Carbon-carbon bond formation in acid deep eutectic solvent: Chalcones synthesis: Via Claisen-Schmidt reaction

Article abstract of DOI:10.1039/c6ra04721a

One of the most studied properties of novel organic solvents is represented by their use as media for many chemical reactions. In this field Ionic Liquids (ILs) and more recently Deep Eutectic Solvents (DESs) have been playing significant roles for their smart properties. DESs are increasing their relevance thanks to their low toxicity, and because of their simple and cheap preparation that can be carried out by simply mixing two compounds. In this work we present the studies of the use of an acid DES obtained from 3-(cyclohexyldimethylammonio)propane-1-sulfonate and (1S)-(+)-10-camphorsulfonic acid (SB3-Cy/CSA) as reaction media and catalyst for carbon-carbon bond formation reaction via Claisen-Schmidt condensation. This powerful and widely used aldol condensation was performed without the use of any catalysts that are usually needed in this reaction, because of the presence of acid CSA in the DES components. We synthesised fourteen substituted chalcones from benzaldehydes and substituted benzaldehydes in combination with acetophenone and substituted acetophenones as probe reactions. The advantages of the use of this DES in this relevant reaction are represented by: the green properties of the media and its low toxicity; the absence of harmful acids to catalyse the aldol condensation because of the camphorsulfonic acid composing the DES mixture; the recycling and the re-use of the DES in subsequent reaction cycles; the mild conditions and the excellent conversions and yields observed.

Full text of DOI:10.1039/c6ra04721a

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DOI: 10.1039/C6RA04721A
Carbon-Carbon bond formation in acid deep eutectic
solvent: chalcones synthesis via Claisen-Schmidt
reaction
Matteo Tiecco, Raimondo Germani*, Fabio Cardellini
CEMIN, Centre of Excellence on Nanostructured Innovative Materials, Department of
Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, I-06123
Perugia, Italy.
*Corresponding author: Raimondo Germani,
Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto
8-I 06123 Perugia, Italy
E-mail: raimondo.germani@unipg.it
Phone: + 39 075 585 5538
Fax: +39 075 585 5560

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DOI: 10.1039/C6RA04721A
ABSTRACT
One of the most studied properties of novel organic solvents is represented by their use as
media for many chemical reactions. In this field Ionic Liquids (ILs) and more recently Deep
Eutectic Solvents (DESs) have been playing significant roles for their smart properties. DESs
are increasing their relevance thanks to their low toxicity, and because of their simple and
cheap preparation that can be carried out by simply mixing two compounds.
In this work we present the studies of the use of an acid DES obtained from 3-
(cyclohexyldimethylammonio)propane-1-sulfonate and (1S)-(+)-10-Camphorsulfonic acid
(SB3-Cy / CSA) as reaction media and catalyst for carbon-carbon bond formation reaction via
Claisen-Schmidt condensation. This powerful and widely used aldol condensation was
performed without the use of any catalysts that are usually needed in this reaction, because of
the presence of acid CSA in the DES components. We synthesised sixteen substituted
chalcones from benzaldehydes and substituted benzaldehydes in combination with
acetophenone and substituted acetophenones as probe reactions.
The advantages of the use of this DES in this relevant reaction are represented by: the green
properties of the media and its low toxicity; the absence of harmful acids to catalyse the aldol
condensation because of the camphorsulfonic acid composing the DES mixture; the recycling
and the re-use of the DES in subsequent reaction cycles; the mild conditions and the excellent
conversions and yields observed.
KEYWORDS: C-C bond formation; chalcones; acid DES; sulfobetaine; camphorsulfonic acid.

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DOI: 10.1039/C6RA04721A
INTRODUCTION
The design of innovative reaction media and of novel synthetic strategies has increased its
relevance in the green chemistry framework, with the goal of obtaining more environmental
friendly processes. Novel organic solvents such as ionic liquids (ILs) play a key-role in this
field1-3. These liquids are formed by organic cations and organic or inorganic anions; they are
liquid at temperatures under 100°C, and they have many “green” advantages compared to
other typical organic solvents. They have, in fact, low vapour pressure, high thermal stability
and low flammability. These properties pushed the researchers to apply these solvents as
ecological friendly reaction media4-7. Unfortunately the ILs showed low biodegradability and
low biocompatibility, and therefore low sustainability7-10; the synthesis and purification of
these media often requires extensive use of organic solvents7.
Deep Eutectic Solvents (DESs) represent a step forward on novel green media production, and
they are an innovative and promising class of liquids still to be fully described and analysed11-
15. For their simplicity of preparation, the atom economy, and the low cost of many starting
reagents, DESs have gained particularly attention as substitutes of conventional volatile
organic solvents and of ILs in many chemical processes16-21. A class of DES can be prepared, in
fact, simply mixing high-melting point salts (such as ammonium or phosphonium ones) with
hydrogen bond donor compounds. The hydrogen-bond interaction that occurs within the
donor and the acceptor molecules determines a considerable reduction of the melting point of
the mixtures, therefore a liquid system formation, even at room temperature22. One of the
advantages of the use of the DESs instead of the ILs is represented by their low or absent
toxicity, as shown in recent papers13, 22-25. DESs have been studied and used in the recent
literature as solvents for chemical processes, but also as catalysts26. A non-exhaustive list of
these reactions is represented by: Knoevenagel condensations27, 28, Paal-Knorr reaction29,
halogenation reactions30, N-alkylation of aromatic primary amines31, synthesis of N-aryl
phthalimide derivatives32, oxidation of alcohols33, and so on.
Aldol condensation is a powerful and well-known tool for C-C bond formation between two
carbonyl derivatives34, 35. It has numerous applications in the synthesis of fine chemicals and
it can be accomplished both via basic36 and acid37, 38 catalysis. The aldol condensation was
deeply investigated in ILs, as they can act as reaction media39, 40 and also as catalysts41: this is
the case of protic-ILs, a relevant acidic sub-class of these liquids5. The Claisen-Schmidt
reaction is an important sub-class of aldol condensation involving an aldeide/ketone and a
carbonyl compound lacking an alpha-hydrogen. This reaction is generally used for the
synthesis of chalcones, an important class of molecules with relevant pharmaceutical

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properties42-44. The syntheses were investigated in ILs reaction media in literature45; Dong
DOI: 10.1039/C6RA04721A
and co-workers and Qian and co-workers performed the Claisen-Schmidt reactions in acid-ILs
media under N2 atmosphere at 120°C and 140°C respectively46, 47. Aldol condensation reaction
was carried out even in deep eutectic solvents media in literature, but the DESs used in these
works were not able to accomplish both the roles of reaction media and catalysts, calling for
the use of other reagents and of other procedures. Müller and co-workers performed aldol
reactions with tandem catalysis of enzymes and organocatalysts in DESs48, 49. Martínez and
colleagues used L-proline as catalyst to achieve an enantioselective intermolecular aldol
reaction in D-glucose and racemic malic acid DES50. Gotor-Fernández and co-workers
performed recently the promiscuous lipase-catalysed aldol reaction in choline chloride /
glycerol deep eutectic solvent that led to excellent conversions of the reactants51.
Moving forward on our characterizations and on our use of novel “greener” solvents4-6, 52, in
this work we report the use of a DES both as reaction media and Brønsted acid catalyst in the
synthesis of substituted chalcones via Claisen-Schmidt reaction. This is a probe reaction of C-C
bonds formation and it was performed without the use of any other catalysts. 3-
(cyclohexyldimethylammonio)propane-1-sulfonate
(SB3-Cy)
and
(1S)-(+)-10-
Camphorsulfonic acid (CSA) mixture (hereinafter reported as SB3-Cy / CSA) was chosen in a
set of Room Temperature Deep Eutectic Solvents (RTDESs) we recently realized and
characterized22. This DES was chosen in this set (composed by differently structured
sulfobetaines with aliphatic, aromatic and amphiphilic moieties) for many reasons: it is
colourless; it has an intermediate viscosity between the set; it has advantages deriving from
the cost and the availability of the tertiary amine (SB3-Cy) forming it; the DES from this amine
can be easily obtained considering the reactivity of the other aromatic sulfobetaines; it could
prevent emulsion formation in the elaboration processes that can occur in the case of
amphiphilic sulfobetaines use.
This DES has a catalytic behaviour in the reaction between benzaldehydes and acetophenones
due to the acid properties of the CSA composing it. It was prepared by simply mixing the two
solid components that have high melting points (198°C for CSA, 116°C for the sulfobetaine),
and it is a liquid system even at room temperature (9°C). The low conductivity values
observed for this DES in our previous work showed that in the mixture the proton has not
been transferred from the acid to the sulfobetaine, therefore it cannot be considered an acid-
IL.
There are many “green” advantages in the use of SB3-Cy / CSA DES in this probe reaction: it is
an environmental friendly solvent for its properties and for its low toxicity; no harmful acids

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are needed to catalyse the reaction; the high recyclability of the media wDaOsI: 1p0r.1o03v9e/Cd6RAo0n4721A
subsequent reaction cycles. SB3-Cy / CSA DES was chosen as model mixture in our set for its
properties. We used also SB3-MIM (3-(1-methyl-1H-imidazol-3-ium-3-yl)propane-1-
sulfonate) / CSA mixture in one of the reactions in order to improve its conversion and yield
and to demonstrate the applicability of a specific DES for a specific role22. All the reactions
studied in this work were performed at the temperature of 90°C and in times spanning from 4
to 16 hours.
EXPERIMENTAL
Materials and Methods
Solvents, tert-butylbenzene, (1S)-(+)-10-camphorsulfonic acid, N,N-dimethylcyclohexylamine,
1,3-propanesultone, benzaldehyde and substituted benzaldehydes, acetophenone and
substituted acetophenones were purchased of analytical grade from Sigma-Aldrich, Fluka and
Alfa Aesar and were used without further purifications.
Melting points were determined on crystallized products on a Barloworld Scientific Stewart
SMP3 micro melting point apparatus and are uncorrected. Agilent 6850 Series II Network Gas
Chromatography instrument (column DB-35MS l = 30 m, d = 0.32 mm, film = 0.25 mm) was
1
used for GC analysis. H-NMR and 13C-NMR spectra were measured at 25°C with a Bruker
AVANCE III HD 400 MHz and with a Bruker 200 MHz instruments in D2O, CDCl3 and acetone-
d6 solutions with tetramethylsilane ((CH3)4Si) as internal standard.
DES preparation
3-(cyclohexyldimethylammonio)propane-1-sulfonate (SB3-Cy) was prepared via reaction of
N,N-dimethylcyclohexylamine with 1,3-propanesultone according to previous procedures
1
reported in literature, and the recorded melting point and H-NMR spectra agree with the
same literature data22. The DES was prepared following the procedure reported in the same
paper. (1S)-(+)-10-camphorsulfonic acid (CSA) was dried under vacuum over P2O5 prior to
use. SB3-Cy and CSA, in 1:1.5 molar ratio, were directly weighted in a flask fitted with a
stopper. The solid mixture was magnetically stirred and heated at 90°C until a liquid was
formed (20-30 minutes).
General synthetic procedure

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In a 10 ml round-bottomed flask 10 mmol of (1S)-(+)-10-camphorsulfonic acid (CSA) and 7
DOI: 10.1039/C6RA04721A
mmol of 3-(cyclohexyldimethylammonio)propane-1-sulfonate (SB3-Cy) were introduced
(1:1.5 molar ratio). The mixture was heated at 90°C for 20 minutes in a thermostated oil bath
under stirring, until a homogeneous liquid was formed. The aldehyde and the ketone (3.3
mmol, 1:1 molar ratio) were added to the mixture. The mixture was stirred at 90°C for the
time needed for each reaction; then it was cooled to room temperature. The reaction mixture
was quantitatively transferred in a separator funnel and extracted five times with ethyl
acetate. The organic phase was dried under Na2SO4 and filtered through a fluted filter in a
round-bottomed flask. The products were purified with column chromatography with
cyclohexane:ethyl acetate mixture as eluent with different elution gradient; a recrystallization
was made in some of the reactions performed. Every reaction was repeated twice, in order to
determine the conversion via GC and in order to purify the products to determine the isolated
product yield.
Conversion determination procedure
The conversions were determined via GC. The reaction mixtures were cooled to room
temperature, transferred in a separator funnel, and tert-butylbenzene (Sigma-Aldrich, >99%)
was added as internal standard. The mixtures were extracted five times with ethyl acetate.
The organic phases was dried under Na2SO4 and analyzed on GC. The conversion was
determined on the benzaldehyde (γ = 1.78) or acetophenone (γ = 1.45) or 3,4-
dimethoxybenzaldehyde amounts in different experiments.
Characterization of the chalcones
All the spectra are reported in Supporting Information section.
(1) (2E)-1,3-diphenylprop-2-en-1-one53: after chromatographic column the product was
recrystallized with H2O:EtOH 80:20 mixture. A yellow solid was obtained. Yield 64%, m.p. 55-
57°C. 1H NMR (400 MHz, CDCl3) δ 8.09 – 8.02 (m, 2H), 7.85 (d, J = 15.6 Hz, 1H), 7.71 – 7.50 (m,
6H), 7.45 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 190.55, 144.85, 138.22, 134.90, 132.81,
130.57, 128.98, 128.65, 128.53, 128.47, 122.10.
(2) (2E)-3-(4-hydroxyphenyl)-1-phenylprop-2-en-1-one53: the product was purified via
chromatographic column then recrystallized with H2O:EtOH 80:20 mixture. A yellow solid
1
was obtained. Yield 80%, m.p. 179-180°C, H NMR (400 MHz, Acetone-d6) δ 8.16 – 8.09 (m,
2H), 7.81 – 7.69 (m, 4H), 7.69 – 7.59 (m, 2H), 7.59 – 7.49 (m, 2H), 6.98 – 6.91 (m, 2H). 13C NMR

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(101 MHz, Acetone-d6) δ 189.02, 159.95, 144.32, 138.60, 132.48, 130.68, 128.57, 128.27,
DOI: 10.1039/C6RA04721A
126.72, 118.80, 115.84, 29.73.
(3) (2E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one54: the product was recrystallized
1
with H2O:EtOH 80:20 mixture. A yellow solid was obtained. Yield 93%, m.p. 163-164°C. H
NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 7.6 Hz, 2H), 7.88 – 7.77 (m, 4H),
7.71 – 7.60 (m, 2H), 7.55 (t, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 189.62, 148.55,
141.50, 141.05, 137.53, 133.38, 128.95, 128.83, 128.60, 125.71, 124.22.
1
(4) (2E)-3-(2-nitrophenyl)-1-phenylprop-2-en-1-one55: Yield 65%, m.p. 118-120°C. H
NMR (400 MHz, CDCl3) δ 8.17 - 8.13 (d, J = 16 Hz, 1H), 8.10 - 8.03 (m, 3H), 7.78 - 7.69 (m, 2H),
7.64 – 7.52 (m, 4H), 7.37 – 7.33 (d, J = 16 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 190.48, 148.55,
140.19, 137.41, 133.60, 133.17, 131.33, 130.37, 129.26, 128.80, 128.74, 127.34, 125.01.
(5) (2E)-3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one56: Yield 76%, m.p.
92-93°C. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 15.6 Hz, 1H), 7.56 (m,
3H), 7.40 (d, J = 15.6 Hz, 1H), 7.28 – 7.19 (m, 1H), 7.15 (s, 1H), 6.98 (m, 1H), 3.97 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 190.71, 148.34, 146.88, 145.35, 145.32, 145.28, 138.49, 132.59,
128.58, 128.44, 127.45, 123.43, 119.80, 119.76, 114.94, 114.91, 110.08, 110.03, 56.02.
(6) (2E)-3-(2,4-dichlorophenyl)-1-phenylprop-2-en-1-one57: Yield 94%, m.p. 127-128°C.
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 15.7 Hz, 1H), 8.04 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.68
– 7.58 (m, 1H), 7.58 – 7.45 (m, 4H), 7.37 – 7.26 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 190.12,
139.34, 137.77, 136.48, 133.08, 131.86, 130.15, 128.72, 128.50, 127.57, 125.03.
(7) (2E)-3-(2-chloro-5-nitrophenyl)-1-phenylprop-2-en-1-one58: Yield 87%, m.p. 142-
143°C. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.25 – 8.13 (m, 2H), 8.12 – 8.05 (m, 2H), 7.72
– 7.62 (m, 3H), 7.61 – 7.52 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 189.29, 146.79, 141.71,
137.92, 137.34, 134.83, 133.49, 131.33, 129.23, 128.86, 128.70, 128.05, 126.92, 125.07,
122.82, 122.53.
(8) (2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one59: Yield 51%, m.p. = 61-63°C. 1H
NMR (400 MHz, CDCl3) δ 8.09 – 7.98 (m, 2H), 7.81 (m, 1H), 7.68 – 7.39 (m, 6H), 7.02 - 6.91 (m,
2H), 3.88 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.61, 161.69, 144.72, 138.52, 132.56, 130.24,
128.57, 128.42, 127.63, 119.80, 114.43, 55.43.
(9) (2E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one53: the product was recrystallized
1
with H2O:EtOH 60:40, a yellow solid was obtained. Yield 22%, m.p. 90-91°C. H NMR (400
MHz, CDCl3) δ 12.86 (s, 1H), 7.95 (m, 2H), 7.73 – 7.65 (m, 3H), 7.58 – 7.44 (m, 4H), 7.06 (m,
1H), 6.98 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 193.74, 163.61, 145.48, 136.43, 134.60,
130.95, 129.68, 129.06, 128.69, 120.12, 120.03, 118.88, 118.65.

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DOI: 10.1039/C6RA04721A
(10)
(2E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one60:
The
product
was
recrystallized with H2O:EtOH 80:20 mixture, a yellow solid was obtained. Yield 93%, m.p.
1
126-127°C. H NMR (400 MHz, CDCl3) δ 7.85 (m, 1H), 7.71 (s, 1H), 7.68 – 7.47 (m, 4H), 7.41
(m, 4H), 7.18 (m, 2H).13C NMR (101 MHz, CDCl3) δ 191.25, 156.67, 145.71, 139.36, 134.67,
130.80, 129.95, 128.99, 128.62, 121.91, 121.02, 120.95, 120.71, 115.34.
(11)
(2E)-1-(4-methoxyphenyl)-3-phenylprop-2-en-1-one61:
The
product
was
recrystallized with H2O:EtOH 80:20; a yellow solid was obtained. Yield 93%, m.p. 102-103°C.
1H NMR (400 MHz, CDCl3) δ 8.07 (m, 2H), 7.83 (m, 1H), 7.72 – 7.52 (m, 3H), 7.44 (m, 3H), 7.08
– 6.94 (m, 2H), 3.98 – 3.89 (m, 3H).13C NMR (101 MHz, CDCl3) δ 188.72, 163.45, 143.98,
135.09, 131.10, 130.84, 130.46, 130.34, 128.94, 128.57, 128.38, 127.47, 121.89, 113.87,
113.71, 55.51.
(12) (2E)-1-[4-(dimethylamino)phenyl]-3-phenylprop-2-en-1-one62: The product was
recrystallized with H2O:EtOH 80:20 mixture giving a yellow solid. Yield 80%, m.p. 99-100°C.
1H NMR (400 MHz, CDCl3) δ 8.03 (m, 2H), 7.81 (m, 1H), 7.54 (m, 6H), 7.36 (m, 1H), 6.76 (m,
2H), 3.08 (s, 6H).13C NMR (101 MHz, CDCl3) δ 190, 150, 146, 138, 132, 130, 129, 128, 128, 117,
112, 40.
(13)
(2E)-1,3-bis(3,4-dimethoxyphenyl)prop-2-en-1-one63:
The
product
was
recrystallized with H2O:EtOH 70:30 mixture giving a pale yellow solid. Yield 60%, m.p. 110-
112°C. 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 1H), 7.70 (m, 1H), 7.64 (m, 1H), 7.43 (m, 1H), 7.30
– 7.22 (m, 1H), 7.18 (m, 1H), 6.93 (m, 2H), 4.02 – 3.91 (m, 12H). 13C NMR (101 MHz, CDCl3) δ
188.67, 153.12, 151.27, 149.24, 149.22, 144.15, 131.56, 128.06, 122.90, 122.87, 119.66,
111.13, 110.83, 110.21, 109.92, 56.09, 56.08, 56.01, 55.99.
(14) (2E,4E)-1,5-diphenylpenta-2,4-dien-1-one64: An orange solid was obtained. Yield
1
64%, m.p. 102-103°C. H NMR (400 MHz, CDCl3) δ 8.03 (m, 2H), 7.67 - 7.34 (m, 10H), 7.06 -
7.04 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 190.49, 144.86, 141.94, 138.24, 136.12, 132.68,
129.25, 128.88, 128.76, 128.61, 128.41, 127.33, 126.97, 125.44.
DES recycling
In a 10 ml round-bottomed flask 10 mmol of (1S)-(+)-10-camphorsulfonic acid and 7 mmol of
SB3-Cy / CSA mixture (1:1.5 molar ratio) were introduced. The mixture was heated at 90°C
for 20 minutes in a thermostated oil bath under stirring until a homogeneous liquid was
formed. 2-chloro-5-nitro-benzaldehyde and acetophenone were added to the mixture, 3.3
mmol (1:1 molar ratio). The mixture was maintained at 90°C for 4 h under stirring. The
solution was then cooled to room temperature and 2 ml of a mixture of H2O:EtOH 80:20 were

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added. The solid obtained was filtered on a buchner and dried under vacuuDmOI.: 1T0.h10e39/lCiq6RuA0id4721A
phase was transferred into a 10 ml round-bottomed flask and dried under vacuum to remove
the solvent. The recovered DES was used for another cycle of reaction.
RESULTS AND DISCUSSION
We performed the Claisen-Schmidt reaction between mono- and bi-substituted
benzaldehydes and acetophenones in SB3-Cy / CSA DES without any added acid catalyst; the
general reaction is reported in Scheme 1.
R1
O
O
R'1
R1
O
R'1
SB3-Cy / CSA
R2
R3
R'2
R'3
R2
R3
R'2
R'3
H
H3C
+
R4
R4
R1 = H, NO2, Cl
R2 = H, OCH3
R'1 = H, OH
R'2 = H, OH, OCH3
R3 = H, OH, NO2, Cl, OCH3 R'3 = H, OCH3, N(CH3)2
R4 = H, NO2
Scheme 1: Claisen-Schmidt reaction of mono- and bi-substituted benzaldehydes and
acetophenones performed in SB3-Cy / CSA Deep Eutectic Solvent.
Reaction conditions optimization
The ratio of the reagents was maintained as 1 in all the reactions analysed, with the aim of
minimizing the waste. Preliminary studies on the effect of the temperature on the conversion
in the reaction between benzaldehyde and acetophenone showed that in 2h a good and
constant conversion was observed at the temperature of 100°C (Table 1).

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Table 1: Effect of the temperature on the conversion percentage in the reaction between
DOI: 10.1039/C6RA04721A
benzaldehyde and acetophenone after 2ha.
Temperature, °C Conversion, %
80
90
64
79
86
89
100
110
a
Aldehyde : ketone : CSA 1:1:3 molar ratio, 2h, conversion calculated via GC with
tert-butylbenzene as internal standard.
In order to maintain milder conditions, the effect of the time on the conversion at 90°C was
then observed; in 16h the conversion was complete for the benzaldehyde / acetophenone
reaction (Table 2), and the time needed was even shorter for the other reactants. So the
temperature used in all the experiments was 90°C. This permitted to maintain milder
conditions and to obtain complete conversions in good reaction times, spanning from 4 to 16
hours.
Table 2: Effect of the reaction time on the conversion percentage in the reaction between
benzaldehyde and acetophenone at 90°Ca.
Time, h
Conversion, %
1
2
61
79
89
92
96
3
8
16
a Aldehyde : ketone : CSA 1:1:3 molar ratio, 90°C, conversion calculated via GC with tert-
Butylbenzene as internal standard.

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DOI: 10.1039/C6RA04721A
Synthesis of substituted chalcones in DES
In Table 3 and Table 4 the reactions of chalcone synthesis we performed in SB3-Cy / CSA DES
are reported. In the tables the reactants and the products, the reaction times, the conversions
and isolated product yields (calculated via weight of the product after column
chromatography) are shown. In Table 3 the reactions of substituted benzaldehydes with
acetophenone are reported.

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Table 3: Claisen-Schmidt condensations in SB3-Cy/CSA DES of acetophenone with
DOI: 10.1039/C6RA04721A
substituted benzaldehydes a.
Conversionb,
%
Yieldc,
%
Entry
Aldehyde
Ketone
Chalcone
Time, h
O
O
O
H
1
16
96
93
67
80
H3C
O
O
O
O
H3C
H
2
6
HO
HO
O
O
H3C
H
3
4
5
6
16
16
5
97
80
93
65
76
94
O2N
O2N
NO2
O
O
O
NO2
O
H3C
H
O
O
H3CO
HO
H3CO
HO
H3C
H
94
Cl
O
O
O
Cl
O
H3C
H
16
100
Cl
Cl
Cl
O
Cl
O
H3C
H
7
8
4
6
96
96
87
51
NO2
NO2
O
O
O
H3C
H
H3CO
H3CO
a Temperature 90°C, aldehyde : ketone : CSA 1:1:3 molar ratio; b conversion calculated via GC
with tert-butylbenzene as internal standard; c yield calculated by weight of isolated product.

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In Table 4 the synthesis of chalcones in DES from benzaldehyde and substitutedDkOeI:t1o0.n10e3s9/,Cf6rRoA0m4721A
3,4-dimethoxybenzaldehyde and 1-(3,4-dimethoxyphenyl)ethanone and from cinnamic
aldehyde with acetophenone are reported.
Table 4: Claisen-Schmidt condensations in SB3-Cy / CSA DES of benzaldehyde with
substituted
acetophenones,
of
3,4-dimethoxybenzaldehyde
and
1-(3,4-
dimethoxyphenyl)ethanone and of cinnamic aldehyde with acetophenonea.
Time, Conversionb, Yieldc,
Entry
Aldehyde
Ketone
Chalcone
h
%
%
O
OH
O
OH
O
H
H3C
9
16
90
22
O
O
O
H
OH
OH
H3C
10
11
12
13
14
6
6
96
95
90
96
94
93
93
80
60
64
O
O
O
H
H3C
H3C
H3C
OCH3
OCH3
O
O
O
H
6
N
N
O
O
O
H3CO
H3CO
H3CO
H3CO
OCH3
OCH3
OCH3
OCH3
H
16
6
O
O
O
H
H3C
a Temperature 90°C, aldehyde : ketone : CSA 1:1:3 molar ratio; b conversion calculated via GC
with tert-Butylbenzene as internal standard; c yield calculated by weight of isolated product.
The conversions observed were excellent for all the products, spanning from 88% to
quantitative; o-NO2-benzaldehyde, entry 4, showed a slightly lower value of conversion of
80%.
The reactions between the aldehydes and the acetophenone (Table 3, entry 1-8) led to the
chalcones in good yields of isolated product, spanning from 51% to 98%. The presence of

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electron withdrawing groups (EWG) on the aromatic ring of the aldehyde (such as Cl and NO2)
DOI: 10.1039/C6RA04721A
led to excellent yields of isolated product (93%, 94%, and 87% for entry 3, 6 and 7
respectively). In the case of the presence of EDG (electron donating groups), the OH group led
to a yield higher than metoxy group (entry 2 and 8); entry 5 aldehyde (with both OH and
OCH3 groups in the aromatic ring) led to an intermediate yield between the entries 2 and 8.
The steric hindrance of the nitro-group in ortho position led to the conversion value of entry 4
aldehyde; this is lower than the one of the para-substituted one of entry 3 (97% and 80%
respectively); it had impact also on the yields of isolated product (93% and 65%
respectively).
In the reaction between the benzaldehyde and substituted ketones (Table 4, entries 9-12), the
presence of EDG groups led to excellent conversions (96%, 95%, 90%) and isolated product
yields (93%, 93%, 80%) for 10, 11 and 12 entries. On the contrary, entry 9 reaction showed
good conversion (90%) but poor yield (22%); that is because these molecules tend to cyclize
through Michael addition between the OH group and the double bond, forming flavones42.
In the Claisen-Schmidt condensation between a substituted benzaldehyde and a substituted
acetophenone (Table 4, entry 13) excellent conversion was observed (96%). The isolated
product yield observed (60%) could be due to the electron donating properties of metoxy-
substituents that could slightly decrease the yield of chalcone formation in this reaction.
We extended the reaction set using also an aldehyde that does not have an α-hydrogen, such
as cinnamaldehyde (entry 14); also the reaction of this molecule with acetophenone led to the
product with excellent conversion (94%) and good isolated product yield (64%).
The reaction in entry 4 was repeated in another sulfobetaine-based DES: SB3-MIM (3-(1-
methyl-1H-imidazol-3-ium-3-yl)propane-1-sulfonate) / CSA mixture was chosen as solvent /
catalyst. This was made with different aims. The first reason was to increase the conversion
and yields observed, because they were the lowest in the set; the second reason was to show
the possibility of the use of other DESs mixtures in our set in the same probe reaction22. The
aromatic imidazolium-based DES was chosen because of the structural similarity with
aromatic reagents in the reaction. The conversion values observed were almost the same
(81% with SB3-MIM / CSA and 80% with SB3-Cy / CSA) but an increase of the isolated
product yields was observed, passing from 65% to 77%. This data could lead to further
studies on the use of
a
specific DES in
a
set for
a
specific role.
We also performed an aldol reaction of acetophenone in SB3-Cy / CSA DES in order to
evaluate the self-condensation of the ketone in this media. After 48 hours at 90°C the
conversion observed was <10%, these data are not reported in any table.

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DOI: 10.1039/C6RA04721A
DES recycling
Subsequent reaction cycles were performed in order to estimate the recyclability of SB3-Cy /
CSA DES in the Claisen-Schmidt reaction. One of the reactions of the set (2-chloro-5-nitro-
benzaldehyde and acetophenone as reactants, entry 7 in Table 1) was performed in
subsequent experiments and the capability of re-use of the DES was evaluated via an
estimation of the obtained isolated product yields. In Table 5 the isolated product yields in
four subsequent reaction cycles are reported.
Table 5: Recycling and reuse of SB3-Cy / CSA DES in 2-chloro-5-nitro-benzaldehyde reaction
with acetophenone a.
Cycle
Yield, %b
1
2
3
4
87
86
87
85
a Aldehyde : ketone 1:1 molar ratio, 90°C, 4 h; b Yield calculated as weight of isolated product
after purification, 96% of conversion values observed in all the four reaction cycles.
As it can be easily observed, the DES can be recycled in at least four subsequent reaction
cycles without any loss of yields of product obtained. We did not investigate on further
reaction cycles because of the constant values observed. This data promotes the “greenness”
of this reaction media.
CONCLUSIONS
The Claisen-Schmidt reaction is a powerful tool for C-C bonds formation. We successfully
performed this reaction in an acid deep eutectic solvent: SB3-Cy / CSA mixture. We
synthesized substituted chalcones combining benzaldehyde and mono- and bi-substituted
benzaldehydes with acetophenone and mono- and bi-substituted acetophenones as probe
reactions. The reaction media played both the roles of solvent and acid catalyst for this probe
reaction, because of the CSA composing it, so no acid (or basic) catalysts were needed.

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The advantages of the use of this reaction media were several: it is an environmental friendly
DOI: 10.1039/C6RA04721A
solvent for its properties and for its very low toxicity as demonstrated in previous works22; it
has the advantage of preventing the use of harmful acids (such as H2SO4) to catalyse the aldol
condensation because of the camphorsulfonic acid composing it. Over four reaction cycles can
be performed in it without any loss of activity. It permitted to achieve in mild conditions
(90°C, 4 to 16 hours of reaction times) excellent conversions of the reactants (spanning from
88% to quantitative) and very good yields of isolated products after column chromatography.
The work was extended with the use of another sulfobetaine-based DES (SB3-MIM / CSA: 3-
(1-methyl-1H-imidazol-3-ium-3-yl)propane-1-sulfonate / (1S)-(+)-10-camphorsulfonic acid
mixture) in one of the analysed synthesis. This was successfully made in order to improve the
conversion and the yield of the reaction and in order to demonstrate the applicability of a
specific DES in specific reaction for structural similarities of the reactants and the DES’s
components and it could lead to further studies on specific liquids for specific reactions.
This study on the Claisen-Schmidt reaction promotes the use of acid Deep Eutectic Solvents in
other acid-catalysed reactions as both reaction media and catalysts.
AKNOWLEDGEMENTS
The authors thank the Ministero per l’Università e la Ricerca Scientifica e Tecnologica, MIUR
(Rome, Italy) [PRIN “Programmi di Ricerca di Interesse Nazionale” 2010-2011, n.
2010FM738P] for funding.
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