U.S. patent application number 13/689930 was filed with the patent office on 2013-04-18 for magnetic nanoparticle-supported glutathione as a sustainable organocatalyst.
This patent application is currently assigned to The United States of America as represented by the Administrator of the United States Environment Pr. The applicant listed for this patent is The United States of America as represented by t, The United States of America as represented by t. Invention is credited to Vivek Polshettiwar, Rajender S. Varma.
Application Number | 20130096334 13/689930 |
Document ID | / |
Family ID | 43625827 |
Filed Date | 2013-04-18 |
United States Patent
Application |
20130096334 |
Kind Code |
A1 |
Varma; Rajender S. ; et
al. |
April 18, 2013 |
Magnetic Nanoparticle-Supported Glutathione as a Sustainable
Organocatalyst
Abstract
This invention relates to the use of nano-organocatalysts, and,
more specifically, to the use of magnetic nanomaterial-supported
organocatalysts. It is an object of the present invention to
provide "green" catalysts and protocols. According to one
embodiment of the invention, a nano-organocatalyst in the form of a
magnetic nanomaterial-supported organocatalyst is provided.
According to other embodiments of the invention, glutathione and
cysteine are provided as organocatalysts and magnetic
nanomaterial-supported glutathione and magnetic
nanomaterial-supported cysteine are provided for use as
nano-organocatalysts. According to another embodiment of the
invention, a method of using a recyclable magnetic
nanomaterial-supported organocatalyst using a totally benign
aqueous protocol, without using any organic solvent in the reaction
or during the workup, is provided. According to a further
embodiment of the invention, a recyclable magnetic
nanomaterial-supported organocatalyst for various organocatalytic
reactions, including but not limited to Paal-Knorr reactions,
aza-Michael addition and pyrazole synthesis, is provided.
Inventors: |
Varma; Rajender S.;
(Cincinnati, OH) ; Polshettiwar; Vivek;
(Cincinnati, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The United States of America as represented by t; |
Washington |
DC |
US |
|
|
Assignee: |
The United States of America as
represented by the Administrator of the United States Environment
Pr
Washington
DC
|
Family ID: |
43625827 |
Appl. No.: |
13/689930 |
Filed: |
November 30, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12553681 |
Sep 3, 2009 |
8324125 |
|
|
13689930 |
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Current U.S.
Class: |
556/146 |
Current CPC
Class: |
B01J 31/0254 20130101;
C07C 227/10 20130101; C07C 227/10 20130101; C07C 227/10 20130101;
C07D 207/323 20130101; B01J 31/0228 20130101; B01J 31/0271
20130101; C07C 227/10 20130101; C07C 323/60 20130101; C07D 207/325
20130101; C07C 229/14 20130101; C07D 405/06 20130101; B01J 37/0209
20130101; C07C 229/12 20130101; C07C 229/18 20130101; B01J 35/0033
20130101 |
Class at
Publication: |
556/146 |
International
Class: |
B01J 31/02 20060101
B01J031/02 |
Claims
1. A nano-organocatalyst comprising a magnetic
nanomaterial-supported organocatalyst, wherein an organocatalyst
comprises a compound having a thiol group and wherein the
organocatalyst is anchored to a magnetic nanomaterial through the
thiol group.
2. The nano-organocatalyst of claim 1, wherein the organocatalyst
is selected from the group consisting of glutathione and
cysteine.
3. The nano-organocatalyst of claim 1, wherein the magnetic
nanomaterial is selected from the group consisting of nano-ferrite,
nano-nickel ferrite, nano-cobalt ferrite, nano-iron, and
nano-cobalt and their bimetallic derivatives.
4. A nano-organocatalyst comprising magnetic nanomaterial-supported
glutathione, wherein glutathione is anchored to magnetic
nanomaterial.
Description
CROSS-REFERENCE TO PRIORITY APPLICATION
[0001] The present application is a division of commonly assigned
U.S. patent application Ser. No. 12/553,681 for a Magnetic
Nanoparticle-Supported Glutathione as a Sustainable Organocatalyst,
filed Sep. 3, 2009, (and published Mar. 3, 2011 as U.S. Patent
Application Publication No. 2011/0054180), now U.S. Pat. No.
8,324,125. Each of the foregoing patent application, patent
publication, and patent is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] Manufacturing protocols can be improved economically and
environmentally (made more "green") and made more sustainable
through the design and use of catalysts that reduce chemical waste
that is harmful to human health and the environment. It is an
object of the present invention to provide "green" catalysts and
protocols. This invention relates to the use of
nano-organocatalysts, and, more specifically, to the use of
magnetic nanomaterial-supported organocatalysts.
BACKGROUND OF THE INVENTION
[0003] Catalysis lies at the heart of countless chemical protocols,
from the academic research laboratories to the chemical industry. A
variety of products, such as medicines, fine chemicals, polymers,
fibers, fuels, paints, lubricants, and a myriad of other
value-added products essential to humans, would not be feasible in
the absence of catalysts. These active compounds arbitrate the
mechanism by which chemical transformations take place, thus
enabling the commercially viable creation of desired materials.
[0004] A homogeneous catalyst, where the catalyst is in the same
phase as the reactants, is often desirable. One attractive property
is that all catalytic sites are accessible because the catalyst is
generally a soluble metal complex. Furthermore, it is possible to
tune the chemo-, regio- and enantioselectivity of the catalyst.
Homogeneous catalysts have a number of other advantages such as
high selectivities, better yield, and easy optimization of
catalytic systems by modification of ligand and metals. They are
widely used in a number of commercial applications, but the
difficulty of catalyst separation from the final product creates
growing economic and environmental barriers to broaden their
scope.
[0005] Despite the advantages of homogeneous catalytic systems and
their wide use in a number of applications, many homogeneous
catalytic systems have not been commercialized because of the
difficulty encountered in separating the catalyst from final
reaction product and the solvent. Removal of trace amounts of
catalyst from the end product is essential since metal
contamination is highly regulated especially by the pharmaceutical
industry. Even with the extensive and careful use of various
techniques such as distillation, chromatography, or extraction,
removal of trace amounts of catalyst remains a challenge.
[0006] Heterogeneous catalyst systems appear to be the best logical
solution to overcome the separation problems in homogeneous
catalysis. The majority of the novel heterogenised catalysts are
based on silica supports, primarily because silica displays some
advantageous properties, such as excellent stability (chemical and
thermal), good accessibility, porosity, and the fact that organic
groups can be robustly anchored to the surface to provide catalytic
centers. The common structural feature of these materials is the
entrapment or anchoring of the dopant (catalytic) molecule in the
pores of silica, a phenomenon which imparts unique chemical and
physical properties to resulting hybrid silica. Anchoring can be
achieved by covalent binding of the molecules or by simple
adsorption; however covalent anchoring is robust enough to
withstand the harsh reaction conditions and the catalyst can be
reused several times. A vast majority of the industrial
heterogeneous catalysts are high-surface-area solids onto which an
active component is dispersed or attached.
[0007] Although attempts have been made to make all active sites on
solid supports accessible for reaction, allowing rates and
selectivities comparable to those obtained with homogeneous
catalysts, only sites on the surface are available for catalysis
thus decreasing the overall reactivity of the catalyst system.
Another problem is the leaching of active molecule/complex from
solid supports because of breaking of bonds between metal and
ligand during catalytic reactions, which again necessitates
separation of trace metals from final product. Catalyst recovery is
often performed by filtration that reduces efficiency, and
extractive isolation of products requires large amounts of organic
solvents.
[0008] Consequently, new catalyst systems that allow for the rapid,
selective chemical transformations with excellent product yield
coupled with the ease of catalyst separation and recovery are much
sought for "greening" the chemical manufacturing processes.
[0009] Nanomaterials, including nanoparticles, have emerged as
sustainable alternatives to conventional materials, as robust,
high-surface-area heterogeneous catalyst and catalyst supports. The
nano-size of the particles increases the exposed surface area of
active component of catalyst thereby enhancing the contact between
reactants and catalyst dramatically and mimicking the homogeneous
catalysts. The scientific challenge is the synthesis of catalyst in
nano-size to allow facile movement of materials in the reacting
phase and control over morphology of nanostructures to tailor the
physical and chemical properties. The development of solution-based
controlled synthesis of nanomaterials has made this possible
without difficulty. The synthesis and applications of a
micro-pine-structured nanocatalyst, Polshettiwar et al., Chem.
Commun. 2008, 6318-20; Self-assembly of metal oxides into 3D
nano-structures: Synthesis and nano-catalysis, Polshettiwar et al,
ACS Nano. 2009, 3, 728.
[0010] Magnetic nanomaterials are envisaged to have major impacts
on catalysis and many other areas, such as medicine, drug delivery
and remediation. These inexpensive materials are accessible via
simple synthesis and they can be easily enhanced/tuned by
postsynthetic surface modifications. Controlling Transport and
Chemical Functionality of Magnetic Nanoparticles, Latham et al.,
Acc. Chem. Res. 2008, 41, 411-420. Functionalized nanoparticles
have emerged as feasible substitute to conventional materials as a
robust, active, high-surface-area catalyst support. Magnetically
Recoverable Chiral Catalysts Immobilized on Magnetite Nanoparticles
for Asymmetric Hydrogenation of Aromatic Ketones, Hu et al, J. Am.
Chem. Soc. 2005, 127, 12486-87; Expanding the Utility of One-Pot
Multistep Reaction Networks through Compartmentation and Recovery
of the Catalyst, Phan et al., Angew. Chem. Int. Ed. 2006, 45,
2209-12; Metal Supported on Dendronized Magnetic Nanoparticles:
Highly Selective Hydroformylation Catalysts, Abu-Reziq et al., J.
Am. Chem. Soc. 2006, 128, 5279-5282; Tuning Catalytic Activity
between Homogeneous and Heterogeneous Catalysis Improved Activity
and Selectivity of Free Nano-Fe2O3 in Selective Oxidations, Shi et
al., Angew Chem. Int. Ed. 2007, 46, 8866-68; A
Magnetic-Nanoparticle-Supported 4-N,N-Dialkylaminopyridine
Catalyst: Excellent Reactivity Combined with Facile Catalyst
Recovery and Recyclability, Dalaigh et al., Angew. Chem. Int. Ed.
2007, 46, 4329-32; The First Magnetic Nanoparticle-Supported Chiral
DMAP Analogue: Highly Enantioselective Acylation and Excellent
Recyclability, Gleeson et al. Chem. Eur. J. 2009, doi-10.1002/chem.
200900532. In view of their nano-size, the contact between
reactants and catalyst 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.
Nanoparticle-supported and magnetically recoverable palladium (Pd)
catalyst: a selective and sustainable oxidation protocol with high
turnover number, Polshettiwar et. al. Org. Biomol. Chem., 2009, 7,
37-40; Nanoparticle-supported and magnetically recoverable nickel
catalyst: a robust and economic hydrogenation and transfer
hydrogenation protocol, Polshettiwar et. al. Green Chem., 2009, 11,
127-131; Nanoparticle-Supported and Magnetically Recoverable
Ruthenium Hydroxide Catalyst: Efficient Hydration of Nitriles to
Amides in Aqueous Medium, Polshettiwar et. al. Chem. Eur. J. 2009,
15, 1582-1586.
[0011] During the past decade, organocatalysis, a metal-free
approach to the synthesis of organic molecules, has become a
significant area of research. A diverse set of reactions, including
enantioselective C--C, C--N, C--O bond formation, Diels-Alder,
Baylis-Hilman, Mannich, Michael, Friedel-Crafts alkylation,
oxidation, and carbohydrate synthesis, has benefited from the
developments in this area. The advent and development of
organocatalysis, MacMillan, Nature 2008, 455, 304-308. This
relatively green approach has been rendered even greener by efforts
in immobilization and recycling of the organocatalysts on supports,
which involve their adsorption, covalent linkage, and dissolution
in various matrices. Supported proline and proline-derivatives as
recyclable organocatalysts, Gruttadauria et al., Chem. Soc. Rev.
2008, 37, 1666-88; Asymmetric Organocatalytic Domino Reactions,
Karimi et al., Angew Chem. Int. Ed. 2007, 46, 7210-7213; Asymmetric
Aldol Reaction Catalyzed by a Heterogenized Proline on a Mesoporous
Support. The Role of the Nature of Solvents, Doyaguez et al., J.
Org. Chem. 2007, 72, 9353-56; Magnetic nanoparticle-supported
proline as a recyclable and recoverable ligand for the CuI
catalyzed acylation of nitrogen nucleophiles, Chouhan et al. Chem.
Commun. 2007, 4809-4811. Newer strategies include the use of
non-traditional methods such as light, mechanochemical mixing,
microwave (MW), and ultrasonic irradiation. Most of these reactions
are generally carried out in organic solvents, with a few aqueous
phase organocatalytic processes as recent exceptions. Enamine-Based
Aldol Organocatalysis in Water: Are They Really "All Wet"?, Brogan
et al., Angew. Chem. Int. Ed. 2006, 45, 8100-02; Combined
Proline-Surfactant Organocatalyst for the Highly Diastereo-and
Enantioselective Aqueous Direct Cross-Aldol Reaction of Aldehydes,
Hayashi et al., Angew Chem. Int. Ed. 2006, 45, 5527-29; Asymmetric
Diels-Alder Reactions of a,b-Unsaturated Aldehydes Catalyzed by a
Diarylprolinol Silyl Ether Salt in the Presence of Water, Hayashi
et al., Angew Chem. Int. Ed. 2008, 47, 6634-37; Highly Efficient
Asymmetric Direct Stoichiometric Aldol Reactions on/in Water, Huang
et al., Angew Chem. Int. Ed. 2007, 46, 9073-77. Although water is
an environmental benign solvent, and addition of water often
accelerates the reaction, isolation of final organic product from a
reaction mixture is often tedious. Most of the reactions described
in published reports use excessive amounts of toxic organic
solvents for workup and the total amount of water used in the
process is much less. Environmental and economic aspects of both
the reaction step and the product workup stage are important and
are key to determining the greenness of aqueous protocols.
[0012] The efficiency of MW flash-heating has resulted in dramatic
reductions in reaction times, reduced from days to minutes, which
is potentially important in process chemistry for the expedient
generation of fine chemicals. Microwave-Assisted Organic Synthesis
and Transformations using Benign Reaction Media, Polshettiwar et.
al. Acc. Chem. Res. 2008, 5, 629-639. Microwaves initiate rapid
intense heating of polar molecules such as water while non-polar
molecules do not absorb the radiation and in turn not heated. It
was also established that the use of water was advantageous in
microwave chemistry and expedited the protocol with more energy
efficiency. Selective heating can also be exploited in
heterogeneous catalysis protocols. Aqueous microwave chemistry: a
clean and green synthetic tool for rapid drug discovery,
Polshettiwar et. al. Chem. Soc. Rev. 2008, 37, 1546-1557.
[0013] The nano-supported, magnetically recyclable organocatalysts
of embodiments of the present invention may be used for various
organocatalytic reactions, including but not limited to Paal-Knorr
reactions, aza-Michael additions and pyrazole synthesis.
[0014] The Paal-Knorr reaction in which amines are converted to
pyrrole in one step has gained great interest in the synthetic
organic chemistry because these heterocycles are intermediates for
various pharmaceutical drugs. A range of clean protocols has been
developed by using solid supported catalysts such as alumina,
zeolites, phosphates, and ionic liquids. 2,5-Dialkylfurans and
Nitroalkanes as Source of 2,3,5-Trialkylpyrroles, Ballini et al.,
Synlett 2000, 391-93; Layered zirconium phosphate and phosphonate
as heterogeneous catalyst in the preparation of pyrroles, Curini et
al., Tetrahedron Lett. 2003, 44, 3923-25; Pyrrole synthesis in
ionic liquids by Paal-Knorr condensation under mild conditions,
Wang et al., Tetrahedron Lett. 2004, 45, 3417-19. The use of
non-conventional energy sources such as microwave and ultrasound
has also been 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.
Further, the inventors are not aware that this reaction has ever
been accomplished using an organocatalyst.
[0015] Aza-Michael addition is a vital carbon-nitrogen bond-forming
reaction and has been intensively examined as a powerful tool in
organic synthesis. However, most of the aza-Michael additions are
performed in organic solvents. Recently .beta.-cyclodextrin,
ytterbium triflate, surfactant-type asymmetric organocatalyst
(STAO) type catalyst and polystyrenesulfonic acid, have been used
in aqueous medium. .beta.-Cyclodextrin promoted aza-Michael
addition of amines to conjugated alkenes in water, Surendra et al.,
Tetrahedron Lett. 2006, 47, 2125-27; Expanding the Scope of Lewis
Acid Catalysis in Water: Remarkable Ligand Acceleration of Aqueous
Ytterbium Triflate Catalyzed Michael Addition Reactions, Ding et
al., J. Org. Chem. 2006, 71, 352-55; Surfactant-type asymmetric
organocatalyst: organocatalytic asymmetric Michael addition to
nitrostyrenes in water, Luo et al., Chem. Commun. 2006, 3687-89;
Tandem bis-aza-Michael addition reaction of amines in aqueous
medium promoted by polystyrenesulfonic acid, Polshettiwar et al.
Tetrahedron Letters 2007, 48, 8735-8738. Although today's
environmental concerns encourage the development of such greener
synthetic methodology in aqueous medium, many of these methods
suffer from limitations such as the use of expensive and toxic
catalysts and harsh reaction conditions.
[0016] Pyrazoles are an important class of bio-active drug targets
in the pharmaceutical industry, in both lead identification and
lead optimization processes. Recently, several efficient methods
have been developed (Reaction of N-Monosubstituted Hydrazones with
Nitroolefins: A Novel Regioselective Pyrazole Synthesis, Deng et
al., Org. Lett. 2006, 8, 3505-08 and references cited therein,
Greener and rapid access to bio-active heterocycles: room
temperature synthesis of pyrazoles and diazepines in aqueous
medium, Polshettiwar et al. Tetrahedron Letters 2008, 49, 397-400);
however most of these utilize a circuitous route requiring longer
reaction times, and are often conducted in organic solvents.
Although organocatalysis has been extensively explored, much
remains to be accomplished, especially in the context of a truly
sustainable protocol.
[0017] Thus, there is a need for "green" catalysts and, further, a
need for benign aqueous protocols that do not use any organic
solvent in the reaction or during the workup.
BRIEF SUMMARY OF THE INVENTION
[0018] It is an object of the present invention to provide "green"
catalysts and protocols. According to one embodiment of the
invention, a nano-organocatalyst in the form of a magnetic
nanomaterial-supported organocatalyst is provided, wherein an
organocatalyst is anchored to a magnetic nanomaterial. According to
one embodiment of the invention, a magnetic nanomaterial-supported
organocatalyst for various organocatalytic reactions, including but
not limited to Paal-Knorr reactions, aza-Michael addition and
pyrazole synthesis, is provided. According to another embodiment of
the invention, a method of catalyzing a reaction using a magnetic
nanomaterial-supported organocatalyst comprises the steps of
providing a magnetic nanomaterial-supported organocatalyst, wherein
an organocatalyst is anchored to a magnetic material, providing a
reagent composition, and contacting the magnetic
nanomaterial-supported organocatalyst with the reagent
composition.
[0019] A nano-organocatalyst according to one embodiment of the
invention is formed when surfaces of magnetic nanomaterial are
modified by anchoring an organocatalyst to the nanomaterial to
functionalize the nanomaterial. According to another embodiment of
the invention, the organocatalyst comprises a compound having a
thiol group, and as shown in FIG. 1, after sonication, the
organocatalyst is anchored to the magnetic nanomaterial through a
sulfur group, thereby forming the nano-organocatalyst. According to
other embodiments of the invention, glutathione or cysteine is
selected as the organocatalyst and anchored to the magnetic
nanomaterial through the sulfur group, thereby imparting desirable
chemical functionality. In accordance with other embodiments,
recyclable magnetic nanomaterial-supported glutathione and
recyclable magnetic nanomaterial-supported cysteine are provided
for use as nano-organocatalysts.
[0020] According to another embodiment of the invention, a method
of using a magnetic nanomaterial-supported organocatalyst using a
totally benign aqueous protocol, without using any organic solvent
in the reaction or during the workup, is provided. According to one
embodiment of the invention, the magnetic nano-organocatalyst may
be separated from a reaction mixture using an external magnet,
eliminating the requirement of catalyst filtration. According to
further embodiments of the invention, magnetic
nanomaterial-supported organocatalysts as described herein are
recyclable.
[0021] The foregoing, as well as other characteristics and
advantages of the invention and the manner in which the same are
accomplished, are further specified within the following detailed
description and its accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 illustrates the synthesis of magnetic
nanoparticle-supported glutathione, according to one embodiment of
the invention.
[0023] FIG. 2 depicts the FT-IR spectra of (a) glutathione and (b)
magnetic nanoparticle-supported glutathione of one embodiment of
the invention.
[0024] FIG. 3 depicts a powder X-ray diffraction (XRD) pattern for
a magnetic nanoparticle-supported glutathione according to one
embodiment of the invention.
[0025] FIG. 4 depicts the TEM image of as-synthesized magnetic
nanoparticle-supported glutathione, according to one embodiment of
the invention.
[0026] FIG. 5 illustrates nano-organocatalyst promoted Paal-Knorr
reactions according to one embodiment of the invention.
[0027] FIG. 6 illustrates nano-organocatalyst promoted aza-Michael
reactions, according to another embodiment of the invention.
[0028] FIG. 7 illustrates nano-organocatalyst promoted pyrazole
synthesis, according to another embodiment of the invention.
[0029] FIG. 8 depicts, according to one embodiment of the
invention, the Paal-Knorr reaction of benzylamine using magnetic
nanoparticle-supported glutathione in water, before completion of
the reaction.
[0030] FIG. 9 depicts, according to one embodiment of the
invention, the Paal-Knorr reaction of benzylamine using magnetic
nanoparticle-supported glutathione in water, after completion of
the reaction.
[0031] FIG. 10 depicts, according to one embodiment of the
invention, steps of a method of catalyzing a reaction using a
magnetic nanomaterial-supported organocatalyst.
DETAILED DESCRIPTION OF THE INVENTION
[0032] Development in the area of supported organocatalysts will
encourage the production of fine chemicals in a sustainable manner
worldwide. According to one embodiment of the invention, a
nano-organocatalyst in the form of a magnetic
nanomaterial-supported organocatalyst is provided. Surfaces of
magnetic nanomaterial may be modified by anchoring organocatalysts
to the nanomaterial to functionalize the nanomaterial. In one
embodiment, nano-organocatalysts are formed by anchoring benign
organocatalysts to magnetic nanomaterial in a manner that keeps
active sites free for catalysis. Another embodiment of the
invention provides a nano-organocatalyst comprising a magnetic
nanomaterial-supported organocatalyst, wherein an organocatalyst
comprises a compound having a thiol group, and further wherein the
organocatalyst is anchored to a magnetic nanomaterial via
sonication through a sulfur group to functionalize the magnetic
nanomaterial. According to other embodiments of the invention, the
compound having a thiol group is selected from the group consisting
of glutathione and cysteine. Embodiments of the invention are also
described in Magnetic nanoparticle-supported glutathione: a
conceptually sustainable organocatalyst, Polshettiwar et. al. Chem.
Commun., 2009, 1837-1839, incorporated herein by reference.
[0033] Glutathione is a highly benign tripeptide consisting of
glutamic acid, cysteine and glycine units and is a ubiquitous
antioxidant present in human and plant cells. Besides a thiol
group, each molecule also contains amine and carboxylate
functionalities that provide coupling possibilities for further
cross-linking to other molecules. Glutathione and cysteine are
benign compounds that each have highly reactive thiol groups.
According to other embodiments of the invention, glutathione and
cysteine are provided as organo catalysts, and nano-organocatalysts
in the form of magnetic nanomaterial-supported glutathione and
magnetic nanomaterial-supported cysteine are provided. Surfaces of
magnetic nanomaterials may be modified by anchoring glutathione or
cysteine thereon, thereby imparting desirable chemical
functionality. Glutathione and cysteine may be anchored to the
nanomaterial by sulfur groups, keeping active sites free for
catalysis. Postsynthetic surface modification of magnetic
nanomaterial, including but not limited to nanoparticles, by
glutathione or cysteine imparts desirable chemical functionality
and enables the generation of catalytic sites on the surfaces of
ensuing nano-organocatalysts. One embodiment of the invention
provides a nano-organocatalyst comprising magnetic
nanomaterial-supported glutathione, wherein glutathione is anchored
to magnetic nanomaterial via a sulfur group as shown in FIG. 1 to
functionalize the magnetic nanomaterial. Another embodiment of the
invention provides a nano-organocatalyst comprising magnetic
nanomaterial-supported cysteine, wherein cysteine is anchored to
magnetic nanomaterial to functionalize the magnetic
nanomaterial.
[0034] According to another embodiment of the invention, the
magnetic nanomaterial is selected from the group consisting of
nano-ferrite, nano-nickel ferrite, nano-cobalt ferrite, nano-iron,
and nano-cobalt and their bimetallic derivatives. According to a
further embodiment of the invention, the magnetic nanomaterial
comprises magnetic nanoparticles, and according to another
embodiment, the magnetic nanomaterial comprises nano-ferrite in the
form of nanoparticles.
[0035] The nano-organocatalyst of the invention may be prepared in
high yield using the post-functionalization method described in
Magnetic nanoparticle-supported glutathione: a conceptually
sustainable organocatalyst, Polshettiwar et. al. Chem. Commun.,
2009, 1837-1839; The synthesis and applications of a
micro-pine-structured nanocatalyst, Polshettiwar et al., Chem.
Commun. 2008, 6318-20 and Self-assembly of metal oxides into 3D
nano-structures: Synthesis and nano-catalysis, Polshettiwar et al.,
ACS Nano 2009, 3, 728-36, each of which is incorporated herein by
reference.
[0036] The synthesis of nanoparticle-supported glutathione as a
nano-organocatalyst, according to one embodiment of the invention,
is illustrated in FIG. 1. This nano-organocatalyst may be prepared
by sono-chemical covalent anchoring of glutathione molecules
through coupling of a sulfur group and free hydroxyl groups of
ferrite surfaces. As shown in FIG. 1, nano-Fe.sub.3O.sub.4, a
magnetic nanoparticle, is combined with glutathione (reduced) with
water and sonicated at room temperature. In the resulting
nano-organocatalyst, glutathione is attached to the magnetic
nanoparticle by a sulfur group, leaving the terminal carboxylic
acid groups free for catalysis.
[0037] According to one embodiment of the invention, synthesis of a
nano-organocatalyst is accomplished by anchoring to a magnetic
nanomaterial, through a sulfur group, an organocatalyst comprising
a compound having a thiol group. According to another embodiment of
the invention, the organocatalyst is selected from the group
consisting of glutathione and cysteine. According to a further
embodiment of the invention, the magnetic nanomaterial is selected
from the group consisting of nano-ferrite, nano-nickel ferrite,
nano-cobalt ferrite, nano-iron, and nano-cobalt and their
bimetallic derivatives.
[0038] According to one embodiment of the invention, a
nanoparticle-supported glutathione was synthesized as follows:
Nano-Fe.sub.3O.sub.4 (0.5 gm) was dispersed in 15 mL water and 5 mL
methanol and sonicated for 15 minutes. Glutathione (reduced form)
(0.4 gm) dissolved in 5 mL water was added to this solution and
again sonicated for 2 hours. The nanoparticle-supported glutathione
(the nano-organocatalyst) was then isolated by centrifugation,
washed with water and methanol, and dried under vacuum at
50.degree. C. to 60.degree. C. Anchoring of glutathione on the
surface of the resulting nano-organocatalyst was confirmed through
examination by FT-IR spectroscopy, as shown in FIG. 2. The FT-IR
spectra for glutathione is identified as spectra (a) of FIG. 2; the
FT-IR spectra for the magnetic nanoparticle-supported glutathione
as synthesized above is identified as spectra (b) of FIG. 2. Three
characteristic bands (2947 cm.sup.-1 (C--H stretching), 1648
cm.sup.-1 (cysteine-carbonyl), and 1629 cm.sup.-1 (glutamic
acid-carbonyl) confirmed the attachment of glutathione on
nano-ferrite surfaces. The molecule was firmly anchored via a
sulfur group, as the IR band at 2558 cm.sup.-1 for S--H stretching
was diminished in the catalyst. A strong absorption band at 592
cm.sup.-1 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), as shown in FIG. 3; 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 nanocrystalline nature of the material. As
shown in FIG. 4, transmission electron microscopy (TEM) analysis of
the organocatalyst showed uniform-sized particles with spherical
morphology with an average size range of 10-12 nm. This is
comparable to the crystallite size (10.11 nm) calculated from X-ray
spectrum using Scherer formula for the full width at half-maximum
(fwhm) of the (311) reflection.
[0039] The strategy of the invention of immobilization of various
organic molecules on magnetic nano-support can also be used for
designing novel sensors, circuits, and devices on the nano-scale.
This system can also be used for drug delivery, medical imaging,
magnetic field assisted transport, separations and analyses.
Nanoparticle-based targeted drug delivery, Singh et. al. Exp. Mol.
Pathology. 2009, 86 215-223, Nano-oncology: drug delivery, imaging,
and sensing, Portney et. al. Anal. Bioanal. Chem. 2006, 384,
620-630, incorporated herein by reference.
[0040] Reactions may be catalyzed using the magnetic
nanomaterial-supported organocatalyst of embodiments of the
invention described herein. According to another embodiment of the
invention, a method of catalyzing a reaction using a magnetic
nanomaterial-supported organocatalyst comprises the steps of:
providing a magnetic nanomaterial-supported organocatalyst, wherein
an organocatalyst is anchored to the magnetic nanomaterial;
providing a reagent composition; and contacting the magnetic
nanomaterial-supported organocatalyst with the reagent composition.
According to a further embodiment, the method includes a step of
separating the magnetic nanomaterial-supported organocatalyst from
a reaction product with a magnet. According to one embodiment of
the invention, the organocatalyst comprises a compound having a
thiol group and the organocatalyst is anchored to the magnetic
nanomaterial through a sulfur group after sonification. According
to other embodiments of the invention, the organocatalyst comprises
glutathione or cysteine. According to another embodiment of the
invention, the magnetic nanomaterial is selected from the group
consisting of nano-ferrite, nano-nickel ferrite, nano-cobalt
ferrite, nano-iron, and nano-cobalt and their bimetallic
derivatives. According to another embodiment, the magnetic
nanomaterial comprises nano-ferrite in the form of
nanoparticles.
[0041] Although the nano-organocatalysts of the invention may be
used with organic solvents, according to one embodiment of the
invention, a nano-organocatalyst assisted reaction is conducted in
a benign solution comprising water, polyethylene glycol, or a
mixture thereof. Another embodiment of the invention is a method of
catalyzing a reaction wherein a magnetic nanomaterial-supported
organocatalyst and reagent composition are contacted in an aqueous
medium.
[0042] Separation of the catalyst and isolation of products are the
main operations in aqueous organocatalysis. Catalyst recovery is
often performed by filtration that reduces efficiency, and
extractive isolation of products requires large amount of organic
solvents. According to another embodiment of the invention, a
method of using a recyclable magnetic nanomaterial-supported
organocatalyst using a totally benign aqueous protocol, without
using any organic solvent in the reaction or during the workup, is
provided. According to one embodiment of the invention, a method of
catalyzing a reaction comprises a step of separating the magnetic
nanomaterial-supported organocatalyst from a reaction product with
a magnet. When phase separation of the desired reaction product
from the aqueous media occurs, the isolation of crude product by
simple decantation rather than tedious extraction processes is
facilitated. In cases in which solid product precipitates out, the
product may then be isolated by simple filtration after removal of
the nano-organocatalyst. Consequently, the use of volatile organic
solvents may be reduced during product workup.
[0043] According to another embodiment of the invention, the
nano-organocatalyst may be used under MW irradiation conditions.
The efficiency of MW flash-heating has resulted in dramatic
reductions in reaction times, reduced from days to minutes, which
is potentially important in process chemistry for the expedient
generation of fine chemicals. Microwave heating depends on
composition and structure of molecules (i.e. their dielectric
properties) and this property can facilitate selective heating.
MW-assisted chemistry allows rapid heating of a reaction mixture to
required temperatures and allows the precise control of the
reaction temperature as a result of the efficiency of the
interaction of MWs with the polar nano-catalyst. The magnetic
nanomaterial-supported organocatalysts may also act as susceptors,
materials that efficiently absorb microwave irradiation and
transfer the generated thermal energy to molecules in the vicinity
that are weak microwave absorber. Because MW-assisted reactions are
rapid, the residency time of nano-catalyst at high temperature is
minimum. Catalytical processes with such shorter reaction times
safeguard the catalyst from deactivation and decomposition,
consequently increasing the overall competence of catalyst as well
as entire protocol. It appears that this approach of fusing MW
technique with nano-catalysis and benign water (as a reaction
medium) can offer an extraordinary synergistic effect with greater
potential than these three individual components in isolation.
[0044] According to another embodiment of the invention, a
recyclable magnetic nanomaterial-supported organocatalyst for
various organocatalytic reactions, including but not limited to
Paal-Knorr reactions, aza-Michael addition and pyrazole synthesis,
is provided. According to one embodiment of the invention,
nano-organocatalysts are used in connection with Paal-Knorr
reactions in which amines are converted to pyrrole in one step. To
the best of the inventors' knowledge, Paal-Knorr reactions have
never before been accomplished using an organocatalyst. The
nano-organocatalyst promoted Paal-Knorr reactions are illustrated
in FIG. 5. In these reactions, an amine is combined with
tetrahydro-2,5-dimethoxyfuran. The nano-organocatalysts of
embodiments of the invention display high catalytic activity for
Paal-Knorr reactions and a variety of amines react efficiently with
tetrahydro-2,5-dimethoxyfuran to afford the desired pyrrole
derivates in good yields. The rates were essentially the same for
both the aliphatic or aromatic nature of the amines, showing the
high activity of the catalyst.
[0045] In the case of the Paal-Knorr reactions, the insoluble
character coupled with paramagnetic nature enables easy separation
of these nano-organocatalysts from the reaction mixture using an
external magnet, which eliminates the requirement of catalyst
filtration. In the Paal-Knorr reactions, the entire process was
carried out in an aqueous medium without using organic solvent in
the reaction or during the workout. Because of the
super-paramagnetic nature of the material, within a few seconds
after stirring is stopped, the nano-organocatalyst may be deposited
on the magnetic bar which may be easily removed using an external
magnet. Due to the selective absorption of microwaves by reactants,
polar nano-organocatalyst, and the aqueous medium, these biphasic
reactions functioned well in an aqueous medium without the need for
any phase-transfer catalyst. After completion of the Paal-Knorr
reactions, the phase separation of the desired product from the
aqueous media occurred in most cases, as shown in FIG. 8 and FIG.
9. In a few cases, solid product precipitated out; the product
could then be isolated by simple filtration. FIG. 9 depicts a
Paal-Knorr reaction of benzylamine using magnetic
nanoparticle-supported glutathione in water after completion of the
reaction; FIG. 8 shows the reactants and catalyst before the
reaction. As can be seen in FIG. 9, the top layer of material, the
product, may be isolated by simple decantation rather than tedious
extraction processes. Consequently the use of volatile organic
solvents is reduced during product workup.
[0046] FIG. 10 depicts, according to one embodiment of the
invention, steps of a method of catalyzing a reaction using a
magnetic nanomaterial-supported organocatalyst, wherein an
organocatalyst is anchored to a magnetic nanomaterial. According to
this embodiment, a magnetic nanomaterial-supported organocatalyst
and a reagent composition are provided and combined in an aqueous
solution. After the reaction, the magnetic nano-organocatalyst may
be separated from the solution with a magnet. The reaction product
may be removed from the solution by decantation without the need
for a phase-transfer catalyst.
[0047] According to a further embodiment of the invention, the
nano-organocatalyst is recyclable. For the Paal-Knorr reaction of
benzylamine, the nanoparticle-supported glutathione
nano-organocatalyst may be recycled five or more times without any
change in activity.
[0048] According to another embodiment of the invention,
nano-organocatalysts are used in connection with aza-Michael
addition, a vital carbon-nitrogen bond forming reaction. The
nano-organocatalyst promoted aza-Michael reactions are illustrated
in FIG. 6. According to another embodiment of the invention, an
amine is combined with a reagent selected from the group consisting
of methyl and butyl acrylate. No phase separation was observed in
the aza-Michael reactions because of the high solubility of the
product in water due to the presence of free --NH group.
[0049] According to another embodiment of the invention,
nano-organocatalysts are used in connection with pyrazole
synthesis. The nano-organocatalyst promoted pyrazole syntheses are
illustrated in FIG. 7. According to another embodiment of the
invention, a reagent composition comprises a first reagent selected
from the group consisting of hydrazines and hydrazides and a second
reagent selected from the group consisting of diketones and
.beta.-keto esters. In the pyrazole synthesis, the product was
isolated by simple decantation (in some cases) as well as
extraction by ethyl acetate.
EXAMPLES
[0050] All the solvents and reagents in the Examples discussed
below 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 qualitative 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.
[0051] Both glutathione and cysteine were tested for Pall-Knorr
reaction under homogeneous condition in water medium, to compare
their catalytic activity, and glutathione appeared to be more
active in comparison to cysteine. A nanoparticle-supported
glutathione was used in the following Examples.
[0052] The nanoparticle-supported glutathione used in the Examples
shown in Tables 1-4 (FIG. 1), was synthesized as follows:
Nano-Fe.sub.3O.sub.4 (0.5 gm) was dispersed in water (15 mL) and
methanol (5 mL) and sonicated for 15 minutes. Glutathione (reduced
form) (0.4 gm) dissolved in water (5 mL) was added to this solution
and again sonicated for 2 hours. The glutathione-functionalized
nanomaterial (nano-organocatalyst) was then isolated by
centrifugation, washed with water and methanol, and dried under
vacuum at 50 to 60.degree. C.
Paal-Knorr Reaction
[0053] In the Examples of Tables 1 and 2, the magnetic
nanoparticle-supported glutathione described above was used in
connection with the Paal-Knorr reaction.
[0054] Reaction conditions were optimized for the Paal-Knorr
reaction using benzyl amine as a substrate, using the
nano-organocatalyst under MW irradiation conditions. The reaction
was first conducted in toluene as a reaction medium at 120.degree.
C. and a poor conversion was observed (entry 1). Increasing the
reaction temperature to 140.degree. C. provided no significant
increase in conversion (entry 2). However, when the reaction was
carried out in a mixture of toluene and water, good conversion was
achieved (entry 3). When the reaction was carried out in pure
water, 92% conversion was achieved in 20 min at 140.degree. C.
under MW irradiation (entry 5). In pure water at 140.degree. C.
under MW irradiation, 95% conversion was achieved in 30 minutes
(entry 6).
TABLE-US-00001 TABLE 1 Optimization of reaction conditions..sup.a
No. Solvent R. temp. (.degree. C.) R. time (min) Conversion (%) 1
Toluene 120 30 >5 2 Toluene 140 30 >5 3 Toluene + H.sub.2O
140 30 80 4 H.sub.2O 120 30 70 5 H.sub.2O 140 20 92 6 H.sub.2O 140
30 95 .sup.a1 mmol of benzyl amine, 25 mg of
nano-organocatalyst
[0055] Deploying the above optimized reaction conditions, the scope
of the magnetic nanoparticle-supported glutathione
nano-organocatalyst was then investigated for Paal-Knorr reaction
using a variety of amines.
[0056] In the Examples of Table 2, (A) the amines (1 mmol), (B)
tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and (C)
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 thoroughly mixed. The reaction tube was then placed inside the
cavity of a CEM Discover focused MW synthesis system, operated at
140.+-.5.degree. C. (temperature monitored by a built-in infrared
sensor), power 50 to 250 Watt, and pressure 50 to 180 psi for 20 to
30 minutes (Table 2). After completion of the reaction, the phase
separation of the desired product from the aqueous medium occurred,
facilitating the isolation of crude product by simple decantation,
which was further purified by simply passing through short silica
column. All products are known in the literature and were
identified by comparison of their GC-MS spectra with standard Wiley
mass spectral library.
TABLE-US-00002 TABLE 2 Paal-Knorr reaction of amines using
nano-organocatalyst.sup.a Yield Entry Substrate Product (%) 1
##STR00001## ##STR00002## 92.sup. 2 ##STR00003## ##STR00004##
90.sup. 3 ##STR00005## ##STR00006## 90.sup. 4 ##STR00007##
##STR00008## 86.sup. 5 ##STR00009## ##STR00010## 88.sup. 6
##STR00011## ##STR00012## 85.sup. 7 ##STR00013## ##STR00014##
82.sup. 8 ##STR00015## ##STR00016## 78.sup. 9 ##STR00017##
##STR00018## 72.sup. 10 ##STR00019## ##STR00020## NR 11
##STR00021## ##STR00022## NR 12 ##STR00023## ##STR00024## 90.sup.
13 ##STR00025## ##STR00026## 84.sup. 14 ##STR00027## ##STR00028##
86.sup.b 15 ##STR00029## ##STR00030## 85.sup.b 16 ##STR00031##
##STR00032## 72.sup.c .sup.aReactions 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.degree. C. for 20 min
under MW irradiation, .sup.bsolvent extraction was needed to
isolate the product, .sup.c2.2 mmol of
tetrahydro-2,5-dimethoxyfuran, reaction temperature 150.degree. C.,
time 90 min.
[0057] As demonstrated in Table 2, the magnetic
nanoparticle-supported glutathione nano-organocatalyst displayed
high catalytic activity for Paal-Knorr reactions and a variety of
amines reacted efficiently with tetrahydro-2,5-dimethoxyfuran to
afford the desired pyrrole derivatives in good yields. The rates
were barely influenced by the aliphatic or aromatic nature of the
amines, showing the high activity of the nano-organocatalyst.
Chiral (S)-.alpha.-methylbenzylamine and
(R)-.alpha.-methylbenzylamine yielded corresponding 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, attempts to use amide (entry 10) and
hydrazine (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. In the case of
diamines, mono- and di-pyrrole derivatives can be synthesized just
by changing the mole ratio and reaction time. For diamines, by
changing the mole ratio and reaction time, mono-(entry 15) and di-
(entry 16) pyrrole derivatives were obtained. These biphasic
reactions functioned well in an aqueous medium without the need for
any phase-transfer catalyst, which is believed to be due to the
selective absorption of microwaves by reactants, polar
nano-catalyst, and aqueous medium.
[0058] To evaluate lifetime and level of reusability of the
catalyst, experiments were conducted 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 developed catalyst could be used at least 5 times
without any change in activity. Alternatively, the reaction could
be carried out by simply removing the product layer and adding
fresh benzylamine and tetrahydro-2,5-dimethoxyfuran, and similar
results were obtained.
Aza-Michael Reactions
[0059] This magnetic nanoparticle-supported glutathione
nano-organocatalyst was also examined for MW-assisted aza-Michael
reaction in aqueous medium as shown in FIG. 6. Using the reaction
conditions developed above (140.degree. C. under MW irradiation, 20
to 30 minutes), the scope and efficiency of this aqueous approach
was explored for the reaction of various amines with methyl and
butyl acrylate (Table 3). All reactions proceeded expeditiously 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.
[0060] The amines (1 mmol) and alkyl (1.2 mmol) 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
140.+-.5.degree. C. (temperature monitored by a built-in infrared
sensor), power 50 to 250 Watt, and pressure 50 to 180 psi for 20 to
30 minutes (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.
TABLE-US-00003 TABLE 3 Aza-Michael addition using a magnetic
nanoparticle- supported glutathione nano-organocatalyst. Yield
Entry R.sup.1 R.sup.2 Product (%) 1 PhCH.sub.2 Me ##STR00033## 92 2
PhCH.sub.2 Bu ##STR00034## 90 3 Ph Me ##STR00035## 92 4 Ph Bu
##STR00036## 90 5 Cy Me ##STR00037## 90 6 Cy Bu ##STR00038## 92 7
4-ClPh Me ##STR00039## 90 8 4-ClPh Bu ##STR00040## 90
Pyrazole Synthesis
[0061] This magnetic nanoparticle-supported glutathione
nano-organocatalyst nano-organocatalyst was also examined in
connection with the synthesis of pyrazole derivatives as shown in
FIG. 7. Various hydrazines and hydrazides reacted efficiently with
1,3-diketones to afford the desired pyrazoles in good yields (Table
4). The .beta.-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 20 to 30
minutes. In some cases, the product was isolated by simple
decantation, in others, it was extracted by ethyl acetate.
[0062] 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
140.+-.5.degree. C. (temperature monitored by a built-in infrared
sensor), power 50 to 250 Watt, and pressure 50 to 180 psi for 20 to
30 minutes (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.
TABLE-US-00004 TABLE 4 Pyrazole synthesis using nano-organocatalyst
Yield Entry Hydrazine Diketone Product (%) 1 ##STR00041##
##STR00042## ##STR00043## 96 2 ##STR00044## ##STR00045##
##STR00046## 80 3 ##STR00047## ##STR00048## ##STR00049## 84 4
##STR00050## ##STR00051## ##STR00052## 82 5 ##STR00053##
##STR00054## ##STR00055## 78 6 ##STR00056## ##STR00057##
##STR00058## 84 7 ##STR00059## ##STR00060## ##STR00061## 88 8
##STR00062## ##STR00063## ##STR00064## 84
[0063] In the specification and/or figures, typical embodiments of
the invention have been disclosed. The present invention is not
limited to such exemplary embodiments. Unless otherwise noted,
specific terms have been used in a generic and descriptive sense
and not for purposes of limitation.
* * * * *