N-Butyl-2,4-dinitro-anilinium p-toluenesulfonate as a highly active and selective esterification catalyst

Article abstract of DOI:10.1016/j.tetlet.2013.09.132

N-Butyl-2,4-dinitro-anilinium p-toluenesulfonate (1) was found to be a very active esterification catalyst that promotes condensation of equal mole amount of carboxylic acids and alcohols under mild conditions. This catalyst is also highly selective towards carboxylic acid and alcohol substrates at ambient temperature.

Full text of DOI:10.1016/j.tetlet.2013.09.132

Tetrahedron Letters 54 (2013) 6665–6668
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-Butyl-2,4-dinitro-anilinium p-toluenesulfonate as a highly active
and selective esterification catalyst
Narsimha Sattenapally a, Wei Wang b, Huimin Liu a, Yong Gao a,
⇑
a Department of Chemistry and Biochemistry, Southern Illinois University, 1245 Lincoln Drive, Carbondale, IL 62901, USA
b Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and Wuhan University, School of Pharmaceutical Sciences, Wuhan 430071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Butyl-2,4-dinitro-anilinium p-toluenesulfonate (1) was found to be a very active esterification catalyst
that promotes condensation of equal mole amount of carboxylic acids and alcohols under mild condi-
tions. This catalyst is also highly selective towards carboxylic acid and alcohol substrates at ambient
temperature.
Received 12 September 2013
Revised 24 September 2013
Accepted 28 September 2013
Available online 3 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Esterification
Catalyst
Selectivity
Anilinium p-toluenesulfonate
Highly active esterification catalysts1 that show selectivity to-
wards carboxylic acids and alcohols are needed for the laboratory
synthesis of complicated molecules and industrial production of
pharmaceuticals and their intermediates with diverse functional-
ities. For example, a selective esterification catalyst will allow a
primary alcohol to react with a carboxylic acid—without the need
to go through protection and de-protection steps for a secondary or
a tertiary alcohol group co-present in the substrate. However, de-
spite tremendous progress in uncovering esterification catalysts,1,2
only a few highly selective esterification catalysts have been re-
ported so far, most of which are organic catalysts.3 As a result, re-
search work to develop active and highly selective esterification
catalysts is still required.
Rational designs to introduce steric hindrance to the catalytic
centre of an organic catalyst could enable the catalyst to demon-
strate steric selectivity towards carboxylic acid and/or alcohol sub-
strates. In addition, an organic catalyst can be more easily removed
out of the reaction mixture than a metal catalyst during work-up,
which avoids repeated recrystallization steps or multiple chroma-
tography purifications to remove the leached metal out of a drug
intermediate. Recently, we reported a group of lipid-modified
pyridinium p-toluenesulfonate salts for promoting methylation of
carboxylic acids.4 The hydrophobic catalytic centre drives out
water byproduct and thus shifts the reaction equilibrium towards
the esterification product.
O2N
NO2
NO2
O2N
O2N
O2N
NO2
n-Bu
n-Bu
n-Bu
N
N
N
N
H2
H2
H2
9
SO3
H2
SO3
SO3
OAc
1
2
3
4
>99%
10%
87%
<5%
Figure 1. Anilinium salts as esterification catalysts. The GC yields of a test reaction
of 4-phenylbuturic acid and 1-octanol are shown.
Unfortunately, these catalysts do not show significant selectiv-
ity towards substrates and their activities towards a secondary or a
tertiary alcohol are generally poor. In this Letter, we would like to
report our more recent study of N-butyl-2,4-dinitro-anilinium p-
toluenesulfonate (1, Fig. 1) as a very active esterification catalyst
with high substrate selectivity.
Four anilinium salts were synthesized and evaluated as esterifi-
cation catalysts (Fig. 1). The synthetic protocols of these salts are
reported in Supplementary data. The protonated aniline serves as
a Brønsted/Lewis acid while the nitro group is used to enhance
its acidity. Aromatic rings as well as alkyl side chains are to provide
a hydrophobic local environment that shifts the reaction equilib-
rium to favour the formation of an esterification product. The con-
densation of 4-phenylbutyric acid (2 mmol) and 1-octanol
(2 mmol) in 4 mL of isooctane under reflux was employed to gauge
the catalytic activities of these four anilinium salts. The amount of
catalyst was 1 mol % and the reaction progress was monitored by
⇑
Corresponding author. Tel.: +1 618 453 4904; fax: +1 618 453 6408.
E-mail address: ygao@chem.siu.edu (Y. Gao).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.132

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N. Sattenapally et al. / Tetrahedron Letters 54 (2013) 6665–6668
Table 1
Catalyst 1-promoted esterification reactionsa
1
catalyst
O
O
(1 mol%)
HO R2
R2
+
H O
2
+
R1
OH
isooctane
refluxing
R1
O
5a-o
Entry
Product
(R1COOR2)
Time
(h)
Yield (%)
GC
Yield (%)
Isolated
O
1
2
3
Ph
n-C8H17
5a
5b
5c
2
>99
91
92
72
97
O
3
O
Ph
Ph
Ph
CH3
24
3.5
O
O
O
3
O
>99
Ph
Ph
3
O
4
5d
3
87
77
3
O
5
6
Ph
Ph
5e
5f
19
24
>99
79
92
54
O
O
3
O
3
O
Ph
Ph
O
O
3
7
5g
28
75
73
3
O
O
Ph
O
8
9
5h
5i
115
19
67
95
59
92
3
OCH3
O
n-C8H17
O
O
n-C8H17
10
11
12
5j
24
18
22
98
91
80
91
80
54
O
O
n-C8H17
5k
5l
O
O
n-C8H17
O
O
O
n-C8H17
n-C8H17
13
14
5m
5n
25
44
>99
76
93
64
O
O
O
OCH3
O
O
O
15
5o
44
56
46
OCH3
Unless otherwise shown, the reaction was carried out with a carboxylic acid (2 mmol), an alcohol (2 mmol) and catalyst 1 (1 mol %) in isooctane (4 mL) under reflux.
a

N. Sattenapally et al. / Tetrahedron Letters 54 (2013) 6665–6668
6667
Table 2
Selective condensation of 4-phenylbutyric acid with various alcohols by catalyst 1a
O
Ph
OH
3
O
3
O
3
(1 mmol)
Ph
Ph
R2OH R2'OH
2 mmol 2 mmol
O
R2
catalyst 1
isooctane
O R2'
I
II
Entry
R2OH
R20OH
Conditions
Yield (%)
Molar ratiob
(I+II)
(I/II)
95/5
99/1
24 h, 25 °C,
2 mol % 1
1
2
CH3OH
OH
72
98
2 h, reflux
1 mol % 1
OH
MeO
MeO
OH
OH
6
20 h, reflux
1 mol % 1
3
4
>99
>99
96/4
Ph
OH
OH
116 h, 25 °C,
4 mol % 1
OH
85/15
6
a
Unless otherwise shown, the reaction was carried out with 4-phenylbutanoic acid (1 mmol), two alcohols (2 mmol each) and catalyst 1 in isooctane (4 mL) under various
temperatures.
b
Determined by GC analyses. The structures of products were confirmed by 1H NMR and MS experiments after flash chromatography purification.
GC analysis. Figure 1 shows the GC yields after 2 h of reaction. The
acetic acid salt of aniline (4) only led to less than 5% formation of
the ester product. This may suggest that the aromatic ring of p-tol-
uenesulfonate plays an important role in the formation of a local
hydrophobic catalytic centre, which is in agreement with our
previous observations in the study of lipid-modified pyridinium
salts. Compared with 2, the presence of two nitro groups on the
anilinium ring greatly enhanced the activities of 1 and 3. A long
C11 chain of 3 is sterically demanding and it actually reduced
the condensation yield of 1-octanol and 4-phenylbutyric acid to
87% yield. N-Butyl-2,4-dinitro-anilinium p-toluenesulfonate (1)
showed the highest catalytic activity (>99%) and was subsequently
selected for further investigations.
Table 1 lists catalyst 1-promoted condensation reactions be-
tween a group of carboxylic acids and alcohols. In a typical exper-
iment, an equal mole amount (2 mmol) of a carboxylic acid and an
alcohol were mixed in isooctane with 1 mol % 1 under reflux. GC
experiments were used to monitor reaction progresses and the
products were isolated and purified by flash chromatography. En-
tries 1–8 in Table 1 show condensation of 4-phenylbutyric acid
with various alcohols with 1 mol % catalyst 1. Within 2 h, catalyst
1 converted >99% 1-octanol into an ester and 92% isolation yield
was obtained (entry 1). In entry 2, after 24 h, a GC yield of 91%
and the isolation yield of 72% were obtained for its methyl ester.
The lower yield could be due to the partial loss of methanol and
the methyl ester during reaction and workup. Methanol and
methyl 4-phenylbutyrate are volatile chemicals. The condensation
between benzyl alcohol and 4-phenyl butyric acid (entry 3) also
led to excellent GC and isolation yields. Reactions of the acid with
secondary alcohols like cyclohexanol (entry 4) and 1-phenyl-1-
ethanol (entry 5) gave rise to moderate or excellent yields, respec-
tively. Catalyst 1 also led to the formation of a number of esters of
4-phenyl-butyric acid with an olefinic alcohol (entry 6), a diol (en-
try 7) and a phenol (entry 8) albeit with lower yields. Other carbox-
ylic acids have also been examined for esterification reactions
under 1 mol % 1, which include bulky 1-adamantanecarboxylic
acid (entries 9 & 14) and 2-ethyl-butanoic acid (entry 12), a phenol
(entries 10 & 15), an allylic acid (entry 11) and a di-acid (entry 13).
Many of these catalytic reactions gave rise to moderate or excellent
yields under 1 mol % catalyst 1.
equimolar amounts of two alcohols (2 mmol each) were treated
with 1 mmol of 4-phenylbutyric acid in isooctane (4 mL) with 1–
4 mol % catalyst 1. The molar ratio of two ester products from each
reaction was determined by GC experiments and was further con-
firmed by 1H NMR analyses after flash chromatography purifica-
tion. Entries 1 & 4 show that a primary alcohol (methanol and 1-
octanol) is preferred to react with the acid in the presence of a sec-
ondary alcohol (cyclohexanol). The molar selectivities are 95/5 and
85/15, respectively. A primary alcohol (1-octanol) (entry 2) is a
preferred substrate over a phenol with the selectivity of 99/1. Entry
3 also suggests that a secondary alcohol reacts faster with the acid
than the phenol substrate. Ambient temperature (25 °C) is required
for good selectivities between a primary alcohol and a secondary
alcohol (entries 1 & 4). Excellent selectivities can still be obtained
even at a higher temperature under reflux (>99 °C) when a primary
alcohol or a secondary alcohol is mixed with a phenol substrate
(entries 2 & 3).
The selectivity of catalyst 1 towards acids was also examined
by mixing 4-phenylbutryic acid (6) (2 mmol), 2-ethylbutryic acid
(7) (2 mmol) and 1-adamantanecarboxylic acid (8) (2 mmol) in
isooctane (4 mL) with a primary alcohol of either benzyl alcohol
(2 mmol) or methanol (2 mmol) under 1 mol % catalyst 1 (Ta-
ble 3). In entries 1–4, catalyst 1 prefers a sterically less hindered
carboxylic acid—4-phenylbutyric acid (6) over 2-ethylbutryic
acid (7). Very bulky 8 led to no detectable ester products (entries
2–4) or a very low yield (2%, entry 1). The carboxylic acid selec-
tivity also depends on the reaction temperature. At an ambient
temperature (25 °C) (entry 3), a high selectivity of 99/1/0 was
achieved for III/IV/V when benzyl alcohol was used as the alcohol
substrate.
Although the mechanism of selectivity is not clear at this stage,
it is reasonable to hypothesize that at an ambient temperature, cat-
alyst 1, alcohol and carboxylic acid substrates form a stable com-
plex. The hydrophobic catalytic centre of
1 promotes the
esterification reaction while its bulky aromatic rings and the butyl
chain prefer the adoption of a sterically less demanding substrate
to the catalytic centre. This size preference induces steric selectiv-
ity of 1 towards alcohol and carboxylic acid substrates. Raising the
reaction temperature will enhance the catalytic activity of 1, but
could also destabilize the catalytic complex and reduce the selec-
tivity of 1. However, more experiments will be needed to validate
our working hypothesis.
The selectivity of catalyst 1 towards alcohols was examined and
the results are reported in Table 2. In a typical experiment,

6668
N. Sattenapally et al. / Tetrahedron Letters 54 (2013) 6665–6668
Table 3
the reaction temperature is lowered. Such a highly active and
selective esterification catalyst can be a useful tool for synthetic or-
ganic chemists. Our study also suggests that rational deigns are a
good strategy that can potentially lead to novel esterification
catalysts.
Selective condensation of benzyl alcohol and methanol with various carboxylic acids
by catalyst 1a
O
O
3
O
O
3
Ph
R2
R2
OH
Ph
O
O
OH
HO R2
Acknowledgment
III
IV
(2 mmol)
7
6
catalyst 1 (1 mol%)
2 mmol
2 mmol
This work was supported in part by the NIH (2R15EB007074-
02).
isooctane
O
R2
OH
O
O
Supplementary data
V
Supplementary data (experiment procedures, 1H & 13C NMR, IR
and MS characterizations of compounds) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.09.132.
8
2 mmol
Entry
R2OH
Conditions
Yield (%)
(III+IV+V)
Molar ratiob
(III/IV/V)
1
2
3
4
PhCH2OH
PhCH2OH
PhCH2OH
CH3OH
4 h, reflux
19 h, 60 °C
135 h, 25 °C
68 h, 25 °C
>99
>99
96
72/26/2
58/42/0
99/1/0
References and notes
1. Otera, J.; Nishikido, J. Esterification: Methods, Reactions, and Applications, 2nd ed.;
Wiley-VCH: Weinheim, 2010.
76
87/13/0
2. (a) Hatano, M.; Ishihara, K. Chem. Commun. 2013, 1983; (b) Sato, A.; Nakamura,
Y.; Maki, T.; Ishihara, K.; Yamamoto, H. Adv. Synth. Catal. 2005, 347, 1337; (c)
Mantri, K.; Komura, K.; Sugi, Y. Green Chem. 2005, 7, 677; (d) Houston, T. A.;
Wilkinson, B. L.; Blanchfield, J. T. Org. Lett. 2004, 6, 679.
3. (a) Ishihara, K.; Nakagawa, S.; Sakakura, A. J. Am. Chem. Soc. 2005, 127, 4168; (b)
Sakakura, A.; Koshikari, Y.; Akakura, M.; Ishihara, K. Org. Lett. 2012, 14, 30; (c)
Manabe, K.; Limura, S.; Sun, X.-M.; Kobayashi, S. J. Am Chem. Soc. 2002, 124,
11971; (d) Ishihara, K.; Kosugi, Y.; Umemura, S.; Sakakura, A. Org. Lett. 2008, 10,
3191; (e) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5047; (f) Tian, J.;
Gao, W.-C.; Zhou, D.-M.; Zhang, C. Org. Lett. 2012, 14, 3020; (g) Noonan, C.;
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a
Unless otherwise shown, the reaction was carried out with a mixture of three
carboxylic acids (2 mmol each), benzyl alcohol or methanol (2 mmol each) and
catalyst 1 (1 mol %) in isooctane (4 mL) under various temperatures.
b
Determined by GC analyses. The structures of products were confirmed by 1H
NMR and MS experiments after flash chromatography purification.
In summary, in this Letter we report N-butyl-2,4-dinitro-anilin-
ium p-toluenesulfonate (1) as an active organic catalyst that can
promote condensation between carboxylic acids and alcohols with
high selectivity. The selectivity of this catalyst is improved when
4. Wang, W.; Liu, H.; Xu, S.; Gao, Y. Synth. Commun. 2013, 43, 2906.