2,2,6,6-Tetramethylpiperidinium triflate (TMPT): a highly selective and self-separated catalyst for esterification

Article abstract of DOI:10.1016/j.tetlet.2016.09.061

An eco-friendly and readily accessible 2,2,6,6-tetramethylpiperidinium triflate was found as highly-selective and self-separated catalyst for esterification under solvent-free condition. The X-ray crystallography revealed that it formed a ‘hydrophobic wall’ which could effectively eliminate the generated water from the reactive sites. Moreover, it could precipitate from the reaction system with excellent recovery ratio (>99%) and be reused for ten times without any significant loss of activity.

Full text of DOI:10.1016/j.tetlet.2016.09.061

Accepted Manuscript
2, 2, 6, 6-Tetramethylpiperidinium triflate (TMPT): A highly selective and self-
separated catalyst for esterification
Lan Gao, Taoping Liu, Xiaochun Tao, Yongmin Huang
PII:
S0040-4039(16)31231-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.061
TETL 48131
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 August 2016
11 September 2016
18 September 2016
Please cite this article as: Gao, L., Liu, T., Tao, X., Huang, Y., 2, 2, 6, 6-Tetramethylpiperidinium triflate (TMPT):
A highly selective and self-separated catalyst for esterification, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.09.061
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1
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Tetrahedron Letters
journal homepage: www.elsevier.com/ locate/tetlet
2, 2, 6, 6-Tetramethylpiperidinium triflate (TMPT): a highly selective and self-
separated catalyst for esterification
Lan Gaoa, Taoping Liub, Xiaochun Taoa,*, Yongmin Huanga,*
aKey Laboratory of Specially Functional Polymeric Materials and Related Technology, School of Chemistry and Molecular Engineering, East China University
of Science and Technology, 130 Meilong Road, Shanghai 200237, P.R. China
bSuzhou Eleco Chemical Industry CO., Ltd. 608 Xiao Shu Road, Kunshan, Jiangsu 215341, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An eco-friendly and readily accessible 2, 2, 6, 6-tetramethylpiperidinium triflate was
found as highly-selective and self-separated catalyst for esterification under solvent-
free condition. The X-ray crystallography revealed that it formed a “hydrophobic
wall” which could effectively eliminate the generated water from the reactive sites.
Moreover, it could precipitate from the reaction system with excellent recovery ratio
(>99%) and be reused for ten times without any significant loss of activity.
Available online
Keywords:
Alkyl piperidinium sulfonates
Esterification
2009 Elsevier Ltd. All rights reserved.
Selectivity
Steric hindrance
Self-separation
Introduction
higher selectivity and activity in esterification. However, the
costly raw materials and complicated synthetic procedures
Esters are important products and intermediates in material
science and chemical industries, they play a main role in organic
synthesis.1-4 Generally, esters are produced by acid-catalyzed
dehydration reaction of carboxylic acids and alcohols in the
presence of stoichiometric dehydrating reagents.5 Traditional
acidic catalysts such as H2SO4, HCl ect. are usually adopted, but
they are quite contaminative and corrosive, which always result
in poor selectivity, high energy-consuming and seriously
environmental pollution.6-9 Besides, separate the dehydrating
agents and catalysts from crude products require considerable
time and energy. Therefore, “green” synthetic approaches for
esters have attracted much attention, nevertheless wide varieties
of achievements have been exploited in recent years, the
developing for environmentally benign and cost-effective
method is still highly requested. 5, 10-19
limited their application.
Non-metallic organocatalysts with simple structure and low
molecular weight are promising alternatives in organic synthesis,
because they possess non-toxic, high-efficiency and eco-friendly
features.20,21 In 2000, Tanabe et al.22 developed the N,N-
diphenylammonium triflate (DPAT) as an esterification catalyst.
This metal-free organocatalyst displayed superior catalytic
capability without the use of any dehydration system, but the
selectivity of acid-sensitive alcohols is still poor because it is a
strongly acidic salt.23 Afterwards, Ishihara et al.23-26 reported the
Scheme 1. The strategy to prepare a practical and selective catalyst based on
Tanabe’s and Ishihara’s catalysts.
Based on these research, we discovered the readily accessible 2,
2, 6, 6-tetramethylpiperidinium triflate (TMPT), which showed
excellent selectivity and induced a spontaneous self-separation
process in esterification (Scheme 1). In our research, we
designed a series of piperidinium sulfonates to investigate the
effects of acidity and steric group on catalytic activity.
Furthermore, we examined the selectivity and catalyst reusability.
Herein, we report the results catalyzed by alkyl piperidinium
sulfonates under solvent-free condition.
bulky
N,N-diarylammonium
pentafluorobenzenesulfonates
([Ar2NH2]+[O3SC6F5]-) which have a weaker acidity and showed
 Corresponding author.
Tel.: +139 1893 6495; e-mail: huangym@ecust.edu.cn
Tel.: +136 0185 5978; e-mail: xctao@ecust.edu.cn

2
Results and Discussion
groups around the reactive site, TMPT formed a hypothetical
“hydrophobic wall”25 which could effectively prevent the
generated water from approaching to the reactive sites and thus
inhibiting the inactivation of the catalyst by water. (Figure 2c).
While PPT was unstable as it could not form any special
structure (Figure 3).32 Hence, we deduced that the hydrophobic
effect deriving from the steric hindrance was of great importance
for the high catalytic activity. Apparently, among all the
catalysts, TMPT showed the best performance.
Scheme 2. The simple alkyl piperidinium sulfonates of 1a-c and 2a-c.
The alkyl piperidinium sulfonates (1a-c and 2a-c) were prepared
from a strongly basic alkyl piperidine and a strongly acidic
sulfoacid, the combination made them have a weaker acidity
(Scheme 2). Firstly, to investigate their catalytic activities, the
esterification of phenylacetic acid with an equimolar amount of
n-hexanol was performed in the presence of 5 mol% catalysts
under solvent-free condition. The conversion of phenylacetic
acid over the reaction time was evaluated by GC analysis. It was
shown that despite the esterifications were conducted without the
removal of water, they proceeded smoothly within a short time
(Figure 1). 1a-c gained conversions of 83%, 80%, and 76% in 6
hours, while 2a-c appeared more active, they obtained 99%, 91%
and 87% conversions, respectively. By comparison, we found
that the sulfoacid acidity considerably affected the catalytic
activity. Generally, CF3SO3H > TsOH > CH3SO3H in terms of
acid strength, and the catalytic activities were in accordance with
the sequence, i.e. triflates > tosylates > mesylates. Additionally,
the experimental data also revealed that the bulky 2, 2, 6, 6-
tetramethylpiperidinium sulfonates (2a-c) were superior to
piperidinium sulfonates (1a-c). Take piperidinium triflate (PPT,
1a) and 2, 2, 6, 6-tetramethylpiperidinium triflate (TMPT, 2a)
for comparison, the latter was 16% higher in conversion,
however, the former was more acidic because 2, 2, 6, 6-
tetramethylpiperidine (pKa (protonated 2, 2, 6, 6-tetramethyl-
piperidine) = 11.25) is more basic than piperidine (pKa
(protonated piperidine) = 11.05).27,28 It seemed that the bulky
methyl groups around NH2+ in TMPT made greater contribution
than the acidity to promote the reaction.
Figure 2. X-ray crystallography structure of TMPT (2a): N = blue, O = red,
F = green, S = yellow; (a) ORTEP diagram (drawn at 50% probability); (b)
space-filling diagram; (c) Schematic diagram of the “hydrophobic wall”
(green) and reactive site (yellow).
Figure 3. X-ray crystallography structure of PPT (1a): N = blue, O = red, F =
green, S = yellow. (a) ORTEP diagram (drawn at 50% probability); (b)
space-filling diagram.
Figure 4. Photographs of the esterification of phenylacetic acid with an
equimolar amount of n-hexanol over 5 mol% TMPT at 120 oC. (a) Liquid-
solid biphase before the reaction: TMPT and phenylacetic acid were white
solid at the bottom (contained a Teflon-coated magnetic stir bar), n-hexanol
was colorless liquid in the upper level; (b) homogeneous system during the
reaction, the bottom was the Teflon-coated magnetic stir bar; (c) turbid
system near the completion of the reaction; (d) liquid-solid biphase after the
reaction.
Figure 1. The conversion of phenylacetic acid over the reaction time was
evaluated by GC analysis.
To verify our hypothesis, the X-ray crystallographic analysis of
PPT and TMPT were carried out. It was illustrated that TMPT
formed a dimeric compound consisted of two triflate anions and
two 2, 2, 6, 6-tetramethylpiperidinium cations.29 The two
ammonium cations were linked by four intermolecular N-H···O
hydrogen bonds, which made the dimeric cyclic ion pairs a ring-
shaped structure (Figure 2a, 2b).30,31 On account of the bulky
The difficulty of recycling is usually the main drawback in use
of homogeneous catalysts. To our surprise, an obvious phase
transformation occurred in 1a-c and 2a-c after the esterifications

3
(Figure 4). Initially, they were completely dissolved in the
reaction system, forming a homogeneous solution (Figure 4b).
However, they were spontaneously precipitated from the reaction
medium to form a liquid-solid biphase at the end of the reaction
(Figure 4d). The unique phenomenon might attribute to their
excellent solubility in polar alcohols and very poor dissolubility
in apolar esters. We recovered 1a-c and 2a-c from the reaction
system and found that 2a (TMPT) had the highest recovery ratio
(99%), the excellent result might owe to its high reaction
conversion (99%) and hydrophobic environment. Different from
the traditional soluble catalysts, such self-separated salts which
were readily recycled could act as heterogeneous ones.
Encouraged by the above-mentioned results, we investigated the
generality and scope of the selective esterification catalyzed by
TMPT. So the dehydration reaction between diverse carboxylic
acids and alcohols were examined under solvent-free condition.
As shown in Table 1, phenylacetic acid, phenylbutyric acid,
straight-chain aliphatic acid and primary alcohols were smoothly
condensed to produce the desired esters in good yields (entries 1-
6). Benzoic acid, and α, β-unsaturated carboxylic acids were also
effective candidates for their esterifications in good yields
(entries 12-14) by adding more amount of the catalyst and
prolonging the reaction time. Oleic acid was similarly
transformed into the corresponding ester (entry 11). Although
acid-sensitive alcohols were commonly dehydrated into alkenes
under acidic condition, the use of TMPT could dramatically
overcome such trouble, providing the corresponding esters in
excellent yields and high selectivity (entries 7-10).
As we all known that acid-sensitive alcohols were easily
dehydrated to produce alkenes in acid-catalyzed esterification, a
moderately acidic is very important for the synthesis of the
desired esters. Since TMPT was a much milder salt than
Tanabe’s DPAT22, we compared the catalytic selectivity of the
two catalysts by conducting the esterification of cyclododecanol
with phenylacetic acid (1.1 equiv) in the presence of 5 mol%
catalysts under solvent-free condition (Figure 5). For DPAT, the
conversion of cyclododecyl 2-phenylacetate was only 63% while
the yield of the undesired cyclododecene was up to 37%. Besides,
the substrates would turn black in the presence of DPAT, which
implied the deactivation of the catalyst. In comparison, TMPT
was much more stable under the same condition and it showed
higher selectivity than that of DPAT in spite of its slightly lower
activity. For TMPT, the conversion of the cyclododecyl 2-
phenylacetate was more than 89% but the side product33 of
cyclododecene could be suppressed as low as 2%. The results
proved that TMPT could be adapted to acid-sensitive alcohols
very well. Apart from the weaker acidity, the steric hindrance of
TMPT also conduced to its high selectivity, because the bulky
catalyst activated carboxylic acids prior to the more-hindered
acid-sensitive alcohols, and effectively suppressed the
dehydrative elimination of these alcohols to produce alkene.
Figure 5. Esterification of cyclododecanol with phenylacetic acid catalyzed
by TMPT and DPAT (graph (a) and graph (b), respectively). The ratio of
cyclododecanol (blue line), cyclododecyl 2-phenylacetate (red line) and
cyclododecene (black line) over time was evaluated by 1H NMR analysis.8
Table 1 Esterification between diverse carboxylic acids and alcohols catalyzed by TMPTa
Entry
R1CO2R2
Time (h)
Yieldb (%)
Entry
8c
R1CO2R2
Time (h)
Yieldb (%)
87(2)
85(2)
84(2)
87
1
2
3
4
PhCH2CO2C6H13
PhCH2CO2C12H25
PhCH2CO2Bn
6
6
8
8
97
94
91
93
C11H23CO2C6H11
PhCH2CO2C12H23
Ph(CH2)3CO2C12H23
C17H33CO2C6H13
11
12
15
24
9d
10d
11e
Ph(CH2)3CO2C6H13
5
Ph(CH2)3CO2C8H17
9
92
12e
24
89
6
C11H23CO2C6H13
PhCH2CO2C6H11
9
93
13e
14f
24
36
86
87
7c
10
89(2)
PhCO2C6H13
a Unless otherwise noted, a solution of carboxylic acid (2.0 mmol) and alcohol (2.2 mmol) was heated at 120 oC in the presence of TMPT (5 mol%) under
solvent-free condition.
b Isolated yields of esters, the yields of alkenes were evaluated by 1H NMR and shown in parentheses.
c Cyclohexanol (C6H11OH) was used.
d Cyclododecanol (C12H23OH) was used.
e 10 mol % TMPT was used.
f Molar ratio / carboxylic acid : alcohol = 1: 1.5, 10 mol % TMPT was used.
As TMPT could be recycled without the need for activation, it
was reused for ten times in esterifications under the identical
conditions while the recovery ratio (>99%) and activity was not
significant reduced (Table 2). The S, N residual amounts in first,
fifth and last upper clear solution were detected by Sulfur and
Nitrogen Fluorescence Analyzer (calibration curve method), the
N is about 21.6-23.2 mg/L (22.0-24.7 ppm) and S is about 50.2-
52.6 mg/L (51.2-53.7 ppm), the data also proved the loss of
TMPT was less than 1%.

4
18. Sakakura, A.; Koshikari, Y.; Akakura, M.; Ishihara, K. Org. Lett, 2011,
14, 30-33.
Table 2 Reusability of TMPT
19. Koshikari, Y.; Sakakura, A.; Ishihara, K. Org. Lett. 2012, 14, 3194-3197.
20. Gruttadauria, M.; Giacalone, F,; Noto, R. Chem. Soc. Rev. 2008, 37,
1666-1688.
21. Ferré, M.; Pleixats, R.; Man, M. W. C.; Cattoën, X. Green. Chem. 2016,
18, 881-922.
run
1
2
3
4
5
6
7
8
9
10
98
conv.(%) a
99
99 99 99
99 99 98
98 98
22. Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y. Tetrahedron. Lett.
2000, 41, 5249-5252.
a The conversion of phenylacetic acid was evaluated by GC analysis.
23. Ishihara, K.; Nakagawa, S.; Sakakura, A. J. Am. Chem. Soc. 2005, 127,
4168-4169.
Conclusion
24. Ishihara, K.; Nakagawa, S.; Sakakura, A. Tetrahedron. 2006, 62, 422-433.
25. Ishihara, K.; Nakagawa, S.; Sakakura, A. Nat. Protoc. 2007, 2, 1746-
1751.
In summary, alkyl piperidinium sulfonates showed excellent
performance in esterifications without the use of any dehydrating
or azeotropic agents to remove the generated water. Especially,
the sterically hindered catalyst TMPT displayed remarkable
selectivity and could be conveniently reused for ten times
without considerable loss of its activity. Herein, we have
developed a cheap, eco-friendly method for esterification with
easy operation, which will be promising in large-scaled
preparation of esters.
26. Ishihara, K.; Sakakura, A.; Watanabe, H.; Nakagawa, S. Chem-Asian J.
2007, 2, 477-483.
27. Hall-Jr, H. K. J. Am. Chem. Soc. 1957, 79, 5441-5444.
28. Hall-Jr, H. K. J. Am. Chem. Soc. 1957, 79, 5444-5447.
29. Crystallographic data for the structure reported in this paper were
collected on a Bruker CCD area-detector diffractometer equipped with a
graphite-monochromated MoKa radiation (λ
= 0.71073 Å). The
crystallographic data have been deposited with Cambridge
Crystallographic Data Centre, the data can be obtained free of charge on
application CCDC no. 12 Union Road, Cambridge CB2 1EZ, UK [fax:
(+44) 1223-336-033, e-mail:deposit@ccdc.cam.ac.uk. TMPT (CCDC-
1478246): Mw = 291.33, C10H20F3NO3S, space group Pbca, crystal
dimensions 0.220×0.170×0.130 mm3, T = 293(2) K, orthorhombic, a =
8.6964(11) Å, b = 16.499(2) Å, c = 19.395(2) Å, α = β = γ = 90o, V =
2782.9(6) Å3, Dcalcd = 1.391 g cm-3, Z = 8, μ = 0.268 mm-1, F(000) =
1232, 15047 reflections were corrected, 2592 independent, 175
parameters were used for the solution of the structure, non-hydrogen
atoms were refined anisotropically, R1 = 0.0558, wR2 = 0.1524, GOF =
1.056.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21476071) and Shanghai Leading
Academic Discipline Project (B502).
Supplementary data
1
Supplementary data (Experimental details, H NMR data and
spectra, 13C NMR data and spectra, FT-IR data and spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/000000.
30. Gamrad, W.; Dreier, A.; Goddard, R.; Pöschke, K. R.
Angew. Chem. Int. Ed. 2015, 54, 4482-4487.
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crystal dimensions 0.220×0.180×0.100 mm3,
T
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Graphical Abstract

6
Highlights
1. Green and practical synthetic approaches with easy operation.
2. Excellent activity and selectivity.
3. Homogeneous catalyst with a self-separation feature.
4. The catalyst is reusable up to ten times without any significant loss of activity.