1

CHAPTER 1
A BRIEF REVIEW ON GREEN CHEMISTRY

1.1 Introduction
Over the past few years, the chemistry community has been mobilized to
develop new chemistries that are less hazardous to human health and the environment.
This new approach has received extensive attention and goes by many names
including Green Chemistry, Environmentally Benign Chemistry, Clean Chemistry,
Atom Economy and Benign by Design Chemistry. Under all of these different
designations there is a movement toward pursuing chemistry with the knowledge that
the consequences of chemistry do not stop with the properties of the target molecule or
the efficacy of a particular reagent.
One obvious but important point- nothing is benign. All substances and all
activity have some impact just by their being. What is being discussed when the term
benign by design or environmentally benign chemistry is used is simply an ideal.
Striving to make chemistry more benign wherever possible is merely a goal. Much like
the goal of "zero defects" that was espoused by the manufacturing sector, benign
chemistry is merely a statement of aiming for perfection.
While it has already been mentioned that nothing is truly environmentally
benign, there are substances that are known to be more toxic to humans and more
harmful to the environment than others. By using the extensive data available on
human health effects and ecological impacts for a wide variety of individual chemicals
and chemical classes, chemists can make informed choices as to which chemicals
would be more favourable to use in a particular synthesis or process. Simply stated,
Green Chemistry is the use of chemistry techniques and methodologies that reduce or
 2

eliminate the use or generation of feedstock, products, by-products, solvents, reagents,

etc., that are hazardous to human health or the environment. Green Chemistry is an
approach to the synthesis, processing and use of chemicals that reduces risks to
humans and the environment. Much innovative chemistry has been developed over the
past several years that are effective, efficient and more environmentally benign. These
approaches include new synthesis and processes as well as new tools for instructing
aspiring chemists how to do chemistry in a more environmentally benign manner. The
benefits to industry as well as the environment are all a part of the positive impact that
Green Chemistry is having in the chemistry community and in society in general.
It is important that chemists develop new Green Chemistry options even on an
incremental basis. While all elements of the lifecycle of a new chemical or process
may not be environmentally benign, it is nonetheless important to improve those
stages where improvements can be made. The next phase of an investigation can then
focus on the elements of the lifecycle that are still in need of improvement. Even
though a new Green Chemistry methodology does not solve at once every problem
associated with the lifecycle of a particular chemical or process, the advances that it
does make are nonetheless very important.
Green Chemistry that possesses the spirit of sustainable development was
booming in the 1990s,1 and has attracted more and more interest in the 21st century.
The study of the organic reactions from the point of view of its greenness must have in
mind first of all that a general synthetic method must be based on complete and
efficient conversions of well defined selectivity and that greenness is more a term for
comparison than an absolute kind of qualification. In order to evaluate the greenness
of a particular process attention must be paid in the first instance to issues related to
safety, health and protection of the environment, due to reactants (substrates and
reagents), auxiliaries (mainly solvents) and waste. This enumeration is obviously
incomplete, but can be useful at present. The question about how green a reaction is
most frequently refers to a particular conversion, to the comparison between two or
more alternative processes for the same synthetic target, or between the synthetic
pathways for the manufacture of alternative compounds. The study of the greenness of
the organic reaction is completed by a short overview of recent contributions indented
to achieve efficient, safe and clean conversions that are susceptible to becoming
general synthetic procedures.
 3

With the increasing concerns about the environmental protection, synthesis of

organic compounds from raw materials through a Green Chemistry procedure is
desirable. Certainly the area of environmentally benign solvents has been one of the
leading research areas of Green Chemistry with great advances seen in aqueous
(biphase) catalysis2,3 and the use of supercritical fluids4 in chemical reactions. While
the greenness of ionic liquids5,6 and fluorous media7 will ultimately depend on their
individual properties with respect to health and the environment, the sustainability of
new biobased solvents8 has to be proven as well. There has been a renewed focus on
the age-old pursuit of the organic chemist to design and successfully apply the ideal
synthesis in terms of efficiency, with atom9-11and step economy11 being a major goal.
New catalytic processes continue to emerge to advance the goals of Green Chemistry,
while techniques such as microwave12-14 and ultrasonic synthesis15 as well as in situ
spectroscopic methods16-17 has been used extensively, leading to spectacular results.
These research areas are a glimpse of some of the many topics directly relevant to
Green Chemistry being pursued by researchers around the world. The development of
asymmetric reactions stereoselective formation of C-C bond based on green protocol
is also of paramount interest. In recent year’s asymmetric metal, organo-metal
catalysis has been intensively studied and several efficient methods for the synthesis of
enantiomerically pure compounds have been developed. Our work which is based on
green protocol by developing metal and organo-metal promoted synthesis of some
organic compounds in aqueous media is also described. This chapter provides
background to the present work by reviewing literature on Green Chemistry. The
concept of Green Chemistry, its principles and different types of reactions are
presented.

1.2 Definition
The term Green Chemistry is defined as -“The invention, design and
application of chemical products and processes to reduce or to eliminate the use and
generation of hazardous substances”.18
While this short definition appears straightforward, it marks a significant
departure from the manner in which environmental issues have been considered or
ignored in the up-front design of the molecules and molecular transformations that are
at the heart of the chemical enterprise. Looking at the definition of Green Chemistry,
the first thing one sees is the concept of invention and design. By requiring that the
 4

impacts of chemical products and chemical processes are included as design criteria,
the definition of Green Chemistry inextricably links hazard considerations to
performance criteria.
Another aspect of the definition of Green Chemistry is found in the phrase “use
and generation”. Rather than focusing only on those undesirable substances that might
be inadvertently produced in a process; Green Chemistry also includes all substances
that are part of the process. Therefore, Green Chemistry is a tool not only for
minimizing the negative impact of those procedures aimed at optimizing efficiency,
although clearly both impact minimization and process optimization are legitimate and
complementary objectives of the subject.
Finally, the definition of Green Chemistry includes the term “hazardous”. It is
important to note that Green Chemistry is a way of dealing with risk reduction and
pollution prevention by addressing the intrinsic hazards of the substances rather than
those circumstances and conditions of their use that might increase their risk.
The definition of Green Chemistry also illustrates another important point
about the use of the term “hazard”. This term is not restricted to physical hazards such
as explosiveness, flammability, and corrodibility, but certainly also includes acute and
chronic toxicity, carcinogenicity, and ecological toxicity. Furthermore, for the
purposes of this definition, hazards must include global threats such as global
warming, stratospheric ozone depletion, resource depletion and bioaccumulation, and
persistent chemicals. To include this broad perspective is both philosophically and
pragmatically consistent. It would certainly be unreasonable to address only some
subset of hazards while ignoring or not addressing others. But more importantly,
intrinsically hazardous properties constitute those issues that can be addressed through
the proper design or redesign of chemistry and chemicals.
Green Chemistry definitions change based upon focus. Green Chemistry is
often described within the context of new technologies But Green Chemistry is not
beholden to ionic liquids,19 microwave chemistry,20 supercritical fluids,21
biotransformations,22 fluorous phase chemistry,23 or any other new technology. Green
Chemistry is outside of techniques used but rather resides within the intent and the
result of technical application.
Some view Green Chemistry as something process chemists do already.....
Good process chemistry. While often enabling “greener” synthesis, good process
chemistry is not equivalent to Green Chemistry. A robust, efficiency, and cost-
 5

effective chemical process is likely accepted as good process chemistry. Green

Chemistry is not simply good process chemistry; it is the highest efficiency potential
that exists for each chemical process, serving as both an inspiration for and a measure
of the best process chemistry. Others feel Green Chemistry is a purely environmental
agenda, and a condemnation of industrial chemistry or of scientists. This picture
neglects the direct relationship between Green Chemistry principles and highly
efficient and environmentally benign chemistry. Green Chemistry is a concept for
scientists envisioned by scientists for higher efficiency, not a mandate or a
condemnation from outside of the scientific community.
In short, Green Chemistry is neither a new type of chemistry nor an
environmental movement, a condemnation of industry, new technology, or “what we
do already”. Green Chemistry is simply a new environmental priority when
accomplishing the science already being performed... regardless of the scientific
discipline or the techniques applied. Green Chemistry is a concept driven by efficiency
coupled to environmental responsibility.
Green Chemistry philosophy24 provides a design for chemical evolution and a guide
for scientists to accomplish sustainable practices during chemical research,
development, and manufacturing. It has been proposed that evolution toward Green
Chemistry has recently crested a summit25 and gained momentum enough that general
technical exemplification is both imminent and inevitable. Clearly, scientist better
recognize and acknowledge the need for greater synthetic efficiency and
environmental concern. Unfortunately, the scientific community as a whole has yet to
commit the necessary resources to enable this higher level of efficiency through
greener chemistry. What has been accomplished is a sea change in the attitude of
many academic and industrial scientists, and a wide acceptance that the philosophy of
Green Chemistry offers great potential economically and environmentally.
Green Chemistry insists that our synthetic objectives are achieved while
assuming additional considerations related to the unnecessary environmental burden
created during operations. If using a toxic reagent, one should inquire if a less toxic
reagent might accomplish similar ends. A literature search may provide no current
alternative with similar efficiency and reduced toxicity, but many do not realize that
the simple act of inquiry toward reduced toxicity already indicates a new priority and
intent, a higher level of awareness and environmental stewardship, and is Green
Chemistry! In some cases a safer reagent will exist. Application will improve the
 6

process environmental profile and reduce risk related to working with a toxic reagent
while maintaining or improving synthetic efficiency. Some believe an environmental
priority will add time and cost. Just the opposite, time and cost are reduced by
incorporating higher synthetic efficiency the first time, and new methods can be
applied toward parallel and future endeavours to enhance overall productivity.
Green Chemistry is defined as environmentally benign chemical synthesis.
Green Chemistry may also be defined as the invention, design, and application of
chemical products and processes to reduce or eliminate the use and generation of
hazardous substances. The synthetic schemes are designed in such a way that there is
least pollution to the environment. As on today, maximum pollution to the
environment is caused by numerous chemical industries. The cost involved in disposal
of the waste products is also enormous. Therefore, attempts have been made to design
synthesis for manufacturing processes in such a way that the waste products are
minima, they have no effect on the environment and their disposal is convenient. For
carrying out reactions it is necessary that the starting materials, solvents and catalysts
should be carefully chosen. For example, use of benzene as a solvent must be avoided
at any cost since it is carcinogenic in nature. If possible, it is best to carry out reactions
in the aqueous phase. With this view in mind, synthetic methods should be designed in
such a way that the starting materials are consumed to the maximum extent in the final
product. The reaction should not generate any toxic by-products.
Since its birth over a decade ago, the field of Green Chemistry has seen rapid
expansion, with numerous innovative scientific breakthroughs associated with the
production and utilization of chemical products.26 The concept and ideal of Green
Chemistry now goes beyond chemistry and touches subjects ranging from energy to
societal sustainability. The key notion of Green Chemistry is ‘‘efficiency’’, including
material efficiency, energy efficiency, man-power efficiency, and property efficiency
(e.g., desired function vs toxicity). Any ‘‘wastes’’ aside from these efficiencies are to
be addressed through innovative Green Chemistry means. ‘‘Atom-economy’’27 and
minimization of auxiliary chemicals, such as protecting groups and solvents, form the
pillar of material efficiency in chemical productions.
Green Chemistry is an approach to the design, manufacture and use of
chemical products to intentionally reduce or eliminate chemical hazards.28 Goal of
Green Chemistry is to create better, safer chemicals while choosing the safest, most
efficient ways to synthesize them and to reduce wastes. Chemicals are typically
 7

created with the expectation that any chemical hazards can somehow be controlled or
managed by establishing “safe” concentrations and exposure limits.

1.3 Principles of Green Chemistry

Green Chemistry aims to eliminate hazards right at the design stage. The
practice of eliminating hazards from the beginning of the chemical design process has
benefits for our health and the environment, throughout the design, production,
use/reuse and disposal processes.29 Practitioners of Green Chemistry strive to protect
the environment by cleaning up toxic waste sites and by inventing new chemical
methods that do not pollute and that minimize the consumption of energy and natural
resources. In 1998, two US chemists, Dr. Paul Anastas and Dr John Warner outlined
Twelve Principles of Green Chemistry to demonstrate how chemical production could
respect human health and the environment while also being efficient and profitable.30
Guidelines for developing Green Chemistry technologies are summarized in the
“Twelve Principles of Green Chemistry,” shown in the following.
1. It is better to prevent waste than to treat or clean up waste after it is formed.
It is most appropriate to carry out a synthesis by following a pathway so that
formation of waste is minimum or absent. One type of waste product common and
often avoidable is the starting material or reagent that remains unreacted. The well
known saying “Prevention is better than cure should be followed”.
2. Synthetic methods should be designed to maximize the incorporation of all the
materials used in the process into the final product.
If one mole of the starting material produces one mole of the product, the yield
is 100 %. However, such a synthesis may generate significant amount of waste or by
product which is not visible in the above calculation. Such a synthesis, even though
gives 100% yield, is not considered to be green synthesis.
In order to find, if a particular reaction is green, the concept of atom economy
was developed by Berry Trost of Stanford University. This considers the amount of
stating materials incorporated into the desired final product. Thus by incorporation of
greater amounts of the atoms contained in the starting materials (reactants) in to the
formed products, fewer waste by products are obtained. In this way, using the concept
of atom economy along with ideas of selectivity and yield, “greener” more efficient
synthesis can be developed. The atom economy for a reaction can be calculated using
the following equation:
 8

Percent atom economy = Molecular weight of desired product X 100%

Molecular weights of all reactants
To illustrate the benefits of atom economy, consider the synthesis of ibuprofen.
In the former process, developed in the 1960s, only 40% of the reactant atoms were
incorporated into the desired ibuprofen product; the remaining 60% of the reactant
atoms found their way into unwanted by-products or waste that required disposal .The
new method requires fewer reaction steps and recovers 77% of the reactant atoms in
the desired product. This ‘green’ process eliminates millions of pounds of waste
chemical by-products every year, and it reduces by millions of pounds the amount of
reactants needed to prepare this widely used analgesic.
3. Whenever practicable synthetic methodologies should be designed to use and
generate a substance that poses little or no toxicity to human health and the
environment.
Wherever practicable, synthetic methodologies should be designed to use and
generate substances that pose little or no toxicity to human health and the
environment. Redesigning existing transformations to incorporate less hazardous
materials is at the heart of Green Chemistry.
4. Chemical products should be designed to preserve efficiency of function while
reducing toxicity.
The designing of safer chemical is now possible since there have been great
advances in the understanding of chemical toxicity. It is now fairly understood that a
correlation exist between chemical structure e.g. presence of functional groups and the
existence of toxic effects. The idea is to avoid the functionality related to the toxic
effect. Chemical properties of a molecule, such as water solubility, polarity etc. so that
they can manipulate molecules to the desired effects.
5. The use auxiliary substances (e.g. solvents, separating agents) should be made
unnecessary wherever possible and innocuous when used.
An auxiliary substance is one that helps in manufacture of a substance, but does
not become an integral part of the chemical. Such substances are used in the
manufacture, processing at every step. Major problem with many solvents is their
volatility that may damage human health and the environment. Even processes like
recrystalisation require energy and substances to change the solubility. The problem of
solvents has been overcome by using such solvents which do not pollute the
environment. Such solvents are known as green solvents. Examples include liquid
 9

carbon dioxide (supercritical CO2), ionic liquid water. Even reactions have been
conducted in solid state. For example the condensation reaction of orthoesters with o-
phenylenediamines in presence of KSF clay under solvent free conditions using
microwave.
Many solvents used in traditional organic synthesis are highly toxic. The Green
Chemistry approach to the selection of solvents has resulted in several strategies. One
method that has been developed is to use supercritical carbon dioxide as a solvent
.Supercritical carbon dioxide is formed under conditions of high pressure in which the
gas and the liquid phases of carbon dioxide combine to a single –phase compressible
fluid that becomes an environmentally benign solvent (temperature 31oC, 7280 kPa, or
72 atmospheres). Supercritical CO2 has remarkable properties .It behaves as a material
whose properties are intermediate between those of a solid and those of a liquid .The
properties cab be controlled by manipulating temperature and pressure .Supercritical
CO2 is environmentally benign because of its low toxicity and easy recyclability.
Carbon dioxide is not added to the atmosphere; rather, it is removed from the
atmosphere for use in chemical processes. It is used as a medium to carry out a large
number of reactions that would otherwise have many negative environmental
consequences. It is even possible to perform stereoselective synthesis in supercritical
CO2.
Some reactions can be carried out in ordinary water, the most green solvent
possible. Recently, there has been much success in using near-critical water at higher
temperatures where water behaves more like an organic solvent .Eckert and Liotta
were able to run Friedel-Crafts reactions in near –critical water without the need for
the acid catalyst AlCl3, which is normally used in large amounts in these reactions. In
the past 5 years, many new ionic liquids have been developed with a broad range of
properties. By selecting the appropriate ionic liquid, it is now possible to carry out
many types of organic reactions in these solvents. In some reactions, a well –designed
ionic solvent can lead to better yields under milder conditions than is possible with
traditional solvents.
Another approach to making organic chemistry greener involves the way in
which a reaction is carried out ,rather than in the selection of starting material,
reagents, or solvents. Microwave technology can be used in some reactions to provide
the heat energy required to make the transformation go to completion .With
microwave technology ,reactions can take place with less toxic reagents and in a
 10

shorter time, with fewer side reactions, all goals of Green Chemistry. Microwave
technology has also been used to create supercritical water that behaves more like an
organic solvent and could replace more toxic solvents in carrying out organic
reactions.
Another Green Chemistry approach is the use of a catalyst which facilitates
transformations without the catalyst being consumed in the reaction and without being
incorporated in the final product. Therefore, use of catalyst should be preferred
whenever possible.
6. Energy requirements should be recognized for their environmental and
economic impacts and should be minimized.
Energy generation, as we know has a major environmental effect. The
requirement of energy can be kept to a base minimum in certain cases by the use of a
catalyst. For example in conversion of benzyl chloride into benzyl cyanide if we use
phase transfer catalyst, the conversion goes to completion in a very short time.
C6H5CH2Cl + aq KCN C6H5CH2CN + KCl

Benzyl chloride
Benzyl cyanide

Conventionally, we have been carrying reaction by heating on wire gauze, in

oil bath or heating mantels. It is now possible that the energy to a reaction can be
supplied by using microwaves, by sonication or photo chemically. Simple examples
are,
(a) C6H5CONHC6H5 C6H5COOH
MW,12 MINS
Esterification
(b) RCOOH + ROH RCOOR
H2SO4,Ultrasound

7. A raw material or feedstock should be renewable rather than depleting,

whenever technically and economically practicable.
Non reversible or depleting sources can exhausted by their continual use. So
these are not regarded as sustainable from environmental point of view. The starting
materials which are obtained agricultural or biological processes are referred to as
renewable starting materials. Substances like carbon dioxide (generated from natural
sources or synthetic routes like fermentation etc) and methane gas (obtained from
natural sources such as marsh gas, natural gas etc) are available in reasonable amounts
and so are considered as renewable starting material. Methane, a constituent of biogas
 11

and natural gas can easily be converted into acetylene by partial combustion.
Acetylene is a potential source of number of chemicals such as ethyl alcohol,
acetaldehyde, vinyl acetate etc.
8. Unnecessary derivatization (blocking group, protection, deportation,
temporary modification of physical/chemical processes) should be avoided
whenever possible.
A commonly used technique in organic synthesis is the use of protecting or
blocking group. These groups are used to protect a sensitive moiety from the
conditions of the reaction, which may make the reaction to go in an unwanted way if it
is left unprotected. This procedure adds to the problem of waste disposal.
9. Catalytic reagents (as selective as possible are superior to stoichiometric
reagents.
The catalyst as we know facilitates transformation without being consumed or
without being incorporated into the final product. Catalysts are selective in their action
in that the degree of reaction that takes place is controlled, e.g. mono addition v/s
multiple addition. A typical example is that reduction of triple bond to a double bond
or single bond.
5% Pd-C or 5% Pd-BaSO4
CH CH

Alkenes
HC CH
Alkynes

CH2 CH2
PtO2 or Raney Ni
Alkanes

In addition to the benefits of yield and atom economy, the catalysts are helpful in
reducing consumption of energy. Catalysts carry out thousands of transformation
before being exhausted.

10. Chemical products should be designed so that at the end of their function they
do not persist in the environment and break down into innocuous degradation
products.
It is extremely important that the products designed to be synthesized should be
biodegradable. They should not be persistent chemicals or persistent bio accumulators.
It is now possible to place functional groups in a molecule that will facilitate its
 12

biodegradation. Functional groups which are susceptible to hydrolysis, photolysis or

other cleavage have been used to ensure that products will be biodegradable. It is also
important that degradation products do not possess any toxicity and detrimental effects
to the environment. Plastic, Pesticides (organic halogen based) are examples which
pose to environment.
11. Analytical methodologies need to be further developed to allow for real time,
in process monitoring and control prior to the formation of hazardous
substances.
Methods and technologies should be developed so that the prevention or
minimization of generation of hazardous waste is achieved. It is necessary to have
accurate and reliable reasons, monitors and other analytical methodologies to assess
the hazardous that may be present in the process stream. These can prevent any
accidents which may occur in chemical plants.
12. Substances and the form of a substance used in a chemical process should be
chosen so as to minimize the potential for chemical accidents, including
releases, explosions and fires.
The occurrence of accidents in chemical industry must be avoided. It is well
known that the incidents in Bhopal (India) and Seveso (Italy) and many others have
resulted in the loss of thousands of life. It is possible sometimes to increase accidents
potential inadvertently with a view to minimize the generation of waste in order to
prevent pollution. It has been found that in an attempt to recycle solvents from a
process (for economic reasons) increases the potential for a chemical accident or fire.

1.4 Solvent Free Reactions

Environmental concerns in synthetic chemistry have led to a reconsideration of
reaction methodologies. This has resulted in investigations into atom economy,31 the
use of supercritical CO2,32 ionic liquids,33 and other procedures to reduce the disposal
problems associated with most chemical reactions. One obvious route to reduce waste
entails generation of chemicals from reagents in the absence of solvents.34 Therefore
the design of green processes with no use of hazardous and expensive solvents, e.g.,
“solvent-free” reactions, has gained special attention from synthetic organic
chemists.35 As a result, many reactions are newly found to proceed cleanly and
efficiently in the solid state or under solvent-free conditions.36 Less chemical
 13

pollution, lower expenses, and easier procedures are the main reasons for the recent
increase in the popularity of solvent-free reactions.
While an obvious approach to chemical synthesis, there are many problems
associated with this approach, the chief of which is the role of diffusion/interactions
between reactants. Further, it is never clear that the reactions in the solid state will
generate the same products as those found in the presence of solvents.37 Generally,
Michael additions are conducted in a suitable solvent in the presence of a strong base
either at room temperature or at elevated temperatures.38 Due to the presence of the
strong base, side reactions such as multiple condensations, polymerizations,
rearrangements and retro-Michael additions are common. These undesirable side
reactions decreases the yields of the target adduct and render their purification
difficult. Better results can be obtained by employing weaker bases such as piperidine,
quaternary ammonium hydroxide, tertiary amines etc.39 There have been some reports
on Michael reactions catalyzed by potassium carbonate in organic solvents,40 and
water in the presence of surfactants41 or phase-transfer catalysts.42 To a large extent,
mild bases restrain the formation of side products, thus improving the yield of the
desired Michael adducts. Recently, non-conventional procedures like conducting the
reaction on the surface of a dry medium43 or under microwave irradiation44 were found
to facilitate the Michael reaction. For the purposes of eco-friendly “Green Chemistry”,
a reaction should ideally, be conducted under solvent-free conditions with minimal or
no side-product formation and with utmost atom-economy.45 Even though microwave-
assisted solvent-free Michael addition reactions on BiCl3 or CdI2,46 EuCl3,47
CeCl3.5H2O,48 and alumina49 surfaces are known. Rao50 and Jothilingam have studied
Michael addition of some active methylene compounds (2a-f) to four Michael
acceptors (1a-f) viz (i) 1, 3-diphenyl-2-propene-1-one (chalcone), (ii) phenyl vinyl
ketone, (iii) 1, 4-diphenyl-2-butene-1,4-dione (dibenzoylethylene), and (iv) methyl
vinyl ketone on potassium carbonate surface under microwave irradiation (Scheme 1).
 14

O R2
O
X
K2CO3,MW,450 W, X
+ R1
R1 R2 2-10 MIN.,52-97%.
Y Y
1a-f 2a-f 3a-f

1a:R1=R2=C6H6
1b:R1=4ClC6H4,R2=C6H5
1c:R1= 4-CH3C6H4,R2=C6H5
1d:R1=C6H5,R2=COC6H5
1e:R1=C6H5,R2=H
1f:R1=CH3,R2=H
2a:X=Y=COOEt
2b:X=COOEt,Y=CN
2c:X=CO(CH2)4,Y=H
2d:X=COOEt,Y=COC6H5
2e:X=CO(CH2)5,Y=H
2f:X=COC6H5,Y=H

Scheme 1

Loh et al.51 have developed an efficient and environmentally friendly protocol

for Mukaiyama aldol reaction of ketene silyl acetyls (5) with different aldehydes (6) in
the presence of a catalytic amount of DBU under solvent free conditions at room
temperature (Scheme 2).

OTMS OH O
R2
O R2
+ 1.DBU/neat,R.T.,24
R1 OMe
1 R2 2.1M HCl/THF
R H OMe
R2
6 5 7
R1 =2-NO2C6H4, R2=CH3
R1 =2-NO2C6H4, R2=H
R1 =4-ClC6H4, R2=H
R1 =C6H5 ,R2=H

Scheme 2

Atul Kumar and Akanksha52 described Zirconium chloride to be a new and

highly efficient catalyst which catalyzed aldol reaction of appropriately substituted
aromatic aldehydes (8) with a broad variety of aromatic ketones (9) to obtain the
corresponding 1, 3-diaryl-2-propenones (10) with good to excellent yields in short
span of time without the formation of any side product under solvent free conditions,
at room temperature. The reaction is very fast, clean and environmentally benign for
the synthesis of variety of 1,3-diaryl-2-propenones. Zirconium chloride also found to
be compatible with various solvents and gave the aldol product in acceptable yield
(56–70%) but the excellent yield was obtained in solvent free condition. The higher
 15

mol% of the catalyst (zirconium chloride) yielded the 1, 4-Michael adduct along with
the aldol product (Scheme 3).

R1 O O R1 O

H
+ ZnCl4
R3 R2 R4 20 mol% R3 R2 R4
R5 10 R 5
8 9

Scheme 3

Goswami and Das53 reported a series of conjugated dienones and enones which
were synthesized by a reaction of both conjugated and simple aldehydes, respectively,
with 1,3-dicarbonyl compounds (11) and aldehydes (12) under solvent-free
conditions at room temperature in the presence of 10 mol % of L-proline as catalyst.
All the products were obtained selectively as E-isomers with the exception of allyl
acetoacetate which gave a mixture of both E and Z isomers with an E-isomer in the
predominant form (Scheme 4).

O O

O O R2
L-proline
R2

R1
R1 13a
+ OR
CHO

R1= Me,b=Ph R3
R3
R3
R3 O
11
L-proline O O

12 R1
13b

R2=OMe,OEt,OCMe3 ,Me,Ph,OCH2-CH=CH2
R3= H,Me

Scheme 4

The multi-component reactions (MCRs) involve three or more reactants which

are combined together in a single reaction flask to generate a product incorporating
most of the atoms contained in the starting material. Due to intrinsic atom economy,
 16

selectivity underlying such reaction, simpler procedure, equipment, time and energy
saving as well as environmental friendliness MCRs are gaining much importance in
both academia and industry.54-57 1, 4-Dihydropyridines (1, 4-DHPs) and their
derivatives are important class of bioactive molecules in the field of drug and
pharmaceuticals. These compounds are well known as calcium channel modulators
and have emerged as one of the most important classes of drugs for the treatment of
hypertension.58 1,4-Dihydropyridine derivatives possess a variety of biological
activities such as HIV protease inhibition,59,60 MDR reversal,61-63 adioprotection,64
vasodilator,65 antitumour, bronchodilator and hepatoprotective activity.66

The catalytic property of small organic molecules like cinchona alkaloids and
amino acids have been shown as quite promising and highly efficient organocatalysts
for multi-component reactions.67-70 Recently, Atul Kumar71 and Ram Awatar Maurya
reported an organocatalysed multi-component reaction of an aldehyde (14),
acetoacetate ester (15), cyclic 1,3-diketone (16) and ammonium acetate to form
72
polyhydroquinoline derivatives (17). Thus, they use the organocatalysts for the
multi-component reaction of acetoacetate ester, cinnamaldehyde and anilines to yield
N-aryl 5-unsubstituted or 5,6-unsubstituted 1,4-dihydropyridines (Scheme 5). The
reaction is generally very fast and the products are obtained in high yield. The
catalytic activity of small organic molecules like amino acids (acidic, basic and
neutral), ephedrine and cinchona alkaloids was studied.

R
O NH2
R1 O
R3 Organocatalyst
( 10 mol % ) R2
+ R6
+
r.t.solvent free
R1 1 hr
R4
O N
R2
R5
R3
15 16
CHO
Organocatalyst = (-)-Cinchonidine
14 (-)-Ephedrine R4
L-Proline
L-Lysine R5
L-Histidine
L-Glutamic acid
L-Pipecolic acid 17

Scheme 5

Recent developments in the classical Cannizaro reaction involve the use of

various Lewis acidic reagents,73,74 heterogeneous catalytic systems,75,76 and
 17

supercritical solvents.77,78 Mojtahedi et al.79 reported that a selective conversion of

aldehydes (18) with no α-hydrogen to their respective alcohols (19) and/or carboxylic
functionalities (20) of choice is practically attainable under catalysis of lithium
bromide80(LiBr) in the presence of triethylamine ( Et3N) at room temperature in a
solvent free environment (Scheme 6).
O 1. LiBr (0.5 equiv) O
Et3N (1.5 equiv) HO
2d,rt
Ar H + OH
2. H2O
Ar
20
18 19
Ar = C6H5
Ar = p-MeOC6H5
Ar = p-O2NC6H4

Scheme 6

Ranu et al.81 reported a convenient and efficient procedure for the synthesis of
quinolines and dihydroquinolines (23a, 23b) by a simple one-pot reaction of anilines
(21a, 21b) with alkyl vinyl ketones (22a, 22b) on the surface of silica gel
impregnated with indium(III) chloride under microwave irradiation without any
solvent (Scheme 7).

O R3
R2
R2
R3 InCl3/SiO2
R
R +
MW
R1 N
R1
NH2
21a 22a 23a

O R3

InCl3/SiO2
R R
+
MW
N
NH2 H

21b 22b 23b

Scheme 7

Manvar et al.82 described the hydrazones of 3-acetyl-4-hydroxycoumarin (24)

undergo ring cyclization to give 3-methyl-1-substituted phenyl-1H-chromeno [4,3-
c]pyrazol-4-ones (25) under the influence of microwave irradiation by using Zn[l-
proline]2, a novel Lewis acid catalyst. The overall yields of the products were found to
 18

be 82–93%. Without use of the catalyst, no reaction progress was observed. The
reusability of the catalyst was also checked and found up to seven cycles (Scheme 8).

O O

O O
MW/120oC

Zn[l-proline]2 Me
Me
R-NHNH2
5-10 min N N
82-93% R
OH O

25 26

Scheme 8

Villemin and Martin83 have synthesized 5-nitrofurfurylidine by the

condensation of 5-nitrofurfuraldehyde with active methylene compounds under
microwave irradiation using K 10 and ZnCl2 as a catalyst. The useful synthesis
84a
coumarins via the microwave promoted Pechmann reaction has been extended to
solventless systems wherein salicyladehydes (28) undergo Knoevenagel condensation
with a variety of ethy acetate derivatives (27) under basic conditions (piperidine) to
afford coumarins (29) (Scheme 9).84b

CHO R2
R2 Piperidine
+
CO2Et MW
R OH R O O

R1 R1

28 27 29
Scheme 9

Ballini et al.85 reported the Conjugate addition of both linear and cyclic α-nitro
ketones (30) to conjugated enones (31) under heterogenous, solvent-free and mild
acidic conditions by mixing at room temperature stoichiometric amounts of substrates
with silica (silica/substrate = 350 mg mmol-1) and leaving the mixture at room
temperature for the suitable reaction time giving good yields of 2-nitro-1,5-
diones(32) and it is worthy to note that no products arising from the cleavage of a-
nitro cycloalkanones were observed under these reaction conditions (Scheme 10).
 19

O
R'' O O
R' SiO2
R +
neat, r.t. R R''
O
NO2 NO2
R'
30 31 32

Scheme 10

1.5 Microwave induced green synthesis

With increasing community concern over possible influences of chemicals and
chemical practices on the environment microwave induced green synthesis has
received considerable attention for direct, efficient, and environmentally unobtrusive
synthesis. The first microwave-assisted organic syntheses was reported in 1986.86 By
using this technique , considerably shorter reaction times than normal had been
obtained for common organic transformations such as esterification, hydrolysis,
etherification, addition, and rearrangement. Inadequate controls in the rudimentary
equipment employed, however, generated hazards, including explosions.86,87 In the
electromagnetic radiation spectrum, microwaves (0.3 GHz–300 GHz) lie between
radio wave (Rf) and infrared (IR) frequencies with relatively large wavelength.
Microwaves, a non-ionizing radiation incapable of breaking bonds, are a form of
energy and not heat and are manifested as heat through their interaction with the
medium or materials wherein they can be reflected (metals), transmitted (good
insulators that will not heat) or absorbed (decreasing the available microwave energy
and rapidly heating the sample). Microwave reactions involve selective absorption of
electromagnetic waves by polar molecules, non-polar molecules being inert to
microwaves. When molecules with a permanent dipole are submitted to an electric
field, they become aligned and as the field oscillates their orientation changes, this
rapid reorientation produces intense internal heating. The main difference between
classical heating and microwave heating lies in core and homogenous heating
associated with microwaves, whereas classical heating is all about heat transfer by
preheated molecules. In microwave induced organic reactions, the reactions can be
carried out in a solvent medium or on a solid support in which no solvent is used .For
reactions in a solvent medium, the choice of the solvent is very important.88,89
Microwave chemistry generally relies on the ability of the reaction mixture to
efficiently absorb microwave energy, taking advantage of “microwave dielectric
heating” phenomena such as dipolar polarization or ionic conduction mechanisms.90 In
most cases this means that the solvent used for a particular transformation must be
 20

microwave absorbing. The ability of a specific solvent to convert microwave energy

into heat at a given frequency and temperature is determined by the so-called loss
tangent (tan δ), expressed as the quotient, tan δ= ε′′/ε′, where ε′′ is the dielectric loss,
indicative of the efficiency with which electromagnetic radiation is converted into
heat, and ε′ is the dielectric constant, describing the ability of molecules to be
polarized by the electric field.90 A reaction medium with a high tan δ at the standard
operating frequency of a microwave synthesis reactor (2.45 GHz) is required for good
absorption and, consequently, efficient heating.
Microwave ovens offer a clean and sometimes cheaper alternative to oil baths
for many organic reactions. Microwave synthesis can be performed either under
sealed-vessel or open-vessel conditions. Reactions performed in sealed vessels can
reach temperatures much higher than the boiling point of the solvent used at elevated
pressure. In open-vessel microwave assisted reactions, reactions are carried out at
atmospheric pressure; yet solvents can still reach temperatures that are 10-20°C above
their boiling points,91-94 which may be explained by the occurrence of instantaneous
hot spots.93,95 An excellent solvent in a domestic microwave oven is N, N-
dimethylformamide (DMF) (b.p.160oC). Open-vessel synthesis allows for any gases
that may be generated in a reaction to evolve from the reaction environment possibly
causing reactions to progress further to completion than when performed in a sealed
vessel. Also, open-vessel reactions can be performed using standard laboratory
glassware, such as round-bottom flasks and reflux condensers, in the microwave
cavity allowing reactions to be carried out on a larger scale.
Since microwave synthesis was introduced in the literature, there has been an
explosion of applications to organic synthesis, inorganic synthesis, and organometallic
synthesis.96 Loupy has described a solvent free/microwave method for the synthesis of
aromatic ethers by the SNAr reaction of 4-nitro-substituted halogenobenzenes or 2-
halonaphthylenes, but only phenol was employed.97a Similar results have been
achieved by Bogdal, who prepared a range of aromatic ethers by reaction of phenols
with primary alkyl halides under microwave heating, however, in the presence of
TBAB.97b Also Fan has employed the same strategy for the reaction of 1-chloro-4-
nitrobenzene and phenolates, affording 4-nitrodiphenyl ethers.97c Li et al.98 reported
the microwave-assisted coupling of phenols (33), including those having a strong
electron-withdrawing group, with aryl halides (34) in the presence of potassium
carbonate providing diverse diaryl ethers (35) with high to excellent yields within 5-
 21

10 min. (Scheme 11). Rather, the reaction under microwave irradiation is very clean
and no by-products have been detected. Therefore, the workup procedure involves
only a simple filtration of the precipitation followed by washing with water. In all
instances, the products can be obtained in purity higher than 98% as indicated by GC-
MS and 1H NMR analysis.
OH X O
K2CO3/DMSO
R1 + R2 R1 R2
MW,5-10 min,
74-98%

33 34 35
R1 = Cl, OMe, CF3, NO2, CN; R2 = CN, NO2; X= F, Cl, Br

Scheme 11

The development of cleaner technologies is a major emphasis in Green

Chemistry. The search for a non-volatile and recyclable alternative is thus holding a
key role in this field of research. The use of fused organic salts, consisting of ions, is
now emerging as a possible alternative. A proper choice of cations and anions is
required to achieve ionic salts that are liquids at room temperature and are
appropriately termed room-temperature ionic liquids (RTILs). Common RTILs consist
of N, N´-dialkylimidazolium, alkylammonium, alkylphosphonium or N-
alkylimidazolium as cations.99 Most of these ionic salts are good solvents for a wide
range of organic and inorganic materials and are stable enough to air, moisture, and
heat. Rajendra et al.100 reported an efficient method for the preparation of ionic liquids
by simply exposing neat reactants in open glass containers to microwaves using an
unmodified household MW oven. A general schematic representation for the
preparation of mono (36) and dicationic (37) 1, 3-dialkylimidazolium halides is
depicted below (Scheme 12).
 22

N N

MW X-R-X MW
R-X

X X
X
N N N N
N N R R
R

36
37

Scheme 12

Matthew et al.101 reported a microwave-assisted, one-pot, solvent-free

synthesis of methylenedioxyprecocene (MDP) (38), a natural insecticide with anti-
juvenile hormone activity in some insects, on basic Montmorillonite K10. It is a
cleaner chemical reaction and forms an important component of Green Chemistry. The
reported synthesis, a clay-catalyzed, microwave-assisted condensation of sea amol
with 3-methyl-2-butenal (Scheme13), is a unique example of Green Chemistry
reaction.

O OH

K10-K HO
O H

+ MWI
HO O
O OH

-H2O

O O

O O O
O

MDP
38

Scheme 13
 23

The application of microwave irradiation in conjunction with the use of

catalysts or mineral-supported reagents, under solvent-free conditions, enables organic
102-106, 107, 108
reactions to occur expeditiously at ambient pressure. thus providing
unique chemical processes with special attributes such as enhanced reaction rates,
higher yields, and the associated ease of manipulation. Rajender S. Varma109 described
the synthesis of thioketones (39), thiolactones (40), thioamides, thionoesters (41), and
thioflavonoids (42) simply by mixing the carbonyl compounds (i-iv) with neat
Lawesson’s reagent (0.5 equiv.) (43) and irradiating under solvent-free conditions that
do not require any acidic or basic media giving high-yield conversion of ketones,
flavones, isoflavones, lactones, amides, and esters to the corresponding thio analogs
(Scheme 14).

R
R2 O
S

R1 R OR1

42 S iv 41
iii
MW MW
S
S
H3CO P P OCH3
S
S
LAWESSON'S REAGENT
43
MW MW
ii S
i

X 39

40
R2 O R
O
i= iv =
R1

O
O
ii = O iii =

X R OR1
X= O, NH

Scheme 14
 24

1.6 Aqueous mediated synthesis

Aqueous mediated reactions offer useful and more environmentally friendly
alternatives to their harmful organic solvent versions and have received increasing
interest in recent years. Furthermore, water has unique physical and chemical
properties, and by its utilization it would be possible to realize reactivity or selectivity
that cannot be attained in organic solvents. Water is the most abundant, cheapest, and
non-toxic chemical in nature. It has high dielectric constant and cohesive energy
density compared to organic solvents. It has also special effects on reactions arising
from inter and intramolecular non-covalent interactions leading to novel solvation and
assembly processes. Water as a reaction medium has been utilized for large numbers
of organic reactions.110 Utility of aqueous reactions is now generally recognized.111 It
is desirable to perform the reactions of compounds containing water of crystallization
or other water-soluble compounds in aqueous media, because tedious procedures to
remove water are necessary when the reactions are carried out in organic solvents.
Moreover, aqueous reactions of organic compounds avoid the use of harmful organic
solvents.112 Thus; development of an efficient and convenient synthetic methodology
in aqueous medium is an important area of research. Recent literature survey revealed
that water as reaction solvent exhibit several applications on organic reactions such as
Barbier allylation reaction mediated by several metals such as zinc, indium,
manganese and others in aqueous medium, metal mediated reactions mediated by zinc,
tin and indium in aqueous medium as reported by Wu et al.113 for the synthesis of
metallic indium in situ via Sn/InCl3.4H2O system in THF-H2O (8/1) mixture in open
air and its application in reductive cyclodimerization of arylidenecyanoacetates to
afford cyclopentamine derivatives with high stereoselectivity under milder conditions,
in the synthesis of a great variety of thioether compounds with heterocycle having
broad –spectrum biological activities such as fungicidal, insecticidal, herbicidal and
plant growth regulative activities using metal catalyst in water ,organocatalytic
asymmetric direct aldol and Michael reaction in water by using L-proline based
organocatalyst such as zinc-proline complex, dipeptide etc. Here a brief literature
survey on various organic reactions in aqueous media is highlighted.
Since Kobayashi showed that a chiral copper complex can act as a water
tolerant catalyst for the Mukaiyama–aldol reaction,114 several other Lewis acids have
been utilized in asymmetric aldol reactions in aqueous solvents.115 More recently,
Kobayashi reported that Fe(II) and Fe(III) salts showed considerable activity in
 25

stereoselective Mukaiyama–aldol reactions in aqueous THF,116 especially when the

reaction was carried out in the presence of catalytic amounts of surfactants.117
Jankowska et al.118 reported recently the application of a zinc-based chiral Lewis acid
in an asymmetric Mukaiyama–aldol reaction in aqueous media. They described a
water stable chiral Lewis acid (47, 48) containing an iron (II) ion and a pybox-type
ligand. The resulting cationic aqua complex of C2-symmetry is an effective Lewis acid
catalyst for asymmetric Mukaiyama–aldol reactions in aqueous media. The aldol
products (46) have been obtained in good yields, syn-diastereoselectivities and ca.
70% levels of enantioselectivity by reacting siyl enol ether (44) with benzaldehyde
(45)(Scheme 15).

N O N O
O O

N N N N

48
47
OH HO

TMSO OH O
CHO Fe-salt (n mol%)
47 or 48 (n mol%)
+ solvent
0oC/5h
44 45 46

Scheme 15

In recent years, there has been increasing recognition that water is an

attractive medium for many organic reactions.119 The aqueous medium with
respect to organic solvents is less expensive, less dangerous and environment-
friendly, while it allows a right control of the pH. In addition, the low
solubility of most reagents in water is not an obstacle to the reactivity which, on
the contrary, is often improved.120 Recently, Lubineau and Auge121 published the
first example of the Michael addition of nitroalkanes in water with the help of
sugars. Roberto et al.122 described that the Michael reaction of various
nitroalkanes (47) wth conjugated enones (48) can be performed in aqueous media
using a solution of sodium hydroxide 0.025 M in the presence of catalytic
amount of cetyltrimethylammonium chloride (CTACl) as cationic surfactant
giving products (49) with good yield (Scheme 16).
 26

NO2 R2
NO2
NaOH, 0.025 M R
R3 R3
+
R R1 CTACl, r.t.
R1 R2 O
O
47 48 49

R = Me, Et, n-Bu, CH3(CH2)9

R1 = H, Me
R2= H, Me
R3 = Me, Et, n-Pr

Scheme 16

Recently, Janda123a and Barbas123b have reported the accomplishment of cross-

aldol reactions in buffered aqueous medium using nornicotine and other pyrrolidine
based catalysts. Chimni et al.124 also reported that heteroaromatic (50) and aromatic
aldehydes (50) undergo fast direct cross-aldol reactions with ketones (51) in water in
the presence of a catalytic amount of pyrrolidine affording the aldol addition product
(52a, 52b, 54a, 54b) in 93% yield (Scheme 17, 18). Since the use of water as reaction
solvent has many positive effects in terms of cost, safety, and environmental impact.125
However, early studies about the use of chiral organic catalysts in aqueous medium
met with only limited success.126 Only very recently Barbas127 and Hayashi128 reported
very efficient proline-derived chiral catalysts for the aldol condensation “in water”.
Other examples of organocatalysts developed for stereoselective reactions in aqueous
solvent were tryptophan,129 small peptides,130 pyrrolidine-based catalysts,131 or proline-
related systems.132 Guizzetti et al.133 reported the direct aldol condensation of
cyclohexanone and other ketones (51) with different aldehydes (50) in the presence
of a massive amount of water by using 1,1′-Binaphthyl-2,2′-diamine-based (S)-
prolinamides in the presence of stearic acid affording aldol products (55) with very
good yields, high diastereoselectivity, and up to 99% ee (Scheme 19). From the
literature survey, it is known that aldol reaction in aqueous media usually require
Lewis acid activation of the acceptors and the use of silyl enol ethers as aldol donors
catalyzed by a good small organic-molecule catalyst.134 In one case ,aldol reactions
were also catalyzed by a by a proline-like molecule in a buffer solution with 10%
DMSO.135 Peng et al.136 investigated environmentally benign Aldol reactions of
ketones (51) with nitrobenzaldehydes (56) in aqueous SDS micelle affording product
(57) (Scheme 20).
 27

O
OH O
pyrrolidine, rt
RCHO + CH3COCH3 +
50 51 H2O R
R
52a 52b

R= O S NH
N
N
a b c d e

N N
H
f COOEt
g

Scheme 17

CHO OH O O
R2 O R4 R4
pyrrolidine,30 mol%
+ +
water
R4 R3 R1 R2 R1 R2
51 R3
R1 R3
54a 54b
53

R1 = NO2; R2 =R4 =H
R1 = H; R2 =NO2; R3=R4 = H
R1 = Cl; R2 =R3=R4 = H
R1 = H; R2 =Cl; R3 =R4 = H
R1 =R2 =R3 =R4 =H
R1 =OCH3; R2 = R3 = R4 = H
R1 = OCH3; R2 =H; R3=R4= OCH3
R1 = N(CH3)2; R2 =R3=R4 =H
R1 = OH; R3 =NO2; R2=R4 =H

Scheme 18
 28

O OH

O
O R
10 mol% Cat.

additive, H2O
R H

50
ee up to 99%
55
51 O
H
N

Catalyst= NH

R'

Scheme 19

SDS 20 mol%
O OH
O
O2N proline 40 mol% NO2
R2 + CHO R1
R1 H2O
51
56
R2

51a:Acetone 56a:p-nitro 57
51b:2-Butanone 56b:m-nitro
51c:Cyclopentanone 56c:o-nitro
51d:Cyclohexanone
51e:Benzylmethylketone
Scheme 20

Xing et al.137 reported a simple environmentally benign and efficient method

for the asymmetric synthesis of chiral 3-allyl isoindolinone compounds by treating 2-
formylbenzoate imine (58) with indium (60) and allylbromide (59) in saturated
aqueous NaBr affording products (61) with excellent diastereoselectivities (>99:1 dr)
138
( Scheme 21).
 29

R1 R1

R2 COOR R2 COOR
sat. aq NaBr, rt
Br H
+ + In
N O N O
R3 S R3 S
59 60
R4 R4

58

rt HCl, MeOH

R1 O
R2
NH
R3
R4

61
Scheme 21

Vishnumaya et al.139 described a chiral diamine (63) (Scheme 22), having

substituted nonpolar dibenzylic type groups in the tertiary amine part where the
binaphthyl group would enhance the hydrophobic hydration when the reaction is done
in aqueous medium and should also work in organic medium due to the aromatic
nature of the binaphthyl part and was found to catalyze enantioselective addition of
ketones (51) to nitroolefins (61) in queous/saline/organic media. The products (62)
were obtained with excellent diastereo-selectivities (syn/anti) (99:1) and
enantioselectivities up to 99%. The reaction could be facilitated using a mild acid.
Recently, it was also described that Michael addition of dicarbonyl compounds,
nitroalkanes and thiols to the 2-cyclohexen-1-one can be accomplished in water
without phase transfer agents. The reaction is extremely sensitive to the pH of the
reaction media, and depending on the nucleophile, the optimized pH is different. It
was studied that the Michael addition of thiophenol (64) to nitro olefins (61) in
aqueous media to afford nitrosulfides (65a, 65b) (Scheme 23).140
 30

N
H
63
O Ar
O NO2 10 mol% 1,10 mol %
TFA,brine,rt NO2
+
Ar uo to 98% yield
R R
R R 61
51 62

Scheme 22
NO2 NO2
NO2 R R
H2O
+ PhSH
R base +

SPh SPh
61 64
2- anti 2- syn

65a 65b

R = Ph, Et, iPr

Scheme 23

Li et al.141 have successfully employed an indium catalyst in a number of

carbon–carbon bond forming reactions conducted in water. Allylation of 1, 3-
dicarbonyl compounds (66), for example, is efficiently promoted in water using an
indium catalyst affording product (67) (Scheme 24). Metal-mediated reactions in
water have found applications in cyclization, ring expansion, and isomerisation
reactions.

O O

R1 OH
Cl Cl R1 R2
O O O
In/H2O
Cl
R1 base R2

66
67

Scheme 24
 31

1.7 Catalytic approach to Green Chemistry

Catalysis is one of the fundamental pillars of Green Chemistry, the design of
chemical products and processes that reduce or eliminate the use and generation of
hazardous substances. The design and application of new catalysts and catalytic
systems are simultaneously achieving the dual goals of environmental protection and
economic benefit. From feed stocks to solvents, to synthesis and processing, Green
Chemistry actively seeks ways to produce materials in a way that is more benign to
human health and the environment. Utilizing Green Chemistry for pollution
prevention demonstrates the power and beauty of chemistry: through careful design,
society can enjoy the products on which we depend while benefiting the environment.
Developing Green Chemistry methodologies is a challenge that may be viewed
through the framework of the “Twelve Principles of Green Chemistry”.142 These
principles identify catalysis as one of the most important tools for implementing Green
Chemistry. Catalysis offers numerous Green Chemistry benefits including lower
energy requirements, catalytic versus stoichiometric amounts of materials, increased
selectivity, and decreased use of processing and separation agents, and allows for the
use of less toxic materials. Catalysis is principally divided in two branches:
homogenous catalysis, when the catalyst is in the same phase as the reaction mixture
(typically in liquid phase), and heterogeneous catalysis, when the catalyst is in a
different phase (typically solid/liquid, solid /gas/liquid/gas). One of the main
advantages of homogenous molecular catalysts, when they operate under ideal
conditions, is that their active sites are spatially well separated from one another, just
as they are in enzymes. Heterogeneous catalysis, in particular, addresses the goals of
Green Chemistry by providing the ease of separation of product and catalyst,
bifunctional phenomena involving reactant activation/spill over between support and
active phases, thereby eliminating the need for separation through distillation or
extraction. In addition, environmentally benign catalysts such as clays and zeolites,
may replace more hazardous catalysts currently in use.
The choice of the catalyst is of prime importance in these environmentally
conscious days. Green Chemistry demands the replacement of highly corrosive
hazardous and polluting acid catalysts with eco-friendly and renewable solid acid
catalysts. Zeolites, solid acids and especially those based on micelle-templated silicas
and other mesoporous high surface area support materials are beginning to play a
significant role in the greening of fine and speciality chemicals manufacturing
 32

processes. A wide range of important organic reactions can be effectively catalyzed

by these materials, which can be designed to provide different types of acidity as well
as high degrees of reaction selectivity. The solid acids generally have high turnover
numbers and can be easily separated from organic compounds. Zeolites have excellent
thermal and chemical stability and have been incredibly successful in vapour phase
chemistry. Solid acids can be described in terms of their Bronsted/Lewis acidity, the
strength and number of these sites, and the morphology of the support (typically in
terms of surface area and porosity). Zeolites, clays, sulphated metal oxides, and
mesoporous materials provide a convenient catalytic route for protecting the carbonyl
group during organic synthesis. Environmentally benign solid acid catalysts such as
SO42-/ZrO2, SO42-/TiO2,143 Ce-exchanged montmorillonite,144 acidic zeolites,145-147
mesoporous silica,148 and siliceous mesoporous material149,150 have also been reported
to be active for the acetylization reactions. Thomas et al.151 described a simple,
efficient, and highly eco-friendly protocol for the chemoselective acetalization of three
ketones namely, cyclohexanone, acetophenone, and benzophenone at ambient
temperatures utilizing rare earth exchanged (Ce3+, La3+, RE3+) MgFAU-Y zeolites, K-
10 montmorillonite, and cerium-exchanged montmorillonite as catalysts. Microporous
rare earth exchanged Mg-Y zeolites and mesoporous K-10 montmorillonite and Ce-
mont clays were found to effectively catalyze the reaction between carbonyl
compounds and methanol producing dimethyl acetal at ambient temperatures.
Mesoporous molecular sieves act as a versatile catalysts or catalyst supports to
convert large molecules.152The large pore diameter of mesoporous materials enables
the catalysis of large molecules or incorporation of large active species to realize, and
among these materials SBA-15 attracts more attention owing to its excellent
hydrothermal stability, less condensed structure and unique micro-mesoporosity,
which is paramount for the candidate of supports or catalyst. Zhengying et al.153
reported a direct synthesis method of preparing MgO, Fe2O3 or ZnO modified SBA-15
or MCM-41 supporting mesoporous materials by directly introducing metallic salts as
precursors in the strong acidic solution. The mesoporous structures and properties of
resulting samples are similar to those of impregnation ones, but the former is more
energy- and time-efficient, offering a new strategy for synthesizing functional
materials. MCM-41 can be synthesized in either a pure silica form, or with both
tetrahedrally coordinated silicon and aluminum atoms incorporated into the
framework. The large regular pore structure of MCM-41 materials make them suitable
 33

for liquid-phase acid catalysis by enabling rapid diffusion of reactants and products
through the pores, thus minimizing consecutive reactions. Liquid-phase Friedel–Crafts
alkylation and acylation reactions154-158 have been reported using aluminosilicate
MCM-41. The advantages of increased pore size are clearly demonstrated in the
alkylation of 2,4-di-tert-butylphenol using cinnamyl alcohol154 MCM-41 has also been
used for the acylation of 2-methoxynapthalene with acetic anhydride.157 A variation of
the MCM family of materials was reported by Pinnavaia et al.159 who developed a
neutral templating method using long-chain alkylamines to form hexagonal
mesoporous molecular sieves (HMS materials). Iron loaded MCM-41 materials are
remarkable for their molecular and electronic diversity and have received much
attention because of their redox properties and unusual activity in alkylation and
oxidation reactions160-162 which is higher compared to conventional mineral
acids,163 Lewis acids,164 ion exchange resins,165 mixed oxides166 and iron supported
zeolites, clay catalysts.167-168 The use of iron loaded mesoporous materials as catalyst
can also eliminate the hurdles like pore size constraint, recyclability, thermal and
hydrothermal stability etc. posed by other support materials. Esther et al.169 reported
the synthesis of benzyl aromatics (70a,70b) by using benzylchloride (69) and
substituted benzene (68) over three different types of catalytic amounts of iron loaded
MCM-41 like Fe/Al-MCM-41; Si/Al=25, Fe/Al-MCM-41; Si/Al=50 and Fe/Al-
MCM-41;Si/Al=100 (Scheme 25).
R1 R2

R1 R1 R3
R2
Cl
Catalyst R4 R4
+ R4 +
Reflux

R3 R2

R3
68 69

Major Minor

70a 70b

Scheme 25

The use of mesoporous supports has enabled supported reagents and catalysts
to be used in reactions of much bulkier substrates than could be considered for
microporous (zeolite) materials.170 The synthesis of pure Lewis or Bronsted solid acids
is a particularly important challenge where some progress has been made. Chemically
modified MTS materials (71) as analogues for sulfonic acids have recently been
reported and show great promise as solid Bronsted acids (Figure 1).171-173 Pure Lewis
 34

acids are more difficult to achieve, because Bronsted acidity often arises from Lewis
acid-base complexation (72) (Figure 2).

( CH2)xSO3H
O
Si Si
O

71
Figure 1 (MTS-sulfonic acids prepared via in situ sol-gel or post grafting)
Mn+
 
O O H
O
Si Si Si
O O

72
Figure 2 (Bronsted acidity arising from Lewis complexation on a silica surface)
Aluminium chloride is the most widely used of Lewis acids. Silica supported
BF3 is a mild solid acid. In the alkylation of phenols, one advantage of this is that
ethers (73) can be C-alkylated without the rearrangement of the ether to give poly ring
–alkylated products (74, 75), as occurs with unsupported BF3 (Scheme 26).174 Tanabe
and Hattori have made solid superacids based on silica-supported antimony
pentafluoride.175 Antimony trifluride is a milder Lewis acid that still may be capable of
reacting with a hydroxylated surface to form covalent bonds.
OR

CH2CH2R'
Silica
OR - BF3/ROH
catalyst
74

+ R'CH=CH2
OH

Homogenous
73 BF3 catalyst

R CH2CH2R'
75

Scheme 26 (Selective C-alkylation of ethers using silica-supported BF3)

 35

Leena Rao176 described natural clays can be used as catalysts for organic
reactions. They have both Bronsted and Lewis acidic catalytic sites. They have a
lamellar structure and provide a large surface area for reaction. They can be easily
impregnated with salts used as Lewis acids. ‘Clayzic’ (76) is zinc chloride
impregnated in K 10 montmorillonite clay (Scheme 27).

'clayzic'
76
+ CH2Cl
40o C

' clayzic' O
76
OCH3 + COCl C OCH3
160 o C,5 min
Friedel- Crafts
reaction

Scheme 27

Lewis acids have also been impregnated in clays such as Kaolinite and
montmorillonite clays. Both these clays have surface acidities comparable to
concentrated nitric and sulfuric acids and as such are good solid acids on their own.
The Bronsted acidity of these clays is boosted when there is ionic exchange with high
valent ions such as ferric ions. This is used in performing aromatic chlorinations of
anisole (77) affording products (78, 79), an example of which is given below (Scheme
28).

OCH3 OCH3 OCH3

Cl
K 10 / FeCl3
+
m-chlorobenzoic acid
CH2Cl2 ,25 min
room temperature
Cl
77
78 79

Scheme 28

Ionic liquids are those organic solvent consisting of ions (cations and anions )
which are stable at room temperature ,air, moisture and heat .They are polar(but
consists of poorly coordinating ions ), are immiscible with a number of organic
 36

solvents, and provide polar alternatives for biphasic systems. ILs have also been
identified as one of the new classes of solvents that offer opportunities to move away
from traditional chemical processes to new, clean, Green technologies in which waste
streams are minimized with the goals of atom –efficiency and resulting environmental
and cost benefits. Ionic liquids are often portrayed as Green Solvents; however,
‘Greeness’ can only be measured in the context of the overall process. Ionic liquids
have negligible vapour pressure, ease of handling, accelerated reaction rates, potential
for recycling, and compatibility with various organic compounds and organometallic
catalysts.177 Also, the products from reactions conducted in ionic liquids can be easily
extracted using various organic solvents. The ionic liquids based on 1, 3-
dialkylimidazolium is becoming more important for several synthetic applications.
Functionalized ionic liquids (FILs, or task-specific ionic liquids, TSILs) are endowed
with catalytically active groups which are used as reusable homogenous supports,
reagents, and catalysts with green credential.178 Sanzhong et al.179 reported that
functionalized ionic liquids (80-84) with chiral secondary amine groups which were
synthesized using the ‘chiral pool’ strategy with L-prolinol as the starting material
(Scheme 29).180 and could be used to efficiently catalyze the asymmetric aldol addition
reaction of nitrobenzaldehyde (56) with various ketones (51) affording products
(85,86) using FILs (89-84) as reusable catalyst) (Scheme 30).
 37

N N Na
OH
(1) Boc2O
N CH2OTos
(2) TosCl N
H

Boc
N N
(1) C4H9Br
N N
N C4H9
(2) NaX N X
Boc
Boc
(1) HCl/ dioxane

Sat. NaHCO3 N N
C4H9 80a : X= Br
N X 80b : X= BF4
80c : X= PF6
H

N N N N OH
C4H9
N X N Br
CH3 R
H H
81a : X= BF4
82a :R= H
81b : X= PF6
82b :R= CH3

N N
C8H17
N N N
C4H9 H Br
N
H Br

83 84

Scheme 29

OH O O
FIL Catalyst ( 20 mol%)
CHO O 80-84
+
+

O2 N O2 N O2 N

56 51 85 86

Scheme 30
 38

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