P-Sulfonic acid calix[n]arenes as homogeneous and recyclable organocatalysts for esterification reactions

Article abstract of DOI:10.1016/j.tetlet.2012.01.078

Esterification yields were significantly improved using calix[n]arenes catalysts under simple conditions. p-Sulfonic acid calix[4]arene and p-sulfonic acid calix[6]arene were powerful organocatalysts in several esterification reactions, which showed activity comparable or even superior to other well-established acids catalysts, such as, sulfuric acid, p-toluenesulfonic acid, and p-hydroxybezenesulfonic acid described in the literature.

Full text of DOI:10.1016/j.tetlet.2012.01.078

Tetrahedron Letters 53 (2012) 1630–1633
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
p-Sulfonic acid calix[n]arenes as homogeneous and recyclable
organocatalysts for esterification reactions
⇑
Sergio Antonio Fernandes , Ricardo Natalino, Poliana Aparecida Rodrigues Gazolla, Márcio José da Silva,
Gulab Newandram Jham
Grupo de Química Supramolecular e Biomimética (GQSB), Departamento de Química, CCE, Universidade Federal de Viçosa, Viçosa, MG, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Esterification yields were significantly improved using calix[n]arenes catalysts under simple conditions.
p-Sulfonic acid calix[4]arene and p-sulfonic acid calix[6]arene were powerful organocatalysts in several
esterification reactions, which showed activity comparable or even superior to other well-established
acids catalysts, such as, sulfuric acid, p-toluenesulfonic acid, and p-hydroxybezenesulfonic acid described
in the literature.
Received 25 November 2011
Revised 18 January 2012
Accepted 19 January 2012
Available online 28 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Esterification reaction
p-Sulfonic acid calix[n]arene
Organocatalyst
Catalyst recovery
Introduction
calix[n]arenes have been used as catalysts in organic reactions.
Liu et al. described the catalytic use of sulfonic calix[n]arenes in
After a decade of intensive research, organocatalysis have been
established as a powerful method for chemical transformations,
filling the gap between enzyme and metal-based catalysis.
This explosive growth can be ascribed to the fundamental
advantages, such as, stability in water and air, non-toxic nature,
and the ready accessibility of starting material from natural or syn-
thetic sources. However, major drawbacks include high catalyst
loadings and difficulties in catalyst separation and recycling.1
Esterification is one of the most fundamental and important
reactions in organic synthesis.2 Esters are key intermediates in
the synthesis of polymers, perfumes, and pharmaceutical interme-
diates, biodiesel or final products.3 The acid-catalyzed reaction
under reflux is the most common procedure adopted for esterifica-
tion.2a Although several methods have been reported, the search
for new environmentally friendly, atom-efficient methods, which
avoid the use of large amounts of condensing reagents and activa-
tors has attracted increasing interest.4 Despite the fact that a wide
variety of catalysts have been used in the esterification reactions,
only a few organic catalysts have been described.5
the allylic alkylation reaction.8 Shoichi et al. reported the use of
calix[n]arenes as catalysts in Mannich-type reactions.9 Recently, de
Fátima and co-workers described the use of calix[n]arenes as organo-
catalysts in the Biginelli reaction.10 Conversely, the use of calix[n]are-
nes still remains little explored for esterification reactions.5c
In this Letter, we report novel studies on esterification using
calix[n]arene catalysts and demonstrate that p-sulfonic acid ca-
lix[4]arene and p-sulfonic acid calix[6]arene are efficient and reus-
able organocatalysts for the synthesis of carboxylic esters. To the
best of our knowledge, this is the first application of p-sulfonic acid
calix[n]arenes as organocatalysts for these esterification reactions.
Results and discussion
The esterification reactions of palmitic acid in deuterated meth-
anol using five catalysts (Fig. 1) were evaluated via 1H NMR
R
R
R
R
SO3
H
SO3
H
Calix[n]arenes macrocycles are formed by the condensation of
para-substituted phenols with formaldehyde in basic medium and
have been widely used as ligands in organometallic catalysis.6 On
the other hand, examples of the use of calix[n]arenes as organocat-
alysts are even less explored.7 For instance, few p-sulfonic acid
O
S
n
HO
OH
HO
OH
OH
OH
O
1
OH
(5)
n = 1 and R = SO3H ( )
n = 3 and R = SO3H (2)
(3)
(4)
Figure 1. Molecular structures of the five catalysts: (1) p-sulfonic acid calix[4]ar-
ene; (2) p-sulfonic acid calix[6]arene; (3) sulfuric acid, (4) p-toluenesulfonic acid
and (5) p-hydroxybenzenesulfonic acid.
⇑
Corresponding author. Tel.: +55 31 3899 3071; fax: +55 31 3899 3065.
E-mail addresses: sefernandes@gmail.com, santonio@ufv.br (S.A. Fernandes).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.078

S. A. Fernandes et al. / Tetrahedron Letters 53 (2012) 1630–1633
1631
catalyst strength.12 Although when in aqueous solution there is a
levelling effect on the acid strength of these catalysts, in ethanol
solutions the same does not occur, especially for p-toluenesulfonic
acid and p-hydroxybenzenesulfonic acid, which are less active. This
later showed a very poor activity comparatively to two proposed
organocatalysts in the reaction herein assessed: while in the p-tol-
uenesulfonic acid and p-hydroxybenzenesulfonic acid-catalyzed
reaction a conversion of only 20% and 31%, respectively was reached
after 300 min (Fig. 3), conversion rates greater than 88% were
obtained in p-sulfonic acid calix[n]arene-catalyzed reactions.
p-Sulfonic acid calix[n]arene can be considered as a cluster of p-
hydroxybenzenesulfonic acids linked by
a methylene spacer,
which provides hydrophobic cavity. For comparison, p-toluenesul-
fonic acid (4) and p-hydroxybenzenesulfonic acid (5) were used
under the same reaction conditions. Based on the above experi-
mental results, it was suggested that the higher catalytic activity
of (1 and 2) comparatively to (4) and (5) may be originated from
the formation of the inclusion complex of p-sulfonic acid calix[-
n]arene (1 or 2) with organic acid.7a,13
Noticeably, best results were obtained in presence of the two
organocatalysts proposed: p-sulfonic acid calix[4]arene (0.125
mol %) and p-sulfonic acid calix[6]arene (0.080 mol %), which were
revealed to be as active as the sulfuric acid catalyst (Fig. 3). They
promoted palmitic acid conversion into deuterated methyl palmi-
tate at the same initial rates, achieving an 85% conversion after
160 min reaction. Moreover, a very close conversion was reached
after 240 min of reaction (ca. 88–90%). Although the final conver-
sion obtained in the sulfuric acid-catalyzed reaction was slightly
higher than that obtained in p-sulfonic acid calix[n]arene-catalyzed
reactions, these latter catalysts have a remarkable advantage: are
easily recyclable.
Best results were obtained in the presence of the three catalysts
p-sulfonic acid calix[4]arene (91%), p-sulfonic acid calix[6]arene
(90%) and sulfuric acid (94%) (Fig. 3). Poor conversion (less than
20% and 31%, respectively even after 300 min reaction) was
obtained with the widely used p-toluenesulfonic acid or and
p-hydroxybenzenesulfonic acid (Fig. 3).
With the objective of potential application in biofuel production
processes, the reusability of p-sulfonic acid calix[4]arene (1) and
p-sulfonic acid calix[6]arene (2) catalysts was examined for the
synthesis of several fatty esters (6f-j) (Table 1). After each catalytic
run, the calix[n]arenes catalysts (1) and (2) were recovered from
the reaction medium by liquid-liquid extraction with water. After
drying, the calix[n]arene catalysts were weighed and used again
in successive reactions. Both p-sulfonic acid calix[4]arene (1) and
p-sulfonic acid calix[6]arene (2) catalysts remained active after
multiple cycles of recovery and reuse (Fig. 4). Even after recycling
the organocatalysts five times, the yields obtained were practically
identical to those observed with fresh catalyst. The inevitable loss
of catalyst during recovery process was less than 10%.
Figure 2. Representative 1H NMR spectra (300.069 MHz, CD3OD, dCHD2OD = 3.30,
323 K). (a) (⁄) RCH2CO2H (palmitic acid); (b) mixture of palmitic acid and
deuterated methyl palmitate; and c) (ꢀ) RCH2CO2CD3 (deuterated methyl
palmitate).
spectroscopy in situ (Fig. 2). NMR spectroscopy showed to be an
efficient monitoring method and allowed the accurate analysis of
the five catalysts assessed.11 No unknown products were detected
during the reaction, indicating the absence of side reactions in the
experimental conditions used herein. Reaction progress was mon-
itored by analysis of the resonance signals (triplet) of the methy-
lene group hydrogen atoms next to the carbonyl group of both
the ester and fatty acid (highlighted in Fig. 2). A typical spectrum
containing resonance signals of the methylene groups of both
deuterated methyl palmitate and palmitic acid obtained in the
p-sulfonic acid calix[4]arene-catalyzed esterification reaction is
presented in Figure 2.
All catalysts were used at the same hydrogenionic concentration
(molar ratio of carboxylic acid:H+; 800:1). The two catalysts more
commonly used in fatty acid esterification reactions (i.e. sulfuric
acid and p-toluenesulfonic acid) and p-hydroxybenzenesulfonic
acid monomer of the calix[n]arene catalysts (1 and 2) were selected
for comparison and used in concentrations equal to 0.25, 0.50 and
0.50 mol %, respectively (Fig. 3). Literature reports that the catalytic
activity in esterification reactions is strongly dependent on the acid
100
90
80
70
The feasibility and applicability of the calix[n]arene catalysts in
esterification reactions were extended to organic acids 6a–p
(Table 1). For this study, all reaction conditions remained constant
as described above and only the nature of the organic acids was
altered.
According to the data in Table 1, high conversions were obtained
in the esterification reactions of linear and saturated carboxylic
acids in the presence of catalysts (1), (2) and (3). Straight-chain
organic acids (compounds 1–10, Table 1) were converted into esters
in yields ranging from 53–99% with the catalysts (1–3). Catalysts (4)
and (5) were not efficient for esterification of 15 carboxylic acids
studied (Table 1). None of the catalysts studied were suitable for
esterification of aromatic organic acids (compounds 11–14). It is
well known that carboxyl group reactivity of the benzoic acid and
their derivates is strongly influenced by conjugation with the
aromatic ring and distorted by the substituent attached to the ring.
60
50
40
30
20
10
0
Sulfuric acid (0.25 mol%)
p-sulfonic acid calix[4]arene (0.125 mol%)
p-sulfonic acid calix[6]arene (0.08 mol%)
p-hydroxybenzenesulfonic acid (0.5 mol%)
p-toluenesulfonic acid (0.5 mol%)
0
25 50 75 100 125 150 175 200 225 250 275 300
Time (minutes)
Figure 3. Effect of catalyst in the esterification reaction with deuterated methanol,
monitored by 1H NMR spectroscopya. aReaction conditions: palmitic acid
(0.08 mmols); catalysts (0.0001 mmols); deuterated methanol (14.80 mmols);
temperature (323 K).

1632
S. A. Fernandes et al. / Tetrahedron Letters 53 (2012) 1630–1633
Table 1
esterification reactions may make this process an interesting and
very useful alternative for the synthesis of straight-chain carboxylic
esters, especially for biodiesel synthesis.
Esters yields obtained in esterification reactions catalyzed by p-sulfonic acid
calix[4]arene (1), p-sulfonic acid calix[6]arene (2), sulfuric acid (3), p-toluenesulfonic
acid (4), and p-hydroxybenzenesulfonic acid (5)a
Experimental section
General procedures
O
O
Catalyst
+ H2O
R
OH
R
OEt
EtOH, Reflux, 4 h
(5a-p)
(6a-p)
All chemicals were obtained from commercially available
sources and used without further purification. Reactions did not
require anhydrous conditions. GC–MS analyses were carried out
on a Shimadzu GC 17A gas chromatograph coupled with a MS-QP
5000 Shimadzu mass spectrometer (Tokyo, Japan), with a DB5
capillary column (30 m length, 0.25 mm id, 0.25 mm film thick-
ness). The 1H and 13C-NMR spectra were recorded on a Varian Mer-
cury spectrometry at 300 MHz and 75 MHz respectively, in CD3OD.
Entry
Product
R
(1)
(2)
(3)
(4)
(5)
Yield (%)
1
2
3
4
5
6
7
8
CH3 6a
94
99
91
89
91
74
66
91
91
88
<5
83
90
85
86
82
53
55
91
89
76
<5
<5
<5
<5
34
97
99
98
99
99
80
94
95
92
90
<5
11
<5
<5
36
<5
28
42
<5
<5
35
16
<5
14
<5
<5
<5
<5
<5
10
<5
<5
<5
<5
<5
42
53
65
44
48
<5
<5
<5
<5
<5
C2H5 6b
C3H7 6c
C5H11 6d
C7H15 6e
C
11H23 6f
C13H27 6g
General procedure for the synthesis of calix[n]arenes
C
C
C
15H31 6h
17H35 6i
17H33 6j
9
10
11
12
13
14
15
The p-sulfonic acid calix[4,6]arenes were synthesized in our
laboratory following the literature procedures. First, p-tert-butyl-
calix[4,6]arene was prepared by the Gutsche and Iqbal method.14
Secondly, the p-tert-butylcalix[4,6]arene was dealkylated by treat-
ment with aluminium chloride in the presence of toluene and phe-
nol according to the method described by Ungaro and co-works.15
Preparation of the p-sulfonic acid calix[4,6]arene was carried
out with the treatment of calix[4,6]arene with concentrated sulfu-
ric acid (98% wt) added to (Shinkai, et al.).16 The reaction mixture
was shaken under nitrogen; the temperature was maintained at
353 K.
C6H5 6l
2-C5H4N 6m
3-NH2C6H4 6n
3,5-NO2C6H3 6o
4-NO2C6H4CH2 6p
<5
<5
<5
46
a
Reaction conditions: palmitic acid (0.40 mmols); catalysts (0.0005 mmols);
ethanol (352.17 mmols).
p-sulfonic acid calix[4]arene
p-sulfonic acid calix[6]arene
The reaction was monitored by removing small aliquots fol-
lowed by the addition of a minimum quantity of water. Complete
solubility indicated complete sulfonation. At this stage the reaction
was stopped. This took about 4 h.
100
80
60
40
20
General procedure for the synthesis of esters
General procedure for the synthesis of compounds (6a–p); or-
ganic acid (0.40 mmol.), and catalyst (0.0005 mmol.) was com-
bined with 20 mL ethanol in a 50 mL round bottomed flask
equipped with a stir bar. Reaction was allowed to stir at reflux tem-
perature for the appropriate amount of time (4 h). After comple-
tion of reaction, the reaction mixture was concentrated in
vacuum to give a crude product which was analyzed by 1H NMR
and GC–MS.
0
Acknowledgments
Fresh
First
Second
Third
Fourth
This work was funded by FAPEMIG, CAPES, FUNARBE, and CNPq.
References and notes
Figure 4. Conversion rates obtained in the calix[n]arene-catalyzed esterification
reactions of palmitic acid with methanol after successive cycles of catalyst
recovery/reuse.
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Conclusion
In this study, a novel and efficient process based on p-sulfonic
acid calix[n]arenes as homogeneous and recyclable organocatalysts
was developed for the synthesis of esters. The calix[n]arene
catalysts were able to efficiently promote the esterification of a
broad variety of organic acids with ethanol in high yields and under
mild reaction conditions. Furthermore, it was also demonstrated
that the catalytic activity of calixarene catalysts remained unaltered
even after several recovery/reutilization cycles. Moreover, this
environmentally friendly methodology avoids the use of metal-
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