Remarkable increase in basicity associated with supramolecular gelation

Article abstract of DOI:10.1039/b904523f

l-Proline derivatives which are able to form supramolecular gels show an amazing basicity increase in the aggregated (gel) state as compared to solution. As a result they behave as enantioselective catalysts for the aldol reaction in solution but produce

Full text of DOI:10.1039/b904523f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Remarkable increase in basicity associated with supramolecular gelation†
Francisco Rodr ´ı guez-Llansola, Beatriu Escuder* and Juan F. Miravet*
Received 5th March 2009, Accepted 8th May 2009
First published as an Advance Article on the web 8th June 2009
DOI: 10.1039/b904523f
L-Proline derivatives which are able to form supramolecular gels show an amazing basicity increase in
the aggregated (gel) state as compared to solution. As a result they behave as enantioselective catalysts
for the aldol reaction in solution but produce a base-catalyzed aldol racemisation in the gel state.
Introduction
Supramolecular catalysis may present several advantageous fea-
tures when compared with conventional homogeneous and het-
erogeneous catalysis. Those are, for instance, precise organization
of catalytic sites, reversibility and the ability for self-correction
1
among others. In particular, supramolecular gels are soft solid
materials formed by the assembly of low molecular weight
compounds through noncovalent interactions. In these materi-
als molecular information (structure and function) is precisely
translated from the molecular into the supramolecular level.
Furthermore, in many cases the fibrillar networks present in a
gel are microcrystalline, with functional groups in a precisely or-
Scheme 1
synthesis and detailed aggregation behaviour of compounds 1a–c
8
has been recently described by us. These compounds form gels
in several organic solvents, with the main driving force being the
formation of an array of intermolecular H-bonds between amide
groups.
Before starting any catalytic study in a gel some experimental
variables have to be established. First, it has to be considered that
a supramolecular gel is a dynamic system in which a fraction of
the molecules remain in solution in equilibrium with the phase
separated fibrillar material. This fraction of molecules stays either
as free molecules or as small oligomers, depending on the degree
2
ganized environment. These characteristics prompted us to study
supramolecular gels as heterogeneous supramolecular catalytic
systems by preparing gelators with active groups on its periphery.
We have already described catalytic Pd-loaded supramolecular gels
designed for use in the aerobic oxidation of alcohols and other Pd
3
catalysed organic processes. There we showed that gelator fibres
9
of cooperativity of the aggregation process and can be easily
quantified by H NMR with the use of an internal standard.
were accessible and capable of interacting with different species—
Pd(II) in that case—after diffusion through the gel matrix.
1
10
Secondly, and in consequence, in any reaction performed in a gel
it has to be determined whether the reaction is taking place in
solution or in the gel fibres as the results may differ considerably.
Keeping all these considerations in mind, we started the study of
the catalytic activity of compounds 1a–c in the aldol reaction be-
tween acetone and 4-nitrobenzaldehyde as a benchmark reaction
Here, we describe the first example of a designed organocatalytic
gel in which a dramatic change in activity is observed upon
aggregation into fibrillar gels. To our knowledge there are only
two previously reported related examples in literature: the first one
was reported by Inoue et al., who serendipitously found that some
cyclic dipeptides were able to catalyse the asymmetric addition
of HCN to aldehydes in the gel phase; a second example has
been recently reported by Stupp et al. in which His-containing
peptides were able to form self-assembled fibres and catalyse ester
11
(Scheme 2). The aldol reaction catalysed by L-Pro and derivatives
is one of the most widely studied organic transformations. The
mainly accepted mechanism implies the formation of an enamine
by reaction of the heterocyclic secondary amino group with a
ketone and further attack on the aldehyde via a six-membered
transition state stabilised by some H-bonds between the aldehyde
O and Pro OH or amide NH. Steric interactions around this
4
hydrolysis. More recently, D o¨ tz et al. described the use of gels
5
formed by benzimidazolium salts as phase transfer catalysts.
Results and discussion
6
transition state are responsible for the observed stereoselectivity.
In our study, gel samples were prepared by dissolving the required
amount of compound in hot acetonitrile and, after quick addition
of acetone, being cooled down to -20 C in order to form a
kinetically trapped gel. Afterwards, the aldehyde was diffused
through the gel and the reaction was kept at this temperature.
Compounds 1a–c (Scheme 1) were initially designed as catalysts
for the aldol reaction as they are built with an L-proline fragment,
◦
6
one of the most studied organocatalysts. The bolaamphiphilic
backbone based on L-valine has been used by us and others as a
7
robust assembling fragment that renders fibrillar aggregates. The
Departament de Qu ´ı mica Inorg a` nica i Org a` nica, Universitat Jaume I,
1
2071 Castell o´ , Spain. E-mail: escuder@qio.uji.es, miravet@qio.uji.es;
Fax: (+34) 964728214
†
Electronic supplementary information (ESI) available: Experimental
details and additional figures. See DOI: 10.1039/b904523f
Scheme 2
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Under these experimental conditions the concentration of free
gelator in solution was determined to be 6.5 mM for 1a and
Table 1 aResults of racemisation of 4-hydroxy-4-(p-nitrophenyl)-2-
butanone
2
.4 mM for 1b and 1c. For that reason, blank experiments with
c
Catalyst
[Catalyst] sol/mM
[Catalyst] gel/mM
e.r. (S : R)
non-aggregated solutions at the same concentration as the solution
coexisting with the gel were studied for comparison.
b
Blank
—
—
—
5.5
—
9.6
—
1 : 4.1
1 : 4.0
1 : 2.9
1 : 4.0
1 : 1.3
1 : 4.0
1 : 1.2
1 : 4.0
1
1
1
1
a sol
a gel
b sol
b gel
6.5
6.5
2.4
2.4
2.4
2.4
24
Results are collected in Fig. 1. As can be seen, yields of the
aldol in the presence and in the absence of gel were quite similar
indicating that most likely the aldol reaction was taking place in
solution. This suggests that the reaction in solution is much faster
than in the fibres or that even it is not taking place there.
1c sol
1
2
c gel
sol
9.6
—
a
◦
b
-
20 C, CH
3
CN; [aldol] = 60 mM; reaction time = 2 weeks. Scalemic
c
aldol mixture prepared as described in ref. 6a. e.r.: enantiomeric ratio.
Scheme 3
the use of acetone-d as reagent did not result in the formation
6
of deuterated aldol. Additionally, racemisation through water
elimination followed by non-stereospecific Michael addition was
also discarded due to the fact that the a,b-unsaturated product was
never detected neither in the aldol reaction nor in the racemisation
experiments. It is important to note that the most acidic centre in
this molecule in acetonitrile corresponds most likely to the benzylic
chiral carbon atom due to the electron-withdrawing effect of the
4
-nitrophenyl group. As a matter of fact, it has been described that
this type of carbon atom is much more easy to deprotonate than
ketone a-methylenes and alcohols in DMSO (pK ca. 20, 26 and
Fig. 1 Results of the aldol reaction between acetone (1.2 M) and
4
-nitrobenzaldehyde (60 mM) in acetonitrile catalyzed by 1a–c in solution
a
and in gel; (top) aldol yield; (bottom) enantiomeric ratio (e.r., R/S).
12
30 respectively).
Therefore, the most plausible mechanism seems to be the
Intriguing results were found for the enantiomeric ratios (e.r.)
of both systems. In the case of the solutions, e.r. were determined
to be about 1 : 5 to 1 : 7 and remained constant over long
reaction times. However, when gels were present a tendency to
racemisation was observed with time, being more pronounced in
the case of compound 1c. This different behaviour suggested that
the presence of the gel phase was responsible for the racemisation.
In order to investigate this possibility, additional experiments
were performed in which a solution of aldol of a given optical
purity was diffused through samples of the gels in acetonitrile.
Results revealed that after 2 weeks the e.r. was reduced consid-
erably in the gel samples whereas it remained unchanged for the
corresponding solutions (Table 1).
base-catalysed deprotonation of the chiral carbon that renders
a stabilized carbanion (Fig. 2). Indeed, when the aldol derived
from benzaldehyde was studied instead of 4-nitrobenzaldehyde,
racemisation was not detected.
Fig. 2 Suggested mechanism of racemisation.
Especially revealing is the comparison of the results obtained
with the gel formed by 1c and with compound 2 (Scheme 3) which
is an analogue of 1c that does not form gels. It can be observed
that, although the gel of 1c and the solution of 2 present the
same equivalents of L-proline units, racemisation is only observed
in the case of the gel sample. These experiments confirmed that
the gel was responsible for the racemisation of the product,
most likely through a base catalysed process. A base catalysed
racemisation through a retro-aldol reaction was discarded because
Furthermore, in order to determine the relative basicity of
compounds 1a–c in solution and in the gel phase they were
compared with several bases whose conjugate acid pK
a
values in
13
CH
3
CN are known. For a semiquantitative naked-eye analysis,
different pH-indicator dyes were employed (Fig. 3A). As can be
seen, the gel formed by 1c in acetonitrile is slightly more basic
than pyrrolidine. The latter produces only a partial change in the
colour of Phenol Red (I ) while the gel sample shows a net reddish
4
colour. Additionally, the gel formed by 1c is clearly more basic
3
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Fig. 4 Gels of compounds 1a–c in acetonitrile in the presence of
-
4
Bromothymol Blue (I
3
conc = 3 ¥ 10 mM). Blue colour appears more
intense for gels of compounds 1b and 1c than for the less basic gel of 1a.
effects between L-Pro residues, several gels were prepared in which
compound 1c was mixed with gelator 3, which lacks the catalytic
7b
moiety, at different ratios. Co-aggregation of 1c and 3 would
provoke a random distribution of L-Pro sites and prevent the
supramolecular enhancement of basicity. For this purpose we
3
prepared two-component gels in the presence of indicator I and
we could clearly observe that upon gradual increase in the molar
fraction of 3 in the mixture the intense blue colour turned greenish
for an equimolar gel and yellow as the L-Pro residues were diluted
14
with 3 (Fig. 5 and ESI†).
Fig. 3 (A) pK
and their solutions with dyes (I
Bromothymol Blue; I : Phenol Red; [I
all the cases but 1c gel (9 mM) and 1c sol (1.8 mM); for other concentrations
of base, see ESI†. (B) Evolution of I colour during gelation of compound
c in CH CN.
a
scale for 1c and other common organic bases in CH
: Congo Red; I : 4-nitrophenol; I
] = 3 ¥ 10 mM; [base] = 18 mM in
3
CN
1
2
3
:
-4
4
n
3
1
3
than the corresponding compound in solution as evidenced with
the use of Bromothymol Blue (I ) as the indicator. Using this
approach, it can be estimated that 1c in solution is less basic than
benzylamine (pK
= 16.9) and that the gel formed by 1c is more
basic than pyrrolidine (pK
= 19.5). Therefore, it can be concluded
that gelation of 1c in acetonitrile provokes approximately a three-
order of magnitude difference in the pK of the conjugate acids. It
is interesting to compare the basicity of compound 1c with soluble
analogue 2. It can be noticed that for the same concentration of
L-proline units, the gel formed by 1c is clearly more basic than 2
3
a
a
Fig. 5 Two-component gels of 1c and 3 in CH
3
CN in the presence of I .
3
Molar fraction of 1c is indicated. Total concentration of gelators: 15 mM.
-4
a
[I
3
] = 3 ¥ 10 mM.
Conclusions
as revealed by the change experienced by indicator I
3
.
Furthermore, experiments were performed in which I
3
was
In summary, compounds 1a–c showed a dual catalytic behaviour
as free molecules and as aggregates. Thus, in solution they behave
as moderately active and stereoselective L-Pro-based organocata-
lysts participating in the aldol reaction, whereas in the gel phase
they turned into basic catalytic residues inactive in the aldol
reaction but active in the non-stereospecific deprotonation of the
aldol product, although at longer reaction times (racemase ac-
tivity). Furthermore, a remarkable supramolecular enhancement
of basicity related to proximity effects could be detected. These
results are especially interesting if one considers the reversible
nature of supramolecular gels and the possibility of controlling the
aggregation state by external stimuli. This may allow, for instance,
the on–off switching of catalytic activity or even the linkage of
sol–gel cascade catalytic events. Currently, we are exploring in
added to a hot solution of compound 1c in acetonitrile and colour
evolution was followed during spontaneous cooling until room
temperature and in parallel with aggregation and gelation. As can
be seen in Fig. 3B, after several minutes the starting yellow (not
basic) solution turned into a blue (basic) gel. Similar results were
obtained with compounds 1a and 1b, although the basicity was
slightly lower, in agreement with the observed slower racemisation
(
Fig. 4).
These facts clearly confirm that there is a supramolecular
enhancement of basicity probably due to the close proximity of
pyrrolidinic residues on the surface of the gel fibres that could
provoke the cooperative assistance of several basic groups (proton
relay system). In order to demonstrate the existence of proximity
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detail basic organocatalysis within supramolecular gels as well as
modifying the original design to achieve the aldol reaction in the
gel phase.
Acknowledgements
F. R.-Ll. thanks Generalitat Valenciana for a FPI fellowship.
Financial support from the Ministerio de Educaci o´ n y Ciencia
(Grant CTQ2006-14984) and Universitat Jaume I – Bancaixa.
Experimental
General procedure for the preparation of catalytic systems for the
aldol reaction
Notes and references
1
Supramolecular Catalysis, ed. P. W. N. M. van Leeuwen, Wiley-VCH,
Weinheim, 2008.
(a) Molecular Gels: Materials with Self-assembled Fibrillar Networks,
ed. P. Terech and R. G. Weiss, Springer, Dordrecht, 2006; (b) F. Fages,
editor, Top. Curr. Chem., 2005, 256, 1.
Catalytic system in gel phase. Typically, 0.066 mmol of the
gelator in CH
3
CN (2 mL) were heated in a screw-capped vial until
2
it was completely dissolved and, afterwards, 0.5 mL of acetone
(
-
6.8 mmol) were added. Then, the mixture was left to cool at
◦
3 J. F. Miravet and B. Escuder, Chem. Commun., 2005, 5796.
(a) J. Oku and S. Inoue, J. Chem. Soc., Chem. Commun., 1981, 229;
b) M. O. Guler and S. I. Stupp, J. Am. Chem. Soc., 2007, 129,
12082.
20 C for 120 minutes to yield a gel.
4
(
Catalytic system in solution.
A suspension of gelator
(
2
0.0364 mmol for 1a, 0.0132 mmol for 1b–c and 0.132 mmol for
) in CH CN (2 mL) was heated in a screw-capped vial until
5 T. Tu, W. Assenmacher, H. Peterlik, G. Schnakenburg and K. H. D o¨ tz,
Angew. Chem., Int. Ed., 2008, 47, 7127.
3
6
(a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000,
it was completely dissolved and, afterwards, 0.5 mL of acetone
1
22, 2395; (b) W. Notz, F. Tanaka and C. F. Barbas III, Acc. Chem.
◦
(
1
6.8 mmol) were added. The mixture was left to cool at -20 C for
Res., 2004, 37, 580; (c) B. List, Acc. Chem. Res., 2004, 37, 548; B. List,
in Modern Aldol Reactions, ed. R. Mahrwald, Wiley-VCH, Weinheim,
20 minutes to yield the homogeneous catalytic system.
2
004, vol. 1, pp. 161.
7
(a) K. Hanabusa, R. Tanaka, M. Suzuki, M. Kimura and H. Shirai,
Adv. Mater., 1997, 9, 1095; (b) B. Escuder, S. Mart ´ı and J. F. Miravet,
Langmuir, 2005, 21, 6776.
General procedure for the aldol reactions
8
9
F. Rodr ´ı guez-Llansola, J. F. Miravet and B. Escuder, Chem. Commun.,
A solution of 4-nitrobenzaldehyde (0.33 mmol) in CH
was cooled at -20 C during 4 h and then it was added to the
3
CN (3 mL)
2
009, 209.
◦
A. R. Hirst, I. A. Coates, T. R. Boucheteau, J. F. Miravet, B. Escuder,
corresponding catalytic system. To stop the reaction the solvent
V. Castelletto, I. W. Hamley and D. K. Smith, J. Am. Chem. Soc., 2008,
1
30, 9113.
was evaporated under a N
was analyzed by H-NMR in CDCl in order to determine the
2
stream and the resulting yellow solid
1
1
1
0 B. Escuder, M. Llusar and J. F. Miravet, J. Org. Chem., 2006, 71,
1
3
7
747.
yield (see ESI†). Afterwards, the crude product was purified by
column chromatography on silica gel (hexane : ethyl acetate, 1 : 1)
to afford the aldol product. The enantiomeric excess of the
corresponding aldol was determined by HPLC using a Chiralpak
IA column, l = 250 nm, hexane–THF (v/v: 75 : 25), flow rate =
1 J. F. Miravet and B. Escuder, Org. Lett., 2005, 7, 4791; J. F. Miravet and
B. Escuder, Tetrahedron, 2007, 63, 7321.
2 (a) F. G. Bordwell, D. Algrim and N. R. Vanier, J. Org. Chem., 1977,
4
2, 1817; (b) W. N. Olmstead, Z. Margolin and F. G. Bordwell, J. Org.
Chem., 1980, 45, 3295; (c) F. G. Bordwell, Acc. Chem. Res., 1988, 21,
456.
-
1
13 I. Kaljurand, A. Kutt, L. Soovali, T. Rodima, V. Maemets, I. Leito and
1
mL min ; t
r
= 9.3 min (minor), 11.5 min (major). The racemic
I. A. Koppel, J. Org. Chem., 2005, 70, 1019.
product was prepared by using diethylamine (20%) in acetonitrile
and the product enriched in the S enantiomer was obtained as
described by ref. 6a (see ESI†).
1
4 Cooperative aggregation was evidenced by the gelation of mixtures
in which both components were below their respective minimum gel
concentration (see ref. 7b).
3
094 | Org. Biomol. Chem., 2009, 7, 3091–3094
This journal is © The Royal Society of Chemistry 2009