Chitosan aerogel: a recyclable, heterogeneous organocatalyst for theasymmetric direct aldol reaction in waterwz Alfredo Ricci,*aLuca Bernardi,aClaudio Gioia,aSimone Vierucci,aMike Robitz
Trang 1Chitosan aerogel: a recyclable, heterogeneous organocatalyst for the
asymmetric direct aldol reaction in waterwz
Alfredo Ricci,*aLuca Bernardi,aClaudio Gioia,aSimone Vierucci,aMike Robitzerband
Franc¸oise Quignard*b
Received 20th May 2010, Accepted 2nd July 2010
DOI: 10.1039/c0cc01502d
Aerogel microspheres of chitosan, an abundant biopolymer
obtained from marine crustaceans, have been successfully applied
to catalyze the asymmetric aldol reaction in water, providing the
products in high yields and with good stereoselectivity (up to
93% ee) and recyclability (up to 4 runs) Yields were favourably
affected by additives such as DNP and stearic acid
The development of heterogeneous catalytic systems for fine
chemical synthesis has become recently a major area of
research The ability to utilise heterogeneous catalysts in the
liquid phase can aid considerably in the separation, recovery
and reuse of catalysts, and can afford the clean separation of
products from the reaction mixture thus making a major
impact on the environmental performance of a synthesis
The majority of these novel catalysts are based on silica and
display many advantageous properties like high surface area,
good accessibility and easy anchoring of organic groups to
provide catalytic centres but are of poor stability in aqueous
basic conditions.1The most recent efforts, however, are being
driven by a shift from the petrochemical-based or inorganic
feedstock toward biological materials Therefore, an increasingly
important key role is being played by the use of biopolymers
for use as polymeric supports for catalysis
Chitosan derived by extensive deacetylation of chitin can be
considered as a natural polyamine.2,3 The flexibility of this
material, its insolubility in the vast majority of solvents along
with its inherent chirality (Fig 1) and its tendency to act as an
absorbent of metals,4–8but also as a support for chiral organic
frameworks9make chitosan an excellent candidate for
build-ing heterogeneous catalysts.10 In contrast with these reports
the direct use of chitosan in base catalysis has been very poorly
explored Chitosan hydrogel has been used as a green and
recyclable catalyst for aldol and Knoevenagel reactions.11 Some of us have shown that chitosan microspheres obtained under supercritical conditions could be used as a catalyst for the synthesis of monoglyceride by fatty acid addition to glycidol.12Indeed aerogel formulation of chitosan affords high surface area materials (up to 350 m2g1) with high accessi-bility to the functional groups (up to 5.2 mmol g1NH2).13 The lack of literature reports dealing with the heterogeneous asymmetric organocatalysis displayed by polysaccharides prompted us to undertake a detailed study of the evaluation
of the chitosan potential in this new frontier area of organo-catalytic reactions To this purpose and considering the poly-amino structure of this renewable natural material, we focused
on the field in which primary amine organocatalysis14 has emerged in the past few years Accordingly, to evaluate the putative chitosan catalytic activity, the direct aldol reaction,15 one of the most important carbon–carbon bond forming reactions,16was investigated in the presence of water17without any organic cosolvent, by using supercritical CO2 dried chitosan as the catalyst (Table 1).13 Initial tests were performed in the prototype reaction between p-nitrobenzaldehyde and cyclohexanone as the pronucleophile aimed at establishing the optimized reaction conditions (Table 1) A catalytic loading
of 22 mol%, referred to the estimated amount of the free amino group functions, afforded, with acceptable reaction rates and in high yields, the expected product 1a The aqueous medium being necessary for the reaction to occur, no sub-stantial variations were noticed on varying the amount of water (compare entries 1–3) We were delighted to see that high enantiomeric excess up to 84% ee for the major diastereo-isomer and up to 60% for the minor were obtained (entry 2) with an anti/syn ratio in the range of 3 : 1 This is to the best of our knowledge the first report on the capability of chitosan to act as an asymmetric organocatalyst under heterogeneous conditions A lower catalyst loading caused a substantial drop
of the conversion without affecting however the enantio-selectivity Moreover, comparison with the monomeric glucos-amine (entry 9) highlighted the superiority of the polymeric bio-material as catalyst with respect to the monomeric amino-sugar In the direct aldol reaction the amine-catalyzed version usually proceeds via an enamine intermediate15whose forma-tion is catalysed by acids matched with the basicity of the amine In line with these assumptions, when the reaction between cyclohexanone and p-nitrobenzaldehyde was per-formed in the presence of 20 mol% of 2,4-dinitrophenol (DNP, pKa= 4.11), a substantial increase of the enantiomeric excess to 92% was observed that however diminished in the presence of 10 mol% of the additive (entries 4–5) This
Fig 1 Chitosan monomer.
a
Department of Organic Chemistry ‘‘A Mangini’’, University of
Bologna, V Risorgimento 4, 40136 Bologna, Italy.
E-mail: ricci@ms.fci.unibo.it; Fax: +39 051 2093654;
Tel: +39 0512093635
b
Institut Charles Gerhardt-Montpellier, Mate´riaux Avance´s pour la
Catalyse et la Sante´, UMR5253 CNRS-ENSCM-UM2-UM1,
8 rue de l’Ecole Normale, 34296 Montpellier, France.
E-mail: quignard@enscm.fr; Fax: +33 467 163 470;
Tel: +33 467 163 460
w Dedicated to Prof Carmen Na´jera on the occasion of her 60th
birthday.
z Electronic supplementary information (ESI) available: Experimental
details See DOI: 10.1039/c0cc01502d
Trang 2improvement could not be observed when a weaker acid such
as p-nitrophenol (pKa = 7.2) was employed Worth noting
also a long chain carboxylic acid like stearic acid increased
reactivity and enantioselectivity up to 93% ee (entry 6) in spite
of its lower acidity (pKa= 10.15) Although the mechanism
through which fatty acids improve yields and stereoselectivity
is presumably complex, the possibility exists that the liquid
organic donor and the acceptor form an emulsion with the
fatty acid in water18 and because of this aggregation
the organic molecules could be favourably driven towards
the intermediate enamine formation Finally, replacing chitosan
aerogel with hydrogel the reaction performed in the presence
of DNP led to slightly diminished yields and to some erosion
of the enantioselectivity (entries 7 and 8) With respect to the recently reported chitosan-supported L-proline complex9 the natural polysaccharide leads to comparable results even though the diastereoselectivity appears to be lower
With the optimised set of conditions in hand, the scope of the direct aldol reaction was inspected using several ketone donors and p-nitrobenzaldehyde and isatin as the acceptors (Table 2) In most cases, reactions afforded the aldol products
1 with good diastereoselectivities and in fairly high yields and
Table 1 Direct aldol reaction of cyclohexanone with p-nitrobenzaldehyde catalyzed by chitosan: optimisation of the reaction conditions a
Entry H 2 O/mL Catalyst Additive (mol%) Time/h Yieldb(%) anti/sync eed(%)
a
Conditions: chitosan 4.5 mg (corresponding to 22 mol% free amino units with respect to aldehyde), p-nitrobenzaldehyde (0.10 mmol), cyclohexanone (2.0 mmol), H 2 O.bIsolated yield after chromatography on silica gel.cDetermined by 1H NMR spectroscopy on the crude mixture.dDetermined by chiral-phase HPLC analyses, results in parentheses refer to the minor diastereomer.eThis figure does not take into account the amount of H 2 O in the hydrogel beads employed, evaluated in ca 0.05 mL.
Table 2 Scope of the aldol reaction catalysed by chitosan aerogel a
Entry Acceptor Donor Product Additiveb Time/h 1-Yieldc(%) anti/synd eee(%)
a Conditions: chitosan aerogel 13.5 mg (corresponding to 22 mol% free amino units with respect to the acceptor), aldol acceptor (0.30 mmol), ketone donor (6.0 mmol), H 2 O (1.5 mL or 0.90 mL), additive b 20 mol% c Isolated yield after chromatography on silica gel d Determined by
1
H NMR spectroscopy on the crude mixture Relative configurations assigned by comparison with literature data or analogy See ESIw.eDetermined
by HPLC analyses, results in parentheses refer to the minor diastereomer Absolute configurations assigned by comparison with literature data or by analogy See ESIw.fNatural chitosan from a commercial source was used.gAfter crystallisation.h12.0 mmol of acetone were used.iConversion.
This journal is c The Royal Society of Chemistry 2010 Chem Commun., 2010, 46, 6288–6290 | 6289
Trang 3enantioselectivities for the major anti diastereomer Besides
cyclohexanone (entries 1–4, and 12–14) other donors like
hydroxyacetone (entries 5–9), tetrahydro-4H-pyran-4-one
(entries 10–11) and acetone (entries 15–17) were used in these
reactions In particular, the reaction with water miscible
acetone yielded the product 1e in good yields but not in
synthetically useful enantioselectivities, a result which parallels
previous literature reports.19 Using isatin as the acceptor
system (entries 12–14) allowed the formation in very high
yields and good enantioselectivity of the oxindole 1d having
a structural moiety of high interest in medicinal chemistry.20
The contrasting diastereoselectivity observed when
cyclo-hexanone and hydroxyacetone were used as donors can be
rationalised with the models shown in Scheme 1 Following
the generally accepted mechanistic picture,14,21cyclohexanone
condenses with chitosan primary amine to give E-enamine A,
whereas hydroxyacetone results predominantly in Z-enamine
B stabilised by an intramolecular hydrogen bond These
enamines then react with the incoming aldehyde, likely activated
by a hydrogen-bond with the 4-hydroxy group in intermediates C
and D, affording as the major products the corresponding
anti-and syn-aldol adducts, respectively However, the possibility
of additional hydrogen-bond interactions between substrates
and other hydroxyl moieties (of the same or adjacent saccharide
units) cannot be ruled out
The efficacy of chitosan aerogel in terms of its reusability as
an organocatalyst in the aldol reaction between cyclohexanone
and p-nitrobenzaldehyde was finally tested After completion
of the reaction and decantation of the organic/aqueous layer
the aerogel did not seem macroscopically affected and could be
reused for at least 3 more additional runs displaying the same
efficiency and stereoselectivity (Table 3) The use of powdered chitosan from a commercial source (entries 2, 6, 8, 13 in Table 2) led to results to some extent comparable to those with the aerogel and hydrogel but the formation of a slurry in the reaction medium prevented the easy recycle and recovery
of the catalyst as a solid-like heterogeneous phase
In summary, we have developed the first direct asymmetric aldol reaction that can be performed in the presence of water using as a heterogeneous organocatalyst chitosan, a renewable feedstock material The simple and environmentally friendly experimental procedure and the recycling of the catalytic system highlight good assets of this catalytic protocol Further studies focusing on a wider scope of these catalyzed asymmetric transformations are currently in progress
We acknowledge financial support from ‘Stereoselezione in Sintesi Organica Metodologie e Applicazioni’ 2007
Notes and references
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L Fornaro, L Sabbatini, N Cioffi and N Ditaranto, Organo-metallics, 2004, 23, 5154.
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11 K R Reddy, K Rajgopal, C U Maheswari and M L Kantam, New J Chem., 2006, 30, 1549.
12 R Valentin, K Molvinger, F Quignard and D Brunel, New J Chem., 2003, 27, 1690.
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Table 3 Recyclability of chitosan aerogel catalyst a
Cycle Yieldb(%) anti/sync eed(%)
a
Conditions: chitosan aerogel 13.5 mg (corresponding to 22 mol%
free amino units with respect to aldehyde), p-nitrobenzaldehyde
(0.30 mmol), cyclohexanone (6.0 mmol), H 2 O (1.5 mL), 48 h Then
after phase separation, the beads were washed with H 2 O and reused.
b
Isolated yield after chromatography on silica gel.cDetermined by
1
H NMR spectroscopy on the crude mixture.dDetermined by chiral
stationary phase HPLC Refers to the major anti diastereomer.
Scheme 1 Proposed reaction pathway.