Nano-organocatalyst: magnetically retrievable ferrite-anchored glutathione for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis

Article abstract of DOI:10.1016/j.tet.2009.11.015

Postsynthetic surface modification of magnetic nanoparticles by glutathione imparts desirable chemical functionality and enables the generation of catalytic sites on the surfaces of ensuing organocatalysts. In this article, we discuss the developments, unique activity, and high selectivity of nano-organocatalysts for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis. Their insoluble character coupled with paramagnetic nature enables easy separation of these nano-catalysts from the reaction mixture using external magnet, which eliminates the requirement of catalyst filtration.

Full text of DOI:10.1016/j.tet.2009.11.015

Tetrahedron 66 (2010) 1091–1097
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nano-organocatalyst: magnetically retrievable ferrite-anchored glutathione
for microwave-assisted Paal–Knorr reaction, aza-Michael addition,
and pyrazole synthesis
,
y
*
*
Vivek Polshettiwar , Rajender S. Varma
Sustainable Technology Division, National Risk Management Research Laboratory, U.S. Environmental Protection Agency, MS 443, Cincinnati, OH 45268, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2009
Accepted 9 September 2009
Available online 10 November 2009
Postsynthetic surface modification of magnetic nanoparticles by glutathione imparts desirable chemical
functionality and enables the generation of catalytic sites on the surfaces of ensuing organocatalysts. In
this article, we discuss the developments, unique activity, and high selectivity of nano-organocatalysts
for microwave-assisted Paal–Knorr reaction, aza-Michael addition, and pyrazole synthesis. Their in-
soluble character coupled with paramagnetic nature enables easy separation of these nano-catalysts
from the reaction mixture using external magnet, which eliminates the requirement of catalyst filtration.
Published by Elsevier Ltd.
Keywords:
Nano-organocatalyst
Microwave irradiation
Aqueous medium
Green chemistry
Paal–Knorr reaction
Aza-Michael addition
Pyrazole synthesis
1. Introduction
approach to the synthesis of organic molecules has attracted
worldwide attention.9–12 A diverse set of reactions, including
Manufacturing protocols can be made economic, greener, and
more sustainable, by designing and vigilant use of catalysts, which
reduces the chemical waste harmful to human health and the en-
vironment. In this regard, magnetic nano-materials showed major
impacts on catalysis and many other areas, such as medicine, drug
delivery, and remediation.1,2 These inexpensive materials are ac-
cessible via simple synthesis and they can be easily enhanced/
tuned by postsynthetic surface modifications.3 Functionalized
nanoparticles have emerged as feasible substitute to conventional
materials as a robust, active, high-surface-area catalyst support.4–8
In view of their nano-size, the contact between reactants and cat-
alyst increases dramatically thus mimicking the homogeneous
catalysts. They offer an added advantage of being magnetically
separable, thereby eliminating the requirement of catalyst filtration
after completion of the reaction.
enantioselective C–C, C–N, C–O bond formation,13 Diels–Alder,14,15
Baylis–Hilman,16,17 Mannich,14,18–20 Michael,14,21,22 Friedel–Crafts
alkylation,23 oxidation,24,25 and carbohydrate synthesis,26 has
benefited from the developments in this area.27–29 This relatively
green approach has been rendered even greener by efforts in im-
mobilization and recycling of the organocatalysts on supports,
which involve their adsorption, covalent linkage, and dissolution in
various matrices.30–33 Newer strategies include the use of non-
traditional methods such as light,34 mechanochemical mixing,
microwave (MW), and ultrasonic irradiation.35 Most of these re-
actions are generally carried out in organic solvents, with a few
aqueous phase organocatalytic processes as recent exceptions.36–39
Although water is an environmental benign solvent,40 and addition
of water often accelerates the reaction, isolation of final organic
product from the reaction mixture is tedious. Most of the reactions
described in published reports use excessive amounts of toxic or-
ganic solvents for workup and the total amount of water used in the
process is much less. As stated by Blackmond, ‘A holistic approach
that consider not only the reaction step but also the economics and
environmental impact of product workup and reagent preparation’,
is the key aspect in deciding about the greenness of aqueous
protocol.41
During the past decade, another exciting field of organocatalysis
has become a very significant area of research and this metal-free
* Corresponding authors. Tel.: þ1 513 487 2701; fax: þ1 513 569 7677.
E-mail addresses: vivekpol@yahoo.com, vivek.polshettiwar@kaust.edu.sa
(V. Polshettiwar), varma.rajender@epa.gov (R.S. Varma).
y
Although extensive amount of research has been carried out
over organocatalysis, following aspects still remained unexplored;
Present address: KAUST Catalysis Center (KCC), King Abdullah University of
Science and Technology Thuwal 23955-6900, Kingdom of Saudi Arabia.
0040-4020/$ – see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.11.015

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V. Polshettiwar, R.S. Varma / Tetrahedron 66 (2010) 1091–1097
(i) totally benign aqueous protocol without using any organic sol-
vent even in workup step; (ii) magnetic nanoparticle-supported
organocatalyst; (iii) use of naturally abundant and benign organo-
catalyst, glutathione. Engaged in the development of greener and
sustainable pathways for organic transformations42–45 and nano-
materials46–48 and after our initial success with nano-organo-
catalyst,49 herein, we report a simple and efficient synthesis of
nano-ferrite-supported, magnetically recyclable organocatalyst for
microwave-assisted Paal–Knorr, Aza-Michael reactions, and pyr-
azole synthesis.
2. Result and discussion
2.1. Design and synthesis of nano-organocatalyst
The first step in the realization of this concept was the selection
of amino acids for the functionalization of magnetic nanoparticles.
We decided to explore cysteine and glutathione, since they have
highly reactive thiol group, which can be used for anchoring to the
nano-ferrite surfaces, keeping active sites free for catalysis. Initially,
both of the amino acids were tested for Paal–Knorr reaction under
homogeneous condition in water medium, to compare their cata-
lytic activity and glutathione appeared to be more active in com-
parison to cysteine. Glutathione is a highly benign tripeptide, an
essential component of plants and human cell systems. The nano-
Figure 2. FTIR spectra (a) glutathione and (b) nano-organocatalyst.
O
HO
O
HO
S
NH2
O
HN
HO
HN
O
O
O
OH
O
NH
N
HN
O
Sonication
RT, H2O
H
O
H2N
S
HS
O
Fe3O4
Fe3O4
OH
HN
S
Magnetic Nano Particle
O
H2N
OH
H
N
O
O
H2N
NH
Glutathione (reduced)
OH
O
O
O
OH
Nano-Organocatalyst
Figure 1. Synthesis of nanoparticle-supported glutathione as an organocatalyst.
organocatalyst was then prepared in high yield using our recently
developed post-functionalization method46 (Fig. 1).
formula for the full width at half-maximum (fwhm) of the (311)
reflection.
Anchoring of glutathione on the surface of magnetic nanoparticles
was examined by FTIR spectroscopy (Fig. 2). Three characteristic
bands 2947 cmꢀ1 (C–H stretching), 1648 cmꢀ1 (cysteine-carbonyl),
and 1629 cmꢀ1 (glutamic acid-carbonyl) confirmed the attachment
of glutathione on nano-ferrite surfaces. The molecule was firmly
anchored via the thiol group, as the IR band at 2558 cmꢀ1 for S–H
stretching was diminished in the catalyst. A strong absorption band
at 592 cmꢀ1 was due to the vibration of the Fe–O bond of ferrite.
The crystalline structures of the organocatalyst were determined
by powder X-ray diffraction (XRD) (Fig. 3a); the diffraction patterns
and relative intensities of all the peaks matched well with those of
magnetite (JCPDS card no. 00-002-1035). Other oxide or hydroxide
phases were not observed and the broad XRD peaks clearly indicate
the nano-crystalline nature of the material. Transmission electron
microscopy (TEM) analysis (Fig. 3b) of the organocatalyst showed
uniform-sized particles with spherical morphology with an aver-
age size range of 10–12 nm. This is comparable to the crystallite
size (10.11 nm) calculated from X-ray spectrum using Scherer
2.2. MW-assisted Paal–Knorr reaction using nano-
organocatalyst in aqueous medium
Paal–Knorr reaction in which amines are converted to pyrrole in
one step has gained great interest in the synthetic organic chemistry,
as these heterocycles are intermediates for various pharmaceutical
drugs.50 A range of clean protocols have been developed by using solid
supported catalyst such as alumina,51 zeolites,52 phosphates,53 and
ionic liquids.54 The use of non-conventional energy sources such as
microwave55 and ultrasound56 was studied. However, most of the
above methods involve the use of excess amounts of catalyst, toxic
organic solvents, and tedious workup and cannot be considered as real
green protocols. Hence, we decided to explore, this glutathione-coated
material as a nano-organocatalyst for Paal–Knorr reactions (Scheme 1)
as this reaction has never been accomplished using an organocatalyst.
Reaction conditions were optimized for the Paal–Knorr reaction
using benzylamine as a substrate, using nano-organocatalyst under

V. Polshettiwar, R.S. Varma / Tetrahedron 66 (2010) 1091–1097
1093
Table 2
Paal–Knorr reaction of amines using nano-organocatalysta
Entry
1
Substrate
Product
Yield
(%)
N
92
NH2
CH3
N
CH3
NH2
2
3
90
90
CH3
N
CH3
NH2
NH2
4
5
N
86
88
NH2
N
O
O
NH2
6
7
85
82
EtO
N
EtO
NH2
N
CH3
NH2
CH3
O
O
8
9
78
72
N
N
N
O
O
HN NH2
HN
N
Figure 3. (a) Powder XRD pattern and (b) TEM image of as-synthesized nano-
organocatalyst.
O
O
10
NR
NH2
N
Nano-Organocatalyst
NH2
N
H2O, MW- 140 o
C
MeO
OMe
O
R
R
Where,
R- alkyl, aryl,
heterocyclic etc
NH2
NH
11
12
NR
90
O2N
N
NH
Scheme 1. Nano-organocatalyst promoted Paal–Knorr reactions.
O2N
N
Table 1
Optimization of reaction conditionsa
NH2
No.
Solvent
R. temp (ꢁC)
R. time (min)
Conversion (%)
NH2
NH2
13
14
84
7
8
N
7
1
2
3
4
5
6
Toluene
Toluene
TolueneþH2O
H2O
H2O
H2O
120
140
140
120
140
140
30
30
30
30
20
30
>5
>5
80
70
92
95
8
86b
HO
HO
N
N
15
85b
72c
H2N
NH2
a
1 mmol of benzylamine, 25 mg of nano-organocatalyst.
H2N
MW irradiation conditions (Table 1). MW-assisted chemistry was
used due to the efficiency of the interaction of MWs with the polar
nano-catalyst,42 as it allows rapid heating of the reaction mixture to
required temperatures and the precise control of the reaction
temperature. The reaction was first conducted in toluene as a re-
action medium at 120 ꢁC and a poor conversion was observed
(entry 1). Increasing the reaction temperature to 140 ꢁC provided
no significant increase in conversion (entry 2). Interestingly, when
the reaction was carried out in a mixture of toluene and water, good
conversion was achieved (entry 3). Encouraged from this result, we
decided to carry out the reaction in pure water; 92% conversion was
achieved in 20 min at 140 ꢁC under MW irradiation (entry 5).
16
H2N
NH2
N
N
a
Reactions were carried out with 1 mmol of amines, 1.1 mmol of tetrahydro-2,5-
dimethoxyfuran, and 25 mg of nano-organocatalyst in 1.5 mL of water at 140 ꢁC for
20 min under MW irradiation.
b
Solvent extraction was needed to isolate the product.
2.2 mmol of tetrahydro-2,5-dimethoxyfuran, reaction temperature 150 ꢁC, time
c
90 min.
Deploying the above optimized reaction conditions, the scope of
this catalyst was then investigated for Paal–Knorr reaction using
a variety of amines (Table 2).

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V. Polshettiwar, R.S. Varma / Tetrahedron 66 (2010) 1091–1097
Table 3
The nano-organocatalyst displayed high catalytic activity for
Aza-Michael addition using nano-organocatalyst
Paal–Knorr reactions and a variety of amines reacted efficiently
with tetrahydro-2,5-dimethoxyfuran to afford the desired pyrrole
derivatives in good yields (Table 2). The rates were essentially the
same for both the aliphatic or aromatic nature of the amines,
Entry
1
R1
R2
Product
Yield (%)
92
Me
O
PhCH2
Me
showing the high activity of the catalyst. Chiral (S)-
a-methyl-
benzylamine and (R)- -methylbenzylamine yielded corresponding
a
NH
O
pyrroles without racemization (entries 2 and 3). Heterocyclic amine
underwent Paal–Knorr reaction with good yield of the respective
pyrrole (entry 8). This protocol is also suitable for acid hydrazide
(entry 9); however, our attempts to use amide (entry 10) and hy-
drazine (entry 11) as substrates yielded no product. Significantly,
substituted amines were selectively converted to pyrroles while
keeping other reactive functional groups, such as ester (entry 6),
ketone (entry 7), olefinic bond (entry 13), alcohol (entry 14), and
amine (entry 15) intact. For diamines, by changing the mole ratio
and reaction time, mono- (entry 15) and di- (entry 16) pyrrole
derivatives were obtained. It is important to point out that these
biphasic reactions functioned well in an aqueous medium without
the need for any phase-transfer catalyst, which is due to the se-
lective absorption of microwaves by reactants, polar nano-catalyst,
and aqueous medium.42
Bu
O
2
3
PhCH2
Bu
90
92
NH
O
O
Ph
Me
N
H
O
Me
O
O
O
4
5
6
7
Ph
Bu
90
90
92
90
N
H
O
Bu
Cy
Me
Bu
2.3. MW-assisted aza-Michael reaction using nano-
organocatalyst in aqueous medium
N
H
O
Me
Aza-Michael addition is a vital carbon–nitrogen bond-forming
reaction and has been intensively examined as a powerful tool in
organic synthesis.57 However, most of the aza-Michael additions
Cy
N
H
O
Bu
are performed in organic solvents. Recently
b
-cyclodextrin,58
ytterbium triflate,59 and surfactant-type asymmetric organo-
catalyst (STAO) type catalyst,60 has been used in aqueous medium.
Although today’s environmental concerns encourage the de-
velopment of such greener synthetic methodology in aqueous
medium, many of these methods suffer from limitations such as the
use of expensive and toxic catalyst, harsh reaction conditions. In
order to study the versatility of the developed organocatalyst, we
examined it for MW-assisted aza-Michael reaction in aqueous
medium (Scheme 2).
Cl
Cl
O
4-ClPh
Me
N
H
O
Me
O
8
4-ClPh
Bu
90
N
H
O
Bu
O
O
Nano-Organocatalyst
H2O, MW- 140 o
R2
R1 NH2
R1
R2
O
N
H
O
C
O
O
N
Nano-Organocatalyst
H2O, MW- 140 o
R1 - Ph, Cy, 4-ClPh, PhCH2,
Bu, Et
R1
NH
NH2
N
C
X
X
R2 - Me, n-Bu
R1 = Me, OEt
X = H, Et, Cl
Scheme 2. Nano-organocatalyst promoted aza-Michael reactions.
Scheme 3. Nano-organocatalyst promoted pyrazole synthesis.
Using the optimized reaction conditions (developed for Paal–
Knorr reaction), the scope and efficiency of this aqueous
approach were explored for the reaction of various amines with
methyl and butyl acrylate (Table 3). All reactions proceeded ex-
peditiously and delivered excellent product yields. However, no
phase separation was observed in these reactions, because of the
high solubility of the product in water due to the presence of free
–NH group.
conducted in organic solvents. We decided to extend the ex-
ploration of nano-organocatalyst for the synthesis of pyrazole
derivatives (Scheme 3).
Various hydrazines and hydrazides reacted efficiently with 1,3-
diketones to afford the desired pyrazoles in good yields (Table 4).
The b-keto esters can also be used as a substitute for diketones in
this synthesis. All these reactions proceeded efficiently in aqueous
medium and were completed in a 20 min. Product was isolated by
simple decantation (in some cases) as well as extraction by ethyl
acetate.
2.4. MW-assisted pyrazole synthesis using nano-
organocatalyst in aqueous medium
Pyrazoles are an important class of bio-active drug targets in
the pharmaceutical industry, in both lead identification and lead
optimization processes.61 Recently, several efficient methods
have been developed62; however most of these utilize a circui-
tous route requiring longer reaction time, and are often
2.5. Recovery and reuse of nano-organocatalyst
Separation of the catalyst and isolation of products are the main
operations in aqueous organocatalysis.41 Catalyst recovery is often

V. Polshettiwar, R.S. Varma / Tetrahedron 66 (2010) 1091–1097
1095
Table 4
Pyrazole synthesis using nano-organocatalyst
Entry
1
Hydrazine
Diketone
Product
Yield (%)
O
O
96
NHNH2
N
N
O
O
Cl
Et
2
80
NHNH2
NHNH2
N
N
Cl
Et
N
N
O
O
3
4
84
82
O
O
O
O
Cl
Cl
NHNH2
Cl
N
N
Cl
Et
5
78
NHNH2
NHNH2
Cl
N
Cl
Et
N
O
O
O
O
O
O
6
7
84
88
Cl
Cl
N
N
O
O
NHNH2
N
N
O
O
8
84
NHNH2
N
O
N
O
performed by filtration that reduces efficiency and extractive iso-
lation of products requires large amount of organic solvents. In the
case of Paal–Knorr reaction, because of the super-paramagnetic
nature of the material, within a few seconds after stirring was
stopped, the reaction mixture turned clear and catalyst was de-
posited on the magnetic bar, which was easily removed using an
external magnet. We observed that after completion of the re-
actions, the phase separation of the desired product from the
aqueous media occurred (Fig. 4) in most cases, thus facilitating the
isolation of crude product by simple decantation rather than te-
dious extraction processes. Consequently, the use of volatile or-
ganic solvents is reduced during product workup. In a few cases,
solid product precipitated out; the product could then be isolated
by simple filtration.
To evaluate lifetime and level of reusability of the catalyst, we
conducted the experiments using the recycled nano-organocatalyst
for the Paal–Knorr reaction of benzylamine. After the completion of
the first reaction, the product layer was removed by decantation
and the catalyst was recovered magnetically, washed with water
and methanol, and dried. A new reaction was then conducted with
fresh reactants under similar conditions. It was found that the de-
veloped catalyst could be used at least five times without any
change in activity. Alternatively, the reaction could be carried out
Figure 4. Paal–Knorr reaction of benzylamine using magnetic nano-organocatalyst in
water, after completion of the reaction.

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V. Polshettiwar, R.S. Varma / Tetrahedron 66 (2010) 1091–1097
by simply removing the product layer and adding fresh benzyl-
amine and tetrahydro-2,5-dimethoxyfuran, and similar results
were obtained.
power 50–250 W, and pressure 50–180 psi for 20 min (Table 3).
After completion of the reaction, products were extracted with
ethyl acetate and washed with sodium bicarbonate solution. After
concentrated in vacuum, the crude product was subjected to flash
column chromatography for further purification. All products are
known in the literature and were identified by comparison of their
GC–MS spectra with standard Wiley mass spectral library.
3. Conclusions
Novel concept of nano-organocatalyst was developed, by sup-
porting totally benign and naturally abundant glutathione on
magnetic nanoparticles. The catalyst showed excellent activity for
microwave-assisted Paal–Knorr, Aza-Michael reactions, and pyr-
azole synthesis. Importantly, in the case of Paal–Knorr reaction of
amines, the entire process was carried out in aqueous medium,
without using organic solvent in the reaction or during the workup.
This novel nano-organocatalyst bridges the gap between homo-
geneous and heterogeneous catalysis thus preserving the desirable
attributes of both the systems.63
4.5. Pyrazole synthesis using nano-organocatalyst
1.0 equiv of 1,3-diketone, 1.1 equiv of hydrazines and nano-
organocatalyst (25 mg) were placed in a 10 mL crimp-sealed thick-
walled glass tube equipped with a pressure sensor and a magnetic
stirrer. Water (2 mL) was added and the reaction mixture was
mixed thoroughly. The reaction tube was then placed inside the
cavity of a CEM Discover focused MW synthesis system, operated at
140ꢂ5 ꢁC (temperature monitored by a built-in infrared sensor),
power 50–250 W, and pressure 50–180 psi for 20 min (Table 3).
After completion of the reaction, products were extracted with
ethyl acetate and washed with sodium bicarbonate solution. After
concentrated in vacuum, the crude product was subjected to flash
column chromatography for further purification. All products are
known in the literature and were identified by comparison of their
GC–MS spectra with standard Wiley mass spectral library.
4. Experimental
4.1. General
All the solvents and reagents were purchased at the highest
commercial quality and used without further purification, unless
otherwise stated. Gas chromatography (GC) was used to monitor
the reactions. The crude products were identified by GC–MS qual-
itative analysis using a GC system with a mass selective detector.
CEM Discover focused microwave synthesis system was used to
carry out all aforementioned organic transformations.
Acknowledgements
V.P. thanks U.S. Environmental Protection Agency, Cincinnati for
ORISE research fellowship.
4.2. Anchoring of glutathione on nano-ferrite surfaces
References and notes
Nano-Fe3O4 (0.5 g) was dispersed in water (15 mL) and metha-
nol (5 mL) and sonicated for 15 min. Glutathione (reduced form)
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again sonicated for 2 h. The glutathione-functionalized nano-
material (nano-organocatalyst) was then isolated by centrifugation,
washed with water and methanol, and dried under vacuum at 50–
60 ꢁC.
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