A magnetic-nanoparticle-supported 4-N,N-dialkylaminopyridine catalyst: Excellent reactivity combined with facile catalyst recovery and recyclability

Article abstract of DOI:10.1002/anie.200605216

(Figure Presented) Quick recovery: The first magnetic-nanoparticle- supported organocatalyst is prepared. The heterogeneous catalyst promotes a range of nucleophilic reactions and can be recovered by exposure to an external magnet (see picture). Furthermore, it can be recycled over 30 times without loss of activity.

Full text of DOI:10.1002/anie.200605216

Angewandte
Chemie
DOI: 10.1002/anie.200605216
Heterogeneous Catalysis
A Magnetic-Nanoparticle-Supported 4-N,N-Dialkylaminopyridine
Catalyst: Excellent Reactivity Combined with Facile Catalyst Recovery
and Recyclability**
Ciarµn Ó Dµlaigh, Serena A. Corr, Yurii Gunꢀko,* and Stephen J. Connon*
Dedicated to Professor A. Frank Hegarty on the occasion of his 65th birthday
By definition, catalysts should remain unchanged after
reaction, and their simple recovery and reuse is highly
desirable from both economic and environmental stand-
points. Since its development in the late 1960s as an acylation
catalyst,[1] 4-N,N-dimethylaminopyridine (DMAP) has risen
to prominence as an active, commercially available “hyper-
nucleophilic” promoter of a diverse range of synthetically
useful transformations.[2] Several strategies have emerged for
the immobilization of DMAP on both organic[3,4] and
inorganic[5,6] heterogeneous polymer supports. However, the
activity of these materials is often inconveniently lower than
that of DMAP itself, and more crucially in our view, while
catalyst recycle and reuse has often been demonstrated, most
often this is limited to five iterative cycles or less. Recently,
Lin and co-workers developed a DMAP derivative immobi-
lized on mesoporous-silica nanospheres (400-nm average
diameter) by an innovative alkoxysilane cocondensation
methodology.[7] This catalyst proved useful for the acylation
of secondary alcohols at elevated temperature (7.5 mol%
catalyst, 2.0 equiv Ac2O, 1.5 equiv NEt3, 608C)[8,9] and could
be recycled 10 times without measurable loss of activity.
McQuade et al. very recently reported heterogeneous micro-
encapsulated polystyrene-bound variants of 4-(N-benzyl-N-
methyl)aminopyridine, which are more active (in the acety-
lation of 1-phenylethanol) than the non-immobilized ana-
logue (but not DMAP) at very low loadings (ca. 0.5 mol%)
and which can be recycled three times with a small loss (5%)
in efficiency.[10] Thus, while remarkable progress has been
made in recent years from both activity and recyclability
standpoints, latitude for further development remains. To our
knowledge, an immobilized heterogeneous[11] DMAP ana-
logue that operates efficiently at room temperature across a
range of reactions at low loadings (ca. 5 mol%) and that has
also been demonstrably recycled more than 10 times without
significant loss of activity has yet to be reported.
A successful design for any useful heterogeneous catalyst
system (i.e., highly active and recoverable) for which the
corresponding unsupported (soluble) catalyst is known to be
active and stable must meet three criteria: 1) substrate access
to the catalytically active sites must be maximized; 2) the
heterogeneous support must be as robust as possible to
prevent degradation upon use/recycle and should not interact
with the catalyst moieties or otherwise interfere (destruc-
tively) with activity; and 3) the support must be compatible
with a facile (relatively free of mechanical loss) recovery
methodology. Recently, magnetic nanoparticles have
emerged as viable alternatives to porous materials for use
as robust, readily available, high-surface-area heterogeneous
supports in catalytic transformations. They possess the added
advantage of being magnetically recoverable, thereby elim-
inating the requirement for either solvent swelling before or
catalyst filtration after the reaction.[12] At the outset of this
study, no example of a nanoparticle-supported organocatalyst
system had been reported,[13] despite the potential inherent
stability and activity of such a (metal-free) species. We were,
thus, intrigued by the possibility of applying nanotechnology
to the design of a novel, active, recyclable, and magnetically
recoverable DMAP derivative for the first time.
The supported DMAP analogue was prepared by the
concise route outlined in Scheme 1. Magnetite (Fe3O4) nano-
particles of 9.6-nm average diameter[14] were prepared by the
coprecipitation technique.[15–17] In a departure from conven-
tional catalyst loading strategies, the particles were then
coated with a silica layer[18] by preliminary dispersion in
aqueous tetramethylammonium hydroxide followed by expo-
sure to sodium silicate.[19] This step was carried out to address
concerns regarding potential particle oxidation and aggrega-
tion[20] and to obviate potential interactions between the iron
oxide particle core and the organocatalyst moiety or reaction
intermediates.[21] Treatment of the silica-coated nanoparticles
with excess triethoxysilane derivative 1[22] in THF at reflux
and subsequent reaction with n-propyltrimethoxysilane to cap
remaining (acidic) surface silanol groups afforded catalyst 2.
It is noteworthy that only a single catalyst-loading step is
necessary. The loading process proceeded cleanly and could
be quantitatively and conveniently monitored (0.20 mmolgÀ1
[*] S. A. Corr, Dr. Y. Gun’ko
Schoolof Chemistry, University of Dubiln
Trinity College, Dublin 2 (Ireland)
Fax: (+353)1-671-2826
E-mail: igounko@tcd.ie
C. Ó Dµlaigh, Dr. S. J. Connon
Centre for Synthesis and ChemicalBiool gy
Schoolof Chemistry, University of Dubiln
Trinity College, Dublin 2 (Ireland)
Fax: (+353)1-671-2826
E-mail: connons@tcd.ie
[**] Financialsupport from the Irish Research Councilfor Science
Engineering and Technology, Science Foundation Ireland, and
Trinity College Dublin is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 4329 –4332
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4329

Communications
high
synthetic
utility
(Table 2). Employing the
same catalyst-recovery meth-
odology as before, we found
that 2 (at a loading as low as
1 mol%) could promote the
recently developed[24] bishy-
droalkoxylation of alkyne 5
to give the monoprotected
1,3-dicarbonyl product 6 (a
Scheme 1. Synthesis of the magnetic-nanoparticle-supported 4-N,N-dialkylaminopyridine catalyst 2.
1
loading, consistent between batches) by H NMR spectros-
Table 1: Evaluation of 2 as a recyclable catalyst for the acetylation of 1-
phenylethanol (3).
copy in the presence of (E)-stilbene as an internal standard.
Transmission electron microscopy (TEM) demonstrates the
core–shell structure of the particles and confirms the presence
of the silica coating (Figure 1).[23]
Entry
Cycle
t [h]
Conversion [%][a]
1
2
3
4
5
6
7
8
9
10
11[b]
12[b]
13
14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
16
16
16
16
16
16
16
16
16
16
16
3
>98
94
97
>98
>98
>98
>98
97
98
97
>98
>98
94
Figure 1. TEM images of a) an aggregate of particles and b) a single
particle of catalyst 2.
1
97
Nanoparticle-supported catalyst 2 was first evaluated as a
promoter of the acetylation of 1-phenylethanol (3) by acetic
anhydride. Gratifyingly, 2 (at 5 mol% loading) exhibited high
catalytic activity, allowing the smooth and quantitative
conversion of 3 to acetyl derivative 4 at ambient temperature
with mechanical agitation (Table 1, entry 1). The catalyst was
easily separated from the products by exposure of the
reaction vessel to an external magnet and decantation of
the reaction solution. The remaining catalyst was washed with
THF to remove residual product and dried under high
vacuum. This material could then be subsequently reused in
13 further iterative cycles, furnishing the acylated product
with 94– > 98% conversion in each case (entries 2–14,
Table 1). The excellent activity and recyclability of 2 in this
reaction is illustrated by the finding that the 14th consecutive
acylation cycle was 97% complete after a reaction time of
only 1 h (entry 14, Table 1). The corresponding reaction in the
absence of 2 (under otherwise identical conditions) gave only
3% conversion to 4. This same catalyst material was
subsequently found to be also active when employed at
loadings as low as 0.2 mol% (Scheme 2).
[a] Determined by 1H NMR spectroscopy. [b] 2.0 equiv Ac2O.
formal alkyne oxidation) in excellent isolated yield in each
of three consecutive cycles (Table 2, entries 1–3).
The robust nature and excellent activity of this catalyst is
further underlined by its subsequent ability to efficiently
promote challenging, yet synthetically useful reactions which
(to our knowledge) have not been previously catalyzed by a
heterogeneous nucleophilic promoter. For example, 2 cata-
lyzes the room-temperature peracetylation of d-glucose
(Table 2, entries 4–6), which requires the catalyst to mediate
five separate acylation events per glucose molecule (which is
also initially insoluble under the reaction conditions), and the
tert-butoxycarbonyl (BOC) protection of indole (entries 7–9,
Encouraged by the results of the preliminary acylation
study, our attention now turned to the issue of reaction scope.
We tested the same batch of 2 used to promote the
15 acylation experiments (Table 1 and Scheme 2) as a nucle-
ophilic catalyst for a number of distinct transformations of
Scheme 2. Acetylation of 1-phenylethanol (3) at a low catalyst loading
(cycle 15).
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Angewandte
Chemie
Table 2: Application of 2 as a recyclable catalyst in reactions of synthetic
interest.
In summary, we have developed the first magnetic-
nanoparticle-supported DMAP analogue for use as a robust
heterogeneous nucleophilic catalyst of unprecedented activity
and recyclability. The catalyst is readily prepared by a concise
route from inexpensive commercially available starting
materials using standard laboratory techniques. It is readily
(quantifiably) loaded onto the support in a single step and is
capable of promoting a range of synthetically useful reactions
at room temperature with loadings (as low as 0.2 mol%) not
generally associated with heterogeneous organocatalysis.[27]
Recovery of the catalyst by decantation of the reaction
mixture in the presence of an external magnet is both
convenient and efficient. The ease of recovery, combined with
the intrinsic stability of both the organic and nanoparticle
catalyst components, allows the catalyst to be recycled over
30 times in a number of transformations without any dis-
cernible loss in activity. Studies to further explore the
potential of this powerful immobilization strategy for the
preparation of other heterogeneous organocatalysts of high
synthetic utility are underway.
Received: December 23, 2006
Revised: February 23, 2007
Published online: May 2, 2007
Keywords: 4-N,N-dialkylaminopyridines ·
.
heterogeneous catalysis · nanostructures ·
nucleophilic reactions · supported catalysts
Entry
Cycle
Substrate
Product
Loading
[mol%]
t
[h]
Yield[a]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
5
5
5
7
7
7
9
9
9
11
11
11
13
13
13
6
6
6
8
8
1
1
1
10
10
10
10
10
10
5
16
16
16
16
16
16
15
15
15
20
20
20
8
91
90
88
96
95
96
97
98
98
91
91
94
94
97
93
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[a] Yield of isolated product.
Table 2). The catalyst is compatible with the hindered
acylating agent isobutyric anhydride (allowing the esterifica-
tion of monoprotected diol 11; entries 10–12, Table 2) and
promotes the rearrangement of O-acyl enolate 13 to afford
the azalactone 14 (entries 13–15, Table 2), which incorporates
a quaternary stereogenic centre.[25,26]
No catalyst degradation (physical or chemical) was
discernable after 30 consecutive catalyst cycles (Tables 1 and
2). To demonstrate that 2 had retained high catalytic activity
at this juncture, the acylation of 3 with 0.2 mol% catalyst
loading (Scheme 2) was repeated. Pleasingly, an almost
identical level of conversion to 4 (80%) was observed in the
31st cycle.
Angew. Chem. Int. Ed. 2007, 46, 4329 –4332
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4331

Communications
[8] The authors reported a slow but appreciable rate of background
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[17] See the Supporting Information for details.
[18] A. P. Philipse, M. P. B. Vanbruggen, C. Pathmamanoharan,
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[19] The nanoparticles were characterized by FTIR and Raman
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[20] L. M. Liz-Marzan, M. Giersig, P. Mulvaney, Langmuir 1996, 12,
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[13] During the preparation of this manuscript, an achiral magnetic-
nanoparticle-supported phase-transfer catalyst based on a qua-
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[14] Calculated from X-ray diffraction (XRD) data, using the
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[21] A particular cause for potential concern in the current study
would be the ammonium-cation-binding properties of uncoated
Fe3O4 nanoparticles; all reactions catalyzed by DMAP pass
through key pyridinium-ion intermediates, while nucleophile-
catalyzed acylations of alcohols in the presence of a stoichio-
metric amine base generate ammonium salts. For a recent report
detailing the binding of magnetite to ammonium cations, see: W.
Li, C. Gao, H. Qian, J. Ren, D. Yan, J. Mater. Chem. 2006, 16,
1852.
[22] 1 can be prepared in one step from commercially available 4-N-
methylpyridine (Aldrich) and (3-chloropropyl)triethoxysilane.
See reference [7] or the Supporting Information for details.
[23] Supplementary TEM images showing particle aggregates can be
found in the Supporting Information.
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[27] We have also found that an analogue of 2 prepared from the
direct coupling of 1 with magnetite nanoparticles (without a
silica layer) can serve as an active and recyclable acylation
catalyst in the BOC protection of indole (under conditions
identical to those in Table 2, entries 7–9). In these experiments,
10 could be prepared from 9 in quantitative conversion in each of
five consecutive cycles.
[15] R. Massart, IEEE Trans. Magn. 1981, 17, 1247.
4332
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