b DBU 2 mol% 4 100 5 2 1 800 96
12b DBU 5 mol% 4 100 6 3 1 400 92
7b 3 1 400 100
All reactions were carried out with 36 (1.0 equiv.), 37 (2.00 equiv. of
sulfur atoms), a respective amount of amine, DMSO (1 mL), r.t. All reactions were carried out with 41 (0.25 mmol), 42 (0.275 mmol),
a
GC samples were taken after the respective time and conversions and HATU (0.30 mmol). a (%) conversion was calculated by 1H-NMR
were calculated using biphenyl (0.25 equiv.) as an internal standard. using 1,4-dinitrobenzene as an internal standard. b DMF was used as
b
Reaction was performed using Cyrene as the solvent, at 40 °C. the solvent.
View Article Online
base for the amide coupling reaction. On increasing the thesis for the reactive functionalities to be accessible. When
amount of the base, they observed that the stirring factor did the resin swelling is not well achieved, reactive functionalities
not play such an important role. are blocked in the polymer matrix and are unable to react.33 As
Having the best conditions in hand, they proceeded by far as PS-Wang resin is concerned, a lower percentage of
expanding the scope of carboxylic acids and amines used.31 Cyrene gave better swelling results; however, for other resins, a
Aryl and alkyl carboxylic acids reacted with primary and sec- higher percentage of Cyrene was more efficient.32 The most
ondary amines affording great to excellent results. The reaction efficient Cyrene mixture was the one with diethyl carbonate in
protocol was successfully implemented in the synthesis of a a 30 : 70 ratio for the PS-Wang-OH (44) resin, which gave a
variety of dipeptides in high yields, using N-protected amino better swelling outcome than DMF. They continued by evaluat-
acids and a series of amino esters bearing side chains with ing the solubility of Fmoc-protected amino acids, more specifi-
alkyl or aryl substituents. In certain occasions, increase of the cally Fmoc-Val-OH was used as the model amino acid
amount of the HATU reagent was needed; however, the results (Scheme 10). Using a Cyrene mixture, the model amino acid
were very promising. The amidation protocol was successfully was not dissolved very well, hence the solubility was increased
applied in a larger scale and for the solid-phase synthesis of by adding a combination of coupling reagents. Among all,
smaller peptides. DIC/Oxyma was the most efficient. With these conditions in
hand, several amino acids were tested. The authors also exam-
Solid-phase peptide synthesis ined other green solvent binary mixtures, which were found
Using a similar concept, in 2019, Cabri and coworkers in many cases to be more efficient than the Cyrene
attempted the solid-phase peptide synthesis (SPPS), which is a mixture. Overall, Cyrene was more efficient than the often
faster synthetic approach for larger peptides (Scheme 10).32 In used solvents for peptide synthesis and this work is proof that
this approach, DMF is mostly used, and there have been many Cyrene may be a valuable green alternative for solid peptide
approaches for the replacement of DMF, due to its toxicity. In synthesis.
SPPS, generally the solvent is involved in the inflation of the
resins used for the synthesis, the washing, the deprotection Amide synthesis
and the coupling. As it was difficult to find a solvent quite In 2019, Camp and coworkers were also interested in amide
efficient for all these steps, a combination of solvents was synthesis, altering the coupling reaction. In that study, the
introduced, to achieve the maximum efficiency. Hence in this authors examined the reaction of acid chlorides with amines
study, Cyrene was combined with dimethyl or diethyl carbon- (Table 6).34 Various solvents can be used for this reaction,
ate. Other solvent mixtures were also examined.32 The evalu- namely DMF, dichloromethane or tetrahydrofuran, nonethe-
ation of the solvent mixture was performed by synthesizing a less they opted for Cyrene as a more sustainable solvent, and
model peptide (Aib-Enkephalin). When the optimum solvent employed 4-fluorobenzoyl chloride (48) to react with pyrrol-
system was found, a more challenging sequence was syn- idine (34), aniline (42) or benzylamine (49), in the presence of
thesized with this protocol. Initially, resin swelling was triethylamine as the base (Table 6).34 Their investigations
assessed.32 Resin swelling is obligatory for the solid-phase syn- began by assessing different work-up and purification
Scheme 10 Solid-phase peptide synthesis in Cyrene.
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Table 6 Optimization of the synthesis of amides 50 in Cyrene Substitution reactions

The first attempts that were carried out to assess the effective-
ness of Cyrene as the solvent mainly involved substitution reac-
tions. As was previously mentioned, in 2014, Sherwood and co-
workers employed Cyrene in two well-known and important

pharmaceutical industry reactions, the Menschutkin reaction
and a fluorination reaction.4
Entry Amine Work-up Yield (%)
1 Pyrrolidine (34) Aqueous; then column 91 (50a) Menschutkin reaction

2 Pyrrolidine (34) Column 75 (50a)
3 Aniline (42) Precipitate 72 (50b) As far as the Menschutkin reaction is concerned, it is a SN2
4 Benzylamine (49) Precipitate 81 (50c) type substitution, which involves two neutral reactants,
leading to a salt. It is widely used for the preparation of imid-
All reactions were carried out with 48 (1.0 equiv.), 34 or 42 or 49 (1.0
equiv.), triethylamine (1.1 equiv.), Cyrene (0.5 mL), 0 °C to r.t., 1 h. azolium containing ionic liquids. Usually, the reaction is per-
formed in polar solvents, such as DMF, so the performance of
Cyrene could be a safe indicator of its ability to substitute toxic
methods. The addition of water and an aqueous work-up was polar solvents. Cyrene afforded better results than widely used
sufficient, when anilines, primary amines or benzylamine were polar aprotic solvents, such as DMF, NMP and dioxane. Only
employed, yet in some cases further purification with column DMSO slightly outperformed Cyrene (Scheme 12).4
chromatography was needed. In addition to their observation
Fluorination reaction
in urea synthesis,29 addition of water did not result in product
precipitation and the produced amides formed an emulsion, A widely used substitution reaction with great pharmaceutical
when pyrrolidine was used.34 interest is the nucleophilic fluoride substitution. For the fluori-
Switching to primary aliphatic or benzylic amines, the nation reaction, the authors assessed the efficacy of Cyrene
desired amides could precipitate. It was also observed that in a nucleophilic aromatic substitution SNAr in 2-chloro-
without the aqueous work-up, lower yields were obtained by 5-nitropyridine (55), to afford 2-fluoro-5-nitropyridine (56)
column chromatography. The authors examined the scope of (Scheme 13).4 Nucleophilic substitutions proceed via the for-
the reaction using a variety of acyl chlorides in the reaction mation of a Meisenheimer intermediate, which can be stabil-
with pyrrolidine (34), aniline (42) or benzylamine (49).34 ized by the employed solvent. Sufficient stabilization of the
Moderate yields were obtained when heterocyclic benzoyl intermediate succors in the augmentation of the reaction rate.
chlorides were used and benzylamine afforded better results Cyclohexanone, Cyrene and NMP performed similarly, but
in comparison to the other amines employed. Moderate yields unfortunately not as well as other polar solvents, like DMSO,
were also obtained from aliphatic acid chlorides. In their DMF or sulpholane. However, their performance did not lead
attempt to investigate the behavior of Cyrene in the presence to major losses, making Cyrene a plausible greener alternative.4
of water, the authors investigated the hydration of Cyrene
(Scheme 11). Cyrene reacts with D2O forming geminal diol 51, Baylis–Hillman reaction
so they examined the effect of water percentage on the In 2020, Hunt and coworkers assessed various alternatives to
hydration of the ketone. Indeed, in a 1 : 1 ratio, the hydration dipolar aprotic solvents.36 One of the reactions studied in this
of Cyrene is favored. When an organic solvent was also process was the Baylis–Hillman reaction between 4-nitroben-
present, the keto form of Cyrene was favored instead. It is
pointed out that the control of the hydration process of Cyrene
facilitates its recycle. Furthermore, the authors reported that
the use of Cyrene along with water facilitates the precipitation
of the desired products more efficiently, compared to the pre-
cipitation protocol using DMF. To sum up, Cyrene seems to be
a plausible solvent for peptide chemistry, but further research
ought to be done, considering the synthesis of larger peptides
and their purification.35 Scheme 12 Menschutkin reaction between 52 and 53 using Cyrene as
the solvent.
Scheme 11 Production of germinal diol 51 from Cyrene. Scheme 13 Fluorination reaction of 55 to afford 56.
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materials. In 2021, Lee and coworkers suggested the formation

of bipyridine derivatives through a multicomponent reaction
under microwave irradiation (Table 7).38 Towards this aim,
they initially used aniline (42), 3-formylchromone (66) and
Scheme 14 Baylis–Hillman reaction between 57 and 58. 2-pyridineacetonitrile (67) under catalyst-free conditions. The
use of Cyrene as the solvent enabled the researchers to attain
an even higher yield than what was previously documented
zaldehyde and methyl acrylate (Scheme 14). A wide variety of using DMF, as the temperature could be elevated, without
solvents was tested, with great results, however, taking their further problems. Under the elevated temperature conditions
toxicity under consideration. NMP, sulfolane and Cyrene led to (150 °C), an impressive yield of 94% was obtained (entry 7,
reaction completion. However, NMP and sulfolane are repro- Table 7).38 It is interesting that the authors did not observe
toxic.7a Thus, Cyrene was the most successful alternative, with any by-product derived from Cyrene. It was also reported that
both great yields and low toxicity.36 In that study, the authors Cyrene’s recovery was easily succeeded from the reaction
examined a variety of potential green solvents in several coup- mixture, just by removing water in vacuo. After removing water,
ling reactions. The rate of the examined reactions varied and Cyrene was available for further use, without additional
depended on the solvent used. They mainly focused in the purification.
Baylis–Hillman coupling reaction, where great results afforded To explore in which extend this reaction could be efficient,
all the different substrates that were tested. Furthermore, the a great variety of aromatic amines was tested.38 Excellent yields
reaction conditions were successfully implemented in a gram were obtained using ortho-, meta- or para-substituted anilines
scale and the results were comparable to the lab scale, proving bearing either electron-withdrawing or electron-donating sub-
that Cyrene is a plausible solvent for the Baylis–Hillman reac- stituents. Excellent results were also afforded using aliphatic
tion for industrial use as well. and cyclic amines irrespective of whether they were primary,
secondary, or even heteroaromatic.
Cyrene as a catalyst–solvent The authors explored the reaction of a variety of 3-formyl-
chromones with aniline (42) or 2-aminopyridine and 2-pyridyl-
In 2022, Yu and coworkers proposed a protocol for the conver-
acetonitrile (67). The presence of an electron-donating or elec-
sion of amines to formamides 63, using CO2 and PhSiH as the
tron-withdrawing group afforded the desired product in excel-
reductant.37 They also successfully applied this protocol in the
lent yields (83–96%). Furthermore, combination of an elec-
synthesis of benzothiazoles 65 from aminothiophenols 64
tron-donating and an electron-withdrawing group on the chro-
(Scheme 15).37 Cyrene presented excellent results playing sim-
ultaneously the role of the solvent and the catalyst, perhaps
due to its polarity. Moreover, NMR mechanistic studies were
Table 7 Optimization of the reaction leading to 68
carried out, indicating that Cyrene polarizes the N–C bond,
making nitrogen a better nucleophile, thus enabling the reac-
tion. Additionally, it was found that it also activates the Si–H
bond via the polarization effect, enabling the insertion of the
CO2. The authors continued their study by examining the sub-
strate scope realizing that electron-rich substituted anilines
afforded higher yields, since the electron-rich benzene ring
increases the nucleophilicity of the nitrogen atom, making the
nucleophilic attack on silanes more favorable.37
Construction of diverse bipyridine analogues

Entry Solvent Temperature (°C) Reaction time (h) Yielda (%)
Bipyridine analogues constitute one of the most important
classes of molecules found in many natural products and 1 — 90 2 40
2 H2O 90 1 —
3 EtOH 90 1 48
4 DMF 90 1 66
5 Cyrene 90 1 76
6 Cyrene 110 1 83
7 Cyrene 130 1 94
8 Cyrene 150 1 91
9b Cyrene 130 24 35
10 DMF 130 1 85
11 — 130 1 32
All reactions were carried out with 42 (1.00 mmol), 66 (1.00 mmol) and
67 (1.00 mmol) under 300 W temperature-controlled microwave
irradiation. a Yield of the isolated product. b Reaction under traditional
Scheme 15 Formation of formamides (63) or benzothiazoles (65). heating.
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mone core did not alter the reaction outcome. Only in the case product was formed with excellent conversion and enantio-
when two electron-deficient groups were present on the chro- meric excess. It was observed that Cyrene’s keto group
mone moiety, the yield of the reaction was slightly lower. remained intact in the presence of the reductive agents, since
Expanding the scope of the protocol, the authors employed no reduction products were attained. However, with the use of
3-( pyridinyl)acetonitrile and 4-( pyridine)acetonitrile, leading some biocatalysts, Cyrene’s concentration seemed to have a
to the desired dipyridine analogue in good yields (72% and significant impact on the conversion and the optical purity.
64%, respectively).38 Adhering to this logic, the authors intro- Another condition that seemed to play an important role was
duced other cyano-containing molecules, such as benzyl the substrate concentration. Generally, when the percentage of
cyanides, instead of the pyridinyl acetonitriles. Excellent Cyrene in the reaction medium was quite low (2.5% v/v), both
results were also afforded in the presence of electron-deficient stereoisomers could be obtained, depending on the ADH that
groups on the aromatic ring, whereas benzyl cyanide, as well was employed.39 In addition, when alcohol dehydrogenase
as 4-methyl derivative, did not afford the desired product. KRED P2-D03 was used, a larger percentage of Cyrene could be
Finally, the reaction products were found to bind with some tolerated (30% v/v), without negatively influencing the reaction
heavy metals, like Hg2+, Fe3+ or Cu2+, which makes them outcome.
useful for various applications, such as catalysis and pollution
monitoring (Scheme 16). Biocatalytic esterification
As was previously noted, in 2016 and 2018, researchers
Biocatalysis attempted the use of Cyrene as the solvent in biocatalytic ester-
ifications, but none of these efforts were successful.21
Bioreduction of α-ketoesters to α-hydroxyesters. In 2020, De
However, in 2020, Guajardo and coworkers successfully accom-
Gonzalo suggested the use of Cyrene as a bio-based solvent,
plished the esterification of benzoic acid 72 with glycerol 73,
since water that has already been studied, led to unwanted
using lipase Novozym 435 and crosslinked aggregates of CAL-B
side reactions, such as hydrolysis of the reactants.39 The
(Scheme 18).40 The authors indicated that the in situ derivati-
authors indicated that Cyrene as the bio-based solvent for bio-
zation of Cyrene can afford a novel family of green solvents
catalysis can replace other solvents, such as 2-Me-THF and
with enhanced properties. Initially, the authors tested the solu-
cyclopentyl methyl ether (CPME). It was the first time that the
bility of the reagents at different concentrations, where Cyrene
use of Cyrene was studied for a reductive process, using
demonstrated excellent solubility, like dioxane. As expected,
alcohol dehydrogenases (ADHs). The authors introduced the
since Cyrene does not perform well under acidic conditions,
bioreduction of α-ketoesters to α-hydroxyesters with the use of
more equivalents of glycerol were added, to decrease the acidic
Cyrene (Scheme 17).39 Initially, ethyl benzoylformate was used
conditions induced by the presence of benzoic acid 72. Not
as a model ketoester and various ADHs were used as biocata-
only the reaction occurred in both occasions, but in the case
lysts (Scheme 17). Additionally, two nicotinamide co-factors or
of CAL-B, the catalyst could be recycled up to six times using
glucose dehydrogenase, coupled with glucose, were employed
phosphate buffer of pH 7, albeit higher biocatalyst loadings
as recycling systems. With every combination used, the desired
were recommended and higher temperatures were required
(60 °C).40 Furthermore, the authors examined Cyrene as the
co-solvent for enzymatic hydrolysis, using the same enzymes
as for the esterification. Cyrene was tested in various pro-
portions to water (0–40%). The authors demonstrated that
increasing the proportion of Cyrene led to the deactivation of
the biocatalyst. This can probably be attributed also to the fact
that upon decreasing the water proportion, the reaction equili-
brium tends to the formation of ester 74. Even though
Cyrene’s performance is poor compared to other systems
reported in the literature, such as deep eutectic solvents (DES),
Scheme 16 The proposed structure of 69 when it binds with a heavy
metal atom.
Scheme 17 Optimized bioreduction of α-ketoesters (70) to 71 in Scheme 18 Lipase-catalyzed esterification of benzoic acid (72) with
Cyrene. glycerol (73) using Cyrene as the reaction medium.
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further optimization might provide new opportunities for its Cyrene for the dispersion of graphene
use in biocatalysis. The augmentation in ink demand makes its production more
systematic. However, most solvents used for the graphene ink
Materials chemistry process are toxic and not environmentally friendly. Thus, their
MOF synthesis. In 2016, Katz and coworkers exploited industrial use is not favored, and new solutions must be found
Cyrene for the synthesis of metal organic frameworks to overcome this problem. In 2017, Salavagione and coworkers
(MOFs).41 MOFs are often synthesized in toxic organic sol- investigated the use of several green solvents for graphene
vents, such as DMF, due to their high boiling points, because exfoliation, including Cyrene.42 Having in mind that an essen-
MOF synthesis requires elevated temperatures. Firstly, the tial factor for graphene dispersion is the solvent surface energy
authors synthesized MOF HKUST-1 using a mixture of Cyrene and that the concentration might influence the solvent
and EtOH as the solvent system and successfully led to the polarity, they conducted a solvent screening to determine
desired crystalline product. The authors observed different which solvents could be efficient. Cyrene was used for the dis-
reaction outcomes in the case where Cyrene was used instead persion of graphene while applying a 15-minute ultrasound
of DMF. More specifically, different orientations were obtained treatment. A high concentration of dispersed graphene was
and larger particles were formed when Cyrene was employed.41 achieved, perhaps due to the greater viscosity of Cyrene, in
Afterwards, they proceeded by evaluating the N2 gas-absorp- comparison to other solvents previously employed. As far as
tion isotherm of HKUST-1. Comparing the surface area (SA) of the quality of the dispersed graphene is concerned, the flakes
the MOF synthesized with the use of DMF, the BET SA was obtained presented some diversity in their thickness and
about 1400 m2 g−1 (Table 8). When a mixture of Cyrene and dimensions. In conclusion, the Cyrene-based process gener-
EtOH mediated the reaction, the SA was determined to be ated better quality graphene than regularly used solvents.
600 m2 g−1. To explain the difference in the N2 gas-absorption In 2018, Pan and coworkers also studied the use of Cyrene
isotherm, the authors examined various ratios of Cyrene/ for the dispersion of graphene.43 More specifically, they com-
EtOH. It was observed that when dry ethanol was used as the pared Cyrene with N-methylpyrrolidone (NMP). NMP is a very
additive with Cyrene, the BET SA was 1400 m2 g−1. The BET SA toxic dipolar aprotic organic solvent whose use is suggested to
of the MOF decreased when the ethanol used was not absol- be reduced, due to its hazardous effects.7 Firstly, conductivity
ute. This was attributed to the fact that in the presence of was evaluated. For the exfoliation of ink, they also used a soni-
water, Cyrene might react to produce the geminal diol and cation treatment. It was observed that the sheet resistance of
other products (Scheme 11). Thus, the use of dry EtOH was the laminate made with Cyrene decreased faster than the one
obligatory. Furthermore, the authors pointed out the necessity made with DMF. By increasing the sonication time, the graph-
of keeping the water content of Cyrene low. Next, the synthesis ite flakes become smaller, so the conductivity decreases, and
of other MOFs using Cyrene was investigated. Four more the sheet resistance rises again. Cyrene was found to be more
MOFs were synthesized: UiO-66, ZIF-8, MOF-74 and effective, since it required less time than NMP to achieve the
Zn2(BDC)2(DABCO) (Table 8). Both DMF and Cyrene gave the same results of conductivity.43 Next, the addition of adhesive
same products in all four cases, with some differences in the materials was examined, which generally decreases the con-
orientations. The authors further investigated the lower SA ductivity. In this case cellulose acetate butyrate (CAB) was
that was observed with the use of Cyrene, but this time they added into the Cyrene-derived graphene ink and different con-
did the investigations with ZIF-8. Although PXRD showed centrations of CAB were tested. Also, the graphite flakes were
different peak intensities, the peaks overall did not differ. characterized and evaluated by atomic force microscopy (AFM)
Fortunately, examination using a microscope revealed the pres- and the stable existence of few-layer graphene nanoflakes was
ence of an aldol condensation product of two Cyrene mole- confirmed.43 For the evaluation, FT-IR spectroscopy and
cules (Scheme 3B) among the crystalline powder of ZIF-8, Raman spectroscopy were also used. In conclusion, graphene/
which could be avoided by decreasing the heating. Finally, it CAB ink was developed by exfoliation and dispersion of gra-
was observed that there is always residual Cyrene especially in phene sheets in Cyrene, achieving great conductivity with and
small-pore aperture MOFs, so further washing and activation without the addition of CAB.
routines might be needed, but were not suggested.
ROM polymerization
Table 8 Obtained BET SA for MOFs

In 2021, the polymerization of levoglucosenyl alkyl ethers 75
was investigated using various green solvents, including
Observed Observed Cyrene.44 The specific polymerization was mostly succeeded by
Expected in DMF in Cyrene employing a Grubb’s catalyst (C793) (Scheme 19). In that work,
Entry MOFs (m2 g−1) (m2 g−1) (m2 g−1)
C793 was used as well and the ROM polymerization of the levo-
1 HKUST-1 1740 1400 1500 glucosenyl alkyl ethers afforded amorphous polyacetals with
2 UiO-66 1700 1300 500 thermoplastic behavior, which were easily degradable by
3 Co-MOF-74 1572 800 200
4 ZIF-8 1950 1700 600 hydrolysis.44 The degrees of polymerization fluctuated around
5 Zn2(BDC)2(DABCO) 1750 1950 1300 100 and molar mass distributions were broad with a dispersity
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thesis.47 In conclusion, the ability to determine the mor-

phologies of the membranes formed by these polymers was
shown. By just altering the temperature and the Cygnet–
Cyrene analogy, different membranes could be formed with
various properties and numerous applications.

In 2022, Paugam and coworkers developed a more sustain-
able method for the fabrication of polymeric membranes by a
phase-inversion technique.48 As the polymeric matrix, the
authors employed poly(hydroxybutyrate-cohydroxyvalerate)
(PHBHV), which is a biopolymer and belongs to a family of
polymers known for their biocompatible properties as

microbial polymers, PHAs. The produced membranes were
permeable to water and they were asymmetric. Various mem-
Scheme 19 Cyrene in the polymerization of levoglucosenyl alkyl branes were produced, with or without additives. All of them
ethers 75. due to their hydrophilicity presented some selectivity towards
MeOH, which depended on the type of each membrane.
Moreover, all of them performed well when stability tests in
of around 2. The products obtained by this polymerization are demanding environments were conducted.48
plausible plastic materials and more importantly, they are sus-
tainably synthesized. Cyrene in the field of antimicrobial susceptibility testing
DMSO is one of the most common solvents used as the vehicle
Cyrene for the preparation of membranes in antimicrobial susceptibility testing. A tendency to find
greener alternatives led Camp and coworkers, in 2020, to
In 2019, Figoli and coworkers proposed the use of Cyrene for
assess the efficiency of Cyrene as an alternative to DMSO.49
membrane preparation.45 More specifically, the use of poly-
Initially, the toxicity of Cyrene and DMSO towards bacteria was
ethersulfone (PES) and poly(vinylidene fluoride) (PVDF) to
compared and found to be quite similar. Next, they were com-
produce membranes was studied. For these procedures, toxic
pared as vehicles for standard antibacterial drugs in minimum
organic solvents are often used, such as N-methyl-pyrrolidone
inhibitory concentration (MIC) tests and a drug discovery
(NMP) or N,N-dimethyl acetamide (DMAc). It was observed
screening protocol was used. Cyrene was found to be equally
that the moisture, the viscosity of the solution and the inter-
effective. They proceeded by testing the activity of antibacterial
actions between the polymer and the solvent played an impor-
drugs in both solvents and concluded that the results were
tant role. Moreover, several factors were assessed to draw a
within the experimental setup, although there were differences
conclusion. The factors evaluated were the membrane mor-
between the two solvents.49 Additionally, their ability to pre-
phology, the pore diameter, their hydrophilic character,
serve long-term dissolved antibacterial drugs was assessed and
thermal behavior, and crystallinity degree. Overall, Cyrene
the results were satisfactory. Finally, dissimilar to DMSO,
proved to be a new choice for sustainable membrane
which protects ESKAPE pathogens from ROS-mediated cell
fabrication.46
death, induced by stress, Cyrene does not protect them from
Another group approached the membrane synthesis using
dying. In conclusion, they confirmed that Cyrene could be a
Cyrene. In 2021, Pellis and coworkers studied membrane fabri-
noteworthy substitute for DMSO in antimicrobial susceptibility
cation with Cyrene using four polymers: cellulose acetate (CA),
testing.
polysulfone (PSf ), polyethersulfone (PES) and polyimide (PI).47
Cyrene and Cygnet (77), a Cyrene derivative, were used Lignins
(Scheme 20). Intriguingly, their mixture seemed to be more
In the past decade many researchers have worldwide focused
efficient as the solvent for the PES polymer. The morphologies
their research on developing new processes to isolate lignin.
of the membranes prepared were highly dependent on the
To obtain better properties, chemical modifications are
ratio of the solvent used. Furthermore, the authors reported
required which are impossible without their solubilization.
the important role temperature played in membrane syn-
However, their solubility presents difficulties, and a small
number of solvents can overcome them and solubilize lignins.
Mostly these solvents are reprotoxic and hazardous for the
environment. In 2021, Averous and coworkers examined
Cyrene’s efficiency as a lignin solvent for lignins Kraft (KL),
soda (SL) and organosolv (OSL).50 Also, their efficacy as sol-
vents for the fractionalization of Kraft lignin (KL) and for the
chemical modifications of lignins was tested. Firstly, the solu-
bility of lignins in Cyrene was assessed. None of the lignins
Scheme 20 Cyrene 2 and Cygnet 77. tested were fully soluble in Cyrene, whilst with the addition of
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water, their solubility increased significantly. This can be Notes and references
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Cyrene A Bio-Based Novel and Sustainable Solvent

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Green Chemistry

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Cyrene: a bio-based novel and sustainable solvent

1. Introduction dimethyl formamide (DMF), N-methylpyrrolidone (NMP),

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since then the interest in its use as a bio-based solvent has

Thessaloniki. In 2012, he was appointed as a postdoctoral fellow

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ble with water, which appears to be a very interesting property,

Scheme 3 (A) Grignard reaction, (B) aldol condensation reaction of

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aﬀording the desired product in excellent yields, as most of

The generated intermediate from the Sonogashira coupling

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Table 3 Suzuki–Miyaura reaction of 19 with 20 using Cyrene as the

Entry Solvent H2O (equiv.) Temperature (°C) Yield (%)

of a medium polarity solvent, such as 40% EtOAc in petroleum

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C–H difluoromethylation reactions

nitrate nanosheets (BNNs). Due to their unique properties,

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approaches. Knowing from the literature that amines could be

Scheme 9 General reaction process for the synthesis of

Table 5 Reaction optimization for the amide coupling in Cyrene

Base Reaction time Conversiona

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Scheme 10 Solid-phase peptide synthesis in Cyrene.

Green Chemistry Tutorial Review

Table 6 Optimization of the synthesis of amides 50 in Cyrene Substitution reactions

workers employed Cyrene in two well-known and important

1 Pyrrolidine (34) Aqueous; then column 91 (50a) Menschutkin reaction

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materials. In 2021, Lee and coworkers suggested the formation

Construction of diverse bipyridine analogues

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Tutorial Review Green Chemistry

Table 8 Obtained BET SA for MOFs

Green Chemistry Tutorial Review

thesis.47 In conclusion, the ability to determine the mor-

various properties and numerous applications.

polymers known for their biocompatible properties as

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some diﬃculties.50 US20110219679A1, 2011.

Green Chemistry Tutorial Review

23 H. A. Le Phuong, L. Cserti, G. F. S. Whitehead, A. Garforth, 257.

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