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Green Chemistry Letters and Reviews

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“Greener” chemical syntheses using mechanochemical

mixing or microwave and ultrasound irradiation
a
Rajender S. Varma
a
Sustainable Technology Division, National Risk Management Research Laboratory, US
Environmental Protection Agency, 26 West Martin Luther King Drive, MS 443, Cincinnati, OH,
45268, USA
Published online: 20 Mar 2008.

To cite this article: Rajender S. Varma (2007) “Greener” chemical syntheses using mechanochemical mixing or microwave
and ultrasound irradiation, Green Chemistry Letters and Reviews, 1:1, 37-45, DOI: 10.1080/17518250701756991

To link to this article: http://dx.doi.org/10.1080/17518250701756991

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 Green Chemistry Letters and Reviews
Vol. 1, No. 1, March 2007, 37
45

ORIGINAL ARTICLE
‘‘Greener’’ chemical syntheses using mechanochemical mixing or
microwave and ultrasound irradiation
Rajender S. Varma*

Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency,
26 West Martin Luther King Drive, MS 443, Cincinnati, OH 45268, USA
(Received 9 August 2007; final form 14 September 2007)
Downloaded by [University of North Carolina Charlotte] at 07:48 20 September 2013

Various emerging ‘‘greener’’ strategic pathways, researched primarily in the author’s own laboratory, are
summarized. They include solvent-free mechanochemical methods that involve the use of hypervalent iodine
reagents at room temperature for the synthesis of heterocyclic entities, and useful conversion of ketones into
b-keto sulfones and their a-tosyloxy derivatives in high yields. A solvent-free approach that involves microwave
(MW) exposure of neat reactants (undiluted) catalyzed by the surfaces of less-expensive and recyclable mineral
supports, such as alumina, silica, clay, or ‘‘doped’’ surfaces, is described; it is applicable to a wide range of
cleavage, condensation, cyclization, rearrangement, oxidation, and reduction reactions, including rapid one-pot
assembly of heterocyclic compounds from in situ generated reactive intermediates. The strategy is adaptable to
multi-component reactions, e.g. Ugi and Biginelli reactions, for rapid assembly of a library of compounds.
Synthesis of a wide variety of significant precursors and intermediates, namely enones, imines, enamines,
nitroalkenes, and oxidized sulfur species, is possible and their value in concise MW synthesis of
2-aroylbenzofurans and thiazole derivatives is illustrated. Ultrasound- and MW-assisted solventless preparation
of ionic liquids and their application in alkylation and metal-catalyzed multi-component reactions are described.
With a view to consume greenhouse gas, carbon dioxide (CO2), efficient reaction of epoxides with CO2 provides
ready access to cyclic carbonates using only a catalytic amount of recyclable indium-based ionic liquid. MW
heating in aqueous reaction media enables expeditious N-alkylation reactions of amines and hydrazines to afford
a series of heterocyclic ring systems, such as N-azacycloalkanes, 4,5-dihydropyrazoles, and pyrazolidines.
A general and expeditious MW-enhanced nucleophilic substitution approach uses easily accessible starting
materials such as halides or tosylates in reaction with alkali azides, thiocyanates, or sulfinates in the absence of
any phase transfer catalyst to produce azides, thiocyanates, and sulfones, respectively, wherein a variety of
reactive functional groups are tolerated. A three-component condensation (MCC) approach for the synthesis of
useful 2-amino-2-chromenes is described using a recyclable nanosized magnesium oxide catalyst in aqueous poly
(ethylene glycol) (PEG) medium at room temperature. A general greener approach to shape-selective generation
of nanomaterials is summarized including their potential application as nanocomposites.
Keywords: microwave irradiation; mechanochemical mixing; ultrasound irradiation; Green chemical
synthesis; ionic liquids; heterocycles; nano-materials; solid-supported reactions; aqueous media

Introduction mical synthesis and transformations. The desired

The varied nature of the chemical world requires approach will require new environmentally benign
various greener pathways in our quest towards syntheses, catalytic methods, and chemical products
attaining sustainability. The emerging area of green that are ‘benign by design’ and that utilize renewable
chemistry envisages minimum hazard as the perfor- resources wherever possible (1). One of the thrust
mance criteria while designing new chemical pro- areas for achieving this target is to explore alternative
cesses (1). Rather than end-of-the-pipe remediation efficient reaction conditions and eco-friendly reaction
approach, which involves cleaning up of waste after it media to accomplish the desired chemical transfor-
has been produced, the main objective is to avoid mations with minimized by-products or waste, as well
waste generation in the first place. There are different as eliminating the use of conventional organic
shades of greener processes being developed as we solvents wherever possible. Consequently, several
continue exploring alternatives to conventional che- newer strategies have appeared, such as solvent-free

*Corresponding author. Email: varma.rajender@epa.gov

ISSN 1751-8253 print/ISSN 1751-7192 online

# 2007 Taylor & Francis
DOI: 10.1080/17518250701756991
http://www.informaworld.com
 38 R. S. Varma

O O O

R NH2
OH PhI(OH)OTs SO2R'
RCN R R
CHO N
OH O
O R'SO2Na, TBAB
OH N
H2N NH2 H2O2 Room temp.

RSR' Scheme 3. One-pot solvent-free synthesis of b-keto sulfones

O O from ketones.
S + R S R'
R R'
O
accomplish this task. Most of these processes, how-
Scheme 1. Solventless oxidations using urea hydrogen ever, suffer from drawbacks, such as the use of
peroxide complex. corrosive acids, hazardous peracids, and metallic
compounds that are inherently toxic and generate
(dry media), solid-supported with and without micro- noxious waste streams. A solvent-free oxidation of a
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wave (MW) irradiation (2
6), and mechanochemical variety of organic groups using an inexpensive, safe,
mixing (grinding) (7
9); and the use of room tem- and easily handled reagent, urea-hydrogen peroxide
perature ionic liquids (10,11), supercritical carbon (UHP), is now possible (Scheme 1); oxidations
dioxide, and water (12) as reaction media that can be include hydroxylated aldedydes and ketones (to
combined with MW or ultrasonic irradiation for phenols), sulfides (to sulfoxides and sulfones), nitriles
rapid synthesis. Indeed, the best solvent is ‘‘no (to amides), and N-heterocycles (to N-oxides) (14).
solvent,’’ but in such cases the problems of handling Ideally, the use of molecular oxygen in conjunction
of materials and heat and mass transfer aspects with a heterogeneous catalyst would be the most
persist and need to be addressed in close co-operation preferred alternative (15).
with chemical engineers.
The newer challenges that face the chemical
industry are the safety, security, and changing Mechanochemical reactions
regulatory requirements that dictate the improve- Solid-state chemistry is a rapidly developing frontier,
ments in the manufacturing efficiency via introduc- and several technological applications are appearing
tion of newer and efficient eco-friendly ‘‘greener’’ wherein mechanochemical forces are successfully
technologies. These technologies may help improve utilized in accomplishing the chemical reactions (7

the ‘‘triple bottom line’’ performance of a company, 9). Such reactions between two macroscopic solid
by containing the cost of the new chemical entities by particles have now been well studied and are believed
speeding up the innovation and waste reduction while to proceed via liquefaction where eutectic mixture
complying with the regulations. Presidential Green exists (7b).
Chemistry Challenge Awards, instituted in 1995, have We have studied some oxidative transformations
promoted this activity by identifying manufacturing by mechanochemical mixing of substrates with non-
processes that prevent pollution and are economically metallic hypervalent iodine reagents which enables
competitive, and several such cases have been sum- the syntheses of relatively complex molecules, such as
marized (13). Among several examples, a concise quinoxaline derivatives (16), b-ketosulfones (17), and
synthesis of Ibuprofen, a commonly used analgesic, a-tosyloxy b-ketosulfones (18). The oxidative trans-
summarizes this green chemistry theme by eliminat- formation of arenecarbaldehyde 3-methylquinoxalin-
ing large quantities of waste via a three-step atom- 2-yl-hydrazones to 1-aryl-4-methyl-1,2,4-triazolo[4,3-
economical route which replaced a six-step process a]quinoxalines (Scheme 2) occurs readily by a simple
using aluminium chloride (13). grinding process using a friendlier non-metallic
Oxidative transformations are important in or- oxidant, iodobenzene diacetate, PhI(OAc)2 (16).
ganic synthesis and several reagents are available to This protocol simply involves grinding of the two
N N
solid substrates using a pestle and mortar; a mildly
PhI(OAc)2

N NHN CHAr Grind N N

N O O O O O O
Ar C6H5I(OH)OTs
S S
Ar = C6H5, p-CH3C6H4, p-ClC6H4, p-OCH3C6H4, R R' neat, room temp. R R'
m-OCH3C6H4, p-N(CH3)2C6H4, OTs

Scheme 2. Synthesis of 1-aryl-4-methyl-1,2,4-triazolo[4,3- Scheme 4. Solvent-free synthesis of a-tosyloxy b-keto

a]quinoxalines. sulfones.
 ‘‘Greener’’ chemical syntheses using mechanochemical mixing or microwave and ultrasound irradiation 39

R CHO NH2 R erocyclic compounds from in situ generated reactive

N
Arylaldehydes MW
+
N X R1
N N X intermediates (20
23). Heterocyclic chemistry (21)
Y Clay H
R1 NC Y has been a major beneficiary of MW-expedited
Isonitriles
solvent-free chemistry utilizing mineral-supported
X = Y = C; X= C, Y= N; X= N, Y=C and R, R1= alkyl, aryl reagents which have been exploited for parallel
synthesis, a strategy that is adaptable for multi-
Scheme 5. MW-assisted three-component Ugi reaction. component reactions, such as Ugi (23) and Biginelli
reactions (22), for rapid assembly of a library of
exothermic reaction results in the formation of a compounds (24). A representative multi-component
yellowish eutectic melt and the reaction is completed condensation reaction to create a small-molecule
in a few minutes. library of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyr-
The work has now been extended to the synthesis azines and imidazo[1,2-a]pyrimidines is depicted in
of b-ketosulfones in high yields (17) from ketones Scheme 5 (23).
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employing another hypervalent iodine reagent, hy- In a process that eliminates the use of lachryma-
droxytosyloxy iodobenzene (PhI(OH)OTs), which tory a-haloketones, Varma et al. have synthesized a
involves in situ generation of a-tosyloxyketones variety of heterocyclic compounds (25) via simple
followed by nucleophilic substitution with sodium solvent-free reactions of thioamides, ethylenethiour-
arene sulfinate in the presence of tetra-butylammo- eas, and salicylaldehydes with a-tosyloxyketones,
nium bromide at room temperature (Scheme 3). which are generated in situ from arylmethyl ketones
Similarly, novel a-tosyloxy b-ketosulfones, valu- and [hydroxy(tosyloxy)iodo]benzene (HTIB) under
able precursors for heterocyclic compounds of MW irradiation conditions (Scheme 6).
therapeutic interests, have been prepared under
solvent-free conditions by a simple mechanochemical Solvent- and catalyst-free MW-reactions
mixing of b-ketosulfones with [hydroxyl(tosyloxy) The MW-facilitated reaction between two solids, in a
iodo]benzene (Scheme 4) (18). The research activity solvent- and catalyst-free environment, has been
in this fruitful area continues, as recently exemplified shown to provide rapid access to useful heterocyclic
by a facile and environmentally benign solvent-free hydrazones via the formation of a eutectic melt below
protocol described for the preparation of boronic the melting point of either reactant (26); neat 5- or
esters from the corresponding boronic acids by 8-oxobenzopyran-2(1H)-ones react with a variety of
simply grinding the two components together (19). aromatic and heteroaromatic hydrazines generating
several synthetically useful heterocyclic hydrazones
Solvent-free microwave-assisted reactions (Scheme 7) (26).
Solvent-free approaches that involve MW exposure
of neat reactants catalyzed by the surfaces of less Solvent-free synthesis of ionic liquids
expensive and recyclable mineral supports, such as Ionic liquids, being polar and ionic in charac-
alumina, silica, clay, or ‘‘doped’’ surfaces, are applic- ter, couple to MW irradiation very efficiently,
able (2
6) to a wide range of cleavage, condensation, and, therefore, have been considered MW absorbing
cyclization, rearrangement, oxidation, and reduction candidates for expediting chemical reactions.
reactions, including rapid one-pot assembly of het- Unfortunately, most of the initial preparative pro-

O
OTs

R
R1 CHO
R2
S
Clay/MW OH
HN NH MW
KF-Alumina

R H2N S Clay/MW
R
N R
R1
H S N
N
O O
R2
S

Scheme 6. Synthesis of heterocycles from in situ generated a-tosyloxyketones.

 40 R. S. Varma

R R Clayfen,15-60 sec
O O O O
R1NHNH2 R
CrO3/Al2O3,<40 sec
R
MW
IBD/Al2O3,1.5-2 min
NHCOPh NHCOPh
OH O
O N Solventless / MW
1
R HN R R'
R R'
R1HN
O Oxone/Al2O3,2-3 min

O O O O MnO2/SiO2,20-60 sec
R1NHNH2
MW CuSO4/Al2O3,2-3.5 min
NHCOPh NHCOPh
Scheme 9. MW-assisted solvent-free oxidation of alcohols
Scheme 7. Solvent-free preparation of hydrazones using to carbonyls.
microwaves.
The intrinsic reactivity of these low temperature
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cesses for the preparation of ionic liquids involve molten salts, especially from the viewpoint of altered
several hours of heating in refluxing solvents, and reactivity of dissolved substrate, has recently been
use a large excess of alkyl halides/organic solvents reviewed (35).
that diminish their true potential as ‘‘greener’’
solvents. The first solventless preparation of the
Microwave-assisted reactions on solid supports
1,3-dialkylimidazolium halides via MW heating has
been described by Varma et al. (Scheme 8); the MW protocols using immobilized reagents on solid
reaction time was reduced from hours to minutes supports have been extensively explored as inexpen-
and the use of a large excess of alkyl halides/organic sive kitchen MW ovens provided the usual heating
solvents as the reaction medium was avoided medium (2).
(10,27,28). The approach has been extended to other
ionic salts bearing tetrafluoroborate anions, and
Oxidation reactions
involves exposing N, N’-dialkylimidazolium chloride
and ammonium tetrafluoroborate salt to MW irra- The simple oxidation reactions involve solvent-free
diation (Scheme 8) (28), using dedicated MW mixing of neat substrates with, for example, clay-
equipment (29). Similarly, gallium and indium con- supported iron (III) nitrate (clayfen) (36) or iodoben-
taining ionic liquids (30,31) have been prepared and zene diacetate (IBD) as an oxidant (37), and brief
used in catalytic amounts for the reaction of MW irradiation for 15
60 sec (Scheme 9) (2
6). The
epoxides with carbon dioxide, affording a greener solid state utility of clayfen-iron(III) nitrate on clay as
route to useful cyclic carbonates (32); this strategy an oxidant has afforded higher yields and is more
focuses on the utilization of greenhouse gas, carbon efficiently supported on clay since the amounts used
dioxide, to generate valuable materials. The surge of in these protocols are half those used earlier in
interest continues in this area for the use of solution phase reactions.
ultrasonic pathways to prepare these solvents (11) The oxidation of sulfides is achieved in a similar
and their use as catalysts for alkylation of isobutane manner using MW irradiation with desired selectivity
with 2-butene (33), for ruthenium-catalyzed tandem to either sulfoxides or sulfones over sodium periodate
migration (34a), and silver-catalyzed coupling reac- (NaIO4) on silica (20%) (Scheme 10) (38). A note-
tions (34b). worthy feature of the protocol is its applicability to
long chain fatty sulfides, which are insoluble in most
solvents, and are consequently difficult to oxidize.
N N
Further, it circumvents the use of oxidants, such as
R X X R X nitric acid, hydrogen peroxide, chromic acid, and
MW MW peracids, conventionally used for the oxidation
X- X- X-
N N N N N N Clayfen, 15–60 sec
R R
O NaIO4 –Silica O
NaIO4 –Silica
R1 S R2 R1 S R2 R2 S R1
NH4BF4 0.5–2.5 min
X- BF4 - O
N N N N Sulfides Sulfoxides
R MW R IBD–Alumina, 40–90 sec Sulfones

where X = Cl, Br, I

Scheme 10. MW-assisted oxidation of sulfides to sulfoxides
Scheme 8. Solventless MW ionic liquid preparation. and/or sulfones.
 ‘‘Greener’’ chemical syntheses using mechanochemical mixing or microwave and ultrasound irradiation 41

O OH Microwave-assisted reactions in aqueous medium

R2 MW R2
Organic synthesis in aqueous media (12,41,42) is
NaBH4 - Alumina R1
R1 rapidly gaining ground in view of the fact that the
H CHO H CH2OH use of many toxic and volatile organic solvents,
MW
H H particularly chlorinated hydrocarbons, contributes
1 equiv. NaBH4 - Alumina to pollution. Utilization of water as a reaction
medium in conjunction with MW irradiation is one
Scheme 11. Solvent-free reduction of carbonyls on
alumina. of the emerging non-conventional methods being
recognized as viable environmentally benign alter-
natives (43
45). The nucleophilic substitution reac-
of sulfides to the corresponding sulfoxides and
tion of alkyl halides with amines is accelerated by
sulfones. MWs because of the polar nature of the reactants;
such N-alkylations proceed in basic water without
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Reduction reactions any phase transfer reagent (Scheme 13) (46).

The same nucleophilic substitution chemistry can
The relatively inexpensive and safe sodium borohy-
be manipulated by means of MWs to afford a variety
dride (NaBH4) has been extensively used as a
of cyclic amines as building blocks in natural product
reducing agent because of its compatibility with syntheses via double N-alkylation (47,48) of primary
protic solvents. Varma et al. have reported a simple amines (Scheme 14). The protocol circumvents the
method for the expeditious reduction of aldehydes difficulty associated with running multi-step reactions
and ketones that uses alumina-supported NaBH4 and to assemble N-aryl azacycloalkanes and avoids the
proceeds in the solid state accelerated by MW use of expensive metal catalysts in building aryl C
N
irradiation (Scheme 11) (39a). The useful chemose- bonds. Further, reactive functional groups, such as
lective feature of the reaction is apparent from the carbonyl, ester, and hydroxyl, remain unaffected
reduction of trans-cinnamaldehyde. under these mild reaction conditions. The N-alkyla-
The reaction rate improves in the presence of tion reaction is now also extended to hydrazines to
moisture and the reaction does not proceed in the deliver dihydropyrazoles, pyrazolidines, and dihy-
absence of alumina. The alumina support can be drophthalazines (Scheme 14) (47,48).
recycled and reused for subsequent reduction, repeat- It is noteworthy that this reaction is not a
edly, by mixing with fresh borohydride without any homogeneous single-phase system as neither reactant
loss in activity. In terms of safety, the air used for is soluble in the aqueous alkaline reaction medium.
cooling the magnetron ventilates the MW cavity, thus The selective absorption of MWs by polar molecules
preventing any ensuing hydrogen from reaching and intermediates in a multiphase system could
explosive concentrations. substitute as a phase transfer catalyst without using
Solvent-free reductive amination protocol for any phase transfer reagent, thereby providing the
carbonyl compounds using sodium borohydride sup- observed acceleration, as has been observed for
ported on moist montmorillonite K10 clay is facili- ultrasonic irradiation (49,50). The experimental ob-
tated by MW irradiation (Scheme 12) (39b). Clay servation is consistent with the mechanistic postula-
serves the dual purpose of a Lewis acid and also tion wherein the polar transition state of the reaction
provides water from its interlayers that enhance the is favored by MW irradiation with respect to the
dielectric polarization nature of MW energy transfer
reducing ability of NaBH4.
(47,48,51). In large scale experiments, the phase
This approach has been elegantly utilized for the
separation of the desired product in either solid or
MW-enhanced solid-state deuteriation reactions
liquid form from the aqueous medium can facilitate
using sodium borodeuteride impregnated alumina
product purification by simple filtration or decanta-
(40a). Subsequent extension of these studies to
tion instead of tedious column chromatography,
specific labeling has been explored (40b) including distillation, or extraction processes, which eventually
deuterium exchange reactions for the preparation of reduces the usage of volatile organic solvent required
reactive intermediates (40c). for extraction or column chromatography.

R1 R1 NaBH4 - Clay R1 R3
O + H2N R3 cat. Clay N R3 N
R2 MW R2 MW R2 H

Scheme 12. Reductive amination of carbonyls using clay-supported borohydride.

 42 R. S. Varma

R1
R1 H2O
MW R X + M+Nu- R Nu
R X + H N R N MW
NaOH/H2O
R2 R2 X = Br, Cl, I, OTs; M = K, Na; Nu = N3, SCN, SO2R'

R = Alkyl, allyl R1 = H, alkyl, allyl

Scheme 15. Microwave-enhanced nucleophilic substitution
X = Cl, Br, I R2 = alkyl, allyl
reactions.
Scheme 13. MW-assisted N-alkylation of amines by alkyl
halides in basic water. lyst, PSSA, for their synthesis using the Biginelli
reaction (Scheme 17) (54).
MW-assisted synthesis of azides, thiocyanates, Again, this efficient protocol for the synthesis of
and sulfones (52) has also been developed, starting substituted 3,4-dihydropyrimidin-2(1H)-ones proceeds
from readily available halides or tosylates (Scheme efficiently in water in the absence of organic solvent,
15), and has proved a useful alternative which avoids under MW irradiation conditions. Also, the use of
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the use of environmentally detrimental volatile chlori- polymer-supported, low toxic, and inexpensive PSSA
nated hydrocarbons (52). Various functional groups, as a catalyst renders this method eco-friendly, with a
very simple isolation procedure that simply entails the
such as ester, carboxylic acid, carbonyl, and hydrox-
filtration of the precipitated products.
yl, were unaffected under the mild reaction conditions
employed. This method involves simple experimental
method, benign product isolation protocol, and
Miscellaneous reactions
avoids the use of phase-transfer catalysts, and is
expected to contribute to the development of a Metal-catalyzed reactions
greener strategy for the preparation of various azides, The application of MW heating in the transition
thiocyanates, sulfones, and other useful compounds. metal-catalyzed homogeneous reactions has been
Dioxane rings are common structural motifs in very well explored resulting in robust and selective
numerous bioactive molecules, such as ()-dactylo- methods (55a); a variety of coupling as well as
lide (a cytotoxic agent), derivatives of 2-substituted- asymmetric catalysis reactions have been developed.
1,3-dioxanes (antimuscarinic agents), and ()-SCH Suzuki reaction. Polyethylene glycol (PEG) is an
351448 (a novel activator of low density lipoprotein inexpensive and non-toxic reaction medium for the
receptor promoters). Varma et al. have developed a MW-assisted Suzuki cross-coupling of arylboronic
one-pot protocol for their synthesis via a tandem bis- acids with aryl halides (Scheme 18) (55b). This
aldol reaction of ketone with paraformaldehyde, environmentally friendly MW protocol offers the
catalyzed by polystyrenesulfonic acid (PSSA) in ease of operation and enables the recyclability of
aqueous medium (Scheme 16) (53). catalyst and the synthesis of a variety of substituted
This reaction may find a useful place in drug biaryls employing palladium chloride as catalyst and
discovery for the synthesis of bio-active molecules potassium fluoride as the base. PEG offers a con-
bearing 1,3-dioxane moiety. It is noteworthy that venient, non-toxic, thermally stable, inexpensive and
these reactions proceed well in an aqueous medium recyclable reaction medium for Suzuki coupling by
without using any phase transfer catalyst (PTC). This substituting for volatile organic solvents. The MW
may be due to selective absorption of MWs by heating offers a rapid and clean alternative at high
reactants, intermediates, and polar aqueous medium, solid concentration and reduces the reaction time
which accelerate the reaction even in the absence of from hours to minutes. Further, the deployment of
PTC. inexpensive forms of palladium (palladium chloride)
Dihydropyrimidinones are an important class of as the catalyst and tolerance of a variety of functional
organic compounds that show prominent biological groups bodes well for the general utility of the
activity and we have used the aforementioned cata- reaction. The recyclability of the catalyst makes the
reaction economically and potentially viable for
K2CO3, H2O commercial applications.
R NH2 + X(CH2)nX R N (CH2)n + 2HX
MW
3 4 O O O
NH2 R R K2CO3,H2O N R4
R2 NH + R2 N + 2HX PSSA/H2O
X X MW (CHO)n O
1200C, MW
R3 O O
R, R1, R2 = H, alkyl, aryl; R3, R4 = H, alkyl; X = Cl, Br, I, TsO.

Scheme 14. MW-assisted formation of cyclic amines. Scheme 16. Bis-aldol reaction of flavanone in water.
 ‘‘Greener’’ chemical syntheses using mechanochemical mixing or microwave and ultrasound irradiation 43

R2

O O O X O
PSSA/H2O
R1
O H H2N NH2 80 OC, MW R1O NH

R2 N X
H

Scheme 17. Biginelli reaction in aqueous medium.

Multi-component one-pot condensation reaction for using vitamin B2 is that it is the most frequently
A nanosized magnesium oxide catalyzed three- encountered organic cofactor in nature and it can
component condensation reaction of aldehyde, mal- assume three different redox states: fully oxidized,
ononitrile, and a-naphthol proceeds rapidly in one-electron reduced, and fully reduced. Each of
water/PEG to afford corresponding 2-amino-2-chro- these redox states exists in a cationic, neutral, and
menes in high yields at room temperature (Scheme anionic form, depending on the pH of the solution,
Downloaded by [University of North Carolina Charlotte] at 07:48 20 September 2013

19) (56). and can transfer electrons. This environmentally

The greener protocol is found to be fairly general benign approach provides facile entry in producing
and the catalyst is reused in subsequent reactions with multiple shaped noble nanostructures that could find
consistent activity. The attractive features of this widespread technological and medicinal applications
protocol are the simple experimental procedure, use (57).
of benign reaction solvents, cost effectiveness, the Bulk and shape-controlled synthesis of gold (Au)
recyclability of catalysts, and its adaptability for the nanostructures with various shapes, such as prisms,
synthesis of a diverse set of substituted 2-amino-2- cubes, and hexagons, can also be accomplished via
chromenes (56). MW-assisted spontaneous reduction of noble metal
salts using an aqueous solution of a-D-glucose,
sucrose, and maltose (58). The expeditious reaction
Green synthesis of nanomaterials is completed under MW irradiation in 30
60 sec and
Nanometals. In the synthesis of metal nanoparticles can be applied to the generation of nanospheres of
via the reduction of the corresponding metal ion salt silver (Ag), palladium (Pd), and platinum (Pt). The
solutions, there are three areas of opportunity to noble nanocrystals undergo catalytic oxidation with
engage the green chemistry principles: (i) choice of monomers, such as pyrrole, to generate noble nano-
solvent, (ii) the reducing agent employed, and (iii) the composites that have potential functions in catalysis,
capping agent (or dispersing agent). In this context, it biosensors, energy storage systems, nanodevices, and
would of great interest to identify environmentally ever expanding other technological applications (58).
friendly materials that are multifunctional. The The MW strategy has also been extended to combus-
synthesis and self-assembly of noble nanometals are tion synthesis of porous nanocrystalline titania and
carbon-coated titania using dextrose as template (59);
carried out by reacting respective metal salts with
such ‘‘doped’’ titania may be utilized for photode-
vitamin B2 dissolved in solvents of varying densities,
gradation of pollutants in the visible light. This
such as ethylene glycol (r 1.113), acetic acid (r 
general method and eco-friendly protocol utilizes
1.049), N-methyl pyrrolidinone (NMP; r 1.03),
benign natural polymer dextrose and can be extended
water (r 0.998), isopropanol (r 0.790), acetone
to other transition metal oxides, e.g. ZrO2, Al2O3 and
(r 0.790), and acetonitrile (r 0.782) at room
SiO2, and may find widespread applications, such as
temperature (57). The vitamin B2 used in this study
fuel cell, membrane, dielectrics, and catalysis (59).
functions both as a reducing as well as a capping
agent for Au and Pt metals. In addition to its high Nanocomposites. The environmental impact of hand-
water solubility, biodegradability, and low toxicity ling nanomaterials is being debated at this time both
compared to other reducing agents, such as sodium by industry and the government. To avoid such
borohydride (NaBH4) and hydroxylamine hydrochlo- handling, one can envision the generation of these
ride, it appears to be an ideal multifunctional agent materials in the medium of choice, for example
for the production of nanomaterials. The rationale coating or membrane materials. We have developed
a facile method utilizing MW irradiation that accom-
HO PdCl2, KF plishes cross-linking reaction of poly (vinyl alcohol)
Br + B
HO PEG-400 (PVA) with metallic and bimetallic systems. Nano-
MW, 50sec
composites of PVA cross-linked metallic systems,
Scheme 18. Suzuki cross-coupling of arylboronic acids with such as Pt, Cu, and In and bimetallic systems, such
aryl halides. as Pt-In, Ag-Pt, Pt-Fe, Cu-Pd, Pt-Pd, and Pd-Fe, are
 44 R. S. Varma

OH

O NH2
CN MgO
RCHO
H2O/PEG
CN CN

Scheme 19. MgO catalyzed three-component condensation reaction.

prepared expeditiously by reacting respective metal Acknowledgements

salts with 3 wt% PVA under MW irradiation The author wishes to thank his collaborators and associates
maintaining a temperature at 1008C, a radical im- listed in the references, past and present, for their invalu-
provement over the literature methods to prepare able contributions.
cross-linked PVA (60). The general preparative Disclaimer. A US Government employee authored this
Downloaded by [University of North Carolina Charlotte] at 07:48 20 September 2013

procedure is versatile and provides a simple route to article as part of his official duties. In view of Section 105 of
manufacturing useful metallic and bimetallic nano- the Copyright Act (17 U.S.C. Section 105) the work is not
composites with varying shapes, such as spheres, subject to US copyright protection. The views expressed in
dendrites, and cubes (60). This general approach this article are those of the individual authors and do not
necessarily reflect the views and policies of the US
has also been adopted for cross-linking reaction of
Environmental Protection Agency. The use of trade names
PVA with single-wall carbon nanotubes (SWNT), does not imply endorsement by the US Government.
multi-wall carbon nanotubes (MWNT), and Buck-
minsterfullerene (C-60) using MWs (61). Nanocom-
posites of PVA cross-linked with SWNT, MWNT
and C-60 are prepared expeditiously by reacting
References
respective carbon nanotubes with 3 wt% PVA under
MW irradiation maintaining a temperature of 1008C. (1) Anastas, P.T.; Warner, J.C. Green Chemistry: Theory
This preparative and versatile MW procedure pro- and Practice; Oxford University Press: New York,
vides a simple route to manufacture useful SWNT, 1998.
(2) Varma, R.S. In A Loupy, Ed., Microwaves in Organic
MWNT, and C-60 nanocomposites (61). The use of
Synthesis; 2nd edn., Chapter 8, Wiley-VCH: Wein-
abundant biodegradable materials, such as carbox- heim, 2006, pp. 362
415.
ymethyl cellulose (CMC), in generating thin films (3) Varma, R.S. Pure Appl Chem. 2001, 73, 193.
with embedded nanometals is being pursued (62) (4) Varma, R.S. Green Chem. 1999, 1, 43.
under similar conditions. (5) Pillai, U.; Sahle-Demessie, E.; Varma, R.S. J Mater
Chem. 2002, 12, 3199.
(6) Varma, R.S. Tetrahedron. 2002, 58, 1235.
Conclusions (7) (a) Tanaka, K.; Toda, F. Chem Rev. 2000, 100, 1025;
The eco-friendly advantages of the synthetic alter- (b) Cave, G.W.V.; Raston, C.L.; Scott, J.L. Chem
natives based on unconventional activation via MW Commun. 2001, 2159.
or ultrasound irradiation or the use of friendly (8) (a) Toda, F.; Tanaka, K.; Sekikawa, A. J Chem Soc
Chem Commun. 1987, 279; (b) Bose, A.K.; Pednekar,
reaction media, such as water and PEG (55b), are
S.; Ganguly, S.N.; Chakraborty, G.; Manhas, M.S.
becoming increasingly apparent and may be adopted Tetrahedron Lett. 2004, 45, 8351.
by the chemical and pharmaceutical industry to (9) Kaupp, G.; Naimi-Jamal, M.R.; Stepaneneko, V.
reduce or eliminate volatile organic solvents, thus Chem Eur J. 2003, 9, 4156.
preventing pollution ‘‘at source.’’ The acceleration of (10) Varma, R.S. In Ionic Liquids as Green Solvents.
synthesis processes by MW/ultrasonic irradiation to Progress and Prospects; Rogers, R., Seddon K.R.,
shorten the reaction time and elimination or mini- Eds.; Chapter 7, ACS Symposium Series 856,
mization of side product formation is already finding American Chemical Society; Washington, DC, 2003,
acceptance in the pharmaceutical industry (combina- pp 82
92.
(11) Namboodiri, V.V.; Varma, R.S. Org Lett. 2002, 4,
torial chemistry) and polymer syntheses and may
3161.
pave the way towards a greener and more sustainable (12) (a) Wei, W.; Keh, C.C.K.; Li, C.-J.; Varma, R.S. Clean
approach to chemical syntheses (63). The newer Tech Environ Policy. 2005, 7, 62; (b) Varma, R.S.
strategies to generate nanomaterials in a variety of Organic Chemistry Highlights, Clean Chemical Synth-
media for their safer use may benefit from the esis in Water, 1 February, 2007, URL: http://www.orga
practice of green chemistry principles (64). nic-chemistry.org/Highlights/2007/01February.shtm.
 ‘‘Greener’’ chemical syntheses using mechanochemical mixing or microwave and ultrasound irradiation 45

(13) Cann, M.C., Connelly, M.E. Real World Cases in (39) (a) Varma, R.S.; Saini, R.K. Tetrahedron Lett. 1997,
Green Chemistry. American Chemical Society: 38, 4337; (b) Varma, R.S.; Dahiya, R. Tetrahedron.
Washington, DC, 2000, pp 19
24. 1998, 54, 6293.
(14) Varma, R.S.; Naicker, K.P. Org Lett. 1999, 1, 189. (40) (a) Erb, W.T.; Jones, J.R.; Lu, S.Y. J Chem Res (S).
(15) Sigman, M.S.; Jensen, D.R. Acc Chem Res. 2006, 39, 1999, 728; (b) Elander, N.; Jones, J.R.; Lu, S.Y.;
221. Stone-Elander, S. Chem Soc Rev. 2000, 29, 239; (c)
(16) Kumar, D.; Chandra Sekhar, K.V.G.; Dhillon, H.; Fodor-Csorba, K.; Galli, G.; Holly, S.; Gacs-Baitz, E.
Rao, V.S.; Varma, R.S. Green Chem. 2004, 6, 156. Tetrahedron Lett. 2002, 43, 4337.
(17) Kumar, D.; Sundaree, S.; Rao, V.S.; Varma, R.S. (41) Li, C.-J. Chem Rev. 2005, 105, 3095.
Tetrahedron Lett. 2006, 47, 4197. (42) Narayan, S.; Muldoon, J.; Finn, M.G.; Fokin, V.V.;
(18) Kumar, D.; Sundaree, S.; Patel, G.; Rao, V.S.; Varma, Kolb, H.C.; Sharpless, K.B. Angew Chem Int Ed. 2005,
R.S. Tetrahedron Lett. 2006, 47, 8239. 44, 3275.
(19) Schnurch, M.; Holzweber, M.; Mihovilovic, M.D.; (43) Bose, A.K.; Manhas, M.S.; Ganguly, S.N.; Sharma,
Stanetty, P. Green Chem, 2007; 9, 139. A.H.; Banik, B.K. Synthesis. 2002, 1578.
(44) Leadbeater, N.E. Chem Commun. 2005, 2881.
Downloaded by [University of North Carolina Charlotte] at 07:48 20 September 2013

(20) (a) Varma, R.S. Microwave Technology ? Chemical

Synthesis Applications: Kirk-Othmer Encyclopedia of (45) An, J.; Bagnell, L.; Cablewski, T.; Strauss, C.R.;
Trainor, R.W. J Org Chem. 1997, 62, 2505.
Chemical Technology; 5th edn. Volume 16, 2004, pp
(46) Ju, Y.; Varma, R.S. Green Chem. 2004, 6, 219.
538
594; (b) Varma, R.S. Advances in Green Chem-
(47) (a) Ju, Y.; Varma, R.S. Org Lett. 2005, 7, 2409; (b) Ju,
istry: Chemical Syntheses Using Microwave Irradia-
Y.; Varma, R.S. J Org Chem. 2006, 71, 135.
tion; AstraZeneca Research Foundation India:
(48) Ju, Y.; Varma, R.S. Tetrahedron Lett. 2005, 46, 6011.
Bangalore, India, 2006, John Wiley & Sons. (49) (a) Varma, R.S.; Naicker, K.P. Tetrahedron Lett.
(21) Varma, R.S. J Heterocyclic Chem. 1999, 35, 1565. 1998, 39, 2915; (b) Varma, R.S.; Naicker, K.P.;
(22) Kappe, C.O.; Kumar, D.; Varma, R.S. Synthesis. Aschberger, P. Synth Commun. 1999, 29, 2823.
1999, 1799. (50) Varma, R.S.; Naicker, K.P.; Kumar, D. J Mol Cat A:
(23) Kumar, D.; Varma, R.S. Tetrahedron Lett. 1999, 40, Chemical. 1999, 149, 153.
7665. (51) Loupy, A.; Varma, R.S. Chim Oggi (Chemistry To-
(24) Kappe, C.O. Angew Chem Int Ed. 2004, 43, 6250. day). 2006, 24, 36.
(25) Varma, R.S.; Kumar, D.; Liesen, P.J. J Chem Soc (52) Ju, Y.; Varma, R.S. J Org Chem. 2006, 71, 6697.
Perkin Trans. 1998, 1, 4093. (53) Polshettiwar, V.; Varma, R.S.J. Org Chem. 2007, 72,
(26) (a) Ješelnik, M.; Varma, R.S.; Polanc, S.; Kocevar, M. 7420.
Chem Commun. 2001, 1716; (b) Green Chem. 2002, 4, (54) Polshettiwar, V.; Varma, R.S. Tetrahedron Lett. 2007,
35. 48, 7443.
(27) (a) Varma, R.S.; Namboodiri, V.V. Chem Commun. (55) (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc Chem
2001, 643; (b) Varma, R.S.; Namboodiri, V.V. Pure Res. 2002, 35, 717; (b) Namboodiri, V.V.; Varma, R.S.
Appl Chem. 2001, 73, 1309. Green Chem. 2001, 3, 146.
(28) Namboodiri, V.V.; Varma, R.S. Tetrahedron Lett. (56) Kumar, D.; Reddy, B.; Mishra, B.G.; Rana, R.K.;
2002, 43, 5381. Nadagouda, M.N.; Varma, R.S. Tetrahedron. 2007,
(29) Deetlefs, M.; Seddon, K.R. Green Chem. 2003, 5, 181. 63, 3093.
(30) Kim, Y.-J.; Varma, R.S. Tetrahedron Lett. 2005, 46, (57) Nadagouda, M.N.; Varma, R.S. Green Chem. 2006, 8,
1467. 516.
(31) Kim, Y.-J.; Varma, R.S. Tetrahedron Lett. 2005, 46, (58) Nadagouda, M.N.; Varma, R.S. Crystal Growth De-
7447. sign. 2007, 7, 686.
(32) Kim, Y.-J.; Varma, R.S. J Org Chem. 2005, 70, 7882. (59) Nadagouda, M.N.; Varma, R.S. J Smart Mater
(33) Yoo, K.; Namboodiri, V.V.; Smirniotis, P.G.; Varma, Struct. 2006, 15, 1260.
R.S. J Catal. 2004, 222, 511. (60) Nadagouda, M.N.; Varma, R.S. Macromol Rapid
(34) (a) Yang, X.-F.; Wang, M.; Varma, R.S.; Li. C.-J. J Commun. 2007, 28, 465.
Mol Cat A Chem. 2004, 214, 47; (b) Li, Z.; Wei, C.; (61) Nadagouda, M.N.; Varma, R.S. Macromol Rapid
Chen, L.; Varma, R.S.; Li, C.-J. Tetrahedron Lett. Commun. 2007, 28, 842.
2004, 45, 2443. (62) Nadagouda, M.N.; Varma, R.S. Biomacromolecules.
(35) Chowdhury, S.; Mohan, R.S.; Scott, J.L. Tetrahedron. 2007, 8, in press.
2007, 63, 2363. (63) Strauss, C.R.;Varma, R.S. Top Curr Chem; (M Larhed
(36) Varma, R.S.; Dahiya, R. Tetrahedron Lett. 1997, 38, and K Olofssson, Eds.), Springer-Verlag, 2006; 266,
2043. 199
231.
(37) Varma, R.S.; Dahiya, R.; Saini, R.K. Tetrahedron (64) (a) Nadagouda, M.N.; Varma, R.S. Green Chem.
Lett. 1997, 38, 7029. 2007, 9, 632; (b) Nadagouda, M.N.; Varma, R.S.
(38) Varma, R.S.; Saini, R.K.; Meshram, H.M. Tetrahe- Green Chem. 2007, 9, communicated; (c) Nadagouda,
M.N.; Varma, R.S. Macromol Rapid Commun. 2007
dron Lett. 1997, 38, 6525.
28, 2106.