Esterification catalysis by pyridinium p -toluenesulfonate revisited - Modification with a lipid chain for improved activities and selectivities

Article abstract of DOI:10.1080/00397911.2012.749990

The lipid analogs of pyridinium p-toluenesulfonate (PPTS) were examined for catalysis of the condensation of an equimolar mixture of carboxylic acids and alcohols under mild conditions without removal of water. Although PPTS is a poor catalyst, the introduction of a lipid chain and nitro group significantly improved the activity of PPTS and led to selectivity at suppressing the elimination side reactions of alcohols. 2-Oleamido-5-nitro-pyridinium p-toluenesulfonate (6) is a lead catalyst that promoted various esterification reactions with yields up to 99%.

Full text of DOI:10.1080/00397911.2012.749990

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Esterification Catalysis by Pyridinium p-
Toluenesulfonate Revisited—Modification with a Lipid
Chain for Improved Activities and Selectivities
Wei Wang a , Huimin Liu b , Shaoyi Xu b & Yong Gao b
a Current address: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry
of Education and School of Pharmaceutical Sciences, Wuhan University , Wuhan 430071 , P.R.
of China
b Department of Chemistry and Biochemistry , Southern Illinois University , Carbondale ,
Illinois , 62901-4409
Accepted author version posted online: 31 May 2013.
To cite this article: Wei Wang , Huimin Liu , Shaoyi Xu & Yong Gao (2013): Esterification Catalysis by Pyridinium
p-Toluenesulfonate Revisited—Modification with a Lipid Chain for Improved Activities and Selectivities,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.749990
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Esterification Catalysis by Pyridinium p-Toluenesulfonate Revisited—Modification
with a Lipid Chain for Improved Activities and Selectivities
Wei Wang1, Huimin Liu2, Shaoyi Xu2, Yong Gao2,
1Current address: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery,
Ministry of Education and School of Pharmaceutical Sciences, Wuhan University,
Wuhan 430071, P.R. of China 2Department of Chemistry and Biochemistry, Southern
Illinois University, Carbondale, Illinois 62901-4409
To whom correspondence should be addressed. , Phone: (618)453-4904; Fax: (618)453-
6408; E-mail: ygao@chem.siu.edu
Abstract
The lipid analogues of pyridinium p-toluenesulfonate (PPTS) were examined for
catalyzing the condensation of an equimolar mixture of carboxylic acids and alcohols
under mild conditions without removal of water. Although PPTS is a poor catalyst, the
introduction of a lipid chain and nitro group significantly improved the activity of PPTS
and led to selectivity at suppressing elimination side reactions of alcohols. 2-Oleamido-
5-nitro-pyridinium p-toluenesulfonate (6) is a lead catalyst that promoted various
esterification reactions with yields up to 99%.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
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INTRODUCTION
During recent years, there is increasing interest in exploring the use of organic catalysts
for promoting acid-alcohol esterification reactions. For example, the employment of
diarylammonium arenesulfonates1 and pyrosulfates2 as dehydrative condensation
catalysts and use ofp-dodecylbenzenesulfonic acid for catalytic esterification reactions in
water were reported.3 Histidine sulfonamide,4N-alkyl-4-boronopyridinium iodide5,
iodosodilactone6, proline7 and carbenes8were also examined as catalysts for promoting
esterification reactions. One of the advantages of using organic esterification catalysts
over metal catalysts9 is that an organic catalyst can be removed out of reaction mixtures
more easily than a metal counterpart during work-up. In a pharmaceutical process,
repeatedrecrystallization steps or multiple chromatography purifications are needed to
remove a leached metal catalyst out of the drug intermediate since the metal content has
to be controlled under several ppm. The adoption of an organic esterification catalyst
will avoid the metal contamination problem in a drug production process.
Pyridinium p-Toluenesulfonate (PPTS) has been extensively explored as an organic
catalyst for promoting chemical transformations such as synthesis and cleavage of
acetals,10 and deprotection of silyl or tetrahydropyranyl groups.11 This pyridinium salt
can be facilely prepared from pyridine and p-toluenesulfonic acid and has good solubility
in organic solvents like methylene chloride, chloroform, acetone and ethanol. PPTS is a
mild acid which is especially usefulwhen a reaction substrate is unstable to strong acids.
However, PPTS typically shows weak catalytic activity in promoting esterification
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condensation reactions and the use of PPTS in esterification reactions, to the best of our
knowledge, has not yet been widely reported.
RESULTS AND DISCUSSION
In this communication, we report the design, synthesis and investigation of a group of
lipid analogues of PPTS (1) (Figure 1) for catalyzing esterification reactions. An
esterification process involves the condensation of an acid and an alcohol and water is
generated as the byproduct. Continuous removal of water out of the reaction mixture
with the assistance of molecular sieves, evaporative distillation, etc., is a common
strategy to shift the reaction equilibrium towards the ester product for a better reaction
yield.12 Our approach to improve the activity of PPTS involves the attachment of a lipid
chain onto the pyridinium ring to create a local hydrophobic environment that has less
affinity to water molecules. Such a hydrophobic reaction center will help shift the
equilibrium towards the ester product. In addition, steric hindrance created by the long
lipid chain could also lead to selectivity towards some reaction substrates and
intermediates.
PPTS and its lipid analogues in Figure 1 were synthesized via simple chemical
transformations and the details of our synthesis protocols are reported in the Supporting
Information (available online). Catalysts (5 mol%) were evaulated using 4-phenylbutyric
acid (2 mmol) and 1-octanol (2 mmol) at 25 oC in 4 mL of isooctane (Table 1). The
reaction progress was monitored by GC and TLC analyses. After 72 hours, the products
were isolated, purified by flash chromatography and characterized by1H NMR, 13C NMR,
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IR and high-resolution mass spectrometry. Table 1 lists the GC yields of the ester
products after 72 hours. PPTS (1) is a weak catalyst that failed to generate the ester
product (entry 1)and no esterification product was determined by our GC experiments at
ambient temperature and 80 oC. The short C2 acetyl chain on the pyridinium ring of 2
did not improve the activity of 2 as no formation of the esterification product was
detected (entry 2). A longer C18 chain derived from oleic acid in catalyst 3 led to a yield
of 16% (entry 3). The introduction of a nitro group at the meta-position in the pyridinium
ring of 4 improved its catalytic activity as 48% of the esterification product was
uncovered (entry 4). -NO2 is an electron-withdrawing group that increases the acidity of
4 and thus improvingits activity. The acetyl chain in 5 gave a yield of 49% (entry 5)—
which re-confirms that a short chain of C2 does not help improve the activity of the
catalyst. However, a much longer C18 chain in catalyst 6 significantly boosted its
activity. A yield of 76% was observed for 6 at 25 oC after 72 hours (entry 6) while a
higher yield of 99% was obtained when the reaction temperature was raised to 80 oC.
Pyridinium salts with an alternative anionic group like pentafluorobenzoate in 7 (entry 7),
or trifluoromethanesulfonate in 8 (entry 8) or acetate in 9 (entry 9) all failed to generate
detectable esterification products.
The higher activity of catalyst 6 over that of compound 4 in Table 1 confirms that a long
C18 alkyl chain can help improve the activity of pyridinium salts. Catalyst 6 was further
explored for facilitating a group of esterification reactions of an equimolar mixture of
carboxylic acids and alcohols with diverse functional groups (Figure 2). A typical
procedure of these reactions (Table 2) involves the addition of 6 (1-10 mol%) to a
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mixture of an acid (2 mmol) and an alcohol (2 mmol) in 4 mL of isooctane under various
temperatures. These esters in Figure 2 were synthesized from 4-phenylbytric acid (12a-
h), bulky acids like 2-ethylbutanoic acid (12i) and 1-adamantanecarboxylic acid (12k),
benzoic acid (12j), a vinyl acid (12l) and a di-acid (12m). The alcohols used for
constructing esters include methanol (12d), 1-octanol (12a, 12i-m), phenol (12h), an
allylic alcohol (12c), a secondary alcohol (12e), a diol (12f) and an amino-diol (12g).
Moderate to excellent yields ranging from 40% to 99% were observed via our GC
experiments (Table 2). The esterification products were further isolated, purified via
flash chromatography and extensively characterized.
It is noteworthy that no significant formation (<1%) of dehydrative elimination
byproducts from alcohols, especially from cyclohexanol (entry 5) was detected by our
GC experiments. Steric hindrance created by the alkyl chain suppresses the elimination
of water from the alcohol—a competitive side reaction frequently encountered in the acid
mediated-esterification reaction of secondary alcohols.1 A yield of 99% for the
esterification of 1-adamantanecarboxylic acid (entry 11) suggests that 6 is a robust
catalyst that can accommodate a large number of substrates including a very bulky acid.
However, yields were lower for less active acids like benzoic acid (entry 10) and 2-
methyl-propenoic acid (entry 12).
CONCLUSIONS
In conclusion, a group of lipid analogues of PPTS were synthesized and examined for
catalyzing esterification reactions. PPTS itself is a weak catalyst, but the introduction of
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a lipid C18 chain and a nitro group on the pyridinium ring significantly improved its
catalytic activity. 2-Oleamido-5-nitro-pyridinium p-toluenesulfonate (6) is a lead catalyst
that facilitated the synthesis of a large number of esters from diverse substrates. This
catalyst also demonstrated selectivities in suppressing competitive elimination of water
molecules from alcohols. Our investigations here suggest that rational modifications of
PPTS can lead to unusual activities and selectivities. Further studies to elucidate the
detailed structure and mechanism of PPTS lipid analogues and their applications to other
types of organic transformations are now underway.
EXPERIMENTAL
Most chemicals were purchased from Acros Organics (Somerville, NJ), and Aldrich
(Milwaukee, WI) and used as received without further purification. Amino acids were
bought from Bachem Bioscience (King of Prussia, PA). Water was obtained from a
Milli-Q reagent water system purchased from Millipore Corporation (Milford, MA). The
heavy metal and bacterial contaminant levels in Milli-Q water are below 10 ppb. 1H
NMR and 13C data were obtained on a Varain VXR-300 system with an Oxford wide-
bore magnet and the chemical shifts were reported in parts per million (ppm) downfield
relative to tetramethylsilane using the residual proton resonance of solvents as the
references (1H NMR): CDCl3δ 7.27; CD2Cl2δ 5.32 and (13C NMR): CDCl3δ 77.2;
CD2Cl2δ 54.0. Elemental analyses were done in Galbraith Laboratories, Inc. (Knoxville,
TN). GC analyses were carried out on a Varian 3900 system equipped with a TCD
detector. A Varian Factorfour Capillary Column VF-1ms, 15 mx 0.25 mm. LC-MS
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experiments were carried out in the Mass Spectrometry Laboratory in the University of
Illinois at Urbana-Champaign.
General Procedure For Preparing Catalysts
A mixture of pyridine or its analogues (1 mmole) with an acid (1 mmole) in in 10 mL
toluene was refluxed for 2 hours. Then, the solution was cooled down to ambient
temperature and the solvent was removed in vacuo to yield a pyridinium acid salt as a
catalyst for our esterification investigations.
General Procedure For Catalytic Esterification Reactions
To a mixture of an acid (1 eq.) and an alcohol (1 eq.) in isooctane (4 mL) was added a
catalyst ranging from 1-10 mol%. The resultant reactions were carried out at various
temperatures and the reaction progresses were monitored by GC and TLC analyses. Then,
the solvent was removed in vacuo and the products were isolated, purified by flash
chromatography and characterized by 1H NMR, 13C NMR, IR and high-resolution mass
spectrometry.
SUPPORTING INFORMATION
Full experimental details, spectroscopic characterizations (1H &13C NMR, IR and high-
resolution mass spectrometry) of all compounds. This material can be found via the
Supplemental Content section of this article’s Webpage.
Supporting Information Available Online: Characterization data of new compounds.
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ACKNOWLEDGEMENT
We thank Narsimha Sattenapally for collecting some preliminary laboratory data. This
work was supported in part by the NIH (1R15EB007074-01, 2R15EB007074-02), and
NSF (CAREER Award CHE-0343440).
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(9) For some leading references on metal-mediated esterification reactions: (a) Sato, A.;
Nakamura, Y.; Maki, T.; Ishihara, K.; Yamamoto, H. Adv. Synth. Catal.2005, 347, 1337-
1340. (b) Mantri, K.; Komura, K.; Sugi, Y. Green Chem.2005, 7, 677-682. (c) Houston,
T. A.; Wilkinson, B. L.; Blanchfield, J. T. Org. Lett.2004, 6, 679-681. (d) Bartoli, G.;
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Synth. Catal.2005, 347, 33-38. (e) Mikami, K.; Mikami, Y.; Matsumoto, Y.; Nishikido,
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J.; Yamamoto, F.; Nakajima, H. Terhedron Lett. 2001, 42, 289-292. (f) Dyke, A. C.;
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Table 1. Evaluation of the Catalytic Activities of PPTS Lipid Analogues (Figure 1) using
an Esterification Reaction of 4-Phenylbutyric Acid with 1-Octanola
entry catalyst
yield of ester (%)b
1
2
3
4
5
6
7
8
9
PPTS (1) n.d.c
2
3
4
5
6
7
8
9
n.d.
16
48
49
76/99d
n.d.
n.d.
n.d.
a Conditions: 4-phenylbutyric acid (2 mmol), 1-octanol (2 mmol), and catalyst (5 mol%)
b
c
in isooctane (4 mL) at 25 oC for 72 h. Determined by GC analysis. Not detected by
GC experiments. d The yield of 76% at 25 oC and 99% at 80 oC, respectively.
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Table 2. Syntheses of Esters Listed in Figure 2 under 6a
entry RCOOR’ GC yield of
isolated yield of
reaction condition
12
12a
ester (%)
ester (%)
1
2
3
4
5
6
99
97
70
78
99
81
95
83
61
76
93
81
catalyst 1 mol%, 80 oC, 5 h
catalyst 1 mol%, 80 oC, 6 h
catalyst 1 mol%, 80 oC, 30 h
catalyst 5 mol%, 25 oC, 24 h
catalyst 1 mol%, reflux, 16 h
catalyst 1 mol%, 2 eq. acid,
reflux, 30 h
12b
12c
12d
12e
12f
7
12g
92
83
catalyst 1 mol%, 2 eq. acid,
reflux, 48 h
8
12h
12i
55
61
40
99
74
84
59
50
33
93
64
78
catalyst 10 mol%, reflux, 96 h
catalyst 1 mol%, reflux, 48 h
catalyst 10 mol%, reflux, 144 h
catalyst 1 mol%, reflux, 96 h
catalyst 10 mol%, reflux, 40 h
catalyst 10 mol%, 2 eq.
alcohol, reflux, 48 h
9
10
11
12
13
12j
12k
12l
12m
a Unless otherwise noted, an acid (2 mmol), an alcohol (2 mmol) in isooctane (4 mL).
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Figure 1. PPTS (1) and Its Lipid Analogues (2-9).
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Figure 2. Esterification Products Synthesized under 6.
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