Supported Catalytically Active Supramolecular Hydrogels for Continuous Flow Chemistry

Article abstract of DOI:10.1002/anie.201909424

Inspired by biology, one current goal in supramolecular chemistry is to control the emergence of new functionalities arising from the self-assembly of molecules. In particular, some peptides can self-assemble and generate exceptionally catalytically active fibrous networks able to underpin hydrogels. Unfortunately, the mechanical fragility of these materials is incompatible with process developments, relaying this exciting field to academic curiosity. Here, we show that this drawback can be circumvented by enzyme-assisted self-assembly of peptides initiated at the walls of a supporting porous material. We applied this strategy to grow an esterase-like catalytically active supramolecular hydrogel (CASH) in an open-cell polymer foam, filling the whole interior space. Our supported CASH material is highly efficient towards inactivated esters and enables the kinetic resolution of racemates. This hybrid material is robust enough to be used in continuous flow reactors, and is reusable and stable over months.

Full text of DOI:10.1002/anie.201909424

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Supported Catalytically-Active Supramolecular Hydrogels for
Continuous Flow Chemistry
Authors: Jennifer RODON FORES, Miryam CRIADO-GONZALEZ,
Alain CHAUMONT, Alain CARVALHO, Christian
BLANCK, Marc SCHMUTZ, Christophe A. SERRA, Fouzia
BOULMEDAIS, Pierre SCHAAF, and Loïc JIERRY
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909424
Angew. Chem. 10.1002/ange.201909424
Link to VoR: http://dx.doi.org/10.1002/anie.201909424
http://dx.doi.org/10.1002/ange.201909424

10.1002/anie.201909424
Angewandte Chemie International Edition
COMMUNICATION
Supported Catalytically-Active Supramolecular Hydrogels for
Continuous Flow Chemistry
Jennifer Rodon Fores,[a] Miryam Criado-Gonzalez,[a],[b] Alain Chaumont,[c] Alain Carvalho,[a] Christian
Blanck,[a] Marc Schmutz,[a] Christophe A. Serra,[a] F. Boulmedais,[a] Pierre Schaaf*[a],[b] and Loïc
Jierry*[a]
Dedicated to Professor Jean-Marie Lehn on the occasion of his 80th birthday.
Abstract: Inspired from biology, one current goal in supramolecular
chemistry is to control the emergence of new functionalities arising
from self-assembly of molecules. In particular, some peptides can
self-assemble and lead to exceptional catalytically-active fibrous
networks able to underpin hydrogels. Unfortunately, the mechanical
fragility of these materials is incompatible with process
developments relaying this exciting field to academic curiosity. Here,
we show that this drawback can be circumvented using enzyme-
assisted self-assembly of peptides initiated at the walls of a
supporting porous material. We apply this strategy to grow an
esterase-like catalytically-active supramolecular hydrogel (CASH) in
an open-cell polymer foam, filling the whole interior space of it. Our
so-supported-CASH is highly efficient toward inactivated esters and
shows kinetic resolution of racemates. This hybrid material is robust
enough to be used in continuous flow reactors, reusable and stable
over months.
based on the substrate solution diffusing into a CASH in order to
let the chemical transformation taking place within the gel, the
recovering of the product formed requires the entire destruction
of the CASH to be isolated. Last but not least, all CASH are not
mechanically robust, restricting their handling and use in a
chemical reactor.5
To provide mechanical robustness to highly soft materials
such as hydrogels, the use of polymer foams as internal
skeleton that will rigidify the matter is an interesting approach.6
In case of peptide-based hydrogels, a first technological issue
that needs to be resolved is the spatial localization of the
hydrogel growth from the surface of the polymer foam in order to
link the hydrogel and the polymer material. This can be achieved
by immobilizing a (bio)catalyst on a planar surface.7,8,9,10 We use
the surface immobilization of an enzyme able to transform non-
self-assembling precursors present in solution into self-
assembling building blocks.11 The confinement of these building
blocks at the material-water interface induces the growth of
nanofibers anchored on the surface and underpinning the
hydrogel.12,13,14
The development of a supported-CASH is based on the
appropriate choice of the precursor which has to fulfill two
essential conditions: (i) generate self-assembling derivatives in
the presence of an adequate enzyme and (ii) to result in a
supramolecular hydrogel exhibiting catalytic activity. Up to now,
no such precursor of LMWH has been described. Among the
catalytically-active supramolecular hydrogel examples reported
in literature,15 our attention focused on the following peptide
sequence Nap-GFFYGHY (Nap=naphthalene) described by
Yang et al.16 This peptide is not soluble in water at room
temperature but when a suspension of this peptide is heated
close to 100°C and then cooled slowly, an esterase-like hydrogel
is obtained, reactive towards the activated ester 4-nitrophenyl
acetate (PNA). The most interesting aspect of this heptapeptide
regarding to our goal lays in the presence of two tyrosine
residues (Y) in positions 4 and 7: the phosphorylation of the two
phenol groups was necessary to obtain a bis-phosphorylated
heptapeptide Fmoc-GFFpYGHpY (Fig. 1a) well soluble in water
(ESI section 2).
When alkaline phosphatase (AP) is added to a 1% mol.
solution of Fmoc-GFFpYGHpY, a quasi-translucent hydrogel
forms almost instantaneously (Fig. 1b) constituted of 97% of the
twice dephosphorylated Fmoc-GFFYGHY (Fig. S1). This
resulting peptide produced enzymatically in situ leads to an
entanglement of several micrometers long fibers observable by
transmission electron microscopy (TEM) (Fig. 1c). Magnification
of these fibers suggests a ribbon shape of 27 nm in width,
having a right-handed twist with roughly 300 nm pitch when two
or more ribbons are associated together (Fig. 1d). The CD
One current goal in supramolecular chemistry is to control
the emergence of new functionalities coming from self-
assembled organizations built using a bottom up approach.1,2
Recently, supramolecular hydrogels prepared from the self-
assembly of low molecular weight hydrogelators (LMWH), mainly
peptide derivatives, exhibiting catalytic properties were
reported.3,4 Based on the specific organization of peptide
hydrogelators in nanofibers, the network displays enzyme like
features. Unfortunately, their catalytic activity used to be
evaluated on solely model substrates. For instance only very few
works have been reported on supramolecular hydrogels
displaying esterase activity on non-activated substrates. In
addition, the use of CASH is not obvious: these reported
hydrogels must be first vortexed to get a liquid solution of
catalytic self-assembled fibers, complicating their separation
from the product formed. Furthermore, when the process is
[a]
Jennifer Rodon Fores, Dr. Miryam Criado-Gonzalez, Alain Carvalho,
Christian Blanck, Dr. Marc Schmutz, Pr. Dr. Christophe A. Serra, Dr.
Fouzia Boulmedais, Pr. Dr. Pierre Schaaf and Pr. Dr. Loïc Jierry
Université de Strasbourg, CNRS, Institut Charles Sadron (UPR22)
23 rue du Loess, BP 84047, 67034 Strasbourg Cedex 2, France.
E-mail: schaaf@unistra.fr; loic.jierry@ics-cnrs.unistra.fr
Dr. Miryam Criado-Gonzalez and Pr. Dr. Pierre Schaaf
Institut National de la Santé et de la Recherche Médicale, INSERM
Unité 1121, 11 rue Humann, 67085 Strasbourg Cedex, France,
Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue
Sainte Elisabeth 67000 Strasbourg, France.
[b]
[c]
Dr. Alain Chaumont
Université de Strasbourg, Faculté de Chimie, UMR7140, 1 rue
Blaise Pascal, 67008 Strasbourg Cedex, France.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201909424
Angewandte Chemie International Edition
COMMUNICATION
spectrum is consistent with a β-sheet structure, in agreement
with literature for similar assemblies of peptides.17 IR spectra
confirms that roughly 66% of peptides are associated in β-sheet
structures.18,19 Rheological study of this CASH hydrogel has
provided 3,6 kPa and 0.3 kPa values at 0.3 Hz for G’ and G’’
respectively (Section 20 in SI). The hydrogelation process takes
place in less than one minute. Below a strain value of 6% the
supramolecular network behaves as a gel whereas above it
becomes liquid-like. When the hydrogel is put in contact with a
PNA solution (1 mM) as depicted in Fig. 1e (section 14 in ESI),
the gel turns spontaneously to yellow due to para-nitrophenol
production (Fig. S3). But this way to produce carboxylic acid
derivatives is not practical: in addition to the mechanical fragility
of such supramolecular hydrogel, the time to let the substrate
penetrate within the CASH and the low reaction time to get a full
conversion due to the substrate diffusion inside the hydrogel are
long. More importantly, the isolation of the formed carboxylic
acid derivatives requires the dissolution of the CASH followed by
purification steps, sentencing this self-assembled catalytic
material to a single run. Therefore this way to realize the
catalytic reaction is time consuming, expensive and tedious,
Figure 1. a) Enzymatic transformation of Fmoc-GFFpYGHpY in Fmoc-
GFFYGHY; b) Upside down vial containing the Fmoc-GFFYGHY hydrogel; c)
TEM image of Fmoc-GFFYGHY self-assembly nanofibers; d) Magnification of
TEM image; e) Schematic of the process based on the ester substrates
diffusion within the CASH; f) Conversion of esters substrates PNA, 3, 5, 6 and
9; g) Ester substrates and their corresponding carboxylic acids.
To build our supported-CASH we used as porous catalyst
support, a commercial open cell melamine foam displaying
diameter cells of roughly 200 µm (Fig. 2a). The foam was
designed to get a suitable tubular shape and placed inside a
metallic column as shown in Figure 2b (length: 15 cm; diameter:
4 mm). We deposited on the walls of the pores, a polyelectrolyte
multilayer constituted of 2.5 PEI/PSS bilayers (PEI:
poly(ethylene imine); PSS: poly(styrene sulfonate)) covered by
an AP layer by dipping alternately in PEI, PSS and AP solutions
(Fig. 2c). We then flowed a Fmoc-FFpYGHpY solution through
the functionalized column to form the supported-CASH (section
16 in ESI). Using Cryo-SEM (at low etching) of this coated foam
shows that the supported-CASH is filling the whole space of the
polymer foam (Fig. 2d).
motivating
our
investigations
toward supported-CASH
developments.
a.
In order to further characterize the supported-CASH, and
because the use of the multilayer renders the buildup process
independent of the substrate, we investigated it on flat surfaces
where more characterization techniques are available. We
modified the surfaces with an enzymatically-active multilayer
similar to that deposited on the foam walls. The buildup of the
multilayer was first monitored by quartz crystal microbalance
Alkaline
Phosphatase (AP)
3-
- 2 PO4
c.
d.
b.
with dissipation (QCM-D) and leads to
a 19 nm thick
(PEI/PSS)2/PEI/AP film (section 5 in ESI). When this so-modified
substrate was brought in contact with Fmoc-GFFpYGHpY
solution, a huge decrease of all QCM frequencies was observed,
characteristic of a highly hydrated mass deposition. Then this
decrease continues more slowly over 13 hours without levelling
off, suggesting a continuing gelation process over this time (Fig.
S4).13,14 AFM, SEM, HPLC composition analysis and
fluorescence emission intensity measurements confirm the
nanofibrous architecture of the hydrogel made up the
hydrogelator Fmoc-GFFYGHY with Fmoc groups stacking the
resulting assembly (Fig. S5-7).13,17 Cryo-SEM analysis was
realized on CASH grown up from a silica wafer. The sample was
cut in the z-section in order to measure the thickness of the
formed hydrogel when the substrate was 12 hours in contact
with the Fmoc-GFFpYGHpY solution. The CASH thickness is
roughly 31 µm, a regular value all along the sample (Fig. 2e).
Strikingly, we noticed a perpendicular orientation of the fibers
starting from the surface as already observed:20 a fibrous
architecture different from what is observed when the hydrogel is
formed in the bulk. Some of the fibers are collapsed to each
other but thinner fibers are also present (Fig. 2f). As observed by
TEM, these nanofibers seem to have a chiral twisted ribbon
shape (Fig. 2g). A complete ester hydrolysis was observed in
few minutes when this silica wafer-supported hydrogel layer was
dipped into PNA solution (Section 14 and Fig. S8 in ESI).
200 nm
5,8 µm
e.
f.
100 %
100 %
100 %
Drop of
ester
solution
95 %
100
80
60
40
20
0
CASH
62 %
Time
9
PNA
5
6
3
HPLC analysis
Esters
g.
This article is protected by copyright. All rights reserved.

10.1002/anie.201909424
Angewandte Chemie International Edition
COMMUNICATION
CASH. Remarkably, this catalytic reactor can be stored (4°C) at
least for one month and reused again without losing activity (Fig.
S9). Because the catalytic property results from the peptide self-
assembly, this repeatability highlights the robustness of the
nanofibrous network in flow conditions. Moreover, we have also
shown that the value of the applied flow rate which was varied
over two orders of magnitude, does not affect the conversion for
a fixed residence time of the substrate. This is one more proof
that the self-assembled architecture is not affected by the flow in
our conditions (Figure S10). We also verified that the catalytic
activity remains independent of the location along the tubular
reactor (Fig. S11), showing that the catalytic hydrogel formed
along the porous support is homogeneously distributed all over
the tubular foam. Using concentrations of PNA lower than 2.20
mM leads to a full ester hydrolysis and thus 2.20 mM of
paranitrophenol is generated. But when higher concentration of
PNA is used, such as 2.78, 8.20, 10, 22 and 44 mM only 141 ±7
µmoles of PNA is transformed in paranitrophenol corresponding
to 99, 52, 49, 24 and 17 % conversion respectively, as shown in
Fig. 3a. This result suggests that PNA poisons the catalytic self-
assembly when high concentration of this substrate is used.
Actually, paranitrophenyl esters are well-known to be powerful
acyl agents toward imidazole groups.22 By using a non acylating
substrate such as the methyl ester 1, a complete hydrolysis is
observed whatever its concentration: 1.0, 2.2, 8.2, 22.0 to 44.0
mM (Fig. 3c). Because one PNA can acylate only one imidazole
group, it is possible to calculate the number of histidine residues
involved in the catalytic pocket: thus we have determined that
one of eleven peptides is involved in the catalytic self-assembly
(Section 17 in ESI). But the acylation of imidazole is a reversible
reaction and washing the column with adequate amount of water
restores entirely its initial catalytic activity (Fig. S12).23
d.
a.
25 µm
25 µm
b.
Sample collection for HPLC monitoring
15 cm, Ø 4 mm
Flow Reactor
Flow rate :
0.5 - 1.5 mL/min
c. Multilayer film architecture
e.
AP
Alkaline Phosphatase
PEI
Poly(ethylene imine hydrochloride)
PSS
Poly(styrene sodium sulfonate)
Substrate
Silica wafer or polymer foam
AP
(PEI/PSS)2.5
31 µm
Substrate
Silica wafer + Multilayer film
g.
f.
Molecular dynamics show the spatial organization of 16
Fmoc-GFFYGHY (Figures 3b, S13 and section 19 in
ESI) calculated from an initial random distribution state of all
peptides in a cubic simulation box (edge: 5.2 nm). After
equilibration the system was let to evolve during 50 µs. Fmoc
groups are stacked together through π-π interactions with
distances going roughly from 3.97 to 5.10 angstroms (Fig. S13).
Interestingly, two pairs of histidine residues linked together
through hydrogen bonding appear in Figure 3b. The organization
of two histidine residues allows cooperative actions leading to
amplified catalytic properties. The histidine residue is directly
involved in the esterase activity of the assembly where the pKa
of the imidazole group plays a crucial role in the catalytic
efficiency. The pKa of imidazole group in histidine residue is 6.8.
But it is known that the environment can impact this value.24 The
pKa of imidazole of peptide Fmoc-GFFYGHY in the self-
assembled state was determined and is 5.4 ± 0.5 (SI section 21).
This indicates an increase in basicity of the imidazole groups
due to the environment created by the self-assembly. The
diameter of this simulated fiber-like structure is lower than the
one measured on the fibers observed by TEM (Fig. 1d). It can
be expected that lateral interactions between fiber-like structures
may results in nanofibrils organization.
Silica wafer + Multilayer film 3 µm
500 nm
Figure 2. a) Melamine open cell foam observed by SEM; b) Continuous flow
reactor; c) Multilayer film architecture; d) Z-section view of CASH supported
on melamine open cell foam observed by cryo-SEM. Black arrows indicate the
backbone of the polymer foam. White arrows show the fibrous network located
everywhere within the interior space of the hydrogel-filled foam; e) Cryo-SEM
image of the CASH formed on a silica wafer; f) magnification of the interface
substrate/CASH and g) magnification of helical shape nanofibers (white
arrow) .
Evaluation of the catalytic activity of this supported-CASH
in a flow reactor was first done using PNA as substrate at 1 mM
with 1.5 mL/min as flow rate: 98% of hydrolysis is obtained in 2.8
minutes. This duration corresponds to the cumulate residence
time of the substrate spent when passing through the supported
CASH column in a closed loop system. It can be noticed that the
flow for this kind of reactor where it flows through a porous
material, follows a plug flow.21 HPLC analysis confirms also that
no constituting peptide hydrogel, i.e. Fmoc-GFFYGHY, was
released from the column, suggesting the preservation of its
integrity during the catalytic process. Five successive runs have
been realized in identical conditions without loss of catalytic
efficiency highlighting the effective recycling of the supported-
This article is protected by copyright. All rights reserved.

10.1002/anie.201909424
Angewandte Chemie International Edition
COMMUNICATION
a.
c.
120
0.275 mM
0.55 mM
1.35 mM
2.2 mM
2.76 mM
8.2 mM
10 mM
100
100
80
60
40
20
0
80
60
40
20
0
22 mM
41 mM
1 mM
2.2 mM
8.2 mM
22 mM
41 mM
0
50
100
150
200
0.0
0.5
1.0
1.5
2.0
2.5
Residence time (min)
Residence time (min)
Residence time inside the column (min)
Time inside the reactor (min)
b.
2,5 nm
5,2 nm
d.
e.
1.6
1.4
1.2
1.0
0.8
0.6
0.4
41 mM
Y = 0.0481 + 1.3466 * X
R = 0.9999
40
30
20
10
0
22 mM
8,2 mM
Km/Vmax
2,2 mM
1 mM
0.2
1/Vmax
x
0.0
0.0
0.2
0.4
0.6
0.8
1.0
0
100
200
300
1/[S]0 (L.mmol-1)
Time (min)
Time (min)
Figure 3. a) PNA conversion over time; b) (left) Molecular dynamics of 16 peptides Fmoc-GFFYGHY showing a fiber-like spatial arrangement (blue square
represents the unit cubic simulation box to which 3D periodic boundary conditions have been applied. Fmoc groups are not represented for sake of clarity). (right)
The fiber diameter is 2,5 nm. Two pairs of histidine residues linked together through hydrogel bonding are bolded and colored in orange (others histidine are
colored in light yellow); c) Hydrolysis conversion of ester 1 over time; d) Production of the acid 10 over time from ester 9; e) Determination of Vmax and Km
according to the Lineweaver and Burk model (linear regression in dashed red).
more time to be fully hydrolyzed (Fig. S14) and complex
Interestingly, we discovered that this CASH is also highly
effective to hydrolyze a wide panel of inactivated esters, which is
rarely reported, when the substrate has diffused within the
catalytic hydrogel (Fig. 1g). Tertiary ester such as 6 requires
structures such as 3 can self-assemble when its ester moiety is
chemically cleaved25 giving thus rise to a second self-assembled
architecture growing within the CASH (Fig. S15).26 This
substrate versatility is crucial with regard to developments for
This article is protected by copyright. All rights reserved.

10.1002/anie.201909424
Angewandte Chemie International Edition
COMMUNICATION
chemical synthetic tools. Using a flow reactor, the hydrolysis
reaction is fast (Fig. S16). For instance, the inactivated methyl
ester 9 (1 mM) is entirely hydrolyzed into 10 in less than 40
minutes (25°C, 1.5 mL/min). Increasing the concentration of 9
extends the necessary residence time but without inhibition
effect, as expected for this non-acylating substrate (Fig. 3c). A
linear dependence of 1/V0 with 1/[S] where V0 represents the
Fmoc-L-Glu(OtBu)-OH
Fmoc-L-Glu-OH
Fmoc-D-Glu(OtBu)-OH
Fmoc-D-Glu-OH
a.
Flow rate: 0.5 mL/min
100
80
60
40
20
0
reaction rate at the initial time and [S] the substrate
9
concentration (Fig. 3d and Section 18 in ESI) was observed
showing the Michaelis Menten behavior of our enzyme-like
supported-CASH (Fig. S17). We determined the following values
of Km = 28 mM, Vmax = 20,8 µmol.s-1 and kcat = 3.0 x 103 s-1. This
last kcat value is at least ten times higher than those reported for
others CASH determined on activated para-nitrophenol ester
derivatives.27,28
45
0
10
20
30
40
50
60
In the literature, few CASH described enantioselective
processes29,30 and the kinetic resolution of inactivated esters
using CASH is still an unsuccessful challenge.15,27,31 We
observed a strong discrimination from the supported-CASH
between the L and D amino-acid tertiobutyl esters 6: indeed,
after 30 minutes of residence time, we observed that almost
45% of the natural enantiomer L-6 was hydrolyzed whereas the
D-6 was not yet affected (Fig. 4a). By decreasing the flow rate to
0.5 mL/min, it was possible to obtain more than 90% conversion
of the L-6 into its corresponding acid derivative L-8 (Fig. 4b).
After loading the flow reactor with 200 mg of racemic rac-6 and
using a flow rate of 0.5 mL/min, we stopped the reaction after 30
minutes of running. The reaction medium was slightly basified
and extracted with dichloromethane yielding to 95% of a white
solid being the chemically pure acid L-8 with 99% of
enantiomeric excess (ee) from the aqueous phase (Fig 4b,c).
The non-hydrolyzed ester D-6 was isolated with a chemical yield
of 96% and 92% ee from the organic layer. Enantio-enriched L-6
(40% ee) lead quasi-quantitative isolation of both enantiopure L-
8 and the ester D-6 (Fig. S18). Racemic amino-acid tertio-butyl
esters such as the lysine and tyrosine were also tested: in both
Time residence (min)
b.
8.73
1600
1400
1200
1000
800
600
400
200
0
Fmoc-L-Glu-OH 8
8.73 min
95% yield
99% ee
Fmoc-D-Glu-OH 8
7.45 min
0
2
4
6
8
10
12
14
Time (min)
Figure 4. a) Proportion of L-6, D-6 and their corresponding hydrolyzed
derivatives L-8 and D-8 over time using 0.5 ml/min as flow rate; b) (left) ee
determination of isolated L-8 by chiral HPLC and (right) quantitative mass of
cases we observed
a faster kinetic hydrolysis of the L
enantiomer (Fig. 4d-e) highlighting the ability of the catalytic
pocket to react faster with the natural amino-acids. Finally, other
kind of racemic esters can be envisioned such as the oxirane of
4-methoxycinnamic methyl ester were the (R,R) enantiomer is
hydrolyzed faster than the (S,S) one (Fig. S19): this compound
is a key intermediate in the industrial preparation of the
Diltiazem, a drug used to treat high blood pressure, angina and
certain heart arrhythmias.
chemically and enantiomerically pure L-8 using supported CASH in
a
continuous flow process.
Yet supported-CASH proved to be stable with respect to
flow and over time and the catalytic process could be repeated
several times without any catalytic loss. Our designed
supported-CASH gives rise to an efficient esterase-like hydrogel
active towards activated esters but also towards a large panel of
inactivated substrates such as methyl, primary, secondary and
tertiary ester classes, a feature never reported which increases
its interest for the chemist’s community. Last but not least, our
supported CASH shows also kinetic resolution capacity allowing
to isolate quantitative amount of enantiopure carboxylic acids
from racemic or enantio-enriched inactivated esters. The precise
tuning of molecular assembly directing the emergence of
functional nanostructures through a bottom up approach and
leading to highly functional material is a new concept recently
introduced by Ariga.32,33In our work, we have shown that the
spatial control of peptide self-assembly from the surface of
porous polymer materials leads to the growth of nanofibrous
Continuous flow chemistry appears particularly well
adapted for CASH applications since the flow through the
catalytic hydrogel compensates the low diffusion rate of
substrates under static conditions (decreasing thus the reaction
time) and provides also an easy separation way between
products and the catalytic phase. These features were not
obvious because supramolecular hydrogels are physical gels
resulting from the self-assembly of small molecules and thus a
gradual delamination of the CASH through the shear stress
induced by the flow is a scenario that was not possible to rule
out at first sight.
This article is protected by copyright. All rights reserved.

10.1002/anie.201909424
Angewandte Chemie International Edition
COMMUNICATION
[10] B. Yang, D. J. Adams, M. Marlow, M. Zelzer, Langmuir 2018, 34,
15109-15125.
networks. From this nanoorganization arise catalytic properties
allowing to design a functional material for applications in flow
chemistry. We thus highlight that supported-CASH can be a
powerful tool for the design of new nanoarchitectonic systems
and can find an echo in various communities of chemists going
from synthetic chemistry to material science and chemical
engineering.34
[11] Z. Yang, H. Gu, D. Fu, P. Gao, J. K. Lam, B. Xu, Adv. Mater. 2004, 16,
1440-1444.
[12] R. J. Williams, A. M. Smith, R. Collins, N. Hodson, A. K. Das, R. V. Ulijn,
Nat. Nanotech. 2009, 4, 19-24.
[13] C. Vigier-Carrière, T. Garnier, D. Wagner, P. Lavalle, M. Rabineau, J.
Hemmerlé, B. Senger, P. Schaaf, F. Boulmedais, L. Jierry, Angew.
Chem. 2015, 127, 10336-10339; Angew. Chem., Int. Ed. 2015, 54,
10198-10201.
[14] J. Rodon Fores, M. L. M. Mendez, X. Mao, D. Wagner, M. Schmutz, M.
Rabineau, P. Lavalle, P. Schaaf, F. Boulmedais, L. Jierry, Angew.
Chem. 2017, 129, 16200-16204; Angew. Chem., Int. Ed. 2017, 56,
15984-15988.
Experimental Section
All additional figures and experimental protocols are given in the
electronic supporting information.
[15] O. Zozulia, M. A. Dolan, I. V. Korendovych, Chem. Soc. Rev. 2018, 47,
3621- 3639.
[16] C. Yang, H. Wang, D. Li, L. Wang, Chin. J. Chem. 2013, 31, 494-500.
[17] A. M. Smith, R. J., Williams, C. Tang, P. Coppo, R. F. Collins, M. L.
Turner, A. Saiani, R. V. Ulijn, Adv. Mater. 2008, 20, 37-41.
[18] N. Yamada, K. Ariga, M. Naito, K. Matsubara, E. Koyama, J. Am. Chem.
Soc. 1998, 120, 12192-12199
Acknowledgements
This work was financially supported by the Agence Nationale de
la Recherche
(project “EASA”
ANR-18-CE06-0025-03
[19] S. Fleming, P. W. J. M. Frederix, I. R. Sasselli, N. T. Hunt, R. V. Ulijn, T.
Tuttle, Langmuir 2013, 29, 9510-9515.
“MECHANOCAT” ANR-15-CE29-0015-02 and “POLYCATPUF”
ANR-16-CE07-0030-01), the Fondation pour la Recherche en
Chimie (Project number PSC-005), the Labex Chimie des
Systèmes Complexes and Institut Carnot-MICA (Project
POLYSPRAY). J.R.F. acknowledges the International Center for
Frontier Research in Chemistry (Labex CSC, Project number
PSC-016) for PhD fellowship. ICS microscopy platform and ICS
characterization platform are acknowledged. Alexandre Collard
is acknowledged for his technical help in the setup of the flow
reactor.
[20] M. Reches, E. Gazit, Nat. Nanotech. 2006, 1, 195-200.
[21] H. Scott Fogler, Elements of Chemical Reaction Engineering, (3rd Ed.)
1999, Prentice Hall, Upper Saddle River, USA.
[22] M. L. Bender, B. W. Turnquest, J. Am. Chem. Soc. 1957, 79, 1652-
1655.
[23] Y. S. Moroz, T. T. Dunston, O. V. Makhlynets, O. V. Moroz, Y. Wu, J. H.
Yoon, A. B. Olsen, J. M. McLaughlin, K. L. Mack, P. M. Gosavi, N. A. J.
van Nuland, I. V. Korendovych, J. Am. Chem. Soc. 2015, 137, 14905-
14911.
[24] K. Ariga, T. Nakanishi, J. P. Hill, M. Shirai, M. Okuno, T. Abe, J. Am.
Chem. Soc. 2005, 127, 12074-12080.
[25] J. Li, Y. Kuang, J. Shi, J. Zhou, J. E. Medina, R. Zhou, D. Yuan, C.
Yang, H. Wang, Z. Yang, J. Liu, D. M. Dinulescu, B. Xu, Angew. Chem.
2015, 127, 13505-13509; Angew. Chem., Int. Ed. 2015, 54, 13307-
13311.
Keywords: enzyme-assisted self-assembly • gels •
organocatalysis • supported catalysis • kinetic resolution
[26] N. Singh, C. Maity, K. Zhang, C. A. Angulo-Pachon, J. H. van Esch, R.
Eelkema, B. Escuder, Chem. Eur. J. 2017, 23, 2018-2021.
[27] N. Singh, M. P. Conte, R. V. Ulijn, J. F. Miravet, B. Escuder, Chem.
Commun. 2015, 51, 13213-13216.
[1]
J.-M. Lehn, Angew. Chem. 2015, 127, 3326-3340; Angew. Chem., Int.
Ed. 2015, 54, 3276-3289.
[2]
[3]
[4]
G. M. Whitesides, B. Grzybowski, Science 2002, 295, 2418-2421.
M. O. Guler, S. I. Stupp, J. Am. Chem. Soc. 2007, 129, 12082-12083.
F. Rodriguez-Llansola, B. Escuder, J.-F. Miravet, J. Am. Chem. Soc.
2009, 131, 11478-11484.
[28] K. L. Duncan, R. V. Ulijn, Biocatalysis 2015, 1, 67-81.
[29] F. Rodriguez-Llansola, J. F. Miravet, B. Escuder, Chem. Commun.
2009, 7303-7305.
[5]
[6]
R. G. Weiss, J. Am. Chem. Soc. 2014, 136, 7519-7530.
N. Teramoto, O. Shigehiro, Y. Ogawa, Y. Maruyama, T. Shimasaki, M.
Shibata, Polymer J. 2014, 46, 592-597.
[30] N. Singh, K. Zhang, C. A. Angulo-Pachon, E. Mendes, J. H. van Esch,
B. Escuder, Chem. Sci. 2016, 7, 5568-5572.
[31] A. Som, S. Matile, Eur. J. Org. Chem. 2002, 3874–3883.
[32] M. Aono, K. Ariga, Adv. Mater. 2016, 28, 989-992.
[33] M. Komiyama, K. Yoshimoto, M. Sisido, K. Ariga, Bull. Chem. Soc. Jpn.
[7]
A. G. L. Olive, N. H. Abdullah, I. Ziemecka, E. Mendes, R. Eelkema, J.
H. van Esch, Angew. Chem. 2014, 126, 4216-4220; Angew. Chem., Int.
Ed. 2014, 53, 4132-4136.
2017, 90, 967-1004.
[34] L. Zhao, Q. Zou, X. Yan, Bull. Chem. Soc. Jpn. 2019, 92, 70-79.
[8]
[9]
X. Du, J. Zhou, J. Shi, B. Xu, Chem. Rev. 2015, 115, 13165-13307.
C. Vigier-Carrière, F. Boulmedais, P. Schaaf, L. Jierry, Angew. Chem.
2018, 130, 1462-1471; Angew. Chem., Int. Ed. 2018, 57, 1448-1456.
This article is protected by copyright. All rights reserved.

10.1002/anie.201909424
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
CASH flow: Catalytically-Active
Supramolecular Hydrogels generated
from a porous polymer foam using the
enzyme-assisted self-assembly
strategy are ideal catalytic phases for
continuous flow. Highly efficient
catalysis of ester hydrolysis and
kinetic resolution have been illustrated
through a hydrogel prepared from an
original bis-phosphorylated
Jennifer Rodon Fores, Miryam Criado-
Gonzalez, Alain Chaumont, Alain
Carvalho, Christian Blanck, Marc
Schmutz, Christophe A. Serra, Fouzia
Boulmedais, Pierre Schaaf* and Loïc
Jierry*
Page No. – Page No.
Supported Catalytically-Active
Supramolecular Hydrogels for
Continuous Flow Chemistry
heptapeptide.
Layout 2:
COMMUNICATION
Page No. – Page No.
This article is protected by copyright. All rights reserved.