Hydrophobic N,N-diarylammonium pyrosulfates as dehydrative condensation catalysts under aqueous conditions

Article abstract of DOI:10.1021/ol2027366

Oil-soluble N,N-diarylammonium pyrosulfates as nonsurfactant-type catalysts for the dehydrative ester condensation under aqueous conditions are described. Preheat treatment of dibasic sulfuric acid with bulky N,N-diarylamines generates water-tolerant salts of pyrosulfuric acid as active catalyst species. The present catalysts in water can also widely be applied to unusual selective esterifications and dehydrative glycosylation.

Full text of DOI:10.1021/ol2027366

ORGANIC
LETTERS
2012
Vol. 14, No. 1
30–33
Hydrophobic N,N-Diarylammonium
Pyrosulfates as Dehydrative
Condensation Catalysts under
Aqueous Conditions
Akira Sakakura,† Yoshiki Koshikari,‡ Matsujiro Akakura,§, and Kazuaki Ishihara*,‡,
EcoTopia Science Institute, Nagoya University, Japan, Graduate School of Engineering,
Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan, Department of
Chemistry, Aichi University of Education, Japan, and JST, CREST, Japan
ishihara@cc.nagoya-u.ac.jp
Received October 12, 2011
ABSTRACT
Oil-soluble N,N-diarylammonium pyrosulfates as nonsurfactant-type catalysts for the dehydrative ester condensation under aqueous conditions
are described. Preheat treatment of dibasic sulfuric acid with bulky N,N-diarylamines generates water-tolerant salts of pyrosulfuric acid as active
catalyst species. The present catalysts in water can also widely be applied to unusual selective esterifications and dehydrative glycosylation.
Water is a cheap, safe, and environmentally benign
solvent when compared with organic solvents. Use of
water will reduce the use of harmful organic solvents and
is regarded as an important subject in green chemistry. In
addition, water has unique physical and chemical proper-
ties, which allow us to realize reactivities that cannot be
attained in organic solvents. Therefore, the use of water as
a reaction solvent has received much attention in synthetic
organic chemistry.1 The dehydrative ester condensation
reaction is one of the most fundamental organic transfor-
mation reactions.2 Although several efficient catalysts
have been exploited for the direct dehydrative ester con-
densation of an equimolar mixture of carboxylic acids and
alcohols, it is very difficult to conduct the dehydrative
condensation in water, since a large amount of water also
promotes hydrolysis of the condensation products. In
2001, Kobayashi and colleagues reported the dehydrative
ester condensation between long-chain fatty acids and
long-chain alcohols in water using p-dodecylbenzenesul-
fonic acid (DBSA) as a surfactant-type catalyst.3 They
claimed that DBSA and long-chain substrates would form
emulsion droplets in water to accelerate the dehydration
(3) (a) Manabe, K.; Sun, X.-M.; Kobayashi, S. J. Am. Chem. Soc.
2001, 123, 10101. (b) Kobayashi, S.; Iimura, S.; Manabe, K. Chem. Lett.
2002, 31, 10. (c) Manabe, K.; Iimura, S.; Sun, X.-M.; Kobayashi, S.
J. Am. Chem. Soc. 2002, 124, 11971. (d) Aoyama, N.; Kobayashi, S.
Chem. Lett. 2006, 35, 238. (e) Shirakawa, S.; Kobayashi, S. Org. Lett.
2007, 9, 311.
(4) (a) Ishihara, K.; Nakagawa, S.; Sakakura, A. J. Am. Chem. Soc.
2005, 127, 4168. (b) Sakakura, A.; Nakagawa, S.; Ishihara, K. Tetra-
hedron 2006, 62, 422. (c) Sakakura, A.; Watanabe, H.; Nakagawa, S.;
Ishihara, K. Chem.;Asian J. 2007, 2, 477. (d) Sakakura, A.; Nakagawa,
S.; Ishihara, K. Nat. Protoc. 2007, 2, 1746.
(5) (a) Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y. Tetra-
hedron Lett. 2000, 41, 5249. (b) Funatomi, T.; Wakasugi, K.; Misaki, T.;
Tanabe, Y. Green Chem. 2006, 8, 1022. (c) Gacem, B.; Jenner, G.
Tetrahedron Lett. 2003, 44, 1391. (d) Mercs, L.; Pozzi, G.; Quici, S.
Tetrahedron Lett. 2007, 48, 3053.
† EcoTopia Science Institute, Nagoya University.
‡ Graduate School of Engineering, Nagoya University.
§ Department of Chemistry, Aichi University of Education.
CREST.
€
(1) (a) Lindstrom, U. M., Ed. Organic Reactions in Water; Blackwell,
Oxford, 2007. (b) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
(c) Uozumi, Y.; Yamada, Y. M. A. Chem. Rec. 2009, 9, 51. (d) Raj,
M.; Singh, V. K. Chem. Commun. 2009, 6687. (e) Chanda, A.; Fokin,
V. V. Chem. Rev. 2009, 109, 725.
(2) (a) Ishihara, K. Tetrahedron 2009, 65, 1085. (b) Otera, J.; Nishikido,
J. Esterification, 2nd ed.; WILEY-VCH: Weinheim, 2010.
r
10.1021/ol2027366
Published on Web 11/29/2011
2011 American Chemical Society

reactions. Previously, we developed bulky N,N-diarylam-
monium pentafluorobenzenesulfonates as mild and highly
active dehydrative ester condensation catalysts.4,5 They
successfully catalyze the reaction of an equimolar mixture
of carboxylic acids and alcohols in less polar solvents
such as heptane, even without the removal of the water
produced. The high catalytic activity is attributed to
the hydrophobic effect of bulky aryl groups of the
catalysts.4c However, these bulky N,N-diarylammo-
nium salt catalysts are almost inert under aqueous
conditions, probably due to the transfer of pentafluor-
obenzenesulfonic acid to the aqueous layer. We report
here the dehydrative ester condensation reactions cat-
alyzed by N,N-diarylammonium pyrosulfates under
aqueous conditions.
Disappointingly, [1d•acid]A also gave similar results with
the corresponding acids (data are not shown). Next,
[1d•acid]A were heated at 80 °C for 0.5 h (method B) before
being used as catalysts for the dehydrative condensation
reaction (Figure 1). N,N-Diarylammonium salts prepared
by method B are represented as [1d•acid]B. Very surpris-
ingly, [1d•H2SO4]B, which was a salt of extremely hydro-
philic H2SO4, showed excellent catalytic activity under
aqueous conditions and gave 1-dodecyl 4-phenylbutyrate
in 85% yield. In contrast, N,N-diarylammonium salts of
sulfonic acids [1d•RSO3H]B were almost inert.
Table 1. Catalytic Activities of Brønsted Acids and Their Am-
monium Salts with 1d in Watera
yield of
ester (%)c
yield of
ester (%)c
acid [pKa]b
[1d•acid]B
TfOH [ꢀ0.74]
H2SO4 [7.0]
TsOH [8.5]
6
15
23
9
[1d•TfOH]B
[1d•H2SO4]B
[1d•TsOH]B
[1d•CSA]B
9
85
11
7
CSA [9.0]
C6F5SO3H [9.2]
11
[1d• C6F5SO3H]B
13
a Conditions: 4-phenylbutyric acid (1.1 equiv), 1-dodecanol (4 mmol),
and catalyst (5 mol %) in water (2 mL) at 60 °C for 6 h. b pKa values
were measured in CD3CO2D.12 c Determined by 1H NMR analysis.
Figure 1. N,N-Diarylammonium salt catalysts [1•acid] for the
dehydrative ester condensation in water.
The catalytic activities of [1•H2SO4]B, which were as-
sessed by their initial rates (vi) of the dehydrative ester
condensation under aqueous conditions, significantly de-
pended on the steric bulkiness around ammonium protons
(Figure 2).4b The use of N,N-diarylamines 1cꢀf bearing
substituents at each ortho-position successfully accelerated
the reaction. The most sterically hindered [1f•H2SO4]B
showed the highest catalytic activities. The catalytic activ-
ity of [1f•H2SO4]B (vi = 0.13 M hꢀ1) was almost the same
as that of DBSA (vi = 0.13 M hꢀ1) and was ca. 60 times
higher than that of [1a•H2SO4]B (vi = 0.0023 M hꢀ1) under
aqueous conditions.
We first examined the catalytic activities of various
Brønsted acids and their ammonium salts with bulky N,
N-diarylamine 1d4 (Figure 1) under aqueous conditions.
The reaction of 4-phenylbutyric acid (1.1 equiv) with
1-dodecanol (4 mmol) was conducted in water (2 mL) at
60 °C for 6 h (Table 1). As a result, hydrophilic Brønsted
acids such as trifluoromethanesulfonic acid (TfOH), sul-
furic acid (H2SO4), p-toluenesulfonic acid (TsOH), 10-
camphorsulfonic acid (CSA), and pentafluorobenzenesul-
fonic acid (C6F5SO3H) were almost inert under aqueous
conditions,6 although they can catalyze the same reaction
in less polar solvents,4 ionic liquids,7 or under solvent-
free conditions.8 N,N-Diarylammonium salts, which were
represented as [1d•acid]A, were prepared by mixing an
equimolar amount of 1d and an acid in a homogeneous
solution at ambient temperature and then evaporation
of the solvent (method A). [1•acid]A would be dimeric
complexes composed of two N,N-diarylammonium
cations and two sulfonate anions: [ArNH2þ]2[Xꢀ]2, based
on X-ray crystallographic analysis of [1a•H2SO4]A.4c,9
(6) Liu, Y.; Lotero, E.; Goodwin, J. G., Jr. J. Mol. Catal. A: Chem.
2006, 245, 132.
(7) (a) Wells, T. P.; Hallett, J. P.; Williams, C. K.; Welton, T. J. Org.
Chem. 2008, 73, 5585. (b) Jiang, T.; Chang, Y.; Zhao, G.; Han, B.; Yang,
G. Synth. Commun. 2004, 34, 225.
(8) Sakakura, A.; Koshikari, Y.; Ishihara, K. Tetrahedron Lett. 2008,
49, 5017.
(9) See Supporting Information for details.
Figure 2. Initial rates [M hꢀ1] of ester condensation in water
using [1•H2SO4]B (5 mol %). Conditions: 4-phenylbutyric acid
(1.1 equiv) and 1-dodecanol (4 mmol) in water (2 mL) at 40 °C.
Org. Lett., Vol. 14, No. 1, 2012
31

Next, [1•H2SO4]A and [1•H2SO4]B were compared by 1H
NMR in CD3CN (Table 2). Based on chemical shifts of the
ammonium protons, the active catalyst [1f•H2SO4]B pre-
pared by heat treatment (method B) was a species different
from [1f•H2SO4]A, a simple salt of 1f and H2SO4. In the
case of [1a•H2SO4]A and [1a•H2SO4]B, both of which were
almost inert under aqueous conditions, the chemical shift
of the ammonium protons also shifted downfield by the
heat treatment (7.19 f 8.34 ppm). However, [1a•H2SO4]B
was labile and gradually decomposed to [1a•H2SO4]A
in CD3CN at 60 °C for 6 h (8.34 f 7.29 ppm), while
[1f•H2SO4]B was stable under the same conditions.9 In
addition, the alkaline titration experiment showed that, in
the case of [1f•H2SO4]B, only 29% of H2SO4 was leaked to
the aqueous layer, while large amounts of H2SO4 were
included in the aqueous layer in the cases of [1f•H2SO4]A
and [1a•H2SO4]B.
Figure 3. B3LYP/6-31G(d) optimized geometry of [1f-Hþ]2-
[S2O72ꢀ]. Hydrogen atoms, except for ammonium protons, are
omitted for clarity. C = black, H = white, N = blue, O = red,
S = yellow.
Table 2. Comparison of N,N-Diarylammonium Salt Catalysts
Prepared by Methods A and B
H2S2O7 formed four hydrogen bondings in a bidentate
fashion between two ammonium cations (Ar2NH2þ) and a
pyrosulfate anion (S2O72ꢀ) (Figure 3). These results sug-
gested that the ammonium salts of H2S2O7 should be more
stable than those of H2SO4. This stability would increase
the water tolerance of the active catalyst [1f•H2SO4]B. The
fact that N,N-diarylammonium salts of dibasic sulfonic
acids9 were inert also implied that the formation of pyr-
osulfates was crucial for high catalytic activity.
The present hydrophobic N,N-diarylammonium pyro-
sulfate-catalyzed dehydrative ester condensation could be
applied to the reactions of a variety of substrates (Table 3).
Significantly, [1f•H2SO4]B showed higher catalytic activity
than DBSA for the esterification of rather hydrophilic
substrates (entries 1ꢀ6). For example, the reaction of
hexanoic acid with 1-butanol was successfully catalyzed
by [1f•H2SO4]B to give 1-butyl hexanoate in 80% yield
(6 h), while the use of DBSAgavea 47% yield ofthe ester in
chemical shift
of NH2
content of H2SO4
in aq
yield of
in
catalyst
ester (%)a CD3CN (ppm)
layer (%)
[1f•H2SO4]A
10
85
82
9
7.59
75
29
34
81
82
84
[1f•H2SO4]B
9.01
[1f•H2SO4(SO3)X]A
[1a•H2SO4]A
9.18
7.19
[1a•H2SO4]B
15
13
8.34 (f 7.29)b
7.17
[1a•H2SO4(SO3)X]A
a The reaction of 4-phenylbutyric acid (1.1 equiv) with 1-dodecanol
(4 mmol) in the presence of catalyst (5 mol %) was conducted in water
(2 mL) at 60 °C for 6 h. Yields were determined by 1H NMR analysis.
b Chemical shift of ammonium protons changed at 60 °C during 6 h.
These results showed that the heat treatment of
[1f•H2SO4]A generated some water-tolerant salts as active
catalyst species. According to Halstead’s report that ther-
mal decomposition of ammonium sulfate or ammonium
hydrogen sulfate generates ammonium pyrosulfate,10 we
expected that the active species [1f•H2SO4]B might be
ammonium salts of pyrosulfuric acid (H2S2O7). In fact,
[1f•H2SO4(SO3)X]A, the ammonium salt of 1f with oleum
(containing ca. 30% SO3), also showed high catalytic
activity (82% yield) even without heat treatment before
use. In addition, the chemical shift of ammonium protons
of [1f•H2SO4(SO3)X]A was almost identical to that of
[1f•H2SO4]B. Theoretical calculation of the dissociation
free energy showed that H2S2O7 is more acidic than
H2SO4.9 In the optimized geometry, the salt of 1f and
Table 3. [1f•H2SO4]B-Catalyzed Dehydrative Ester Condensa-
tion of Various Substrates under Aqueous Conditionsa
(10) (a) Halstead, W. D. J. Appl. Chem. 1970, 20, 129. (b) Jariwala,
M.; Crawford, J.; LeCaptain, D. J. Ind. Eng. Chem. Res. 2007, 46, 4900.
(11) (a) Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004, 971.
(b) Hoydonckx, H. E.; De Vos, D. E.; Chavan, S. A.; Jacobs, P. A. Top.
Catal. 2004, 27, 83. (c) Otera, J. Chem. Rev. 1993, 93, 1449. (d) Maegawa,
Y.; Ohshima, T.; Hayashi, Y.; Agura, K.; Iwasaki, T.; Mashima, K.
ACS Catalysis 2011, 1, 1178.
a Conditions: carboxylic acid (1.1 equiv), alcohol (4 mmol), and
[1f•H2SO4]B (5 mol %) in the presence of water (2 mL) at 60ꢀ80 °C.
b Determined by 1H NMR analysis. Data in brackets refer to NMR yield
when DBSA (5 mol %) was used as a catalyst.
(12) Rode, B. M.; Engelbrecht, A.; Schantl, J. Z. Phys. Chem.
(Leipzig) 1973, 253, 17.
32
Org. Lett., Vol. 14, No. 1, 2012

the same reaction time. It is noteworthy that, for the
ammonium salt catalyzed esterification of hexanoic acid
with 1-butanol, the addition of NaOH (10 mol %) to the
reaction mixture gave clear separation between the organic
and aqueous layers, and the crude product could be easily
obtained by simple decantation.9 In contrast, the addition
of NaOH (5 mol %) to the reaction mixture of the DBSA-
catalyzed esterification did not give clear separation be-
tween the two layers, which was probably because DBSA
acted as a surfactant. The esterification of R,β-unsaturated
carboxylic acids and stericallybulky carboxylic acids could
also be catalyzed by [1f•H2SO4]B to give the corresponding
esters in good yields (entries 7 and 8).
the ester of hydrophobic 1-adamantanecarboxylic acid was
predominantly obtained in 81% yield along with the ester of
hydrophilic acetic acid in 5% yield (Scheme 1B). On the other
hand, the same reaction in heptane preferentially gave the
acetate in 85% yield. The selective esterification of cyclodo-
decanol (71%) over ethanol could also be achieved under
aqueous conditions (Scheme 1C).
In addition, the [1e•H2SO4]B-catalyzed dehydrative
glycosylation of 3,5-O-dibenzyl-2-deoxy-D-ribose with
1-dodecanol under aqueous conditions gave the corre-
sponding acetal in 87% yield, while the use of H2SO4 as
a catalyst decreased the yield (28%) (Scheme 2).
The use of N,N-diarylammonium sulfate catalysts under
aqueous conditions has an additional advantage in the
ester condensations of acid-sensitive alcohols. For exam-
ple, the esterification of cinnamyl alcohol with lauric acid
(1.1 equiv) using [1f•H2SO4]B (5 mol %) under aqueous
conditions predominantly improved the yield of the ester
(74%) (Scheme 1A). The use of water as a solvent also
allowed us to achieve unusual selective ester condensations of
two substrates based on the difference in hydrophobicity of
the substrates. For example, when the reaction of a 1:1:1
molar mixture of 1-adamantanecarboxylic acid, acetic acid,
and 1-dodecanol was conducted under aqueous conditions,
Scheme 2. Dehydrative Glycosylation
In conclusion, oil-soluble complexes of hydrophobic N,
N-diarylamines with sulfuric acid successfully catalyzed
dehydrative ester condensation reactions under aqueous
conditions. The preheat treatment of dibasic sulfuric acid
with bulky N,N-diarylamines was crucial for the genera-
tion of water-tolerant aggregated complexes of pyrosulfu-
ric acid as active catalyst species. Further studies to
elucidate the detailed aggregated structure of the N,
N-diarylammonium pyrosulfate catalysts and their appli-
cations to other reactions under aqueous conditions are
now underway. Water is still not commonly used as a
solvent for organic synthesis despite the distinctive pro-
perties. The present nonsurfactant-type Brønsted acid
catalysis will provide a new aspect of organic synthesis
in water.
Scheme 1. Unusual Selective Ester Condensations under Aqu-
eous Conditions
Acknowledgment. Financial support for this project
was partially provided by JSPS.KAKENHI (20245022
and 23350039), NEDO, Yazaki Memorial Foundation
for Scienceand Technology, and the GlobalCOE Program
of MEXT. The computations were performed using Re-
search Center for Computational Science, Okazaki, Japan.
Supporting Information Available. Experimental de-
tails, characterization data of all new compounds, and
crystal information file. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
33