Self-assembled Polydiacetylene Nanoribbons for Semi-heterogeneous and Enantioselective Organocatalysis of Aldol Reactions in Water

Article abstract of DOI:10.1002/cctc.201901960

We report the synthesis, characterization, and supra-molecular assembly of novel diacetylene amphiphilic units bearing a chiral proline-derived head group. In water, these amphiphiles self-assemble into twisted ribbons that are photo-polymerized to afford

Full text of DOI:10.1002/cctc.201901960

Accepted Article
Title: Self-assembled polydiacetylene nanoribbons for semi-
heterogeneous and enantioselective organocatalysis of aldol
reactions in water
Authors: Minh-Duc Hoang, Arun Kumar Ramar, Wai Li Ling, David
Buisson, Edmond Gravel, and Eric Doris
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ChemCatChem
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FULL PAPER
Self-assembled polydiacetylene nanoribbons for semi-
heterogeneous and enantioselective organocatalysis of aldol
reactions in water
Minh-Duc Hoang,[a] Ramar Arun Kumar,[a,b] David A. Buisson,[a] Wai Li Ling,[c] Edmond Gravel,*[a] Eric Doris*[a]
Abstract: We report the synthesis, characterization, and supra-
molecular assembly of novel diacetylene amphiphilic units bearing a
chiral proline-derived head group. In water, these amphiphiles self-
assemble into twisted ribbons that are photo-polymerized to afford
stable nanostructures. The nanoribbons were valorized in the semi-
heterogeneous and enantioselective catalysis of aldol reactions in
water. The system is active on a variety of substrates, operates under
sustainable conditions (room temperature, air atmosphere, low
catalyst loading), provides access to the target compounds with high
enantiomeric excess, and the organocatalyst can be recycled over
several runs with no loss in activity.
enantioselective aldol reactions, synthetically carrying out such
transformations in water remains tricky.[6] As an example,
organocatalytic asymmetric aldol reactions promoted by proline
are usually performed in organic solvents, although the addition
of a small amount of water is likely to accelerate reaction rates
and/or improve enantioselectivities.[7] However, the use of fully
aqueous conditions usually results in low yields and poor
selectivities.[ This has led to the development of new proline-
derived organocatalysts[9] such as the one implemented by
Barbas and co-workers[10] that is active and selective under
aqueous conditions. In their approach, proline-surfactants were
designed in such a way to encapsulate hydrophobic reactants and
isolate the transition state from water. Yet, the catalytic system
could not be recycled.
8]
Introduction
With these results in mind and as part of our longstanding
interest in the supra-molecular chemistry of diacetylene-based
amphiphiles[11] and catalytic systems,[12] we report here the
Catalytic enantioselective reactions are central in the synthesis of
many valuable organic compounds.[1] The ideal catalytic system
should combine several pivotal features that include simple
preparation, mild conditions of use, moderate loadings, easy
recycling, high efficiency (yield/enantioselectivity), and
compatibility with environment-friendly solvents such as water.[2]
In fact, efforts have been devoted, over the last decades, to the
development of water-compatible chemical processes that take
advantage of the peculiar and beneficial features of this solvent
such as cost, safety, waste management, and overall green
aspect of aqueous chemistry.[3] Among key enantioselective
reactions, the aldol reaction stands out,[4] as the β-
hydroxycarbonyl motif is present in the structure of many
biologically active compounds.[5] Whilst in nature specific
enzymes, namely aldolases, efficiently promote aqueous
development of
organocatalyst.
a
semi-heterogeneous polydiacetylene
Under specific conditions, diacetylene
amphiphiles self-organize into bilayered structures such as
ribbons, spirals, and tubes that can be further stabilized by photo-
polymerization under UV light.[13] We conceived that self-
supported organocatalysts, applied to enantioselective aldol
reactions, could be assembled starting from a specifically
designed amphiphile combining an “active” proline center
together with a “structuring” diacetylene lipophilic chain. The
resulting nanostructured material (ribbon) is expected to offer
beneficial features such as a hydrophobic environment for the
reactants in water and the possibility of recycling the catalyst
thanks to the semi-heterogeneous nature of the nanoribbons.
Results and Discussion
[
a]
Dr M.-D. Hoang, Dr R. A. Kumar, D. A. Buisson, Dr E. Gravel, Dr E.
Doris
To this end, we combined, in a single amphiphilic unit hereafter
referred to as DAPro (1), a diacetylene hydrophobic C25 chain
with a proline-derived polar head group. DAPro (1) was readily
synthesized from pentacosa-10,12-diynoic acid (2) that was first
activated into the corresponding N-hydroxysuccinimidyl ester,
before being reacted with ethylene diamine (Scheme 1). The
resulting primary amine-terminated intermediate compound 3
was then coupled to N-Boc-L-proline, followed by deprotection
of the amino group under acidic conditions. The target DAPro
amphiphile (1) was obtained in overall 66% yield.
Service de Chimie Bioorganique et de Marquage (SCBM)
CEA, Université Paris-Saclay
91191 Gif-sur-Yvette, France.
E-mail: edmond.gravel@cea.fr; eric.doris@cea.fr
Dr R. A. Kumar
SRM Research Institute, Department of Chemistry
SRM Institute of Science and Technology
Kattankulathur, 603203 Chennai, India
Dr W. L. Ling
[
b]
c]
[
Univ. Grenoble Alpes, CEA, CNRS, IBS
38000 Grenoble, France
Supporting information for this article is given via a link at the end of
the document.
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ChemCatChem
10.1002/cctc.201901960
FULL PAPER
lipophilic part of amphiphile 1 is positioned at the interface of the
bilayer and creates a hydrophobic domain, the chiral L-proline
polar head is pointing towards the aqueous medium, thus making
the nanoribbons partly dispersible in water. The assembly was
also investigated by circular dichroism (CD) which revealed a
characteristic positive peak at the largest UV-vis absorption (at ca.
5
45 nm, see Figure S2). This CD signal is attributed to the
conjugated polydiacetylene backbone[ and suggests that the
PDA region establishes a supramolecular chiral environment
leading to the twisted conformation observed for the nanoribbons.
The pDAPro catalyst was then evaluated in a model
enantioselective aldol reaction between cyclohexanone (4a) and
p-nitrobenzaldehyde (5a) (Table 1). Water was selected as the
only solvent, the catalyst loading was set at 5 mol%, and the
reactions were run at room temperature. Under these conditions,
the aldol reaction reached 95% conversion after 24 h (Entry 1).
The anti/syn diastereomeric ratio (dr) was 9:1 and enantiomeric
excess (ee) 68%. Increasing the reaction time to 48 h only had a
slight effect on the conversion (Entry 2). In order to improve the
overall efficacy of the transformation, some additives were
selected as activators, since it has been demonstrated by others
that carboxylic acids, in sub-stoichiometric amounts, have
beneficial impacts on the outcome of stereoselective aldol
reactions.[18]
17]
2 2
Scheme 1. Synthesis of the DAPro (1) amphiphile. a) NHS, EDCI-HCl, CH Cl ,
90%; b) ethylenediamine, CH
2 2 3
Cl , 95%; c) Boc-L-Proline, NEt , HOBt, EDCI,
CH Cl , 96%; d) HCl, dioxane, 80%.
2
2
With the DAPro amphiphile 1 in hands, we next looked at its
[
14]
supra-molecular self-assembly properties (Figure 1a and 1b).
−
1
A suspension of 1 in water (10 mg mL ) was sonicated for 30 min.
The clear solution was kept at room temperature for 4 h and
stored at 5 °C for additional 20 h. This led to the formation of an
opaque gel-like milky suspension (Figure S1a) that was subjected
to UV irradiation at 254 nm for 2 min. The resulting dark-blue
suspension was then bath-sonicated for 1 h to disperse the
aggregates. This treatment induced a blue to red transition,[15]
with the concomitant formation of stable small crimson red
nanostructures corresponding to the final polymerized DAPro
material (i.e. pDAPro, Figure 1c).
Table 1. Conditions investigated for the enantioselective aldol reaction.[a]
Time
h)
Conv.
(%)
dr
anti/syn
ee[c]
(%)
Entry
Additive
[
b]
(
1
2
3
4
5
6
-
-
24
48
24
24
24
24
95
99
75
99
99
99
90:10
90:10
90:10
87:13
92:8
68
68
88
64
74
89
TFA (5 mol%)
AcOH (5 mol%)
HCO
PhCO
2
H (5 mol%)
2
H (5 mol%)
93:7
[
a] Conditions: pDAPro catalyst (0.00625 mmol, 5 mol%), additive (if used,
0
.00625 mmol, 5 mol%), 4a (1.25 mmol), and 5a (0.125 mmol) in water (1.0
1
mL) at room temperature. [b] Dete+rmined by H-NMR of the crude product.
[
c] Determined by chiral-phase HPLC analysis for anti-product.
Figure 1. Catalyst synthesis and characterization: a) Schematic representation
of the DAPro amphiphile and b) its assembly into pDAPro ribbons; c) Color
change upon bath sonication; d) TEM image of pDAPro.
The use of 5 mol% of trifluoroacetic acid (TFA) decreased the
conversion rate of the reaction (Entry 3) but significantly improved
the ee to 88%. On the contrary, the use of acetic acid (Entry 4)
proved beneficial on the reaction rate but detrimental to the
enantioselectivity of the transformation. The same comment holds
true for the use of formic acid (Entry 5). The best compromise
between conversion rate and selectivity was found to be the
addition of 5 mol% of benzoic acid (Entry 6) which allowed nearly
full conversion into 6aa within 24 h with dr and ee values of 93:7
and 89%, respectively.
Morphological characterization of the pDAPro assembly was
performed by transmission electron microscopy (TEM) operating
at 200 kV. Close inspection of the TEM images revealed a dense
network of nanostructures made of twisted ribbons with a
homogeneous width of ca. 18 nm (Figure 1d). In fact, these
ribbons are made of a bilayered structure, resulting from tail-to-
tail assembly of DAPro and further polymerization.[16] While the
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To demonstrate the heterogeneous nature of the organocatalyzed
transformation, that is that the catalytic process actually takes
place at the surface of the nanostructures and is not promoted by
To evaluate the scope of the system, the efficacy of the pDAPro
catalyst 1 was tested on a variety of substrates (Table 2) under
the optimized reaction conditions, i.e. 5 mol% pDAPro and 5
mol% phenylacetic acid additive, room temperature in water. We
first investigated the reaction of cyclohexanone with variously
substituted aromatic aldehydes. The system proved very efficient
with electron-deficient aldehydes, both in terms of conversion and
selectivity. In addition to para-nitro benzaldehyde 5a, ortho- (5b,
Entry 1) and meta-nitro benzaldehydes (5c, Entry 2) were also
both well converted (94% and 99% conversion, respectively) with
good selectivity (dr = 87:13 and 91:9, ee = 80% and 86%,
respectively). Methyl ester substituted 5d (Entry 3) was cleanly
transformed (95% conversion) along with very good dr (91:9) and
ee (86%). Halogenated substrates, namely p-chloro (5e, Entry 4)
and p-bromo benzaldehyde (5f, Entry 5), also underwent smooth
“
contaminating” free standing proline-based amphiphiles in
solution, a simple aldol reaction was set under the conditions of
Table 1, Entry 6. The only difference here was that the pDAPro
catalyst suspension was filtered over a 0.2 µm membrane to
remove the solid catalyst prior to the addition of the reagents.
Under these conditions, the reaction rate was significantly
decreased as only 30% conversion was observed after 24 h, and
the aldol products were obtained as racemates.
Table 2. Scope of the pDAPro-catalyzed aldol reaction between
cyclohexanone 4a and various aldehydes.[a]
(
(
88% and 92% conversion, respectively) and selective reaction
dr = 87:13 and 84:16, ee = 84 and 80%, respectively). Similarly,
para-cyano benzaldehyde (5g, Entry 6) was quantitatively
transformed (dr = 81:19, ee = 82%). Unfortunately, simple
benzaldehyde (5h, Entry 7) was poorly reactive under the
pDAPro-catalyzed reaction conditions, leading only to 34%
conversion yet with good selectivity (dr = 90:10, ee = 88%). In a
similar fashion, electron-rich para-methoxy benzaldehyde (5i,
Entry 8) did not afford better than 12% conversion after 72 h, even
though selectivity was satisfactory (dr = 86:14, ee = 82%). The
efficacy of the system was also tested on other aromatic
aldehydes including isonicotinaldehyde (5j, Entry 9) which was
fully converted within 24 h (dr = 82:18, ee = 80%), as well as 1-
naphthaldehyde (5k, Entry 10) which was smoothly (84%) and
selectively (dr = 87:13, ee = 76%) converted. It is to be noted that
the kinetics of the latter reaction was rather slow (8 days of
reaction).
An important feature of (semi)-heterogeneous catalysis is
the possibility of recovering the catalyst and recycling it for
subsequent reactions. In an ideal case, the recovery step should
be as simple as possible, and reusability should not rely on any
treatment or reactivation of the catalytic species. For our nano-
ribbon pDAPro catalyst, a very simple in-flask recovery protocol
was used. After completion of the reaction, the aldol product was
extracted from the aqueous layer with ethyl acetate, leaving the
catalyst in water ready to be used in the next run. We carried out
five consecutive aldol reactions between 4a and 5a with the same
sample of pDAPro catalyst using this recycling protocol and we
were pleased to observe that neither conversion nor selectivity
were affected over the course of the experiments (Table 3, Entries
Conv. dr[b]
ee[c]
Time
h)
Entry
1
Aldehyde
5
(
(%)
anti/syn (%)
5b
24
24
24
94
87:13
91:09
91:09
80
86
86
2
3
5c
99
95
5d
4
5
6
7
8
9
5e
5f
5g
5h
5i
24
24
24
72
72
24
88
92
99
34
12
99
87:13
84:16
81:19
90:10
86:14
82:18
84
80
82
88
82
80
5j
1-5). Aldol products were obtained consistently in all cases with
9
9% conversion, and 93:7 dr / 89% ee. These results emphasize
1
0
5k
192
84
87:13
76
the robustness of the catalytic nanoribbon system that remained
equally active over several cycles.
[
(
a] Conditions: pDAPro catalyst (0.00625 mmol, 5 mol%), benzoic acid
0.00625 mmol, 5 mol%), 4a (1.25 mmol), and 5 (0.125 mmol) in water (1 mL)
1
at room temperature. [b] Determined by H NMR analysis of the crude
reaction mixture. [c] Determined by chiral-phase HPLC analysis of the
anti-product.
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Table 3. Recycling of the pDAPro nanoribbon catalyst 1.[a]
Experimental Section
General procedure for the asymmetric aldol reaction: At room temperature,
to a suspension of pDAPro (0.00625 mmol, 5 mol%) in water (1 mL) was
added benzoic acid (0.00625 mmol, 5 mol%) and ketone 4 (1.25 mmol).
The reaction mixture was stirred for 15 min, before aldehyde 5 (0.125
mmol) was added. The reaction mixture was vigorously stirred for the
indicated time and worked-up by extraction twice with EtOAc. The
combined organic phases were dried over anhydrous Na SO , filtered, and
concentrated under vacuum. The crude product was purified by silica gel
chromatography (cyclohexane/EtOAc) to afford pure aldol products. All
aldol products are known compounds, and their spectroscopic data are in
accordance with literature. Diastereomeric ratios were assessed by 1H-
NMR analysis of the crude reaction mixture and enantiomeric excesses
were measured by chiral HPLC analysis.
Entry
Catalyst
Fresh
1 recycle
Time (h) Conv. (%) dr anti/syn[b] ee[c] (%)
1
2
3
4
5
24
24
24
24
24
99
99
99
99
99
93:7
93:7
93:7
93:7
93:7
89
89
89
89
89
st
2
4
nd
2
3
4
recycle
recycle
recycle
rd
th
[
a] Conditions: pDAPro catalyst (0.00625 mmol, 5 mol%), benzoic acid
(0.00625 mmol), 4a (1.25 mmol), and 5a (0.125 mmol) in water (1 mL) at room
1
temperature. [b] Determined by H NMR analysis of the crude reaction
mixture. [c] Determined by chiral-phase HPLC analysis of the anti-
product.
Recycling procedure: At room temperature, to a suspension of pDAPro
(0.00625 mmol, 5 mol%)) in water (1 mL) was added benzoic acid
(0.00625 mmol, 5 mol%) and cyclohexanone 4a (1.25 mmol). The reaction
mixture was stirred for 15 min, before 4-nitrobenzaldehyde 5a (0.125
mmol) was added. The reaction mixture was vigorously stirred for 24 h.
The mixture was then extracted twice with EtOAc, the combined organic
phases were dried over anhydrous Na SO , filtered, and concentrated
2 4
under vacuum. The crude product was purified by silica gel
chromatography (cyclohexane/EtOAc, 85:15) to afford pure aldol product
The overall performances of our catalyst in water can be
rationalized by the peculiar structure of the nanoribbons which
offers, in addition to the active proline center, a hydrophobic
domain located at the interface of the lipophilic chains. This
domain is likely to accommodate the hydrophobic reagents
involved in the aldol reaction in such a way that it behaves as a
nanoreactor favoring aqueous dispersion of the reagents and
their concentration at the vicinity of the active sites of the catalyst.
At the same time, the hydrophobic domain sequester the
transition state from water, thus minimizing interference of the
aqueous medium on the outcome of the transformation,
especially as regards its selectivity.
6
aa. The remaining aqueous phase was reused to carry out further
reactions, by simple addition of 5 mol% of benzoic acid, cyclohexanone 4a
1.25 mmol) and 4-nitrobenzaldehyde 5a (0.125 mmol) for each additional
(
run.
Acknowledgements
R. A. K. thanks the Enhanced Eurotalents program for support.
Dr. Grégory Pieters is gratefully acknowledged for helpful
discussions. The “Service de Chimie Bioorganique et de
Marquage” belongs to the Laboratory of Excellence in Research
on Medication and Innovative Therapeutics (ANR-10-LABX-0033-
LERMIT). This work used the platforms of the Grenoble Instruct-
ERIC center (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL) within
the Grenoble Partnership for Structural Biology (PSB), supported
by FRISBI (ANR-10-INBS-05-02) and GRAL, financed within the
University Grenoble Alpes graduate school (Ecoles Universitaires
de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). The
electron microscope facility is supported by the Auvergne Rhône-
Alpes Region, the Fondation Recherche Medicale (FRM), the
fonds FEDER and the GIS-Infrastrutures en Biologie Sante et
Agronomie (IBISA).
Conclusions
Novel amphiphiles bearing a proline-derived polar head group
and a diacetylene lipophilic chain were synthesized, self-
assembled in aqueous medium, and further photopolymerized to
afford twisted nanoribbons. The supra-molecular material was
investigated for the promotion of semi-heterogeneous and
enantioselective aldol reactions. The L-proline-based catalyst
was shown to be effective on a variety of substrates in water
without addition of any organic solvents. The assembly acted as
a
nano-reactor in which organocatalysis take place and
contributed favorably to the overall process by allowing, i)
dispersion of the reagents in water, ii) their concentration close to
the catalyst active sites, and iii) sequestration of the transition
states from the aqueous environment, thus minimizing solvent
interference. The system demonstrated excellent reactivity,
diastereo- and enantioselectivities, and was found to be operative
under sustainable conditions (room temperature, air atmosphere,
low catalyst loading, water as unique solvent). In addition, the
catalyst could be recycled over several runs with no loss of activity.
From the above perspectives, it appears that the nanoribbon
catalyst favors compartmentalization of the reagents which leads
to unique selectivities, in a manner similar to that of enzymatic
systems such as aldolases.
Keywords: Aldol • organocatalysis • enantioselective •
polydiacetylene • self-assembly
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ChemCatChem
10.1002/cctc.201901960
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Nano-ribbons bearing proline groups
were valorized in the semi-
heterogeneous and enantioselective
catalysis of aldol reactions in water.
Minh-Duc Hoang, Ramar Arun Kumar,
David A. Buisson, Wai Li Ling, Edmond
Gravel,* Eric Doris*
Page No. – Page No.
Self-assembled polydiacetylene
nanoribbons for semi-heterogeneous
and enantioselective organocatalysis
of aldol reactions in water
This article is protected by copyright. All rights reserved.