A salt made of 4-N,N-dimethylaminopyridine (DMAP) and saccharin as an efficient recyclable acylation catalyst: A new bridge between heterogeneous and homogeneous catalysis

Article abstract of DOI:10.1039/c1cc11556a

Here, we report insights into the new recyclable catalyst 1, (DMAP·saccharin). The DMAP·saccharin-catalysed acylation of alcohols has been successfully carried out more than 8 times. Only 1 mol% of catalyst 1 efficiently promotes acylation with almost equimolar amounts of acid anhydrides, under both base-free and solvent-free conditions.

Full text of DOI:10.1039/c1cc11556a

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A salt made of 4-N,N-dimethylaminopyridine (DMAP) and saccharin
as an efficient recyclable acylation catalyst: a new bridge between
heterogeneous and homogeneous catalysisw
Norman Lu,* Wei-Hsuan Chang, Wen-Han Tu and Chieh-Keng Li
Received 17th March 2011, Accepted 4th May 2011
DOI: 10.1039/c1cc11556a
Here, we report insights into the new recyclable catalyst 1,
to selectively recover a compound tagged with perfluorinated
1
chains from a complex reaction mixture. This strategy
6
(
DMAPÁsaccharin). The DMAPÁsaccharin-catalysed acylation
1
7
18
of alcohols has been successfully carried out more than 8 times.
Only 1 mol% of catalyst 1 efficiently promotes acylation with
almost equimolar amounts of acid anhydrides, under both base-
free and solvent-free conditions.
originally involved fluorous solvents or silica, but the
current trend tends toward simple solubility modulation of
fluorous catalysts in conventional media. For example, the
recovery of a catalyst salt is achieved through precipitation by
1
9,20
adding a non-polar solvent,
as demonstrated in a recent
1
5
Catalytic condensations between the same equivalents of
carboxylic acids and alcohols have been developed over the
last few decades as atom-economically ideal synthetic methods
study by Legros et al. However, the high cost of fluorous
materials might be a concern. Here, we report new insights
into the new recyclable catalyst 1, which is simply a salt
of DMAP and saccharin. The DMAPÁsaccharin-catalysed
acylation of alcohols was successfully and effectively carried
out more than 8 times without a loss in activity.
1
of making esters. However, these methods are problematic
for the esterification of sterically bulky tertiary alcohols, less
nucleophilic phenols, acid-sensitive allyl alcohols and amino
alcohols. Therefore, more efficient alternatives are still in
strong demand. 4-(N,N-dimethylamino)pyridine (DMAP) is
a very effective nucleophilic base catalyst for the esterification
The structure of catalyst 1, DMAPÁsaccharin, was obtained
by diffusion crystallization. Its structure is shown in ESIw
(Fig. A). The DMAP and saccharin can easily stack with each
other, so pure salt could be easily prepared by the crystall-
ization. It is interesting to note that catalyst 1 and similar types
2
–4
5,6
of alcohols with acid anhydrides and other related reactions.
Unfortunately, this powerful organocatalyst exhibits acute dermal
7
toxicity, whereas the corresponding salts only produce local
22
of saccharinate are totally insoluble in hexane or toluene.
7
,8
irritation upon skin contact.
these harmful chemicals in the environment, recyclable
To avoid dissemination of
This special solubility property makes catalyst 1 a good bridge
between heterogeneous and homogeneous catalysis by either
adding or not adding hexane (or toluene) to the reaction
mixture after the reaction. In other words, during the reaction,
very little free DMAP is present in the equilibrium
(DMAPÁsaccharin = DMAP + saccharin), and this free
DMAP can homogeneously and effectively catalyse the
esterification reactions. After the reaction, the salt of DMAP
and saccharin can be easily precipitated by adding hexane to
the reaction mixture. Thus, catalyst 1 and the product can be
heterogeneously separated, and recovered catalyst 1 can then
be reused for the next run.
4
-aminopyridines have been prepared through immobilization
9
–12
on organic or inorganic supports.
Although some remark-
able immobilized systems emerged, those exhibiting significant
activity coupled with complete recyclability are still rare. For
example, in 2007, Connon et al. reported a very elegant
magnetic-nanoparticle-supported DMAP that can be used
several times without loss of activity, which is simply
13,14
12
recovered by using an external magnet.
Similarly, Li et al.
used mesoporous silica nanosphere-supported DMAP for the
acylation of alcohols. However, a limit to the molecular weight
of the support is highly desirable to avoid the use of a quantity
of immobilized catalyst larger than that of the substrate.
Additionally, from Fig. 1, it was found that the protonated
DMAP and saccharinate form the seven-membered ring via
1
5
Alternatively, fluorous techniques offered an attractive way
hydrogen bonding. Although the pK
a
value of saccharin is 2.2,
value is
COOH. Ishihara et al. in
their 2007 paper mentioned that ‘‘these serendipitous findings
DMAP-catalyzed esterification reactions) provide widely
which is more acidic than that of acetic acid, its pK
a
1
5
a f
much less than that (pK = 0) of R
Institute of Organic and Polymeric Materials,
21
National Taipei University of Technology, Taipei 106 TAIWAN.
E-mail: normanlu@ntut.edu.tw; Fax: (+886)2-2731-7174;
Tel: (+886)2-2771-2171 ext. 2417
w Electronic supplementary information (ESI) available: Experimental
procedures, other characterization data, Tables A & B, Figures A–C,
kinetic studies and X-ray and CIF data of CCDC. CCDC 817088. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1cc11556a
(
useful and environmentally benign esterification methods,. . .’’.
It is likely that our results, reported below, are also consi-
dered as serendipitous findings that might provide the
reusable and recyclable catalyst 1 for the benign esterification
methods.
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7227–7229 7227

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anhydride, was also tested 10 times with good recyclability
(
entry 2). In order to make a comparison with other groups’
results, the results of entries 3 and 4, which are cited from
references 15 and 12, respectively, are also shown in Table 1.
Using catalyst 1, the acylation of 1-cyclohexanol in this study
completed within 2.5 h at room temperature, with a yield of
9
9.5% and the recovered catalyst 1 could be reused 9
more times with a high conversion rate. All of the 10 yields
(from 87% to 4 99%) are listed in Table 1. In comparison, in
the case of entry 3,the fluorous approach was used and the
Fig. 1 The 7-membered ring is the primary stabilizing force formed
between the protonated DMAP and saccharinate in the same plane.
Other weak H-bonding interactions are described in the ESIw (Fig. B).
DMAPÁR
f
COOH-catalysed acylation was studied by Legros
1
5
et al. This reaction required 10% of catalyst loading and the
reaction took a longer time. After 8 h of reaction, the yield was
only 85%. In other words, our results on the acylation of
It was known that DMAP can effectively and easily catalyse
2
1
the esterification of anhydrides with primary alcohols. Thus,
reported below are mainly acylations of secondary (21) and
tertiary (31) alcohols, which are chosen as the substrates in
order to demonstrate the feasibility of recycling usage with 1
under solvent-free and base-free conditions, mainly at room
temperature for 0.5–24 h, varying these conditions for each
run. At the end of each cycle, catalyst 1 was precipitated by
adding hexane to the product mixtures and then catalyst 1 was
recovered by decantation. The recovered catalyst 1 was added
to the substrates, and the reaction proceeded to the next cycle.
In Scheme 1, the 1-catalysed esterification of 1-cyclohexanol
is shown, under solvent-free and base-free conditions at room
temperature. The results are shown in entry 1 of Table 1 and
the reaction completes within 2.5 h. Since catalyst 1 can be
easily precipitated by adding hexane, its recycling and reuse
have been demonstrated more than 8 times. Besides acetic
anhydride, a more sterically hindered anhydride, isobutyric
1
-cyclohexanol were much better than those from the fluorous
1
5
approach. In entry 4, the recoverable approach was also
demonstrated, and the results showed that the catalyst loading
was 7.5% and, after 2.5 h at 60 1C, the yield of the reaction
1
2
was 92%. Furthermore, the results from entry 5 (this work)
13
outperformed those reported by Connon et al. in 2007 (entry 7) .
The esterification reactions of other 21 alcohols, e.g. l-menthol,
1
-cyclododecanol and 4-nitrophenol with acetic anhydride or
isobutyric anhydride, have also been successfully carried out.
These results are shown in entries 8–15 in Table 1. For l-menthol
(
entries 8 and 9), which is more bulky than 1-cyclohexanol, the
reactions took more than 8 h to complete.
Furthermore, in order to make a direct comparison between 1
and DMAP, as a catalyst, for the catalysis of the esterification,
the results from the DMAP-catalysed esterification of l-menthol
21
were also added as entries 10 and 11, which are the results from
Ishihara’s 2007 paper for the low-loading (0.5 mol%) of
DMAP-catalysed esterifications. Under the same conditions as
used here, it is surprising to see that the results of using either 1 or
DMAP to catalyse the reactions are similar. From Table 1 results
(entries 8–11), the overall outcomes are about the same for
Scheme 1 The 1-catalysed acylation of 1-cyclohexanol.
a
Table 1 DMAPÁsaccharin-catalysed esterification of alcohols with anhydrides under solvent- and base-free conditions
Entry
Alcohol
Anhydride (R=)
T/1C
t [h]
Yield (%)
1
2
3
4
5
6
7
8
9
1-cyclohexanol
1-cyclohexanol
1-cyclohexanol
1-cyclohexanol
1-phenyl ethanol
1-phenyl ethanol
1-phenyl ethanol
l-menthol
l-menthol
l-menthol
l-menthol
1-cyclododecanol
1-cyclododecanol
4-nitrophenol
Me
iPr
Me
Me
Me
iPr
Me
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
100
100
25
2.5
2
8
2.5
2
2
16
8–12
8–12
9
9
8
499, 499, 499, 97, 97, 97, 98, 94, 93, 87
499, 499, 499, 499, 499, 499, 99, 99, 98, 98
85
b
c
90
499, 499, 499, 499, 499, 499, 499, 499, 499, 499
499, 499, 499, 499, 499, 499, 499, 499, 499, 499
498, 94, 97, 498, 498, 498, 498, 97, 98, 97
97, 96, 96, 96, 95, 92, 95, 98, 92, 87
98, 98, 96, 96, 97, 95, 97, 99, 95, 92
84
98
99, 98, 99, 97, 97, 97, 96, 97, 97
95, 95, 95, 95, 94, 94, 95, 95
499, 499, 499, 98, 499, 499, 97, 96, 96, 96
499, 499, 499, 499, 499, 499, 499, 499, 499, 499
90, 90, 88, 85, 88, 88, 88, 88, 85, 80
499, 499, 499, 99, 96, 94, 93, 91, 90, 89
499, 499, 499, 499
d
e
10
11
12
13
14
15
16
17
18
f
8
2–4
2–4
24
24
0.5
4-nitrophenol
2-phenyl-2-propanol (31)
2-phenyl-2-propanol (31)
3-pyridyl methanol
a
This work; catalyst loading 1%; 25 1C, mainly 2 h, unless otherwise noted; [two anhydrides used are: acetic (R = Me) and isobutyric (R = iPr)
b
c
anhydrides]. ref. 15; reaction conditions: loading 10%; 25 1C, 8 h for 85% yield. ref. 12; reaction conditions: loading 7.5%, 60 1C, 2.5 h for 90%
d
e
yield. ref. 13; reaction conditions: loading 5%; 25 1C, 16h for 4 98% yield + [NEt
loading 0.5% (DMAP only); 25 1C; the yields after 9 h are 84 and 98% for e and f, respectively. ref. 21; reaction conditions: loading 0.5%
DMAP only); 25 1C; the yields after 9h are 84 and 98% for e and f, respectively.
3 2 2
(1–1.5 eq.), 0.4M CH Cl ]. ref. 21; reaction conditions:
f
(
7
228 Chem. Commun., 2011, 47, 7227–7229
This journal is c The Royal Society of Chemistry 2011

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entries 8 and 10. Accordingly, the outcomes are almost the same
for entries 9 and 11 (also see ESIw; Table A).
anhydride was demonstrated for the recovery and reuse. More
than 99% of catalyst was recycled after each cycle for total
8 times (see ESIw; Table B). The mechanism of the DMAP-
As for the 1-cyclododecanol, the reactions took 8 h to finish, and
the recycled 1 could be reused up to 8 times. For the less
nucleophilic phenol (entries 14 and 15), DMAPÁsaccharin-catalysed
acylation of 4-nitrophenol with anhydrides also showed excellent
results, the reactions were completed within four hours and the
reactions could be easily recycled up to ten times with an average
yield of more than 98%. In addition, the sterically hindered
2
4
catalysed reaction has been well studied by Zipse et al. The
rate determining step is base-independent, so all of the reac-
tions carried out in this research were base-free. Furthermore,
the kinetic plot of the esterification of 1-cyclohexanol with
acetic anhydride has been studied and shown in ESIw (Fig. C).
To sum up, a new, efficient, recoverable catalyst 1 was
serendipitously found during this study. DMAPÁsaccharin-
catalysed acylations of alcohols, with an almost equimolar
amount of anhydride, were successfully carried out to demon-
strate the feasibility of recycling catalyst 1 under solvent-free
and base-free conditions. The results of the esterification
reactions exhibited a high conversion rate of products for up
to 10 runs of recycling the catalyst each time. Thus, catalyst 1
is indeed an efficient, inexpensive and recoverable catalyst for
benign esterification methods, which might possibly become a
practical and reliable process in industry.
31 alcohol, 2-phenyl-2-propanol, can also undergo the reactions
at 100 1C for a longer time (24 h). The recovery and reuse of
esterification reactions of 2-phenyl-2-propanol is shown in entries
16 and 17 of Table 1. In particular, the heteroatom-containing
(N atom) alcohol, 3-pyridyl methanol, could also be quickly
esterified without being influenced by its chelating effect (entry 18).
These interesting results show that the DMAPÁsaccharin-
catalysed acylations are superior to those catalysed by nano-
particle-supported silica systems. We are also surprised to see
that 1 outperformed the fluorous catalyst, DMAPÁR
f
COOH. It
is understandable that catalyst 1 is a much better catalyst than
the catalysts from the heterogeneous systems, simply because the
catalysis using heterogeneous systems with a nano-particle
approach is still not as good as that using the intrinsic homo-
geneous system. However, the catalyst 1 being superior to the
We gratefully acknowledge the financial support from the
National Science Council of Taiwan.
Notes and references
1
(a) Asymmetric Heterogeneous Catalysis, ed. K. Ding and
Y. Uozomi, Wiley-VCH, Verlag, Weinheim, 2008; (b) Recoverable
and recyclable catalysts, ed. M. Benaglia, John Wiley and Sons Ltd,
DMAPÁR COOH system with respect to catalytic ability is
f
unusual. The possible reasons are similar to four factors
outlined in ref. 15. They are elaborated upon below. (1) Selective
solubility: catalyst 1 has some special solubility properties
attributed to the saccharinate moiety. For example, saccharinate
2009; (c) E. Marques-Lopez, R. P. Herrera and M. Christmann,
´ ´
Nat. Prod. Rep., 2010, 27, 1138; (d) K. Ishihara, S. Ohara and
H. Yamamoto, Science, 2000, 290, 1140.
2
L. M. Litivinenko and A. I. Kirichenko, Dokl. Akad. Nauk. SSSR,
1967, 176, 97.
22
is totally insoluble in non-polar solvent like hexane or toluene.
3
4
5
E. F. V. Scriven, Chem. Soc. Rev., 1983, 12, 129.
E. Vedejs and S. T. Diver, J. Am. Chem. Soc., 1993, 115, 3358.
J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi,
Bull. Chem. Soc. Jpn., 1979, 52, 1989.
The crystal of DMAPÁsaccharin was actually grown from a
hexane/methanol diffusion system. In comparison, the fluorous
catalyst, DMAPÁR
f
COOH, is known to be able to change its
solubility property by incorporating the fluorous segment.
Obviously, using saccharin in this study to tune the solubility is
better and cheaper than using the reported fluorinated acids,
6 S. K. Chaudhary and O. Hernandez, Tetrahedron Lett., 1979, 20, 99.
7
¨
G. Hcfle, W. Steglich and H. Vorbruggen, Angew. Chem., Int. Ed.
Engl., 1978, 17, 569.
8
With DMAP citrate, the dermal toxicity is reduced to such an extent
that it (12 g per 100 mL) only produces local irritation: also see ref. 7.
9 K. E. Price, B. P. Mason, A. R. Bogdan, S. J. Broadwater,
15,23
R COOH. (2) Regeneration of catalyst 1: the DMAP–HOAc,
f
which is generated at the end of the reaction, is known to be
1
2,13
J. L. Steinbacher and D. T. McQuade, J. Am. Chem. Soc., 2006,
1
soluble in most organic solvents. Thus, supported catalysts
1
28, 10376.
0 D. E. Bergbreiter, J. Tian and C. Hongfa, Chem. Rev., 2009, 109, 530.
11 S. Rubinsztajn, M. Zeldin and W. K. Fife, Macromolecules, 1991,
4, 2682.
5
and fluorous-tags are the common existing methods used to
achieve a recoverable catalyst. For the fluorous approach, the
1
2
acidic C
so DMAPÁR
of C 15COOH is almost 5 orders of magnitude higher than
that of acetic acid (pK = 4.7). In this work, although the pK
7 a
F15COOH (or C10F21COOH) with pK = 0 was used,
1
2 H.-T. Chen, S. Huh, J. W. Wiench, M. Pruski and V. S.-Y. Lin,
J. Am. Chem. Soc., 2005, 127, 13305.
f
COOH can be quickly formed because the acidity
7
F
´
13 C. O. Dalaigh, S. A. Corr, Y. Gun’ko and S. J. Connon, Angew.
´
Chem., Int. Ed., 2007, 46, 4329.
a
a
2
2
14 O. Gleeson, R. Tekoriute, Y. K. Gun’ko and S. J. Connon,
Chem.–Eur. J., 2009, 15, 5669.
value of saccharin is 2.2, it is already acidic enough that
DMAPÁsaccharin could be favorably formed. Additionally,
because the salt of DMAP and saccharin can be easily crystal-
lized, the lattice energy formation also seems to play an
important role in the regeneration of catalyst 1. (3) Active
species (DMAP): even only a trace amount of DMAP can
effectively catalyse the esterification. Because there is no
change in the DMAP ionized from DMAPÁsaccharin, it is,
in the equilibrium, the free DMAP that indirectly catalyses the
acylation. (4) Availability: although DMAP is known to
have harmful dermal toxicity, its salt only causes mild skin
1
5 D. Vuluga, J. Legros, B. Crousse and D. Bonnet-Delpon,
Chem.–Eur. J., 2010, 16, 1776.
1
1
1
1
6 W. Zhang, Chem. Rev., 2009, 109, 749.
7 I. T. Horvath and J. Rabai, Science, 1994, 266, 72.
´ ´
8 W. Zhang and D. P. Curran, Tetrahedron, 2006, 62, 11837.
9 M. Wende, R. Meier and J. A. Gladysz, J. Am. Chem. Soc., 2001,
123, 11490.
2
2
0 L. V. Dinh and J. A. Gladysz, Angew. Chem., Int. Ed., 2005, 44, 4095.
1 A. Sakakura, K. Kawajiri, T. Ohkubo, Y. Kosugi and K. Ishihara,
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¨
23 V. Lutz, J. Glatthaar, C. Wurtele, M. Serafin, H. Hausmann and
7
,8
irritation.
Additionally, in order to prove the excellent
P. R. Schreiner, Chem.–Eur. J., 2009, 15, 8548.
4 S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich and H. Zipse,
Chem.–Eur. J., 2005, 11, 4751.
catalyst recovery, the recovered catalyst was weighed after
each run in which the acylation of 1-cyclohexanol with acetic
2
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7227–7229 7229