A supramolecular hydrogel as a reusable heterogeneous catalyst for the direct aldol reaction

Article abstract of DOI:10.1039/b916250j

An l-proline based supramolecular hydrogel is used as an efficient heterogeneous organocatalyst for the direct aldol reaction with high stereoselectivity (up to 90% ee) and recyclability (up to 3 runs). The reversible nature of this self-assembled supramo

Full text of DOI:10.1039/b916250j

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A supramolecular hydrogel as a reusable heterogeneous catalyst
for the direct aldol reactionw
Francisco Rodrıguez-Llansola, Juan F. Miravet* and Beatriu Escuder*
´
Received (in Cambridge, UK) 6th August 2009, Accepted 26th October 2009
First published as an Advance Article on the web 9th November 2009
DOI: 10.1039/b916250j
An L-proline based supramolecular hydrogel is used as an
efficient heterogeneous organocatalyst for the direct aldol
reaction with high stereoselectivity (up to 90% ee) and recyclability
that form an emulsion in water and act as efficient catalysts for
1
0
this reaction. In the case reported here, an additional
advantage appears, owing to the fact that a hydrogel can be
easily recycled and recovered as a solid-like heterogeneous
phase. Furthermore, due to their dynamic reversible nature,
supramolecular hydrogels can be disassembled in response to
slight environmental changes like temperature or pH, allowing
on–off switching of catalytic activity.
(
up to 3 runs). The reversible nature of this self-assembled
supramolecular system allows for easy recovery and regeneration
of the catalyst.
The development of catalytic systems for organic transformations
in aqueous media presents an enormous interest from an
environmental as well as from an economic point of view
since it combines both atom economy and the greener solvent,
Compound 1 was prepared in high yield following simple
peptide coupling methodology (see ESIw). This compound
formed hydrogels above
a
concentration of
2
mM
1
ꢀ1
water. In this field not only soluble but also heterogeneous
(0.8 mg mL ) after dissolution in hot water and sudden
cooling at 25 1C accompanied by 1 min of sonication. The
morphology of the gel was observed by scanning electron
microscopy (SEM, Fig. 1) revealing the presence of a network
of ribbons of several mm length and less than 300 nm in width.
X-Ray powder diffraction of the xerogel was consistent with a
lamellar structure in which compound 1 formed a bilayer with
intercalation of the alkyl tails (Fig. 2).
systems have attracted the attention of researchers. For
instance, different catalytic organic reactions have been carried
out in aqueous media with organic and inorganic polymer
2
3
supported catalysts, in micellar dispersions or in micro-
4
emulsions among others.
A special class of phase separated organized media
correspond to self-assembled fibrillar networks formed by
low-molecular weight molecules, the so-called supramolecular
Initially catalytic tests were performed by adding reagents
directly on top of the hydrogel at 25 1C (0.16 mmol of
4-nitrobenzaldehyde in 155 mL of cyclohexanone). After 36 h
the reaction was extracted with toluene yielding the aldol
quantitatively (Table 1, entry 1). However, diastereoselectivity
was moderate (anti : syn, 75 : 25) and enantioselectivity was
poor (12% ee). Alternatively, reagents were added on top of
the hydrogel dissolved in 1 mL of toluene. In this case, a
quantitative yield was obtained after 16 h at 25 1C and the
toluene phase could be decanted and, after evaporation of
solvents under an air current, directly analyzed by NMR and
chiral-phase HPLC (entry 2, see ESIw). Remarkably, the
anti : syn diastereoselectivity was improved up to 91 : 9, but
stereoselectivity was still quite low (18% ee). However,
when the reaction was performed at 5 1C, after 24 h the aldol
(S,R)-anti was obtained as the major product (88% ee, entry 3).
This is a very remarkable improvement in the selectivity
considering the relatively small reduction in the reaction
5
hydrogels. In those, small molecules reversibly self-assemble
by non-covalent interactions, being the ‘hydrophobic effect’
the main driving force in water. These fibrillar assemblies may
present enhanced catalytic properties and product selectivity
as a consequence of the appearance of cooperative interactions
by proximity of catalytic groups. For example, Stupp has
described fibrillar aggregates in water that are active catalysts
6
for the hydrolysis of esters. Furthermore, we have recently
described L-proline derivatives which are capable of self-
assembly into organogels and develop catalytic activity for
the Henry nitroaldol reaction only in the aggregated state as a
consequence of a considerable enhancement of basicity due to
7
proximity of L-proline groups in the gel fibers.
Here we describe L-proline amphiphilic derivative 1 as a
strong hydrogelator, and its use in a supramolecular hetero-
geneous catalytic system for the direct aldol reaction between
cyclohexanone and 4-nitrobenzaldehyde (Scheme 1). This
reaction, widely studied in organic solvents with the use of
8
many different L-proline based catalysts, has been also
described to take place in water and a great effort has been
9
devoted to understand the role played by this solvent. In
particular, Barbas has described related amphiphilic catalysts
Universitat Jaume I, Dpt. Quı ´m ica Inorga`nica i Orga`nica,
1
2071 Castello´, Spain. E-mail: escuder@qio.uji.es, miravet@qio.uji.es;
Fax: +34-964729155
w Electronic supplementary information (ESI) available: Synthesis
and characterization of compounds and additional details of catalytic
experiments. See DOI: 10.1039/b916250j
Scheme 1
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Fig. 3 Macroscopic aspect of the catalytic system used for several
runs.
be switched on again by neutralization and gel formation
(heating and sonication) (see ESIw).
Fig.
1
Macroscopic (left) and microscopic (right) aspect of
hydrogel-1; (bar: 300 nm).
Additional experiments were performed in order to investigate
two fundamental questions: (i) which was the catalytic species
and (ii) where was the reaction taking place. Supramolecular
gels are dynamic systems in which a given fraction of free
molecules could remain in solution in equilibrium with the gel
phase. Thus, before assuming that catalysis takes place in the
gel phase it has to be proved that there is not a significant
amount of molecules in solution or that those are not
1
catalytically active. H NMR spectroscopy is a convenient
methodology for that purpose as it is well known that
molecules in the gel phase are NMR silent, and by the addition
of an internal standard the molar fraction of molecules in
Fig. 2 X-Ray powder diffractogram of dried hydrogel-1 and a
11
solution can be easily determined. In the current case, free
1
molecules of 1 could not be detected in the H NMR spectrum
possible bilayer structure.
of the hydrogel in D O at 30 1C (less than 0.2 mM for
2
temperature. This behavior could be related to restricted
mobility of the reactants as well as to the structural rigidification
of the catalytic supramolecular aggregates. Accordingly,
this would allow for a better discrimination of the reaction
pathways that lead to the different stereoisomers.
1
5
00 MHz H NMR)z whereas signals of the hydrogelator
could be observed after addition of TFA and destruction of
the gel (Fig. 4).
The observed catalytic activity could arise from the
disassembly of molecules from the hydrogel that would
catalyze the reaction in the organic phase. For studying this
possibility three different blank samples were prepared
Furthermore, after decantation of the organic layer, the
hydrogel did not seem to be macroscopically affected and
could be reused for at least two additional runs with the same
efficiency and stereoselectivity (entries 4 and 5, and Fig. 3). On
the other hand, the temperature and pH responsiveness of the
hydrogel allowed for complete recovery and regeneration of
the catalytic hydrogel. Thus, after use the gel was mechanically
broken, washed with toluene (2 ꢂ 1 mL) and formed again by
heating and sonication. Alternatively, acidification of the
aqueous phase would lead to protonation and disassembly,
and after exhaustive washing with toluene, the system could
(
see ESIw): (i) blank 1, hydrogel + toluene; (ii) blank 2,
hydrogel + toluene + cyclohexanone; and (iii) blank 3,
hydrogel + toluene + 4-nitrobenzaldehyde. All the samples
were equilibrated at 5 1C over 3 days and then analyzed by
NMR spectroscopy revealing that none of compound 1 was
a
Table 1 Catalytic performance of hydrogel-1
c
Yield (%)
c
d
ee (%)
Entry
T/1C
t/h
anti : syn
b
1
2
3
4
5
25
25
5
5
5
36
16
24
24
24
499
499
98
499
499
75 : 25
91 : 9
92 : 8
93 : 7
92 : 8
12
18
88
87
90
e
f
a
Hydrogel: 0.026 mmol of 1 (0.2 eq.) in water (4 mL); Reagents:
-nitrobenzaldehyde (1 eq.), cyclohexanone (20 eq.) in toluene
4
b
1 mL). Without toluene. Determined by NMR spectroscopy.
c
(
d
1
Fig. 4 H-NMR spectra of 1 in D
2
O ([1] = 20 mM, dioxane was used
e
Determined by chiral-phase HPLC of the anti-product. Entry 3,
f
second run. Entry 3, third run.
as an internal standard (c = 2 mM)). Top: Hydrogel; bottom: solution
obtained after addition of 50 mL of trifluoroacetic acid.
7
304 | Chem. Commun., 2009, 7303–7305
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present in the organic phase. Furthermore, addition of the
remaining reagents to the organic phase isolated from each
blank (for example, cyclohexanone and 4-nitrobenzaldehyde
in blank 1) did not lead to any product after 24 h at 5 1C,
confirming that there were no catalytic species in the organic
phase and demonstrating that reaction is taking place in the
heterogeneous gel phase.
Notes and references
z The absence of catalytic activity in solution at 5 1C has been
confirmed by running reactions on samples where the hydrogel has
been filtered off.
1
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2
In conclusion, the inclusion of L-proline into a low
molecular weight gelator leads to a supramolecular hydrogel
with a remarkable efficiency in a benchmark direct aldol
reaction. Most likely toluene (and also cyclohexanone) is
helping in the transport of 4-nitrobenzaldehyde, poorly
soluble in water, to the hydrophobic regions of the gel
fibers. The results described indicate that this supra-
molecular heterogeneous catalytic system uses one of the
most important non-covalent interactions in the biological
context, the hydrophobic effect, both for the self-construction
of the catalyst as well as for the approach of the substrate
to the catalytic center. As reported for direct aldol
3 Reactions and Synthesis in Surfactant Systems, in Surfactant Science
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K. Holmberg, Eur. J. Org. Chem., 2007, 731.
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reactions catalyzed by L-proline derivatives,
the
8
9
reaction is meant to take place following an enamine-based
mechanism, and accordingly, the supramolecular hydrogel
would be acting as an effective type I aldolase mimetic.
Further work will be carried out in the study of the scope
of substrate selectivity and the influence of co-solvent
on the reaction rate. Finally, a straightforward methodology
has been applied for recycling and regeneration of the
catalytic system allowing for the complete recovery of catalytic
performance.
2
000, 122, 2395; (b) W. Notz, F. Tanaka and C. F. Barbas III, Acc.
Chem. Res., 2004, 37, 580; (c) B. List, Acc. Chem. Res., 2004, 37,
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We thank MEC (Grant CTQ2006-14984) and Universitat
Jaume I-Bancaixa (Grant P1ꢃ1A2006-1) for financial
support. F. R. Ll. thanks Generalitat Valenciana for a FPI
fellowship.
1
1 (a) B. Escuder, M. Llusar and J. F. Miravet, J. Org. Chem., 2006,
1, 7747; (b) A. R. Hirst, I. A. Coates, T. R. Boucheteau,
J. F. Miravet, B. Escuder, V. Castelletto, I. W. Hamley and
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D. K. Smith, J. Am. Chem. Soc., 2008, 130, 9113.
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Chem. Commun., 2009, 7303–7305 | 7305