Rapid and efficient uncatalyzed knoevenagel condensations from binary mixture of ethanol and water

Article abstract of DOI:10.21577/0103-5053.20170240

This paper presents a new green protocol for Knoevenagel condensations of aldehydes and compounds with an active methylene group in a binary mixture of ethanol/water (3:7, v/v). This medium favored the uncatalyzed Knoevenagel reactions and easy workup pro

Full text of DOI:10.21577/0103-5053.20170240

http://dx.doi.org/10.21577/0103-5053.20170240
J. Braz. Chem. Soc., Vol. 29, No. 7, 1382-1387, 2018
Printed in Brazil - ©2018 Sociedade Brasileira de Química
Article
Rapid and Efficient Uncatalyzed Knoevenagel Condensations from Binary Mixture
of Ethanol and Water
João M. G. O. Ferreira,a João B. M. de Resende Filho,b Poliane K. Batista,a
Ercules E. S. Teotonio*,a and Juliana A. Vale*,a
aDepartamento de Química, Universidade Federal da Paraíba, 58051-970 João Pessoa-PB, Brazil
bInstituto Federal de Educação, Ciência e Tecnologia da Paraíba, 58800-970 Sousa-PB, Brazil
This paper presents a new green protocol for Knoevenagel condensations of aldehydes and
compounds with an active methylene group in a binary mixture of ethanol/water (3:7, v/v). This
medium favored the uncatalyzed Knoevenagel reactions and easy workup products can be obtained
by precipitation in this medium and showed good isolated yields (55-100%) in short reaction
times (1-60 min).
Keywords: Knoevenagel condensation, ethanol/water, green approach, binary mixture, active
methylene compounds and aldehydes
Introduction
separation, etc.) for recovery of the catalyst, easier reuse,
stability at high temperatures and pressures, and relatively
low toxicity. Some of these reactions even occur without
solvents, decreasing the toxicity of the reaction medium.29-31
Furthermore, other researchers32-34 have reported solvent-
catalyzed Knoevenagel condensations, generally using
ionic liquids or water (green solvents), under different
conditions.
In our studies, we noted that Knoevenagel condensations
were faster in ethanol than in other solvents (apolar or polar,
protic or aprotic). Many papers have reported this reaction
in ethanol using catalysts,35,36 but none have discussed
this reaction uncatalyzed in ethanol until this report. In
addition, the uncatalyzed Knoevenagel condensations
reported in the literature generally use water37,38 or ionic
liquids39-41 as solvents. Thus, this work presents a new
green approach for the quick and efficient uncatalyzed
Knoevenagel condensation of different substrates in a
mixture of ethanol/water.
The Knoevenagel condensation is an aldol reaction
between carbonylated substances (such as ketones and
aldehydes) and active methylene compounds (–CH2–
attached to two electron withdrawing groups, EWGs)
producing alkenes.1-3 It is one of the most useful reactions
to form C–C bonds, generally used to assist the synthesis
of several compounds with biological relevance4 and other
possible applications, such as drugs,5-10 natural products,11,12
and polymers.13-15
Weak bases, such as amines and basic salts, usually
catalyze these reactions.1-3 The base furthers the
deprotonation of the active methylene compound to create
a carbanion, which, in turn, attacks the carbonyl. In the
earliest works, the amines used to catalyze the reactions
presented a considerable level of toxicity.16,17 Thus, many
papers have been published in recent years concerning
proposals for ecofriendly reaction conditions,18-22 in
accordance with the principles of green chemistry.22-25
From this perspective, many researchers have developed
new catalysts involving the mentioned principles. One
such type, which have received great attention, are the
heterogenized catalysts.26-28 They present certain advantages
compared with their respective homogeneous compounds,
such as facile separation methods (filtration, magnetic
Experimental
Reagents and instruments
The solvents, aldehydes, ketones and active methylene
group compounds (malononitrile and indan-1,3-dione)
were obtained from Sigma-Aldrich Co. Ethanol (200 proof)
was purchased from Tedia. The ethanol/water mixtures
*e-mail: ercteot@gmail.com; julianadqf@yahoo.com.br

Vol. 29, No. 7, 2018
Ferreira et al.
1383
Table 1. The effect of solvents on Knoevenagel condensation of
benzaldehyde and malononitrilea
were prepared in volumetric proportions (1:9, 1:1, 3:7,
7:3, v/v). All chemicals were employed without further
purification.
General procedures for Knoevenagel condensations
entry
1
Solvent
–
timeb / min
540
2880
2160
60
The aldehyde (0.2 mmol) and the compound with the
active methylene group (0.2 mmol) were added to a test
tube followed by the addition of the solvent (ethanol/
water 3:7, 0.8 mL). The system was maintained at 80 °C
and magnetically stirred until the reaction completed.
The reaction progress was monitored by thin layer
chromatography (TLC). The products were obtained
by precipitation with cooled water or by extraction
with ethyl acetate. The extract was purified by column
chromatography. All the products were characterized
by Fourier transform infrared spectroscopy (FTIR),
2
toluene
3
thfc
4
H2O
5
MeOHc,d
60
6
MeOH 99.9%c
EtOHd
30
7
60
8
EtOH 95%c
propanol
30
9
90
10
11
12
13
14
15
16
17
18
isopropanol
butanol
60
1
gas-chromatography mass spectrometry (GC-MS), H
and 13C nuclear magnetic resonance (NMR).
150
540
360
360
10
tert-butanol
cyclohexanol
octanol
Results and Discussion
To examine the effects of the different solvents in
uncatalyzed Knoevenagel condensations it was tested a
standard reaction between benzaldehyde and malononitrile
in solvent-free conditions and in aprotic polar, protic polar
and apolar solvents (Table 1).
EtOH:H2O (7:3, v/v)
EtOH:H2O (1:1, v/v)
EtOH:H2O (3:7, v/v)
EtOH:H2O (1:9, v/v)
6
4
4
aReaction conditions: benzaldehyde (0.1 mmol), malononitrile (0.1 mmol),
0.4 mL of solvent, 75 °C; bthe reactions were monitored by TLC; creflux
temperature: 65 °C; dHPLC grade.
As seen in Table 1, the reaction times in toluene
(entry 2, apolar solvent) and tetrahydrofuran (thf, entry 3,
aprotic polar solvent) were the slowest. These results are
in agreement with the mechanism of these amine-free
reactions.42 This mechanism is well known to involve
carbanion formation and an ionic intermediate (enolate).
Therefore, the reaction in a polar solvent (thf, for example)
would be expected to be faster than in an apolar solvent
(toluene, for example). When this reaction was carried out
under solvent-free conditions (entry 1), the reaction time
was even faster than those mentioned above.
The reactions in protic polar solvents (entries 4-15,
water and alcohols) were considerably faster than in the
aprotic polar and apolar solvents. The reaction times
increased when long carbon chain alcohols were used
as solvents (entries 5, 7, 9-14). In water (entry 4), the
reaction was completed at the same time (60 min) as
the reactions in methanol (entry 5) and ethanol (entry 7)
high-performance liquid chromatography (HPLC) grade
(anhydrous). However, when using ethanol 95% or
methanol 99.9%, the reaction time surprisingly decreased
to 30 min (half the time). This event promoted our
curiosity for the study of this reaction in the mixtures
of ethanol/water (entries 15-18). As can be observed in
the Table 1, when the mixture of ethanol/water presents
a small volume of ethanol the reaction occurs faster than
the one with the largest volume of ethanol. The same
reaction in water (entry 4) or anhydrous ethanol (entry 7)
is considerable slower than any mixture of ethanol/water.
The mixture ethanol/water 3:7 v/v showed the best results
(entry 17) and it was used as a solvent in subsequent
reactions.
In addition, the reaction between benzaldehyde and
malononitrile in ethanol/water, 3:7 v/v, was carried out at
room temperature and under ultrasound conditions (both
150 min). However, these reactions were slower than those
carried out with heating at 75 °C.
The ethanol-water mixture presents particular properties
compared with the isolated solvents that further the
Knoevenagel condensation when performed in the mixed
system: (i) a higher solvation power because of the
formation of molecular chains interacting by hydrogen
bonds (cluster formation); (ii) the lower dielectric constant
of these mixtures when compared with the pure solvents

1384
Rapid and Efficient Uncatalyzed Knoevenagel Condensations from Binary Mixture of Ethanol and Water
J. Braz. Chem. Soc.
Table 2. Knoevenagel condensations of benzaldehyde and different active
methylene compounds in ethanol/water 3:7 (v/v)a
and bis adduct was obtained. Interestingly, the reactions
with Meldrum’s acid in the mixture ethanol/water were a
selective reactions giving only the Knoevenagel product
and no trace of bis adduct was detected.
After the optimization of the conditions for the
Knoevenagel condensations, several aldehydes were
reacted with malononitrile (active methylene compound)
in the selected conditions (Table 3).
Active methylene
entry
1
timeb / h
Isolated yield / %
compound
In general, the reactions showed good isolated yields
in short times (Table 3). The standard reaction with
benzaldehyde and malononitrile (entry 1) was completed in
4 min (yield 82%). The reaction with 4-NO2-benzaldehyde
(entry 2) was faster than mentioned above due to the
presence of the strong electron withdrawing group (NO2)
at the 4-position. In addition, the reactions with an electron
donating group (entries 4 and 5) at the 4-position were
slower than those with an electron withdrawing group at
the same position.
The aldehydes with substituents (electron donating
or withdrawing group) in the 3-position (entries 6 and 7)
and 2-position (entries 8 and 9) exhibited behavior similar
to reactions with those substituents at the 4-position. In
addition, considerable steric hindrance was observed in
the substrates with groups at the 2-position. The reactions
with di-substituted aldehydes (entries 10-12) finished
in 25-45 min and showed good yields. Surprisingly, the
reaction time was very low for the tri-substituted aldehyde,
compound 17 (entry 13), reacting completely in only 3 min,
with isolated yield of 99%.
4
80d
2
4
83c
3
4
16
26
83c
80c
aReaction conditions: benzaldehyde (0.1 mmol), active methylene
comppoouunndd(0(.01.1mmoml)o,l0).,40m.4L EmtLOHE/tHOHO/3H:7O(v/3v:)7, 7(5v°/vC);,bt7h5e r°eCac;tiothnes
b
2
2
c
c
rweearcetimonosniwtoerreedmbyonTiLtoCre;dprboyduTcLtsCo;bptariondeudcbtsy opbretacinpeitdatbioynparnedciwpaitsahtionng
d
awnidthwcaosohlceodowleadtewra;tdeprr;opdruocdtsucotsbtoabintaeidnebdybyexetxratrcatciotinonaannddppuurriififieedd by
chromatographic column.
can favor stronger interactions with small polar molecules
such as malononitrile; (iii) the possibility to increase the
solubility of organic compounds when compared to the use
of water as solvent; and (iv) the ability to form cavities.43-45
Benzaldehyde was chosen to react with different active
methylene compounds such as cyanoesters, Meldrum’s
acid, and betadiketones (Table 2).
As expected, the reaction with malononitrile (entry 17,
Table 1) was faster than with other active methylene
compounds (Table 2). However, the difference of the
reaction times was significant and cannot be simply
explained by the pKa of the methylene groups, suggesting
that other factors are relevant.
The base-catalyzed Knoevenagel condensation of
aldehydes and Meldrum’s acid often gave the bis adduct,
due to the Michael addition with a second molecule of
the Meldrum’s acid. Cunha and Santana46 reported the
uncatalyzed Knoevenagel reactions in water (75 °C,
2 h) and they observed the preferential formation of
Knoevenagel product. Bigi et al.47 found the same results,
however, the uncatalyzed reactions carried out in ethanol
as solvent were unselective and a mixture of Knoevenagel
The reactions with heteroaromatic aldehydes
(entries 20, 22) finished in a short time. As the
n-pyridinecarboxyaldehydes (n = 3 or 4, entries 20,
21) are rather reactive electrophiles and are completely
miscible in water, the reactions with these substrates
were incredibly fast (in seconds). The aliphatic aldehyde
(entry 19) completed at a time close to the substituted
aromatic aldehydes.
These products were easily obtained by precipitation
with the addition of cooled water and any purification
process was used. However, in the cases that the product
are soluble in the mixture of ethanol/water, it was obtained
by extraction with ethyl acetate and after purified by
chromatographic column.
The Knoevenagel condensation of ketones and
malononitrile in the mixture of ethanol/water 3:7
(v/v) was initially verified and presented good results.
The reactions between 4-methylcyclohexanone or
3-methylcyclohexanone and malononitrile, for example,
finished in five and six hours, respectively, with 75%
isolated yield for both. The study of these reactions (with
ketones) in this mixture is still in progress.

Vol. 29, No. 7, 2018
Ferreira et al.
1385
Table 3. Knoevenagel condensations of aldehydes and malononitrile in ethanol/water 3:7 (v/v)a
time
time
timeb /
min
Isolated
yield / %
timeb /
min
Isolated
yield / %
entry
1
Product
(yield / %)c /
min
entry
12
Product
(yield / %)c /
min
4
82d
30 (91)48
45
89e
50 (92)49
2
3
4
1
93d
84d
85d
20 (91)48
30 (94)48
60 (91)48
13
14
3
99e
–
20
60
20
89d
40 (92)53
5
6
50
25
94d
45 (90)49
15
16
30
15
95d
75e
30 (99)26
30 (92)54
72e
50 (93)50
17
18
15
10
55d
30 (94)54
20 (94)55
7
40
75d
90 (92)51
100d
8
3
94e
80d
92e
10 (92)49
15 (90)52
–
19
20
30
1
76e
92e
30 (72)56
3 (86)57
9
50
25
10
21
1
91e
30 (95)58
aReaction conditions: aldehyde (0.2 mmol), malononitrile (0.2 mmol),
0.8 mL of EtOH/H2O 3:7 (v/v), 75 °C; bthe reactions were monitored by
11
25
94d
240 (66)51
c
d
TLC; reaction time and isolated yield reported in literature; products
e
obtained by precipitation and washing with cooled water; products
obtained by extraction and purified by chromatographic column.

1386
Rapid and Efficient Uncatalyzed Knoevenagel Condensations from Binary Mixture of Ethanol and Water
J. Braz. Chem. Soc.
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The mixture of ethanol/water 3:7 (v/v) was used as
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Supplementary Information
Supplementary data are available free of charge at
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