Adsorption of a Chiral Amine on Alginate Gel Beads and Evaluation of its Efficiency as Heterogeneous Enantioselective Catalyst

Article abstract of DOI:10.1002/ejoc.201900247

A representative Lewis base organic catalyst (9-amino-9-deoxy epi-quinine, QNA) can be adsorbed in high yields onto acidic alginate gels (AGs) using a very simple and straightforward protocol. The resulting solvogel beads (QNA@AGs) are active as heterogeneous catalysts in the addition of aldehydes to nitroalkenes, affording the corresponding adducts in good yields and moderate to excellent diastereo- and enantio-selectivities. In these reactions, the carboxylic functions of the biopolymer act as both acidic co-catalyst and non-covalent anchoring site for the tertiary amine catalyst (as observed by IR spectroscopy). Use of heterocationic gels, derived from alkaline earth metal gels by proton exchange, provided materials with better mechanical properties and higher porosities, ultimately resulting in higher catalytic activities. This work represents the first utilization of alginates, abundant and renewable biopolymers, as gel supports/media for asymmetric organocatalytic processes.

Full text of DOI:10.1002/ejoc.201900247

A Journal of
Accepted Article
Title: Adsorption of a Chiral Amine on Alginate Gel Beads and
Evaluation of its Efficiency as Heterogeneous Enantioselective
Catalyst
Authors: Daniel Antonio Aguilera, Lisa Spinozzi Di Sante, Asja
Pettignano, Riccardo Riccioli, Joël Roeske, Luce Albergati,
Vasco Corti, Mariafrancesca Fochi, Luca Bernardi, Françoise
Quignard, and Nathalie Tanchoux
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: Eur. J. Org. Chem. 10.1002/ejoc.201900247
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900247
Supported by

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
Adsorption of a Chiral Amine on Alginate Gel Beads and
Evaluation of its Efficiency as Heterogeneous Enantioselective
Catalyst
Daniel Antonio Aguilera,[a,b] Lisa Spinozzi Di Sante,[a] Asja Pettignano,[a,b] Riccardo Riccioli,[a] Joël
Roeske,[a,c] Luce Albergati,[a,c] Vasco Corti,[a] Mariafrancesca Fochi,[a] Luca Bernardi,*[a] Françoise
Quignard[b] and Nathalie Tanchoux*[b]
Dedication ((optional))
Abstract: A representative Lewis base organic catalyst (9-amino-9-
deoxy epi-quinine, QNA) can be adsorbed in high yields onto acidic
alginate gels (AGs) using a very simple and straightforward protocol.
The resulting solvogel beads (QNA@AGs) are active as
heterogeneous catalyst in the addition of aldehydes to nitroalkenes,
affording the corresponding adducts in good yields and moderate to
excellent diastereo- and enantio-selectivities. In these reactions, the
carboxylic functions of the biopolymer act as both acidic co-catalyst
and non-covalent anchoring site for the tertiary amine catalyst (as
observed by IR spectroscopy). Use of heterocationic gels, derived
from alkaline earth metal gels by proton exchange, provided materials
with better mechanical properties and higher porosities, ultimately
resulting in higher catalytic activities. This work represents the first
utilization of alginates, abundant and renewable biopolymers, as gel
supports/media for asymmetric organocatalytic processes.
properties and applications. Starting from aqueous sodium
alginate solution, the preparation of hydrogel beads by proto- or
iono-tropic dropping gelation processes is straightforward.[2] The
thus obtained, easily manageable, hydrogel beads feature high
.
surface areas (300-700 m2 g-1) and functional group (the
.
carboxylate) density and availability (5.6 mmol
g-1). The
properties of the hydrogel depend on the type of gelling agent, its
concentration and the maturation time in the gelling bath.[3]
Furthermore, the ratio between M and G units in the alginate,
which derives from its natural source, plays a major role in the
mechanical features of the gels; G rich alginates give stiffer and
more resistant materials compared to M rich alginates,[4] enabling
a fine-tuning of the gel properties. Importantly, the structure of the
gel is nearly retained exchanging water with organic solvents
(hydrogel → solvogel), or during a following supercritical drying
(solvogel → aerogel).[2,5] Utilization of alginate gels is thus
possible in different media. All these features make these
renewable biomaterials highly attractive as heterogeneous
supports in the frame of catalytic processes. In this context, a
large number of metal based heterogeneous catalysts prepared
by combining (transition) metals and nanoparticles with alginate
gels have been reported.[6,7] Alginates can thus be considered an
appealing alternative to oil based polymers and inorganic
materials for supporting metal catalysts.[8]
Introduction
Alginates are natural polysaccharides extracted from brown
macro-algae and available in very large amounts at low prices.[1]
Structurally speaking, they are constituted by β-
D-mannuronate
(M) and α-
L
-guluronate (G) monomers, fixed in 4C1 and 1C4
conformations, respectively, and linked in a 1 → 4 fashion (see
Scheme 1). The presence of a carboxylic functional group in each
monomeric unit differentiates these biopolymers from other
natural polysaccharides, such as cellulose, leading to unique
Alginates are also being studied for water remediation
purposes;[2c] we have recently demonstrated that acidified
alginate foams are able to remove a basic dye (methylene blue)
from aqueous solutions by adsorption.[9] This proficiency is mainly
due to an acid-base interaction between the carboxylic acid
functions of the biopolymer and the basic dye. We questioned
whether such acid-base interaction could be leveraged to link an
amine organic catalyst to alginic acid gels, providing the first
example of the utilization of alginates as support for chiral organic
catalysts.[10,11] Even if the retaining of catalyst activity and
selectivity in the gel structure was considered challenging,
literature encouragement to our working plan was given by few
examples of non-covalent immobilization of amine catalysts to
acidic supports.[12] These works demonstrated that, in
aminocatalytic reactions, heterogeneous acids can act as both
supports for the amine catalysts, and weakly acidic co-catalysts.
The mild acidic nature of the carboxylic acid units of alginic acid
(pKa ca. 3.5 in water)[13] could fulfill these purposes. The non-
covalent approach to catalyst immobilization[14] bears some
obvious advantages in terms of simplicity and straightforwardness,
[a]
D. A. Aguilera, L. Spinozzi Di Sante, Dr. A. Pettignano, R. Riccioli, J.
Roeske, L. Albergati, V. Corti, Prof. M. Fochi, Prof. L. Bernardi
Department of Industrial Chemistry “Toso Montanari” & INSTM RU
Bologna
Alma Mater Studiorum – University of Bologna
V. Risorgimento 4, 40136 Bologna (Italy)
E-mail: luca.bernardi2@unibo.it
https://www.unibo.it/sitoweb/luca.bernardi2/en
D. A. Aguilera, Dr. A. Pettignano, Dr. F. Quignard, Dr. N. Tanchoux
Institut Charles Gerhardt
CNRS-ENSCM-UM
8, Rue Ecole Normale, 34296 Montpellier (France)
E-mail: nathalie.tanchoux@enscm.fr
[b]
[c]
https://www.icgm.fr/en/nathalie-tanchoux-en
J. Roeske, L. Albergati
Haute Ecole d’Ingénierie et d’Architecture
Bd. de Pérolles 80, 1705 Fribourg (Switzerland)
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/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
HO
HO2C
O
HO
OH
O
OH
CO2H
O
HO2C
O
O
O
HO
O
HO
OH
O
OH
O
OH
O
CO2H
O
CO2H
O
HO2C
OH
HO
H
OH
H2N
N
Alginate Gels (AGs)
MeO
HO2C
O
HO
ADSORPTION
OH
OH
O
N
+
H
HO2C
O
OH
O
OH
O
H2N
N
O
MeO
HO2C
OH
N
QNA@AGs gel beads
catalyst
QNA
R3
O
H
O
R2
NO2
NO2
+
R3
H
R1
R1 R2
2
1
3
Scheme 1. Adsorption of an organic catalyst (QNA) on acidic alginate gels (AGs) and use of the resulting gel beads (QNA@AGs) as catalysts in a benchmark
asymmetric Michael addition reaction.
compared to the more explored covalent anchoring of the catalyst
to the support, which can lead to modifications of catalyst
structure altering its performances.[10] The latter approach
requires also multiple additional synthetic steps to prepare the
heterogeneous catalyst, while being, on the other hand, less
prone to catalyst leaching issues.
Herein, we present the optimization of the adsorption of a
representative Lewis base organic catalyst (9-amino-9-deoxy epi-
quinine, QNA),[15,16] onto acidic alginate gels (AGs), by varying
the adsorption conditions and the characteristics of the material,
rendering stable gel beads (QNA@AGs), which could be used as
heterogeneous catalysts in the benchmark enantioselective
Michael addition of aldehydes 1 to nitroalkenes 2[17] (Scheme 1).
Although the activity of this heterogeneous catalyst in subsequent
reaction cycles was only moderate, the enantiomeric excesses of
products 3 obtained with this heterogeneous system were
generally very high.
the amount of biopolymer AG-H was tailored to reach 2 equiv. of
carboxylic units per QNA catalyst. These tests were carried out
by adding alginic acid aerogel beads (10 beads, corresponding to
0.028 mmol of carboxylic acid units) to a solution of QNA in the
appropriate solvent (0.014 mmol in 300 μL), leaving the mixture
under gentle magnetic stirring for 18-24 h. As shown in Table 1,
entries 1-9, aprotic apolar solvents were not very efficient in QNA
adsorption, leaving substantial amounts of QNA in solution at the
end of the process. Experiments performed at different
temperatures did not show any significant improvement (entries
2,3). A slight improvement was displayed by increasing the
excess of carboxylic acid units (entry 4), which however was
thought to be detrimental for catalytic activity and was thus not
pursued further. While a protic but lipophilic alcohol such as i-
PrOH (entry 10) behaved similarly to the aprotic solvents, much
better adsorption results were obtained in EtOH as adsorption
medium (entry 11). We rationalize these results on the bases of
the swelling properties of the different solvents, with a polar protic
solvent like ethanol enabling better interactions between QNA
and the acidic protons of the polymer. We tend to exclude that the
different adsorption values are due to the variation of the acidity
of the polymer in the different media (i.e. to a thermodynamic
phenomenon), since washing the QNA@AG-H beads several
times with toluene and then placing them in fresh toluene did not
cause any QNA desorption. This is a key important aspect as the
beads have the right properties to be used as gel catalysts in
different media. Moving to a more polar medium (water) was not
feasible as the gel structure broke gelifying the whole solvent
(entry 12). We believe that the interactions between the carboxylic
groups and QNA are so strong in this medium that the alginic acid
Results and Discussion
We started our investigations by preliminarily testing the capability
of alginic acid gel beads (AG-H) to adsorb and retain the catalyst
QNA, while maintaining a stable gel structure. We studied
guluronic-rich alginic acid (G/M 63:37), since these alginates
feature better mechanical strength compared to other alginates
more rich in mannuronic units. Taking advantage of using a dry
aerogel material, different adsorption media were employed
(Table 1). Considering the usually optimal ratio between acidic co-
catalysts and Lewis base amines in the catalytic reactions,[15,16]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
(a prototropic gel) hydrogel structure is not stable anymore. The
carboxylic groups involved in QNA adsorption play, in fact, a
fundamental role also in the formation of intramolecular H-bonds
between the polymeric chains.[18] The competitive interaction with
the QNA base could thus lead to a partial destabilization of the
gel network.[19]
Table 1. Preliminary tests on the adsorption of QNA on AG-H aerogel beads
in different media.[a]
Entry
1
Solvent
Toluene
Toluene
Toluene
Toluene
CHCl3
T [°C]
25
0
QNAads[b] [mol%]
45
45
37
60
38
50
32
34
31
39
86
-
2
3
45
25
25
25
25
25
25
25
25
25
Figure 1. UV–Vis/DRS spectra of QNA@AG-H (blue line) and AG-H aerogel
beads (red line).
4[c]
5
Solid state FT-IR analysis of the QNA@AG-H beads
confirmed that the main interaction between the biopolymer and
QNA is at the carboxylic acid units (Figure 2). In more detail, the
spectrum of QNA@AG-H (red line, Figure 2) shows a dramatic
decrease of the signal of the carboxylic C=O stretching at 1730
cm-1 compared to the spectrum of AG-H (black line). Likewise, a
new signal appeared at 1595 cm-1. This signal can be assigned to
the stretching of the carboxylate O-C=O group, and is not present
in the parent QNA (blue line). This result indicates that QNA is, at
least partially, deprotonating the carboxylic groups. Taking into
account that in the adsorption process a molar excess of the
carboxylic groups (COOH:QNA 2:1) is used, the disappearance
of the signal of the carboxylic acid at 1730 cm-1 suggests that
QNA interacts with more than one carboxylic groups of the
support, presumably using both primary and tertiary amine groups.
6
CH2Cl2
EtOAc
CH3CN
THF
7
8
9
10
11
12[d]
i-PrOH
EtOH
H2O
[a] Conditions: QNA (0.014 mmol), AG-H (10 aerogel beads, corresponding
to 0.028 mmol of carboxylic acid units), solvent (300 μL), 18-24 h. The
solvent was then removed and the beads washed with fresh solvent 3-4
times. [b] Mol% of QNA adsorbed on AG-H compared to starting QNA.
Determined by 1H NMR using bibenzyl as internal standard after evaporation
of the adsorption and washing solvents. [c] 20 beads of AG-H
(corresponding to 0.56 mmol of carboxylic acid units) were used. [d] Beads
broke.
To confirm the presence of QNA in the structure of the
biopolymeric matrix of alginate, UV–Vis/DRS (Diffuse Reflectance
Measurement) spectroscopy was performed (Figure 1). The blue
line represents the UV–Vis/DRS spectra of the alginate beads
after the adsorption test of QNA in EtOH (QNA@AG-H), and the
red line represents the acidic alginate aerogel AG-H before the
adsorption. Only the absorption spectrum of QNA@AG-H has a
main band centered at ∼333 nm, close to the maximum found in
the UV-Vis spectrum in solution for QNA (∼334 nm, spectrum not
shown). This signal is associated to S0-S1 transition of the
heterocyclic quinoline ring in Cinchona alkaloids.[20] All the above
indicated that the QNA has been adsorbed on AG-H successfully.
Figure 2. FT-IR spectra of AG-H (black line) QNA@AG-H (red line), and QNA
(blue line).
Further refinement and optimization of the adsorption
process led to a fully reproducible and robust protocol consisting
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
in adding slowly a QNA solution to the AG-H beads (tailored to
reach 2.5 equivalents of carboxylic acid units) soaked in EtOH.
High dilution (8 x 10-3 M) was also beneficial to ensure
preservation of the macroscopic properties (shape, size) of the
gel material upon adsorption. On the other hand, in terms of
material morphology, aerogel and ethanol alcogel beads could be
indifferently employed with similar results.
With this new protocol, we studied in more detail the
influence of water on the adsorption process, using EtOH/H2O
mixtures. The kinetics data (using UV-vis spectroscopy, Figure
3a) showed that the adsorptions proceed very fast for the first few
hours, then reaching slowly the maximum value after around 24
h. The addition of 10% water to EtOH had a positive effect with a
slight increase in the final amount of QNA adsorbed (Figure 3b).
Lower percentages of water vs absolute EtOH did not have a
significant effect on the adsorption process. The positive effect of
water may be associated with the ability of the polysaccharides to
swell in aqueous media, which leads to a more dispersed and
accessible structure for the catalyst and therefore more efficient
adsorption, as previously mentioned. On the other hand, the
increase in the amount of water above 10%, led to a dramatic
decrease in the QNA amount adsorbed. This decrease was
associated with altering the structure of the gel of alginic acid,
such as breaking of the beads and new gelation, which was
observed at high water contents in the presence of the basic QNA
(Figure 3c,d).
Figure 3. Adsorption data of QNA on AG-H obtained by UV-vis spectroscopy using appropriate calibration curves. (Conditions: solution of QNA added to AG-H
beads (ratio COOH:QNA 2.5:1, QNA concentration 8 x 10-3 M) at 25 °C). a) Representative adsorption isotherms for the adsorption of QNA on AG-H at different
percentages of water in EtOH at 25°C. b) Influence of the amount of water used as a co-solvent in the percentage of QNA adsorbed on AG-H. c) and d) Examples
of beads breaking and new gelation at high percentages of water (> 10%).
The benchmark reaction between iso-butyraldehyde 1a and
4-trifluoromethyl-β-nitrostyrene 2a in the presence of QNA@AG-
H as catalyst (prepared using the optimized protocol with
EtOH/H2O 9:1 as adsorption medium) was then studied and
optimized (Scheme 2a). Working at 60 °C in toluene, we were
delighted to observe that the gel beads were active in this reaction.
The product 3a was obtained with very good results in terms of
conversion after 24 h. Enantioselectivity was also very good (ee
98%). The heterogeneity of the catalyst (used as toluene
solvogel) was determined by a Sheldon test (Scheme 2b), which
showed good heterogeneity as the reaction did not proceed to a
considerable extent upon beads removal (compare reaction I vs
reaction II), suggesting that catalyst leaching did not occur, and
that the catalytic process takes place in the gel environment.
CF3
Scheme 2. a) Addition of 1a to 2a catalysed by QNA@AG-H (20 mol%). b)
Reaction kinetics and Sheldon test. Conversion determined by 19F NMR. In
QNA@AG-H
(20 mol%)
toluene
a)
reaction II, QNA@AG-H beads were removed after 3 h.
O
O
NO2
60 °C, 24 h
NO2
H
H
+
While enantioselectivity was fully satisfactory and
comparable to the homogeneous versions of this QNA catalysed
reaction,[17] reaction rate was considerably lower. Furthermore,
F3C
1a
2a
3a
: >95% conversion
98% ee
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
some change in shape and size in the beads recovered after the
reaction was observed. In order to improve the properties of the
catalyst, some heterocationic alginate gels, that is gels featuring
both carboxylic and metal carboxylate groups, were applied. The
idea was to use a metal-cation for strengthening/improving the
properties of the support while keeping the acidic moiety for
anchoring the basic QNA catalyst. To this purpose, Ca2+ ion was
first selected as a cross-linking agent based on the fact that it can
generate alginate-based materials with better mechanical
properties than the acidic ones.[21] The heterocationic gels were
prepared from Ca2+ alginate hydrogels AG-Ca as starting
materials, by exchanging some of the Ca2+ cations for H+ by aq.
HCl treatment at different concentrations. The thus obtained
heterocationic hydrogels (AG-Ca:nH) were washed, then
converted to the corresponding ethanol solvogels, which xerogels
were characterized by TGA (thermogravimetric analysis) to
determine the amount of Ca2+ remaining on the gel after the
exchange, which was roughly inversely proportional to the
amount of HCl used (see Supporting Information). The ratio
between carboxylic and carboxylate units in the materials could
thus be calculated (Table 2, entries 3-5). The cation exchange
allowed the control of Ca2+ quantity in the final material by varying
the initial concentration of HCl in solution. However, even with an
excess of HCl (entry 5), a residual amount of Ca2+ in the AG-
Ca:4H was observed. At the macroscopic level, all materials after
the exchange conserved the initial spherical form of AG-Ca.
the carboxylic groups of the AGs and QNA fixed to 2.5. Initially,
the adsorption of QNA using AG-Ca versus AG-H alcogels
(entries 2 and 1) was compared, showing that the AG-Ca had a
very low adsorption capability, as expected considering the lack
of carboxylic acid groups in this gel. However, the partial
replacement of Ca2+ by H+ in AG-Ca:0.5H, AG-Ca:2H and AG-
Ca:4H alcogels led to sharp increase of the adsorption of QNA
(entries 3-5), which reached values comparable or even better
than the adsorption featured by AG-H. The result obtained with
AG-Ca:0.5H indicates that even a relatively large quantity of Ca2+
in the support does not compromise adsorption of QNA (entry 3).
The evaluation of the activity of QNA supported on this
series of heterocationic gels (QNA@AG-Ca:nH) in the reaction
between iso-butyraldehyde 1a and nitroalkene 2a is reported in
Figure 4a.
Table 2. Heterocationic AGs: H+ content and QNA adsorption capability.
Entry
Alcogel[a]
AG-H
-COOH[b] [%]
QNAads[c] [mol%]
1
2
3
4
5
6
7
8
9
100
0
84
16
85
90
91
14
13
93
87
AG-Ca
AG-Ca:0.5H
AG-Ca:2H
AG-Ca:4H
AG-Sr
27
79
95
0
AG-Ba
0
Figure 4. Kinetics of the reaction between 1a and 2a, performed in toluene at
60 °C and catalysed by QNA@AG at 20 mol% catalyst loading based on QNA.
Conversion values were determined by 19F NMR. Product 3a was obtained in
98% ee in all cases. a) Kinetics of the reactions catalysed by QNA@AG-H,
QNA@AG-Ca:0.5H, QNA@AG-Ca:2H and QNA@AG-Ca:4H. b) Kinetics of
the reactions catalysed by QNA@AG-Ca:2H, QNA@AG-Sr:2H, QNA@AG-
Ba:2H and their relative Sheldon tests: in R2, performed in parallel with R1,
beads were removed after 2 h.
AG-Sr:2H
AG-Ba:2H
67
66
[a] AG-M:nH: alcogels obtained from AG-M hydrogels by H+ exchange: M
refers to the metal ion while n refers to the molar ratio between HCl used in
the exchange and the metal present in the hydrogel. [b] Ratio of -COOH vs
overall -COOH + -COO(M)1/2 groups in the AGs, determined by TGA. [c]
Adsorption performed at 25 °C by adding QNA solution in EtOH/H2O 90:10
(0.014 mmol) to AGs beads (amount adjusted to have 0.035 mmol of
carboxylic units) soaked in EtOH/H2O 90:10 (QNA concentration 8 x 10-3 M).
The solvent was then removed and the beads washed with fresh solvent 3-
4 times. Mol% of QNA adsorbed on AGs compared to starting QNA.
Determined by 1H NMR using bibenzyl as internal standard after evaporation
of the adsorption and washing solvents.
An improvement in the activity by using as support
heterocationic gels with low content of Ca2+ could be clearly
observed, as the reactions catalyzed by QNA@AG-Ca:2H and
QNA@AG-Ca:4H went to completion in less than 8 h, compared
to the reaction with QNA@AG-H which required around 24 h. This
improvement can be rationalized considering an increase of
surface area and thus accessibility to substrates for these
heterocationic materials, related to the conservation of the more
The thus obtained alcogels were then used for QNA
adsorption (Table 2, entries 3-5), keeping the molar ratio between
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
disperse initial structure of AG-Ca even after the exchange. In fact, 2a-e reacted well with iso-butyraldehyde 1a, delivering the
the surface areas of AG-H and AG-Ca aerogels were measured
to be close to 250 m2 . g-1 and 350-500 m2 . g-1, respectively.[2b,22]
The catalyst with higher quantity of Ca2+ (QNA@AG-Ca:0.5H)
performed worse under these reaction conditions, albeit
comparably to the previously applied QNA@AG-H. In all cases,
the reactions afforded product 3a in nearly enantiopure form.
Furthermore, QNA leaching was not observed as beads removal
in parallel experiments halted the reactions.
In order to discriminate whether there were differences
between the use of the calcium vs other alkaline earth metals,
heterocationic gels starting from AG-Sr and AG-Ba were
prepared (Table 2, entries 8,9). Perhaps due to the higher affinity
of these cations for polyuronates,[23] exchange with H+ left larger
amounts of Ba2+ and Sr2+ in the gels, compared to AG-Ca (Table
2, compare entry 4 with entries 8,9). Nevertheless, both cations
behaved very similarly to calcium in terms of both adsorption of
QNA (entries 6-9) and catalytic performances. QNA@AG-Sr:2H
and QNA@AG-Ba:2H gave kinetics essentially superimposable
to QNA@AG-Ca:2H in the reaction between 1a and 2a (Figure
4b). Heterogeneity was also comparable.
corresponding products 3a-e in good yields and excellent
enantioselectivities. Variations at the aldehyde partner were also
explored.[24] Other α,α-disubstituted aldehydes (cyclopentane
carbaldehyde 2b and 2-phenylpropionaldehyde 2c), rendered
products 3f and 3g with good results. High diastereoselectivity
was obtained in product 3g bearing a quaternary stereocentre at
the α-position of the aldehyde. In contrast,
a
linear
monosubstituted aldehyde (n-hexanal 2c) afforded the
corresponding product 3h with moderate diastereoselectivity.
However, enantioselectivity was fully satisfactory. In fact, despite
the moderate activity displayed by this heterogeneous QNA@AG-
Ca:2H catalyst system, high enantioselectivities were observed in
most cases, even at 60 °C. The intrinsic chirality of alginates does
not seem to have an effect in these reactions; 9-amino-9-deoxy
epi-quinidine QDA behaves very similarly to QNA both in terms of
adsorption behaviour and catalytic results (see product ent-3a in
Scheme 3, for reaction kinetics see Supporting Information).
Conclusions
Unfortunately, recovery of the heterogeneous catalysts after
reaction and use in subsequent reaction cycles showed a
considerable loss of activity (from full conversion to 75% for
QNA@AG-Ca:2H). Excluding catalyst leaching as the major
factor, we attribute these results to the combination of two
elements, with the second one likely prevailing:
i) QNA deactivation/degradation, which has been observed in all
polymer-supported versions of this catalyst preventing its use for
more than just few cycles;[16]
We demonstrated the possibility of using cheap and renewable
alginate gels (AGs) as support for a model organocatalyst, (9-
amino-9-deoxy epi-quinine QNA), by means of a simple and
efficient adsorption protocol. The adsorption conditions were
optimized, leading to nearly full adsorption of QNA on alginic acid
alcogels using EtOH:H2O 9:1 as adsorption medium under high
dilution (8 x 10-3 M). Crucial parameters, allowing the production
of stable QNA@AG-H gel beads, were found to be the type of
alginate (guluronic rich), the addition order and the amount of
water in the adsorption mixture. IR studies showed that the
interaction between QNA and AG-H takes place mainly between
the basic groups of the alkaloid and the carboxylic groups of the
biopolymer. Heterocationic alginate gels of type M2+-H+ based on
alkaline earth metals (Ca, Sr, Ba) also showed a remarkable
adsorption of the QNA, even with high metal contents. The new
catalytic QNA@AGs systems are fully heterogeneous and
promote efficiently the asymmetric addition of aldehydes (α-
substituted and α,α-disubstituted) to nitroalkenes. The activity
was improved using heterocationic type supports compared to
simple alginic acid (e.g. QNA@AG-Ca:2H vs QNA@AG-H)
showing good yields (up to 93%) for a significant range of
substrates. Although the recyclability is moderate (up to 2 cycles),
the enantioselectivity is high in most products. Forthcoming
studies will assess the influence, if any, of the gel chiral
environment[25] on reaction outcome, with the ultimate goal of
developing uniquely selective systems in this and related
reactions.
ii) pore occlusion by reaction of alginate functionalities with
aldehyde 1a, which is used in excess (5 equiv.) in the reaction.
In fact, control experiments (see Supporting Information) showed
a slow deactivation of the heterogeneous catalyst over the course
of the reaction and a dramatic loss of activity upon pre-treatment
of QNA@-AG catalysts with the aldehyde 1a prior to the reaction.
In contrast, QNA@-AG catalysts appeared to be perfectly intact
upon prolonged heating (60 °C, overnight) in toluene, even in the
presence of nitroalkene 2a. Unfortunately, reducing the amount of
aldehyde donor 1a was not practical, while all attempts to restore
the activity of the catalyst after the reaction by acidic
(EtOH:HCO2H 9:1), basic (EtOH/aq. NH4OH 9:1), aqueous or
thermal (60 °C, overnight) treatments were not successful.
Similarly negative results were obtained by i) changing reaction
solvent to dichloromethane, THF, EtOH, EtOAc or acetonitrile; ii)
increasing or decreasing reaction temperature to 40 °C or 80 °C;
iii) using an inert atmosphere, degassed or dry toluene; iv)
applying different additives, such as drying agents, or adding
water in different amounts (from water saturated toluene to
biphasic mixtures). Nevertheless, it must be noted that the
enantioinduction furnished by all QNA@AG catalysts in
subsequent cycles was always identical to the one displayed in
the first cycle (98% ee).
Experimental Section
Using the QNA@AG-Ca:2H catalyst, we verified the
tolerance of this heterogeneous system to substrate variations
(Scheme 3). By adjusting the reaction time case by case (see
Supporting Information), aromatic and one aliphatic nitroalkenes
Preparation of alginic acid gel (AG-H).[8b] A 2% w/V solution of sodium
alginate was prepared, adding 2 g of sodium alginate (Protanal 200S; G/M
63:37) to 100 mL of distilled water and stirring it until a clear and viscous
solution was obtained. The thus prepared solution was added dropwise
(using a dropping funnel) to 400 mL of 1 mol/L HCl kept under magnetic
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
QNA@AG-Ca:2H
(20 mol%)
toluene, 60 °C
O
R3
O
R2
NO2
NO2
R3
H
+
H
R1 R2
R1
1a-d
2a-e
3a-h
Variation of nitroalkene partner 2:
OMe
Cl
CF3
O
O
O
O
O
NO2
: 88% yield
NO2
H
NO2
NO2
NO2
H
H
H
H
3b
3c: 93% yield
95% ee
3d: 65% yield
97% ee
3a: 74% yield
98% ee
3e: 63% yield
97% ee
95% ee
Variation of aldehyde partner 1:
Reaction with QDA@AG-Ca:2H
catalyst:
CF3
CF3
CF3
CF3
O
O
O
O
NO2
NO2
NO2
NO2
H
H
H
H
Ph
3g
d.r. 20:1
3a
98% ee
: 73% yield
ent- : 64% yield
3f: 68% yield
95% ee
3h: 66% yield
d.r. 1.7:1
85% ee (maj)
92% ee (maj)
Scheme 3. Conditions: Aldehyde 1 (1.05 mmol), nitroalkene 2 (0.21 mmol), QNA@AG-Ca:2H (30 beads, corresponding to 20 mol% QNA catalyst loading), toluene
(0.90 mL), 60 °C. Yields of products 3 after purification by chromatography on silica gel. ee determined by chiral stationary phase HPLC. D.r. of 3g and 3h determined
by 19F NMR spectroscopy on the crude mixtures.
stirring at RT. The resulting mixture was slowly stirred overnight to allow
the maturation of the beads, whose formation is immediately evident. After
filtration, the beads were carefully rinsed with distilled water and
dehydrated by immersion in a series of EtOH/H2O baths, with increasing
alcohol content (10, 30, 50, 70, 90% and absolute EtOH), for 15 min each
[AG-H sample].
gently overnight to allow the exchange. Next, the hydrogels were
converted to alginate alcogels following the same protocol used for AG-H.
The final materials were labelled as AG-Ca:0.5H, AG-Ca:2H, AG-Ca:4H,
AG-Sr:2H and AG-Ba:2H where nH refers to the molar ratio between the
metal in the gels and the H+ used during the exchange process.
Preparation of gel catalysts QNA@AGs: optimised adsorption
protocol. The gel catalysts QNA@AGs were prepared using the
optimized condition for the adsorption of QNA[26] on alginate gels
(EtOH/H2O 9:1 as adsorption medium, native pH, room temperature, and
initial concentration of QNA in the adsorption mixture equal to ca. 8 x 10-3
M). A QNA solution (8 x 10-3 M in EtOH/H2O 9:1) was added dropwise
under gentle stirring to the alcogel beads soaked in EtOH (number of
beads calculated in order to have molar ratio of COOH : QNA of 2.5:1).
The mixture was left overnight under gentle stirring. Then, the beads where
washed twice with EtOH and then exchanged twice with toluene. The
remnant solutions after adsorption, washing and exchange solvents were
combined and evaporated, and the mol% of QNA adsorbed on AGs was
determined by 1H NMR using bibenzyl as internal standard. [QNA@AG-H
and QNA@AG-M:nH samples].
Preparation of M2+ alginate gels (AG-M).[8b] 50 mL of a solution of sodium
alginate (2% w/V) was added dropwise (using a dropping funnel) to 100
mL of a 0.1 mol/L solution of metal chloride (CaCl2, SrCl2, BaCl2) kept
under magnetic stirring at RT. The amount of metal chlorides correspond
to an excess of cations (4 equivalents, considering two uronic units for
complexation of an ion). The resulting mixture was stirred gently overnight
to allow the maturation of the beads, which were then washed carefully
with water. The beads were divided in two groups. The first one for the
preparation of heterocationic gels (see protocol below) and the second
group was exchanged with EtOH following the same protocol used for AG-
H [AG-Ca, AG-Sr and AG-Ba samples].
Preparation of heterocationic gels (AG-M:nH). The heterocationic gels
of M2+-H+ (M2+: Ca2+, Sr2+, Ba2+) were prepared starting with M2+ alginate
hydrogels obtained after maturation and washing with water. The
exchange of the M2+ in the gels with H+ was performed using aq. HCl at
different concentrations (5.2, 21.0, 42.0 mM). The quantity of H+ was
calculated assuming that two moles of H+ are necessary for the exchange
of each mole of M2+ in the gel. For each solution, the system was stirred
Catalytic tests with QNA@AGs catalysts in the addition reaction of
isobutyraldehyde 1a to nitrostyrene 2a. 14-15 Solvogel beads of
QNA@AGs (which correspond to ca. 0.021 mmol of QNA), were added to
a reaction tube equipped with a magnetic stirring bar, followed by 450 µL
of toluene, 22.8 mg (0.105 mmol) of nitrostyrene 2a and 48 µL (0.525
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
mmol) of freshly distilled isobutyraldehyde 1a. The mixture was then
heated to 60 °C with gentle (200 rpm) stirring. The reaction evolution was
followed by 19F NMR analysis on reaction samples. In order to study the
heterogeneity of the catalyst, two reactions (I and II) were carried out in
parallel. As the conversion reaches 20-40%, the catalyst beads were
removed from reactions II; in case of heterogeneity, the reactions stop right
after beads removal. Once complete, the beads of reactions I were washed
three times with 1 mL of toluene, to be ready to be employed in new
reaction cycles. The enantiomeric excess of product 3a was determined
after purification by chromatography on silica gel (7:3 n-hexane/diethyl
ether) by chiral stationary phase HPLC analysis (Chiralcel OD, n-hexane/i-
PrOH 80:20, flow 0.75 mL/min, tmaj = 25.7 min; tmin = 14.2 min, 98% ee).
[5]
[6]
R. Valentin, K. Molvinger, F. Quignard, F. Di Renzo, Macromol. Symp.
2005, 222, 93.
a) A. Pettignano, D. A. Aguilera, N. Tanchoux, L. Bernardi, F. Quignard,
Alginate: a Versatile Biopolymer for Functional Advanced Materials for
Catalysis, in Horizons in Sustainable Industrial Chemistry and Catalysis,
Chapter 4a, (Eds. S. Albonetti, S. Perathoner, A. Quadrelli), Elsevier
2018, in press; b) M. Häring, M. Tautz, J. V. Alegre-Requena, C. Saldías,
D. Díaz Díaz, Tetrahedron Lett. 2018, 59, 3293.
[7]
[8]
a) A. Primo, M. Liebel, F. Quignard, Chem. Mater. 2009, 21, 621; b) M.
Chtchigrovsky, Y. Lin, K. Ouchaou, M. Chaumontet, M. Robitzer, F.
Quignard, F. Taran, Chem. Mater. 2012, 24, 1505.
Furthermore, the catalytic activity of the parent alginic acid and calcium
alginate gels has been demonstrated, see for example: a) D. Kühbeck,
J. Mayr, M. Häring, M. Hofmann, F. Quignard, D. Díaz Díaz, New. J.
Chem. 2015, 39, 2306; b) A. Pettignano, L. Bernardi, M. Fochi, L. Geraci,
M. Robitzer, N. Tanchoux, F. Quignard, New J. Chem. 2015, 39, 4222.
A. Pettignano, N. Tanchoux, T. Cacciaguerra, T. Vincent, L. Bernardi, E.
Guibal, F. Quignard, Carbohydr. Polym. 2017, 178, 78.
General procedure for the addition of aldehydes 1 to nitroalkenes 2
catalysed by QNA@AG-Ca:2H gel catalyst. Thirty solvogel beads of
QNA@AG-Ca:2H (which correspond to 0.044 mmol of QNA), were added
to a reaction tube containing a stirring bar. Then, 900 μL of toluene, 0.21
mmol of appropriate nitroalkene 2 and 1.05 mmol of aldehyde 1 were
added in the reaction tube and the system closed. The reaction was
performed at 60 °C under 200 rpm. In the case of adducts 3g and 3h, the
mixture was filtered on a plug of silica gel, the plug flushed with Et2O, the
solvents evaporated and the residue analysed by 19F NMR to determine
the diastereomeric ratio of 3g and 3h, which were then purified by
chromatography on silica gel (7:3 n-hexane/diethyl ether). In all other
[9]
[10] For general overviews on the heterogenization of organic catalysts: a) M.
Benaglia, A. Puglisi, F. Cozzi, Chem. Rev. 2003, 103, 3401; b) A. F.
Trindade, P. M. P. Gois, C. A. M. Alfonso, Chem. Rev. 2009, 109, 418;
c) J. Lu, P. H. Toy, Chem. Rev. 2009, 109, 815; d) A. Puglisi, M. Benaglia,
V. Chiroli, Green Chem. 2013, 15, 1790; e) C. Rodríguez-Escrich, M. A.
Pericàs, ̀ Eur. J. Org. Chem. 2015, 1173; f) I. Atodiresei, C. Vila, M.
Rueping, ACS Catal. 2015, 5, 1972; g) Recoverable and Recyclable
Catalysts, (Ed.: M. Benaglia), Wiley, Chichester, 2009; h) T. E.
Kristensen, T. Hansen, Eur. J. Org. Chem. 2010, 3179; i) T. Mayer-Gall,
J.-W. Lee, K. Opwis, B. List, J. S. Gutmann, ChemCatChem 2016, 8,
1428; j) S. Itsuno, Md. Mehadi Hassan, RSC Adv. 2014, 4, 52023.
[11] For organic catalysts supported on other polysaccharides via covalent
linkages: a) C. A. Mak, S. Ranjbar, P. Riente, C. Rodríguez-Escrich, M.
A. Pericàs, Tetrahedron 2014, 70, 6169; b) l. Yang, D. Zhou, C. Qu, Y.
Cui, Catal. Lett. 2012, 142, 1405; c) Y. Qin, W. Zhao, L. Yang, X. Zhang,
Y. Cui, Chirality 2012, 24, 640; d) J. M. Andrés, F. González, A. Maestro,
R. Pedrosa, M. Valle, Eur. J. Org. Chem. 2017, 3658.
cases, products
3 were purified directly from the mixture by
chromatography on silica gel (7:3 n-hexane/diethyl ether). The
enantiomeric excess of the products 3 was determined by HPLC analysis
on a chiral stationary phase.
Supporting Information
Additional experimental details, control experiments and product
characterization can be found in the Supporting Information.
[12] Y Liu, X. Xi, C. Ye, T. Gong, Z. Yang, Y. Cui, Angew. Chem. Int. Ed. 2014,
53, 13821; Angew. Chem. 2014, 126, 14041; b) J. Gao, J. Liu, S. Bai, P.
Wang, H. Zhong, Q. Yang, C. Li, J. Mater. Chem. 2009, 19, 8580; c) N.
Haraguchi, Y. Takemura, S. Itsuno, Tetrahedron Lett. 2010, 51, 1205; d)
S. Luo, J. Li, H. Xu, L. Zhang, J.-P. Cheng, Org. Lett. 2007, 9, 3675; e)
J. Li, S. Hu, S. Luo, J.-P. Cheng, Eur. J. Org.Chem. 2009, 132; f) J. Li,
S. Luo, J.-P. Cheng, J. Org. Chem. 2009, 74, 1747; g) J. Li, X. Li, P. Zhou,
L. Zhang, S. Luo, J.-P. Cheng, Eur. J. Org. Chem. 2009, 4486; h) S. Luo,
J. Li, L. Zhang, H. Xu, J.-P. Cheng, Chem. Eur. J. 2008, 14, 1273; i) X.
Zheng, L. Zhang, J. Li, S. Luo, J.-P. Cheng, Chem. Commun. 2011, 47,
12325.
Acknowledgements
This work was co-funded through a SINCHEM Grant. SINCHEM
is a Joint Doctorate programme selected under the Erasmus
Mundus Action 1 Programme (FPA 2013-037). We thank Prof.
Ennio Vanoli and Prof. Roger Marti (Haute Ecole d’Ingénierie et
d’Architecture, Fribourg, CH) for stimulating discussions.
[13] A. Haug, B. Larsen, Acta Chem. Scand. 1961, 15, 1395.
[14] L. Zhang, S. Luo, J.-P. Cheng, Catal. Sci. Technol. 2011, 1, 507.
[15] a) F. Peng, Z. Shao, J. Mol. Catal. 2008, 285, 1; b) Y.-C. Chen, Synlett
2008, 1919; c) G. Bartoli, P. Melchiorre, Synlett 2008, 1759; d) L. Jiang,
Y.-C. Chen, Catal. Sci. Technol. 2011, 1, 354; e) L. W. Xu, J. Luo, Y. Lu,
Chem. Commun. 2009, 1807; f) P. Melchiorre, Angew. Chem. Int. Ed.
2012, 51, 9748; Angew. Chem. 2012, 124, 9886.
Keywords: Alginate • Asymmetric Synthesis • Heterogeneous
Catalysis • Organocatalysis • Renewable Resources
[1]
[2]
A. M. Stephen, Food Polysaccharides and Their Applications, CRC
Press, New York, 1995.
a) K. I. Draget, O. Smidsrød, G. Skjåk-Bræk, Alginates from Algae in
Biopolymers Online, (Ed.: A. Steinbüchel), Wiley-VCH, 2005; b) F.
Quignard, R. Valentin, F. Di Renzo, New. J. Chem. 2008, 32, 1300; c) F.
Quignard, F. Di Renzo, E. Guibal, Top. Curr. Chem. 2010, 294, 165; d)
S. Zhao, W. J. Malfait, N. Guerrero-Alburquerque, M. M. Koebel, G.
Nyrström, Angew. Chem. Int. Ed. 2018, 57, 7580; Angew. Chem. 2018,
130, 7704.
[16] For examples of heterogenization of QNA by covalent linkage to various
supports, see: a) J. Izquierdo, C. Ayats, A. H. Henselera, M. A. Pericàs,
Org. Biomol. Chem. 2015, 13, 4204; b) K. A. Fredriksen, T. E. Kristensen,
T. Hansen, Beilstein J. Org. Chem. 2012, 8, 1126; c) R. Porta, M.
Benaglia, F. Coccia, F. Cozzi, A. Puglisi, Adv. Synth. Catal. 2015, 357,
377; d) J. Zhou, J. Wan, X. Ma, W. Wang, Org. Biomol. Chem. 2012, 10,
4179; e) R. Porta, F. Coccia, R. Annunziata, A. Puglisi, ChemCatChem
2015, 7, 1490; f) A. Ciogli, D. Capitani, N. Di Iorio, S. Crotti, G. Bencivenni,
M. P. Donzello, C. Villani, Eur. J. Org. Chem. 2019, 2020; for a related
cinhonidine catalyst, see: g) W. Wang, X. Ma, J. Wan, J. Cao, Q. Tang,
Dalton Trans. 2012, 41, 5715.
[3]
[4]
a) N. Velings, M. M. Mestdagh, Polym. Gels Networks 1995, 3, 311; b)
C. Ouverx, N. Velings, M. M. Mestdagh, M. A. V. Axelos, Polym. Gels
Networks 1998, 6, 393.
O. Smidrød, Faraday Discuss. Chem. Soc. 1974, 57, 263.
[17] S. H. McCooey, S. J. Connon, Org Lett. 2007, 9, 599.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
[18] E. D. T. Atkins, W. Mackie, K. D. Parker, E. E. Smolko, J. Polym. Sci.
Part B: Polym. Lett. 1971, 9, 311.
2018, 47, 2722; d) F. Rodríguez-Llansola, B. Escuder, J. F. Miravet, J.
Am. Chem. Soc. 2009, 131, 11478; e) C. Vignatti, J. Luis-Barrera, V.
Guillerm, I. Imaz, R. Mas-Ballesté, J. Alemán, D. Maspoch,
ChemCatChem, 2018, 10, 3995; f) F. Rodríguez-Llansola, J. F. Miravet,
B. Escuder, Chem. Eur. J. 2010, 16, 8480; g) Gy. Szőllősi, D. Gombkötő,
A. Z. Mogyorós, F. Fülöp, Adv. Synth. Catal. 2018, 360, 1992; h) W. Fang,
Y. Zhang, J. Wu, C. Liu, H. Zhu, T. Tu, Chem. Asian J. 2018, 13, 712; i)
P. Slavík, D. W. Kurka, D. K. Smith, Chem. Sci. 2018, 9, 8673; j) B.
Escuder, F. Rodríguez-Llansola, J. F. Miravet, New J. Chem. 2010, 34,
1044.
[19] Using a weaker alginic acid material, derived from mannurate-rich
alginate (G/M 33:67), gave gel disruption even when 100% ethanol was
used in the adsorption.
[20] W. Qin, A. Vozza, A. M. Brouwer, J. Phys. Chem. C 2009, 113, 11790.
[21] AG-Ca gels are reticulated by the cation, contrarily to the acidic AG-H
where gels are obtained by precipitation.
[22] R. Valentin, K. Molvinger, C. Viton, A. Domard, F. Quignard,
Biomacromol. 2006, 6, 2785.
[23] A. Haug, O. Smidrød, Acta Chem. Scand. 1970, 24, 843.
[24] Attempts to use ketones (acetone, cyclohexanone) in the reaction with
2a were not successful: the more drastic reaction conditions (>80 °C, >48
h) required with these donors gave a significant catalyst leaching, as
shown by Sheldon tests.
[26] 9-Amino-9-deoxy epi-quinine (QNA) was prepared according to: a) Y.
Wang, K. L. Milikiewicz, M. L. Kaufman, L. He, N. G. Landmesser, D. V.
Levy, S. P. Allwein, M. A. Christie, M. A. Olsen, C. J. Nelville, K.
Muthukumaran, Org. Process Res. Develop. 2017, 21, 408; and purified
as tri-hydrochloride salt according to: b) C. Cassani, R. Martín-Rapún, E.
Arceo, F. Bravo, P. Melchiorre, Nat. Protoc. 2013, 8, 325.
[25] For useful references, see: a) D. Díaz Díaz, D. Kühbeck, R J. Koopmans,
Chem. Soc. Rev. 2011, 40, 427; b) E.-M. Schön, E. Marquéz-López, R.
P. Herrera, C. Alemán, D. Díaz Díaz, Chem. Eur. J. 2014, 20, 10720; c)
B. Altava, M. I. Burguete, E. García-Verdugo, S. V. Luis, Chem. Soc. Rev.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900247
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Gel catalyst. An organic catalyst
derived from quinine can be adsorbed
on alginate gels with a simple
protocol. The resulting solvogel beads
are competent and highly
Daniel Antonio Aguilera, Lisa Spinozzi
Di Sante, Asja Pettignano, Riccardo
Riccioli, Joël Roeske, Luce Albergati,
Vasco Corti, Mariafrancesca Fochi, Luca
Bernardi,* Françoise Quignard, Nathalie
Tanchoux*
stereoselective catalysts for an
asymmetric Michael reaction.
Page No. – Page No.
Adsorption of a Chiral Amine on
Alginate Gel Beads and Evaluation of
its Efficiency as Heterogeneous
Enantioselective Catalyst
This article is protected by copyright. All rights reserved.