Evaluation of the nitroaldol reaction in the presence of metal ion-crosslinked alginates

Article abstract of DOI:10.1039/c4nj02178a

Understanding the ability of biopolymers to promote selective C-C bond formation could provide important insights into the molecular mechanisms underlying evolution, and could help in the design of safer and "greener" catalysts in the future. This work de

Full text of DOI:10.1039/c4nj02178a

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Evaluation of the Nitroaldol Reaction in the Presence of
Metal IonꢀCrosslinked Alginates
a
a
a
Dennis Kühbeck, ‡ Judith Mayr, ‡ Marleen Häring,‡ Martin Hofmann,a Françoise Quignardb and David
Díaz Díaz*,a,c
a Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg,
Germany. b Institut Charles Gerhardt MontpellierꢀUMR 5253 CNRSꢀUMIIꢀENSCMꢀUMI, Matériaux
Avancés pour la Catalyse et la Santé, 8 rue de l'École Normale, 34296 Montpellier Cedex 5, France. c
IQACꢀCSIC, Jordi Girona 18ꢀ26, 08034 Barcelona, Spain
David Díaz Díaz: david.diaz@chemie.uniꢀregensburg.de
‡ These authors contributed equally to this work
Abstract
Understanding the ability of biopolymers to promote selective C−C bond formation could bring
important insights into the molecular mechanisms underlying evolution, and could help to design safer
and “greener” catalysts in the future. This work describes the preparation of metal ionꢀcrosslinked
alginate materials and the evaluation of their potential catalytic activity towards the Henry (nitroaldol)
reaction between a variety of aldehydes and nitroalkanes. The results demonstrated broad substrate
specificity and a remarkable influence of the solvent nature, metal ion, and physical state of the alginateꢀ
based catalysts. In this sense, the use of Ca2+ꢀalginate hydrogel beads in DMSO as heterogeneous and
recyclable catalyst was found to be the most efficient system, although the reaction can proceed also in
aqueous medium. Moreover, both small and largeꢀscale model reactions between 4ꢀnitrobenzaldehyde
and nitromethane were performed successfully at room temperature. The possibility to couple the
reaction with an enzymatic resolution of the soꢀobtained βꢀnitroalcohol products was also assessed. All
materials were characterized by different techniques including, among others, FTꢀIR, TGA, ICPꢀOES,
and FEꢀSEM.
Keywords: Alginate, biopolymers, C−C bond formation, hydrogel, Henry (nitroaldol) reaction.
1

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Introduction
The gradual shift from the utilization of petrochemicalꢀbased feedstocks to inexpensive ecoꢀfriendly
resources and sustainable processes is the unavoidable consequence of the growing concern for the
environment and the stricter regulations of toxic pollutants.1 In this context, the use of biopolymers have
attracted increasing attention during the last decade for numerous applications in different industries
including, among others, automotive, construction, textile, agriculture, optoelectronics, defense,
foodstuffs, health care, biomedical and pharmaceuticals products.2 More recently, the study of natural
polysaccharides as promising supports for heterogeneous catalysis has become a key research topic due
to the unique properties of many of these materials (e.g., unlimited availability as renewable agroꢀ
resources, nonꢀtoxicity, biodegradability, insolubility in most organic solvents, high binding ability for
selected metals, excellent mechanical strength, intrinsic presence of different chemical functionalities
such as amino, hydroxy, or carboxy groups).3 Moreover, the processability and malleability of
polysaccharides allows for the preparation of materials with different shapes and morphologies that
would be most suitable for a particular application. This property turns out to be even more relevant if
we consider that the physical state of several biopolymers plays a significant role in the kinetics of C−C
bond forming reactions, which have a central importance in modern chemistry and are ultimately a
requirement for all life on earth.4ꢀ7
Among the most abundant polysaccharides, alginates are interesting anionic polymers isolated from
brown algae that have been widely applied in drug delivery,8 entrapment of bioactive molecules,8,9 and
as supports in biocatalysis.10ꢀ14 These biopolymers are linear, unbranched block copolymers of (1→4)ꢀ
linked
βꢀDꢀmannuronate (M) and αꢀLꢀguluronate (G) monomers that are organized in blocks (i.e.,
containing (M)m, (G)n, and (M,G)x sequences) along the polymer chain (Figure 1). One of the biggest
advantages of alginates is that their solutions (monovalent metal ions form soluble salts) can readily
form strong hydrogels with water content > 95% upon metal exchange with many divalent or
multivalent cations, especially Ca2+ (a borderline Lewis acid).15 This property is at the core of their
natural function as waterꢀstorage agents in living organisms, as well as of their main applications as
immobilization supports and food thickening agents.16 The 3D network hydrophilic structure of these
gels has been described by the soꢀcalled “eggꢀbox” model where each calcium atom is coordinated to
the carboxylates and hydroxyl groups of four G monomers from two adjacent chains of the polymers
(Figure 1).17,18 The properties of alginate gels are highly influenced by the ratio and sequencing of
uronic monomers,19 concentration of metal ions, and maturation time.20 Importantly, the mechanical
2

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strength of the hydrogels can be tuned by the monomers ratio allowing easy handling into different
shapes (e.g., beads, tubes, membranes).
Figure 1. Structure of the repeating units of sodium alginate (pKa of carboxylic groups ∼ 3−4), and formation of
hydrogel by coordination of Ca2+ cations between adjacent alginate chains as per the “eggꢀbox” model.
The overall potential of metalꢀalginate complexes in the broad field of nonꢀenzymatic heterogeneous
catalysis has been only scarcely explored during the last decade.21 In 2005, Quignard’s lab reported the
effectiveness of Pd(TPPTS)3 complex immobilized on alginate aerogel microspheres as supported
catalyst for the allylic substitution of methylꢀallylcarbonate with morpholine.22 A few years later, Reddy
and his group described the immobilization of Cu2+ ions on alginate gel beads, and their activity towards
both the regioselective 1,3ꢀcycloaddition of alkynes and azides, and the oxidative coupling of 2ꢀ
naphthols and phenols in aqueous medium.23 In 2011, Guibal and coꢀworkers described the use of Pd
supported on alginate/ionic liquid porous monoliths for the hydrogenation of 4ꢀnitroaniline in the
presence of either sodium formate or formic acid as hydrogen donor.24 At the same time, Fe3+ꢀalginate
gel beads were successfully used for the oxidative degradation of azo dyes under visible light
irradiation.25 In 2012, Oudeyer, Dez and coꢀworkers published the catalytic activity of metal or
ammonium alginates in the 1,2ꢀaddition of silyl nucleophiles to carbonyl compounds.26 Quignard’s
group also reported the synthesis of bimetallic alginate aerogels, obtained upon partial exchange of
metal cations with Pd2+, followed by their reduction into Pdꢀnanoparticles, and their excellent catalytic
activity towards SuzukiꢀMiyaura crossꢀcoupling reaction.27 Shi and coꢀworkers also reported the
catalytic activity of binary CuꢀPdꢀalginate dry beads for hydroxylation of phenol.28 Finally, Agꢀ
3

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nanoparticles immobilized on alginate hydrogels have shown good performance in the 4ꢀnitrophenol
reduction.29ꢀ31
The objective of the present study was to perform a critical assessment of the potential ability of
crosslinked monometalꢀalginates complexes to mediate the Henry (nitroaldol) reaction, one of the most
important methods for the formation of C−C bonds.32
Results and discussion
Preparation of Mn+-crosslinked alginate hydrogel beads. A library of different metalꢀion crosslinked
AHG beads was prepared according to the aboveꢀdescribed procedure by using six gelling metals (i.e.,
Ca2+, Cu2+, Co2+, Ni2+, Zn2+ and Fe3+).21,23 In all cases, metal chloride salts were used in order to avoid
any possible catalytic activity caused by other counter ions (e.g., OHꢀ if metal hydroxy salts would be
used) entrapped in the gel matrix.4 The setꢀup used for the preparation of the Mn+ꢀAHG beads at room
temperature is shown in Figure 2. The viscous alginate aqueous solution (2% w/v, ca. neutral pH) was
added dropwise via a dropping funnel to a beaker containing an aqueous solution (0.24 M, ca. neutral
pH) of the corresponding metal chloride. In order to obtain uniform spherical beads, with an average
diameter in the range of 3.6−4.9 mm, the dropping rate (0.5−3 drops per second) and the distance
between the tip of the dropping funnel and the surface of the metalꢀcontaining solution (0.5−2.5 cm)
was slightly adjusted in each case (Table S2). The obtained beads were matured over night at room
temperature in the gelling solution. After this time, the beads were filtered off and washed meticulously
with distilled water to remove the excess of metal cations and counter anions. The metal content of the
crosslinked hydrogel beads were determined by inductively coupled plasma optical emission
spectrometry (ICPꢀOES). A slight increase in the metal loading with increasing diameter was quantified
(Figure S1).
The FTꢀIR spectra of the AHG beads showed the expected absorption bands at 1597 cmꢀ1 and 1411
cmꢀ1 (asymmetric and symmetric stretching bands of the carboxylate functional groups, respectively), as
well as the typical bands for polysaccharides between 1176 and 1028 cmꢀ1 (C−O, C−C, and C−O−H
stretching absorptions). In general, the presence of the divalent/trivalent metal ions in the AHG beads
had no major impact on the main vibration modes of the starting sodium alginate. The broad bands
observed between 3379 and 3076 cmꢀ1 correspond to the stretching vibrations of the –OH functional
groups (Figure S4 – S6).33
4

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Figure 2. A) Setꢀup used for the preparation of Mn+ꢀcrosslinked alginate hydrogel beads. The dropping funnel is
charged with sodium alginate solution (2% w/v), and the beaker with aqueous solution (0.24 M) of the
corresponding metal salt (CoCl2 × 6 H2O was used here to illustrate the process). B) Formation of Co2+ꢀAHG
beads upon coagulation. C) Isolated Co2+ꢀAHG beads. D) Single Co2+ꢀAHG bead (∅ = 4 ± 0.2 mm). E) Ca2+ꢀ
AHG beads obtained using the same procedure and CaCl2 as metal salt.
TGA thermograms of the alginateꢀbased xerogel materials showed a typical gradual weight loss below
100 ºC attributed to the vaporization of adsorbed moisture and lactonization.34 A major and rapid weight
loss starting around 200 ºC can be associated to polymer decomposition via decarboxylation, whereas
further weight loss above 280 ºC is usually ascribed to the degradation of the alginate backbone and
cleavage of numerous hydroxyl groups (Figure S7).35 In agreement with previous studies, a trend of
stability in the interval between 200 ºC and 300 °C could be observed in function of the metal ion (i.e.,
stability increases in the order Fe3+ (lowest stability) < Cu2+ < Na+ < Ni2+ ≈ Co2+ ≈ Zn2+ ≈ Ca2+).36
As part of the materials characterization, SEM images of the xerogels showed porous surfaces with
roughꢀveined structures of high aspect ratios, in contrast to the amorphous structure of commercially
powdered sodium alginate (Figure S10). Although the method used to prepare the xerogels (i.e., airꢀ
drying, freezeꢀdrying) has a clear impact on the observed morphologies,21 the changes were consistent in
all samples (Figure 3). This heterogeneous surface structure of the beads could favor the adsorption of
small molecules presented in the medium via electrostatic, hydrogen bonding, and/or van der Waals
5
interactions. In addition, pore size distribution of these materials are affected in function of the metal

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ion.36 However, the catalytic activity of these materials with different metal ions is lDikOeI:l1y0.1r0e3l9a/Cte4NdJ0to217t8hAe
exact structure of the coordination complexes, which is out of the scope of this manuscript and will
constitute the focus of future studies.
Figure 3. SEM images of different Mn+ꢀalginateꢀbased xerogel materials. Pictures in the same row correspond to
the same metal (left). Xerogels were obtained after either airꢀdrying (left and middle columns) or freezeꢀdrying
(right column) the corresponding Mn+ꢀAHG beads.
6

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Participation of alginate materials in the Henry (nitroaldol) reaction. The Henry reaction, also
called nitroaldol reaction, between nitroalkanes and carbonyl compounds (i.e., aldehydes, ketones) in
the presence of an ionic or nonꢀionic base catalyst is a classical and highly valuable synthetic route to βꢀ
nitroalcohols.32,37 From a mechanistic point of view, the selectivity of the reaction with aromatic
aldehydes is highly influenced by the electron donating/accepting nature of the substituents and their
ability to favor either the ionꢀpair or imine mechanism in the presence of a base.32 Moreover,
enantioselective Henry reactions under dual Lewis acid/amine catalysis have been also reported.38 The
practical importance of the nitroaldol reaction in organic synthesis is supported by the fact that
βꢀ
nitroalcohols are precursors of the important building blocks (e.g., nitroalkenes, ꢀnitroketones, 1,2ꢀ
α
amino alcohols), which are frequently found in numerous pharmaceuticals.39ꢀ42 Nevertheless, a major
shortcoming of this reaction is the formation of several byꢀproducts (e.g., polymerizable nitroalkenes
formed by dehydration of
Cannizaro or Nef reaction) that can complicate the isolation of the desired molecules.32 Therefore, there
is a fundamental interest in the development of “green” processes that can yield selectively the
βꢀnitroalcohols, epimerized products, compounds derived either from
β
ꢀ
nitroalcohols. Among numerous reports dealing with metalꢀcatalyzed43 and organocatalyzedꢀHenry
reactions,44 the solidꢀstate condensation of carbonyl compounds with active methylene compounds in
the presence of lithium bromide as a mild Lewis acid catalyst has also been described.45
Taking everything into consideration, as well as the fact that calcium is one of the cheapest
commercially available metals, the fifth mostꢀabundant element in earth’s crust, and nonꢀtoxic,46,47 we
decided to investigate the ability of Ca2+ꢀcontaining alginate biohydrogels to promote the Henry
reaction. In preliminary experiments with the model reaction between 4ꢀnitrobenzaldehyde (1a) and
nitromethane (2a), we were delighted to observe the gradual formation of the desired βꢀnitroalcohol 3a
in the presence of Ca2+ꢀAHG beads under mild conditions (DMSO, room temperature). Initial
optimization studies revealed that 10 equivalents of 2a and one Ca2+ꢀAHG bead were necessary to drive
the reaction to completion within 24 h (Table S1). It is worth mentioning that the use of 6 mol% of
CaCl2 instead of Ca2+ꢀAHG did not promoted the Henry reaction (i.e., 0% yield of the desired product
was observed after 24 h). Although the Henry reaction is simple to carry out, the elucidation of the
underlying mechanisms under different conditions is always interesting. In the case of Ca2+ꢀAHG a
plausible mechanism would involve the carboxylate groups as moderately basic charged ligands and the
metallic centers as Lewis acids that activate the nitroalkane towards deprotonation, similarly to the
mode of action of copper acetateꢀbis(oxazolines).48,49 Carboxylic acid moieties and/or nitromethane
molecules (used in large excess with respect to the aldehyde) could participate in the protonation step
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of the alcoholate intermediate (Figure S9). In such dualꢀactivation mechanism, the DeOmI: 1b0e.1d03m9/eCn4NtJo02f17t8hAe
metal center in the biopolymer matrix could cause a shielding effect preventing the assembly of a highly
ordered transition state,49 which could explain the observed lack of enantioselectivity.
Table 1 outlines the results of solvent screening for the Ca2+ꢀAHGꢀpromoted Henry reaction. The best
results were achieved in DMSO (> 99% conversion, 88% yield) (entry 1), where the control experiment
in the absence of Ca2+ꢀAHG showed no conversion. On the other hand, only 16% yield could be
achieved in H2O (entry 3), although the addition of a phase transfer additive such as TBAB increased
the yield by almost three times (entry 4). Nevertheless, in sharp contrast to DMSO, the background
reaction (control in the absence of catalyst) in H2O/TBAB system was ca. 6%. Low yields were
observed in EtOH (entry 5), whereas only traces or no product could be detected when the reaction was
carried out in CH3CN, THF, CH2Cl2 or toluene (entries 6ꢀ7). Interestingly, the reaction was able to
tolerate the presence of one of these solvents well if combined with DMSO in a specific ratio (i.e.,
DMSO/toluene 3:1 (v/v), Table S7) (entry 2). Unfortunately, unambiguous correlations between solvent
properties and reaction kinetics could not be drawn at this point (Table S10), suggesting the existence of
a complex relationship between these parameters.
Table 1. Solvent screening study of Ca2+ꢀAHGꢀpromoted Henry reactiona
entry
solvent
yield 3a (%)b
1
2
3
4
5
6
7
DMSO
DMSO/toluened
88 (0c)
83
H2O
16 (< 2c)
44 (6c)
9
H2O/TBABe
EtOH
CH3CN, THF
CH2Cl2, toluene
< 2
0
a
Reaction conditions: 4ꢀNitrobenzaldehyde (1a, 0.1 mmol), nitromethane (2a, 1.0 mmol), Ca2+ꢀAHG bead (1
b
1
bead, ca. 5 mol% of metal with respect to 1a), solvent (0.5 mL), room temperature, 24 h. Determined by H
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NMR analysis of the crude product (9.2 ꢀL of DMA was used as internal standard). Reported values correspond
c
to the average values of at least two independent experiments (STDV = ± 2). Control experiment made in the
absence of Ca2+ꢀAHG bead. d DMSO/toluene ratio = 3:1 (v/v). e Tetraꢀnꢀbutylammonium bromide (0.04 mmol).
In terms of kinetics, the rate of the Ca2+ꢀAHG beadsꢀcatalyzed Henry reaction (Figure 4) was found to
be slower than standard base catalysts such as Et3N, but comparable to other metalꢀcatalyzed reactions
(Table S9). At this point, we hypothesized that lowꢀmolecularꢀweight calcium alkyl carboxylates should
also mediate the formation of βꢀnitroalcohols in good yields under the studied conditions. Indeed, when
the model reaction between 1a and 2a in DMSO was carried out in the presence of soluble calcium 2ꢀ
ethylhexanoate (ca. 2.1 mol%), a wellꢀestablished catalyst for homogeneous industrial polymerizations,
the desired βꢀnitroalcohol 3a was formed in 90% yield within 3 h (Table S3). Despite higher catalytic
activity of calcium 2ꢀethylhexanoate in comparison to Ca2+ꢀAHG beads, heterogeneity and recyclability
are sacrificed in the former case. In addition, and in agreement with the corresponding MSDS, both
calcium 2ꢀethylhexanoate and its dissociation product (i.e., 2ꢀethylhexanoic acid) are known to be
irritating agents to eyes, respiratory system, and skin.
Figure 4. Kinetics analysis of the Ca2+ꢀAHGꢀpromoted Henry reaction between 4ꢀnitrobenzaldehyde (1a) and
nitromethane (2a) as described in Table 1. Each data point represents the average of at least two independent
measurements. C∞ = final concentration at infinite time; Ct = concentration at given time t; C0 = initial
concentration at t = zero time. Apparent rate constant, k = 0.113 ± 0.04 hꢀ1. Inset: Characteristic signal of the
benzylic proton in the 1H NMR spectrum of the
βꢀnitroalcohol product.
Equally importantly from a practical perspective, the scaleꢀup of the target model reaction from 0.1
mmol to 7.5 mmol (1.13 g) of 1a also lead satisfactorily to the formation of 3a with an isolated yield of
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82%. With these results in hand, we chose the model reaction between 1a and 2a inDDOIM: 10S.1O039f/Co4rNfJ0u2r1t7h8Aer
investigations.
Considering the differences in the Lewis acid character of each metal, as well as the fact that both
morphology and porosity of the hydrogel networks are different depending on the metal center,50 we
expected to observe a major effect of the metal nature on the kinetics of the Mn+ꢀAHG beadsꢀcatalyzed
Henry reaction.2,3 Table 2 summarizes the results of this investigation using ca. 4 ± 1 mol% of metal
catalyst with respect to the aldehyde (ESI). The best result was achieved with Ca2+ꢀAHG beads (88%
yield, Table 2, entry 1), although modest yields between 50–60% could be also obtained with Co2+ꢀ
AHG (entry 3) and Ni2+ꢀAHG beads (entry 4). Zn2+ꢀAHG beads afforded the corresponding
βꢀ
nitroalcohol 3a, albeit in lower yields (entry 5), whereas the use of Cu2+ꢀAHG and Fe3+ꢀAHG provided
the desired product in very poor yields (entries 2 and 6 respectively). It is noteworthy that all hydrogel
beads, except Fe3+ꢀAHG, remained physically stable under the reaction conditions without visual
deterioration. It should be noted, however, that further detailed studies by electron microscopy are
necessary in order to precisely evaluate any morphological change of the hydrogels caused by their
immersion into different solvents. Although we have not carried out experiments in order to improve the
lower yields, it is expected that extension of the reaction time and/or slight increase of the temperature
could increase them.7
On the other hand, negligible enantioselectivities (ee ≤ 5%) were detected in all the experiments
(ESI), indicating that the reaction is not sensitive under the reported conditions to the primary chirality
of the polysaccharide backbone or to a possible secondary chirality due to the formation of a helical
conformation upon metal coordination. In general, the lack of enantioselectivity has been also reported
with other catalysts and biocatalysts bearing intrinsic chirality.4,5,51ꢀ53 Moreover, we found that the use
of DMSO as solvent could also frustrate, at least to a certain extent, the formation of highly ordered
transition states necessary to induce stereoselectivity in the Henry reaction. We corroborated this
statement when we run the model reaction in the presence of 2,2ꢀbis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane) as chiral ligand in combination with Cu(OAc)2 × H2O (the ligand was
synthesized as previously reported and displayed the expected spectroscopic data48). In agreement with
previous observations, the bisoxazoline complex showed a significant enantioselectivity (ca. 65% ee) in
MeOH,49 whereas only the racemic product could be isolated in DMSO.
Table 2. Influence of the metal ion in Mn+ꢀAHGꢀpromoted Henry reactiona
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entry
catalyst
yield 3a (%)b
1
2
3
4
5
6
Ca2+ꢀAHG
Cu2+ꢀAHG
Co2+ꢀAHG
Ni2+ꢀAHG
Zn2+ꢀAHG
Fe3+ꢀAHG
88
4
50
59
36
5c
a Reaction conditions: 4ꢀNitrobenzaldehyde (1a, 0.1 mmol), nitromethane (2a, 1.0 mmol), Mn+ꢀAHG (1 bead, 4 ±
b
1
1 mol% of metal with respect to 1a), DSMO (0.5 mL), room temperature, 24 h. Determined by H NMR
analysis of the crude product (9.2 ꢀL of DMA was used as internal standard). Reported values correspond to the
c
average values of at least two independent experiments (STDV = ± 2). Fe3+ꢀAHG bead was not stable and
underwent severe fragmentation during the reaction.
During our previous research regarding the intrinsic catalytic activity of biopolymers and proteins, we
have established that the morphology and/or physical state of the biocatalyst plays an important role in
the kinetics of aldolꢀlike reactions under heterogeneous or semiꢀheterogeneous conditions.2,3 Therefore,
we decided to carry out here a comparative evaluation of the model reaction between 1a and 2a using
different forms of the catalyst in DMSO at room temperature (Table 3). In sharp contrast with the
hydrogel form of the catalyst (entry 1), the xerogels obtained either by freezeꢀdrying (entry 2) or airꢀ
drying (entry 3) the corresponding Ca2+ꢀAHG beads afforded the desired product in very poor yields (<
5%) (Tables S5−S6). Considering the measured water content of the hydrogel beads (i.e., 434 ꢀL per
bead), we carried out another control experiment using the freezeꢀdried form of the catalyst in
combination with the amount of water held in the hydrogel form (entry 4). However, only a slight
improvement could be achieved (i.e., 14% yield of the desired product). This slight positive effect could
be also observed when using commercial available sodium alginate powder (Na+ꢀAP) as catalyst.
Specifically, when the model reaction was run using 0.4 mg of Na+ꢀAP (ca. 2.1 mol%)54 in DMSO, the
desired product was formed in only 6% yield. However, the addition of 434 ꢀL of H2O to the reaction
containing Na+ꢀAP increased the product yield until 13%. Herein, the control reaction performed in
DMSO + H2O (434 ꢀL) in the absence of Na+ꢀAP provided null conversion. Considering the
amorphous microstructure of Na+ꢀAP (Figure S10), the modest positive effect caused by the addition
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of H2O could also be attributed to its potential role as plastifier of polysaccharides, increasing the
accessibility to amorphous domains.22 Moreover, the direct use of commercial amorphous calcium
alginate powder resulted in very poor yields (entry 5).
In general, the aforeꢀdescribed results suggest that the characteristics of the hydrogel play also an
important role in the Henry reaction under the described conditions. In general, catalysts with spongyꢀ
like and roughꢀveined microstructures showed higher activities than those with closed and agglomerated
surfaces where the molecular adsorption is disfavored (Figures 3 and S9). Last but not least, the use of
the mesoporous aerogel form of the catalyst (Table 3, entry 6), prepared by supercritical CO2 drying
(see Experimental Section), provided only slightly superior yields and kinetics (Figure S3 and Table S8)
in comparison to the Ca2+ꢀAHG beads of lower surface area, albeit without significant enantioselectivity
(ee ≈ 6%). Overall, these results suggest the existence of a complex reaction mechanism involving both
diffusionꢀcontrolled processes and surface reactivity. Evidences of surface reactivity instead of
nanoreactor55ꢀ58 activity were also obtained from further experiments where the reactive contact surface
area of the hydrogel beads was modified (Figure S8).
Table 3. Influence of the physical state of Mn+ꢀAHG in the catalyzed Henry reactiona
entry
catalyst
yield 3a (%)b
1
2
3
4
5
6
Ca2+ꢀAHG
Ca2+ꢀAHFDc
Ca2+ꢀAHADd
Ca2+ꢀAHFGe
Ca2+ꢀAPf
88
4
1
14
4
Ca2+ꢀAAGg
89
a Reaction conditions: 4ꢀNitrobenzaldehyde (1a, 0.1 mmol), nitromethane (2a, 1.0 mmol), catalyst (1 bead, ca. 5
mol% of metal with respect to 1a), DMSO (0.5 mL), room temperature, 24 h. b Determined by 1H NMR analysis
of the crude product (9.2 ꢀL of DMA was used as internal standard). Reported values correspond to the average
values of at least two independent experiments (STDV = ± 2). c Freezeꢀdried form of the alginate hydrogel bead. d
Airꢀdried form of the alginate hydrogel bead. The average volume of the obtained xerogel beads was ca. 3% of
e
the average volume of the hydrogel beads. Freezeꢀdried form of the alginate hydrogel bead and 434 ꢀL of
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f
g
H2O. Commercial powder calcium alginate (1 mg). Alginate aerogel bead prepared from the corresponding
hydrogel bead as described in the experimental section.
At this point we explored the substrate scope of the Ca2+ꢀAHGꢀpromoted Henry reaction in DMSO at
room temperature (Table 4). In general, aromatic aldehydes with moderate or strong electronꢀ
withdrawing groups were converted selectively into the corresponding
βꢀnitroalcohols in very good
yields (entries 1–6), and without a dramatic effect of the position of the substituents in 1 (entries 1–3).
Aromatic aldehydes with weak electronꢀwithdrawing groups could be converted into the desired
products, albeit with lower yields (entries 8–10). However, both benzaldehyde and 4ꢀ
methylbenzaldehyde were poorly converted (entries 7 and 11). Remarkably, also heteroaromatic
systems such as 2ꢀpyridinecarboxaldehyde led to 50% yield (entry 12). In contrast, aliphatic aldehydes
could not be converted into the desired product. On the other hand, similar results were obtained when
using either nitromethane (2, pKa = 10.2)59 or nitroethane (4, pKa = 8.6)59 as nucleophiles (entries 2, 6,
10). Therefore, neither the size nor the pKa of the carbanion plays a major role on the outcome of the
reaction. Although the diastereoselectivity (anti/syn ratio) observed in the Ca2+ꢀAHGꢀcatalyzed
reactions with 4 was minor, an interesting trend towards the syn isomer was noticed, which was in
contrast to the outcome of the control experiment where the anti isomer was favored.
Table 4. Substrate scope of the Ca2+ꢀAHGꢀcatalyzed Henry reaction in DMSOa
entry R1CHO
1
R2
H
yield 3 (%)b
88 (0d)
drc
NA
2
3
CH3
H
91 (6d)
86
1:1.3
(1.4:1d)
NA
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4
H
83
NA
5
6
H
91
91
NA
CH3
1:1.3
7
8
H
H
7
NA
NA
32
9
H
18
40
3
NA
10
11
CH3
H
1:1.2
NA
12
H
50
NA
a
Reaction conditions: aldehyde (1, 0.1 mmol), nitroalkane (2, 1.0 mmol), DMSO (0.5 mL), Ca2+ꢀAHG (1 bead,
ca. 5 mol% of metal with respect to aldehyde), room temperature, 24 h. b Determined by 1H NMR analysis of the
crude product. Reported values correspond to the average values of at least two independent experiments (STDV
c
1
d
= ± 3). Diastereomeric ratio (anti/syn) determined by H NMR analysis. NA = Not applicable. Control
experiment performed in the absence of Ca2+ꢀAHG.
Regarding recyclability, Ca2+ꢀAHG beads could be reused at least three times without significant loss
of activity. However, a gradual deactivation was detected after the 3rd cycle (Figure 5A). In agreement
with previous reports, blocking of the catalyst surface by aldehyde molecules,26 poisoning of the
polysaccharide backbone,27 or textural instability22 under the reaction conditions could be responsible
of the observed activity loss
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Figure 5. A) Typical recycling experiment for the Ca2+ꢀAHGꢀpromoted Henry reaction. Reaction conditions: 4ꢀ
Nitrobenzaldehyde (15.1 mg, 0.1 mmol), nitromethane (54 ꢀL, 1.0 mmol), DMSO (0.5 mL), Ca2+ꢀAHG (1 bead),
room temperature, 24 h. B) Control experiment showing the stagnation point of the reaction (green circles) upon
removal of the catalyst (red squares).
Additional control experiments highlighted the heterogeneous nature of the process catalyzed by the
Ca2+ꢀbiohydrogels. For example, one Ca2+ꢀAHG bead was matured for 24 h in DMSO without
substrates, filtered off, and reused in a new mixture including the substrates of the model reaction. In
this case the yields were almost identical to those obtained using freshly prepared Ca2+ꢀAHG beads. A
negligible catalytic effect caused by possible leaching of metal ions was demonstrated by nearly null
catalytic activity (≤ 2% yield) of (1) the maturing solution obtained from the previous experiment or
after a catalytic cycle, and (2) a stock solution containing the maximum theoretically possible leaching
for a given bead (this solution was used as potential catalyst instead of the corresponding Mn+ꢀAHG
bead – i.e., 7.14 mM CoCl2 × 6 H2O solution for M = Co – Table S3). As expected, stagnation of the
reaction after removal of the catalyst was observed (Figure 5B).
15

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In order to access optical pure
lipase PSꢀcatalyzed acyl kinetic resolution (KR) could be carried out.60 Thus, the synthesized racemic
β
ꢀnitroalcohols a combination of the Ca2+ꢀalginate catalysis with a
β
ꢀ
nitroalcohols could be subjected to a KR in the presence of vinyl acetate (VA) as acyl donor and
immobilized Amano lipase PS in toluene at room temperature (Table 5). In reasonable agreement with
previous studies,61 selected
βꢀnitroalcohols were isolated in good yields (ca. 30−40%) and ee values (>
95%) after the KR. A rigorous “oneꢀpot” process was not feasible because (1) the solvents required for
achieving good yields in each step were incompatible (e.g., the lipaseꢀcatalyzed KR was not effective in
DMSO, whereas the Ca2+ꢀalginate catalysis did not proceed in toluene. Moreover, attempts to use
DMSO/toluene mixtures provided unsatisfactory results), and (2) a control experiment carried out by
incubation of alginate beads, nitromethane and VA showed the consumption of the acyl donor.
Nevertheless, we found that VA and lipase PSꢀIM could be added to the reaction flask after completion
of the first step. Further shaking (not stirring!) at room temperature for 18 h allowed for the KR step to
take place in the same flask (e.g., (S)ꢀ2ꢀnitroꢀ1ꢀ(4ꢀnitrophenyl)ethanꢀ1ꢀol could be obtained in 40%
using this procedure).
Table 5. Lipaseꢀcatalyzed kinetic resolution of β
ꢀnitroalcoholsa
entry
Ar
yield 5 (%)b
1
2
3
4
5
4ꢀ(NO2)ꢀC6H4
4ꢀ(Cl)ꢀC6H4
C6H5
31
31
36
38
41
4ꢀ(CH3)ꢀC6H4
4ꢀ(OCH3)ꢀC6H4
a
Reaction conditions: βꢀNitroalcohol (3, 0.1 mmol), vinyl acetate (46 ꢀL, 0.5 mmol), lipase PSꢀIM (50 mg),
toluene (0.5 mL), room temperature, 18 h. b Determined by NMR analysis. HPLC optical purity > 95%.
CONCLUSIONS
In conclusion, Ca2+ꢀAHG beads are able to promote the Henry (nitroaldol) reaction between electronꢀ
deficient aromatic aldehydes and nitroalkanes to form
βꢀnitroalcohols in reasonably good yields
under mild conditions. Neither CaCl2 nor amorphous calcium alginate powder were effective as
catalysts. Therefore, we have revealed an interesting synergism between the metal ion and the
16

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hydrogel network towards the catalysis of C−C bond forming reactions. Moreover, the Henry reaction
proceeded to a different extent in both nonꢀtoxic organic solvents (DMSO)62 and aqueous media
(H2O/TBAB) at room temperature within 24 h. The study highlighted that biohydrogels prepared with
other metal ions (i.e., Co2+, Ni2+, Zn2+) were also active (ca. 40ꢀ60% yields for the model reaction
between 4ꢀnitrobenzaldehyde and nitromethane), although their performance was significantly worse in
comparison to Ca2+ꢀAHG (88% yield). Interestingly, when nitroethane was used as nucleophile the synꢀ
isomer of the reaction product was slightly favoured (1:1.3). Furthermore, the aboveꢀmentioned model
reaction could be scaledꢀup (1 g) providing the corresponding βꢀnitroalcohol in a good isolated yield
(82%), and the catalyst could be recycled at least three consecutive runs without major loss of activity.
We believe that the use of biocompatible and robust biopolymerꢀbased materials bearing intrinsic
surface functionalities, which can be easily massꢀproduced at a low cost and in a reproducible manner,
may contribute to the development of “greener” catalysts in the future.
EXPERIMENTAL SECTION
1
Materials and Methods. H NMR spectra were recorded at 25 °C on a Bruker Avance 300
spectrometer. Chemical shifts are denoted in
δ (ppm) relative to tetramethylsilane (TMS δ = 0) as an
internal standard or relative to residual solvent peaks. Samples were analyzed by chiralꢀphase HPLC
using a Varian 920ꢀLC Liquid Chromatograph and a column Phenomenex Lux Celluloseꢀ1, 4.6 × 250
mm, 5 ꢀm. TLC was facilitated by the use of the following stains in addition to UV light (254 nm) with
fluorescentꢀindicating plates (aluminium sheet precoated with silica gel 60 F254, Merck):
phosphomolybdic acid, vanillin, iodine. The metal content of the hydrogel beads was determined by
inductively coupled plasma optical emission spectrometry (ICPꢀOES) with a Spectro Analytical
Instruments ICP Modula EOP. IR spectra were recorded using a BioꢀRad FTꢀIR Excalibur FTS 3000
equipped with a Diamond ATR (attenuated total reflection) accessory (Golden Gate). The morphology
of the xerogels was observed with a Carl Zeiss Merlin fieldꢀemission scanning electron microscope (FEꢀ
SEM, resolution 0.8 nm) equipped with a digital camera and operating at 5 kV (accelerating voltage)
and 10 ꢀA (emission current). Xerogel specimens were prepared by the freezeꢀdrying (FD) method from
the corresponding hydrogels. The resulting material was placed on top of a tin plate and shielded by Pt
(40 mA during 30 s; film thickness ≈ 5 nm). SEM images were obtained in other cases with a Zeiss
DSM 950 scanning electron microscope operated at 10 kV after sputtering the samples with Au using a
SCD 040 from Balzers Union. Thermal gravimetric analysis (TGA) of the samples was conducted
with a Mettler Toledo Thermowaage TG50 apparatus. The samples were combusted under an argon
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flow (200 mL) during a heating range from 25 to 350 °C with a heating rate of 10 °C minꢀ1. Analyticalꢀ
grade solvents and commercially available reagents were purchased from commercial suppliers and
were used as received, unless otherwise noted. Aldehydes were purchased from TCI Europe (ESI).
Sodium alginate (Cat. No. A2158ꢀ100G; Batch No. 106K0113; CAS 9005ꢀ38ꢀ3; isolated from brown
algae; viscosity 100ꢀ300 cps for a 2% aqueous solution at 25 °C), calcium alginate from brown algae
(Cat. No. 21054ꢀ50G; Batch No. BCBM8132V; CAS 9005ꢀ35ꢀ0), and Amano lipase PSꢀIM
(immobilized on diatomaceous earth, Cat. No. 709603ꢀ10G) were purchased from Sigma Aldrich and
used without further purification. Pure H2O (milliQ) was used in all experiments including water.
Procedures
Typical procedure for the preparation of metal-crosslinked alginate hydrogel beads. 50 mL of a
solution of sodium alginate in milliQ water (2% w/v) was added dropwise at room temperature to 100
mL of aqueous metal chloride solution (0.24 M) via a dropping funnel (diameter of the tip = 4.0 mm).
The volumetric ratio between the sodium alginate solution and the metal chloride solution (1:2) was
kept constant in each case. After complete addition of the alginate solution, the beads were cured in the
metal stock solution over night at room temperature. Finally, the obtained alginate hydrogel (AHG)
beads were filtered over a Buchner funnel and washed with milliQ water until no metal residues could
be detected in the washing solution. Different compounds for metal complexation were used for
qualitative metal detection (Table S2, Figure S2).
General procedure for the preparation of Ca2+-crosslinked alginate aerogel beads. Ca2+ꢀ
crosslinked alginate hydrogel beads were first dehydrated in a series of successive ethanolꢀwater baths
of increasing alcohol concentration (i.e., 10, 30, 50, 70, 90, and 100%) for 15 min each. The soꢀobtained
alcogel beads were then dried under supercritical CO2 conditions (slightly beyond 73 bar and 31 ºC)
using a Polaron 3100 apparatus affording the corresponding aerogel beads.
Representative procedure for the metal AHG-promoted nitroaldol reaction. To a mixture of 4ꢀ
nitrobenzaldehyde (0.1 mmol, 15.1 mg), nitromethane (1 mmol, 54 ꢀL, 10 equiv) and DMSO (0.5 mL)
in a screw cap vial (4 mL), 1 metal AHG bead was added to initiate the reaction. The resulting reaction
mixture was gently stirred for 24 h at room temperature. After completion, EtOAc (1 mL) was added.
The diluted supernatant solution was removed and the remaining catalyst washed with EtOAc (3 × 1
mL) for 5 min during each cycle. The combined organic phases were washed with H2O (2 × 5 mL)
18
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obtain the crude product. To determine the NMR yield, the crude product was dissDoOlvI: e10d.10i3n9/CC4DNJC02l1378(A1
mL) and diphenylmethane (0.1 mmol, 16.7 ꢀL) or dimethyl acetamide (0.1 mmol, 9.2 ꢀL) were added
as internal standards. Random isolation of desired products showed only small differences between
isolated yield and NMR yield (i.e., ca. 5%).
Typical recycling experiment for the Ca2+-AHG-promoted Henry (nitroaldol) reaction. After
quenching the reaction as described above, the catalyst was washed with further DMSO (0.5 mL) to
remove any possible EtOAc residue. The hydrogel beads were subsequently added to a new mixture of
substrates in DMSO. This procedure was repeated for all further cycles. The workꢀup and determination
of the yield was determined as described in the representative procedure for the Mn+ꢀAHGꢀpromoted
Henry reaction.
Representative procedure for the lipase-catalyzed kinetic resolution of racemic mixtures. Amano
lipase PSꢀIM (50 mg) was added in one portion to a solution of the corresponding βꢀnitroalcohol (0.1
mmol) in toluene (0.5 mL) at room temperature. The reaction mixture was shaken at 200 rpm for 18 h at
room temperature. After this time, the reaction mixture was worked up by diluting with EtOAc/EtOH
(1:2, v/v), vortexed for 30 s and filtered through a syringe filter. After repeating these steps four times,
the solvent was evaporated under reduced pressure, and the yield determined by NMR using 1,3ꢀ5ꢀ
trimethoxybenzene as internal standard.
Acknowledgements
Financial support from Universität Regensburg (Anschubfinanzierung von Wissenschaftlichen
Projekten) and CSIC (PIE 200980I059) is gratefully acknowledged. We thank Mr. Matthew Sharum for
some assistance with the preliminary stability tests and initial microscopy of the beads during his
internship, Dr. Munmun Ghosh for preliminary experiments, Mr. Joachim Rewitzer (Universität
Regensburg) for assistance with the ICPꢀOES measurements, and Prof. Vicente GotorꢀFernández
(Universidad de Oviedo) for useful discussions. D.D.D. thanks DFG for the Heisenberg Professorship
Award.
Supporting Information
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Electronic supplementary information (ESI) available: Preliminary optimization experiments, metal
loading, leaching study, kinetics, FTꢀIR spectra, TGA curves, 1H NMR spectra, HPLC chromatograms,
and additional experiments.
Notes and references
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Mcomplex = 744.56 g molꢀ1. The mol% was calculated by following equation: mol% = {(1.55 × 10ꢀ3 g /
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24