01 chapter 1shodhganga.inflibnet.ac.in/bitstream/10603/25448/7/07_chapter_01.… · Water is the matrix of life [7], unique extraordinary and safer reaction medium for organic studies

Chapter 1: Study of Hydrotropes

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CHAPTER 1

Study of Hydrotropes

1.1 Introduction

Organic studies involve various synthetic strategies such as use of

different catalysts, reaction media, reagents etc. They play an important role in

the formation of various medicinally as well as commercially important

products. This traditional organic synthesis usually focuses on optimizing

yields, with very little regard to a chemical impact on the environment. Organic

solvents are conventionally used in organic synthesis and in industrial

processes on large scale. These solvents are often problematic owing to their

toxicity and flammability. There is now a realization that more benign chemical

synthesis is required, as an integral part of developing sustainable technologies

[1]. Eliminating the use of organic solvents can reduce the generation of waste

and this is a requirement of one of the principles of green chemistry. Most

effective alternative available to make process greener is the use of alternative

reaction media including ionic liquids [2], supercritical fluids [3], polyethylene

and polypropylene glycol [4], fluorous media [5] water [6] etc.

Water is the matrix of life [7], unique extraordinary and safer reaction

medium for organic studies comes under the heading of green chemistry [8]. In

the solvent life water meets the valuable demand to enhance the reversible

aggregation processes. In comparison with other solvents, the aqueous

solutions principally support with hydrophobic interactions, albeit with

different strength [9]. Water acts as important mediator in interactions of

proteins [10]. Recently it has been used in supramolecular chemistry [11].

Some of the practical advantages of water such as it is abundant in nature,

inexpensive, nontoxic, nonflammable, nonexplosive etc. are well known. The

aqueous medium is more convenient than organic solvents because it can avoid

protection of functional groups, such as -OH and -COOH, water-soluble

compounds can be used directly without derivatization and the high heat

capacity of water allows the reaction temperature to be easily controlled. The

mineral salts, surfactants, and cyclodextrins can be used as additives. The


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possibility of controlling pH of reaction medium and isolating solid

hydrophobic products by decanting or by filtering thereby avoiding the use of

any organic solvent. The water itself acts as catalyst in many reactions, for

example, the hydrogen-bond stabilized activated complex [12]. The numerous

synthetic transformations proceed in aqueous solution and sometimes these are

more stereo selective in water-rich environment [13]. In essence, water is an

interesting and beneficial solvent in organic synthesis, but the poor solubility of

apolar substances is the main obstacle to the use of water as solvent. However,

a variety of strategies have been investigated to solubalize apolar as well as

other organic compounds in water in order to expand the scope of water based

organic synthesis. Some of such important techniques are:

1. Organic co-solvents

One of the efficient and versatile methods of enhancing solubility of

organic compounds in water is to use organic co-solvent. The co-solvent

reduces the hydrogen bond density of aqueous systems, so that it is less

effective in squeezing out non-polar solutes from solutions. Some of the most

commonly used co-solvents are DMF, acetone and acetonitrile.

2. Ionic derivatisation (pH control)

Adding a positive or negative charge to an ionizable solute usually

brings about a remarkable increase in solubility in water. Adjustment of pH of

solution is therefore an efficient method of solubilizing weak electrolytes in

aqueous medium. This approach, however changes the chemical nature of the

reactant and may limit it’s use as method of solubilzation for synthetic

purposes.

3. Surfactants

An intriguing means of achieving aqueous solubility is by using

surfactants. Surfactant is amphiphilic substances which contain one distinctly

polar and other distinctly non-polar region. In water, surfactants tend to orient

themselves so that they minimize contact between non-polar region and polar

water molecule and when the concentration of surfactant monomer exceeds a

certain critical value then micellization occurs. Micelles are spherical


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arrangement of surfactant monomer with highly hydrophobic interior and a

polar, water- exposed surface. Organic solutes interact with micelles according

to their polarity; non-polar solutes are buried in the interior of the micelles.

Moderately polar molecules locate themselves closer to the polar surface, while

distinctly polar solute will be found at surface of the micelle. This

compartmentalization of solutes is believed to be responsible for observed

catalytic or inhibitory influence on organic reactions in micellar media.

4. Hydrophilic Auxiliaries

The other method to increase the solubility of practically insoluble

compound is by grafting hydrophilic groups on to insoluble reactants. This

strategy has been seldom used for synthetic purposes but has a pivotal role in

pharmaceutical chemistry and modern drug design because of the limited water

solubility of many drugs, which causes limited bioavailability and thus reduced

therapeutic efficacy. One strategy of improving solubility of drugs is by

converting them into water soluble pro-drugs through covalent attachment of a

hydrophilic auxiliary. It is essential that the attachment should be transient and

reversible nature, allowing for release of original drug from the auxiliary upon

distribution, either by enzymatic or chemical means.

5. Phase Transfer Catalysts

A Phase Transfer Catalyst (PTC) is a catalyst that facilitates the

migration of reactants in a heterogeneous system from one phase to another so

that the reaction can take place. This methodology is applicable to a great

variety of reactions in which inorganic and organic anions react with organic

substrates. It consists the use of heterogeneous two-phase systems: one phase

being a reservoir of reacting anions or base for generation of organic anions,

whereas organic reactants and catalyst (source of lipophilic cations) are located

in second, organic phase. The reacting anions are continuously introduced into

the organic phase in the form of lipophilic ion pairs with lipophilic cations

supplied by the catalyst. Most often tetraalkylammonium cations serve this

purpose. The corresponding catalysts for cations are often crown ethers. By

using a PTC process, one can achieve faster reactions, obtain higher conversion


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and yield, make fewer by-products, eliminate the need for expensive or

dangerous solvents which can dissolves all reactants in one phase, eliminate the

need for expensive raw materials and/or minimize waste problems. Phase

transfer catalysts are especially useful in green chemistry since they allow the

use of water thereby reducing the amount of organic solvents.

All the above mentioned methods involving greener approaches for the

organic synthesis and these are environmentally benign.

Green Chemistry

The term Green Chemistry was coined in 1991 by Anastas [14]. “Green

Chemistry is the design, manufacture and use of environmentally benign

chemical products and process that prevent pollution and reduce environmental

and human health risks.”

Green chemistry protects the environment, not by cleaning up, but by

inventing new chemical processes that do not pollute the environment.

Chemists from all over the world are using their creativity and innovation to

develop new synthetic methods, reaction conditions, analytical tools, catalysts

and processes under the new paradigm of Green Chemistry due to their

valuable contribution in research Fig 1.1. Green chemistry approach has

received extensive attention [15-22] and involves many names including Green

Chemistry, Environmentally Benign Chemistry, Clean Chemistry, Atom

Economy and Benign by Design Chemistry.


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Fig 1.1

To enrich the Green methodology the twelve principles play an

important role Fig.1.2. It is widely acknowledged that there is a growing need

for more environmentally acceptable processes in the chemical industry. This

trend towards what has become known as ‘Green Chemistry’ or ‘Sustainable

Technology’ necessitates a paradigm shift from traditional concepts of process

efficiency, that focus largely on chemical yield, to one that assigns economic

value to eliminating waste at source and avoiding the use of toxic and

hazardous substances [23, 24].

Organic transformation in aqueous medium has become a crucial and

demanding research area in modern synthetic chemistry. In the year 1980,

Breslow discovered that huge rate (i.e. 700 times faster reaction rate)

accelerations occurred when the Diels-Alder reaction was performed in water

[25]. This observation increased the interest of synthetic organic chemists to

analyze organic reactions in aqueous medium.


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Fig 1.2

Soon it was discovered that other organic reactions, like the Claisen

rearrangement [26], the Aldol condensation [27], the Benzoin condensation

[28] and the Barbier-Grignard reaction [29] exhibit rate enhancement in water.

To date, many more organic transformations have been carried out in water.

The use of environmentally benign solvents like water [30] and solvent

free reactions represent very powerful green chemical technology from the

economical and synthetic point of view. They not only reduce the burden of

organic solvent disposal, but also enhance the rate of many organic reactions

[31]. Choice of solvent is one of the problems to face to perform eco-efficient

processes.

Water used as solvent in organic synthesis is beneficial but the

insolubility of organic compounds is major disadvantage. This problem is

overcome by the addition of amiphiphiles for example, Hydrotropes and

Surfactants. We initially focused on the use of hydrotropes in aqueous

solution for the solubilisation of apolar compounds. It performs as a greener

reaction media alternative to organic solvent in organic synthesis Fig 1.3. This

is one of the most important synthetic methodologies for organic

transformations in aqueous medium which comes under the heading of green

chemistry.


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Greener Reaction Media

WaterFluorousMedia

Ionic Liquids

SC-fluids

Hydrotrope

Fig 1.3

1.2 Hydrotropes

Hydrotropes are highly water soluble surface active organic salts that at

higher concentration enhance the solubility of sparingly soluble as well as

practically insoluble organic compounds in aqueous medium. This

phenomenon was first reported by Neuberg in 1916 [32]. Hydro means water

and tropes mean something other is called Hydrotrope. The phenomenon of

increasing solubility of normally insoluble or sparingly soluble compounds in

water by a third component or additive is termed as Hydrotropy or

Hydrotropism. The substance that causes the solubility enhancement is called

Hydrotrope or Hydrotropic agents and are characterized by an amphiphilic

association structure [33]. Importance of hydrotropes and their many

synergistic properties appeared when it combined with other amphiphilic

molecules [34, 35].

The molecular characteristic of a hydrotropic molecule is that it is a

saturated hydrotropic ring and ionic compound [36]. Hydrotropes normally

comprise hydrophilic and hydrophobic moieties, the hydrophobic moiety being

typically too small to induce micelle formation [37]. The volume of

hydrophobic parts studied additives roughly evaluated by simple calculations

which show efficiency of hydrotrope. Generally, larger is the parts of additives

better is the hydrotropic efficiency and in contrast the hydrophilic part carrying

a charge or not is of minor importance. Therefore the hydrophobic part of the

molecule is the key matter in hydrotrope [38]. The mechanism of self


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association of hydrotropes being suggested by non-cooperative [39] as well as

cooperative self aggregation [40-42]. Hydrotropes form aggregation in aqueous

solution that are reminiscent of surfactant micelles and the formation of

associated structures important to show hydrotropic effect and they assumed to

aggregate by a stacking mechanism of the planner aromatic ring present in their

chemical structure. For aliphatic hydrotropes the staking mechanism does not

make sense. The characteristic aggregation of hydrotrope induces the origin of

the solubilization process of sparingly soluble hydrophobic compound in water

is analogy to a micillization process [43]. Saleh and co-workers proposed the

necessity of a planer structure is important for association and for the

hydrotropic effect [44].

The ability of hydrotrope to increase the solubility of organic compounds

in water is strongest when the hydrotrope concentration is sufficient to induce

the formation of associated structure and after which solubility remain

unchanged [45]. After certain threshold concentration the sudden increase in

solubilisation by hydrotropes, called as minimum hydrotrope concentration

(MHC). Minimum hydrotropic concentration changes when solution properties

changes such as viscosity, conductivity, surface tension and solubility. The

relatively high concentration required to reach MHC. Kumar et.al reported a

novel approach for reducing the MHC [46]. Aggregation and MHC are the

exact mechanism of solubilisation by hydrotropes [47]. The most important is

the presence of minimum hydrotrope concentration (MHC) analogues to

critical micellar concentration (CMC).

The solubilisation of organics in hydrotropes differ from the other

typical salting-in compounds and co-solvents, in this the solubility increases

sigmoidally depending on the concentration of hydrotrope. The salting-in co-

solutes and co-solvents at higher concentration usually cause a monotonic

increasing solubility without leveling off [43]. Hydrotropes are more effective

in solubilising organic solutes and more selective than the micelle-forming

surfactant [45, 48]. The self aggregation of hydrotropes are differs from that for

micelles [49]. The potential use of hydrotropes in industry was stressed in 1946


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by McKee [50]. Friberg and Blute reported a detailed description of hydrotrope

for their historical development and industrial applications [51]. However,

hydrotropes have received much less attention in chemical literature than

micelle forming surfactants. Despite the lack of attention, hydrotropes are

widely used in drug solubilization, detergent formulation, health care, and

household applications as well as being an extraction agent for fragrances [52,

53]. Hydrotrope have been applied in household liquid detergents, shampoos,

degreasing compounds and printing paste, used to extract pentosans and lignins

in the paper industry and additives for glues used in leather industry [54]. The

various areas have been benefited by the use of hydrotropes.

Aqueous solution of hydrotropes represents the unique properties of an

alternative reaction media for organic synthesis. Besides being a cheap, non-

toxic and environment friendly, aqueous hydrotropic solutions possess the

other physico-chemical characteristics required to be an alternative greener

solvents for organic transformations. The various organic transformations

carried out in hydrotropic aqueous medium are beneficial, for example,

Claisen-Schmidt reaction in hydrotropic aqueous solution [55], in the

microwave-enhanced Hantzsch dihydropyridine ester synthesis [56], in

synthesis of quinolines by Friedlander′s Heteroannulation method [57]. In

addition, hydrotrope enhance the rate of multiphase reaction [58] which can

lead to autocatalysis in the biphasic alkaline hydrolysis of aromatic esters [59].

The hydrotropes are also used in variety of applications other than organic

synthesis such as, in formulation of pharmaceuticals [60-64], extraction and

separation processes [48, 65-66] and the most recent research of hydrotropic

action has been performed on these above two processes. They show influence

on oil-in-water (OW) for micro-emulsions [52, 67] and related cleaning and

washing processes. Their biological action has also received more attention

[50].

As discussed earlier, an intriguing means of achieving aqueous solubility is

by using hydrotropes. Aqueous solutions of certain salts, such as those of

benzoic, salicyclic, benzene-sulfonic, naphthoic and various hydro-aromatic


10

acids have ability of dissolving certain substances that are not soluble in water.

These salts act as hydrotropes. They structurally resemble to surfactants in the

sense that they have hydrophilic and hydrophobic moieties in the same

molecule, but the alkyl chain is shorter. Some representative examples of

hydrotropes are shown in Fig 1.4.

Fig 1.4

Hydrotropes and Surfactants

SURFace ACTive AgenNTS means Surfactants (Fig 1.5), the most

outstanding property of surfactants is their tendency to form the micelles, at

sharply defined critical micelle concentration (CMC) [68]. The most important

difference between Hydrotropes and Surfactants:

� In case of hydrotrope the dissolved solute is precipitated on dilution ,

whereas with surfactant dilution leads to emulsification with

consequent problem of separation.

� The hydrotropic solubilzation occurs in the molar concentration

while surfactant show solubility enhancements at milimolar range.


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� Hydrotropes have strong ionic group and a relatively smaller

hydrocarbon/non-polar group as compared to surfactant.

� Hydrotrope induce maximum solubility of solute at MHC while in

surfactant it occurs at CMC.

� The lamellar liquid crystal region absent in the aqueous solution of

hydrotropes while it is prominent in the micelle-forming surfactant.

� Phase diagram of aqueous solution of hydrotropes display a single

continuous isotropic liquid phase [69-71].

Fig 1.5

Hydrotropic Action

A huge amount of theoretical work has been reported on the behavior of

non-electrolytes in aqueous solutions, but very little information is available on

hydrotropy, probably due to lack of clear distinction between hydrotropes and

salts, and the resulting tendency to group hydrotropes with salting-in

substances. A salting-in substance enhances the solubility of a non electrolyte

in a solvent, that is, the solute is greater in the salt solution than in the

corresponding pure solvent. A more common occurrence, however is, one

where the converse is true that is the solubility of a non electrolyte in a salt


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solution is lower that in the corresponding solvent, a situation refereed to a

generally as the salting-out effect. Assuming that hydrotropes behave in a

similar fashion, the following equation can be used to predict the solubility of

an organic compound in a hydrotropic solution.

log SSH = Ks [H] ………….......Eqn 1.1

Where Ks is the Setsschenow constant, H is the hydrotrope, and SH and

H are the solubilities of an organic solute in water with and without the

hydrotrope, respectively. For a positive hydrotropic effect corresponding to a

salting-in process, Ks is positive, and for a negative hydrotropic effect

corresponding to a salting-out process, Ks is negative. This empirical equation

is applicable to hydrotrope only in a limited concentration range.

Hydrotrope reduce the surface tension of water and at certain

concentration the surface tension become constant. This shows that the

association of the hydrotrope molecules in solution [72]. The balancing of

favorable hydrophobic interaction and unfavorable charge repulsion results in

the hydrotropes being soluble over a large concentration range. Hydrotrope

contains a hydrophobic moiety albeit small, that is able to participate in

relatively strong hydrophobic interaction with an uncharged apolar molecules.

If a hydrophobic moieties are large enough for the hydrophobic interaction to

overcome the charge repulsion, cooperative self-association take place

presumably producing highly dynamic and loose micellar type aggregates.

Hydrotrope designate the increase in solubility in water due to presence of

large amount of additives.

Applications of Hydrotropes in Organic Synthesis

Any technique that enhances the solubility of a sparingly soluble solute

in water finds immediate applications in organic synthesis. One of the

important strategies for organic chemistry is to develop simple, safe,

environmental friendly and inexpensive procedures for the synthesis of

valuable organic compounds. The synthesis of heterocyclic as well as

biologically active compound represent a broad class of compounds, which

have received considerable attention due to their wide range of biological


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activities. Synthesis of these compound through greener and safer methods to

be required and that achieved by use of hydrotrope in aqueous medium. For

synthetic chemistry in aqueous solutions, the use of hydrotropes can be

beneficial and this can be realized from the reported literature.

Khadilkar and Madyar [56] reported a scaling up of dihydropyridine

ester synthesis in aqueous hydrotropic solution under a continuous microwave

reactor. They showed use of aqueous hydrotropic solution as a cheap, safe and

green alternative to organic solvent to carry out homogeneous reaction under

microwave heating (Scheme 1.1).

O

R

COOR1

COOCH3

NH3

N

COOR1COOR1

CH3

CH3

H

R

% NaPTSA

+ +Aqueous hydrotrope

Microwave

50

Scheme 1.1

Chandratre and Filmwala [57] synthesized quinolines by Friedlander′s

Heteroannulation method in aqueous hydrotropic medium. Here, they report

the effect of different concentration of hydrotropes on the yield of product

(Scheme 1.2).

O

R

NH2

+O R1

R2

Aqueous hydrotropeN

R

R2

R1

SXS

Scheme 1.2

Laxman and Sharma [73] showed the ability of hydrotrope to change the

regioselectivity in the reduction of isophorone with sodium borohydride. In this

reaction 1,4-reduction of isophrone by NaBH4 in presence of polyalkylene

glycol as hydrotrope. An anomalous effect of temperature was also observed

using sodium salicylate as hydrotrope (Scheme 1.3).


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CH3

O

CH3

CH3

HO-(CH2-CH

2-O)-H

NaBH4

NaOH

OH

O

O

CH3

CH3 CH

3

O

O

O

O

OO

O

H

H

CH3

O

CH3

CH3

+ n

+

Selective 1,4-attack

Scheme 1.3

In our research laboratory the first application of hydrotropic solution in

facile synthesis of ferrocenylamines [74] using microwaves has been reported

by Salunkhe and co-workers. Microwave-assisted synthesis of secondary and

tertiary ferrocenylamines is achieved by using an amine exchange reaction

between ferrocenylmethyltrimethyl ammonium iodide and aryl amines in

aqueous hydrotropic solution. The synthesis proceeds in excellent yields within

short reaction times (Scheme 1.4).

N

Fe

Me

Me

Me

+I

Ar-NH2

50 % NaPTSA

MW

50 % NaPTSA

MW

Ar-NH-R

Fe

NH Ar

Fe

NAr

R

NH

50 % NaPTSA

MW

Secondary ferrocenylamines

Tertiary ferrocenylamines

Fe

N

Ferrocenyl azoles

Ferrocenylmethyltrimethylammonium iodide

Scheme 1.4


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As hydrotopes are usually salts, their aqueous solutions are likely to

enhance dielectric heating rates in view of above discussion. This factor

coupled with their ability to solubilize organic compounds should make them

highly efficient solvents. Although the use of hydrotopes is barely exploited

field, it won’t be wonder if their aqueous solutions will occupy a unique

position in organic synthesis.

Selection of Hydrotropes

Our investigations began with the selection of appropriate hydrotropes

for the organic synthesis. The different hydrotropes such as Sodium Benzene

Sulphonate (NaBS), Sodium p-Xylene Sulphonate (NaXS) and Sodium p-

Toluene Sulphonate (NaPTS) were selected for this purpose. Our investigation

began with the optimization of aqueous concentration of the selected

hydrotropes. After considerable experimentation, we optimized 50 % aqueous

solution of hydrotropes as solvent since this concentration was suitable for the

solubilization of organic compounds in sufficient quantities. These

hydrotropes are most attractive since they are air and moisture stable salts and

easily accessible by a high yielding method [75]. We decided to use 50 %

aqueous solution of NaPTS as solvent since this concentration was fairly

enough for solubilizing organic compounds in appreciably minimum quantities.

The glycerin used as hydrotrope and it shows excellent hydrotropic

properties [76, 77]. Glycerin is non-toxic, colorless and odorless liquid which is

highly stable and compatible with other solvents. Many compounds are soluble

in glycerin easier than water and alcohol, therefore it acts as excellent solvent.

The dilution of glycerin with water is important because it prevents the liquid

from attaining any staying power, and so the liquid can no longer coat or attach

itself to another surface. After series of experiment we observed that, the 50%

solution of glycerin was suitable for the organic synthesis to solubilise organic

compounds.


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General Method for Preparation of Hydrotropes

Synthesis of Sodium p-Toluene Sulphonate

A mixture of 0.65 mol (60 g) toluene and 33 mL of concentrated

sulphuric acid was taken in a 500 mL three-necked flask, provided with a

sealed mechanical stirrer and a reflux condenser. The mixture was heated with

stirring in an oil bath maintained at 110-120°C. When the toluene layer was

disappeared, the reaction mixture was cooled to room temperature and poured

with stirring into 250 mL cold water. The acid in solution was partly

neutralized by adding cautiously in small portions 30 g of sodium hydrogen

carbonate. The resulting solution was heated to boiling and saturated with 100

g sodium chloride. The hot solution was filtered through a Buchner funnel

previously warmed to about 100°C. The filtrate was cooled in ice with stirring

to form precipitate of sodium p- toluene sulphonate was filtered. The resulting

crude product was recrystalized by dissolving in 200-250 mL of water and

heated to boil and then saturated with sodium chloride. The solution was

allowed to cool somewhat, and then stirred with 2-3g of decolorizing charcoal

and filtered while hot with suction through a previously warmed Buchner

funnel. The warm filtrate was transferred to a beaker and cooled in ice to get

the precipitate of sodium p-toluene sulphonate. The precipitate was pressed

well and finally washed with a little alcohol and was dried in air and finally in

an oven at 100-110°C [78].

Synthesis of Sodium Benzene Sulphonate

The Sodium Benzene Sulphonate was prepared according to reported

method [78].

Sodium Xylenesulphonate

The Sodium salt of Xylenesulphonic acid (ZEONOL) used in the

present study was gifted from the Pharma products, Panvel, Maharashtra.

Characterization of Hydrotropes

Sodium p-Toluene Sulphonate

IR spectrum (Fig 1.10) showed the streching vibrations of aromatic

proton at 3065 cm-1. The characteristic S=O streching vibrations observed at


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1134 cm-1 and 1050 cm-1 respectively. In methyl group the C-H gives strong

starching vibrations at 2919 cm-1. In 1H NMR (Fig 1.11) strong singlet at 2.24

is of methyl proton which is desheilded due to aromatic ring. There are two

peaks of protons Ha and Hb appeared at aromatic region. The doublet at 7.21

having coupling constant J= 7.8Hz is of two Ha protons ortho coupled with Hb

is slightly shielded due to –CH3 group. The doublet at 7.55 having coupling

constant J=8.1 Hz is due to two Hb protons ortho coupled with Ha and is

highly deshielded due to sulphonate group. 13 C NMR (Fig 1.12) showed peak

at 20.4 is of methyl carbon while the four aromatic carbons appeared at 125.3,

129.4, 139.3 and 142.4.

The spectroscopic data of Sodium p- Toluene Sulphonate is follows:

IR (KBr): υ = 3065, 3036, 2919, 187, 1134, 1050, 816, 693 cm-1. 1H NMR(300MHz, D2O, δ ppm): 2.24 (s, 3H), 7.21(d, J= 7.8Hz, 2H), 7.55 (d,

J=8.1Hz, 2H) 13

C NMR (75 MHz, D2O, δ ppm): 20.4, 125.3, 129.4, 139.3, 142.4

Sodium Benzene Sulphonate

The IR spectrum (Fig 1.13) of Sodium Benzene Sulphonate showed the

C-H starching vibarations of aromatic ring at 3059 cm-1. The characteristic

S=O starching vibrations observed at 1136 cm-1 and 1043 cm-1 respectively. 1H

NMR spectra (Fig 1.14) showed two sets of aromatic protons. The multiplate at

δ 7.38 to 7.46 are of three protons Hb, Hb′ and Hc while signal at 7.66 is

doublet of doublet for protons Ha and Ha′ having J value 1.2 Hz and 3.9Hz

respectively and is deshielded due to sulphonate group. In 13 C NMR (Fig 1.15)

there are four sets of carbon, peak at 142.1 is of aromatic carbon attached to

substituted sulphonate group, peaks at 131.5, 128.9 and 125.2 are of ortho,

meta and para carbon respectively.

The spectroscopic data of Sodium Benzene Sulphonate is follows:

IR (KBr): υ = 3059, 1211, 1136, 1043 cm-1. 1H NMR (300MHz, D2O, δ ppm): 7.38 to 7.46 (m, 3H), 7.66 (dd, J=1.2 Hz

and 3.9Hz, 2H) 13

C NMR (75 MHz, D2O, δ ppm): 125.2, 128.9, 131.5, 142.1


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X-ray Diffraction (XRD)

Powder X-ray diffraction pattern of Sodium salt of p-Toluene

Sulphonate was obtained on the Philips diffractometer (PW-3071), using Ni

filtered Cu Kα radiation (λ=1.5406 Å) and scintillation counter as detector. The

pattern was recorded in the 2ө range of 20-60º with step of 0.1º. The phase

purity of the sample was checked by comparing the X-ray diffraction data

simulated from the crystal structure data available in the literature. The

comparison of the simulated and experimental powder XRD pattern of

synthesized compound is displayed in the (Fig 1.6). The exact matching of the

peak positions or reflections originating from the sample under study to the

peak positions in the simulated powder XRD pattern confirms the monoclinic

crystal structure for the Sodium p-Toluene Sulphonate. The absence of extra

reflections other than the monoclinic phase indicates that the sample is free

from any crystalline impurities originating from other phases. The three-

dimensional crystal structure of the salt based on the crystallographic

information reported by Reinke et al is displayed in the (Fig 1.7) viewed along

the ‘b’ axis. Thus from the XRD data we have confirmed the phase purity and

crystal structure of Sodium p-Toluene Sulphonate [79].

25 30 35 40

0

400

800

Inte

nsi

ty (

A.U

.)

2θθθθo

Experimental Simulated

Fig 1.6


19

Fig 1.7

Scanning Electron Microscopy (SEM)

Scanning Electron Microscopy pictures were taken on JEOL JSM to

study the morphology of the synthesized Sodium p-Toluene Sulphonate. The

SEM image (Fig 1.8) shows agglomerates of particals with diameters in the

range of several hundred of nanometer up to micrometers. This observation

suggests the probable layered stacking during crystal growth and is expected,

based on its three dimensional structure derived from XRD data.

Fig 1.8


20

Thermo Gravimetric Analysis (TGA) and Differential Thermal Analysis

(DTA)

TGA-DTA analysis was carried out to study the thermal stability of Sodium p-

Toluene Sulphonate. TGA-DTA profile as shown in (Fig 1.9). Weight loss is

mainly divided into three temperature regions. The first weight loss of probably

corresponds physically bound water species and is around 18.76%. The second

and third weight loss of approximately ~ 8.5% and 34.5 % could be due to the

evaporation of decomposition of organic groups present in the compound. The

residual weight percent was expected to be 16% but might be due to the

incomplete decomposition, we have the residual percentage of ~34%.

Fig 1.9: TGA graph of Sodium salt of p-Toluene Sulphonic Acid


27

1.3 References

[1] P. Anastas, J. C. Warner, Green Chemistry: Theory and Practice 1998 ,

Oxford University Press.

[2] (a) J. D. Holbrey, K. R. Seddon, J. Chem. Soc. Dalton Trans., 1999,

2133; (b) T. Welton, Chem. Rev. 1999, 99, 2071-2084; (c) M. J. Earle,

P. B. McCormac, K. R. Seddon, Green Chem., 1999, 1, 23. (d) M. T.

Reetz, W. Wiesenhöfer, G. Franciò , W. Leitner, Chem. Commun.,

2002, 992; (e)Y. Gu, C. Ogawa, S. Kobayashi, Org. Lett., 2007, 9, 175;

(f) H. Olivier-Bourbigou, L. Magna, J. Mol. Catal. A: Chem. 2002, 182.

[3] Noyori, R. Super critical fluids. Chem. Rev., 1999, 99, 353.

[4] J. Chen, K. Spear, J. G. Huddleston, R. D. Rogers, Green Chem., 2005,

7, 64.

[5] I. T. Horv´ath, Acc. Chem. Res., 1998, 31, 641.

[6] H. C. Hailes, Org. Process Res. Dev., 2007, 11, 114.

[7] P. Ball, “H2O A Biography of Water” Phoenix, London, 2000.

[8] (a) C. J. Li, T. H. Chang, Organic Reactions in Aqueous Media,Wiley:

New York, 1997; (b) P. A. Grieco, Organic Synthesisin Water; Blackie

Academic and Professional: London,1998.

[9] S. E. Thompson, D. B. Smithrud, Am. Che. Soc., 2002, 124, 442.

[10] S. L. Johnson, Adv. Phys. Org. Chem., 1967, 5, 237.

[11] T. C. Bruice, A. Donzel, R. W. Huffman, A. R. Butler, J. Chem. Soc.,

1967, 89, 2106.

[12] G. K. van der Wel, J. W. Wijnen, J. B. Engberts, J. Org.Chem, 1996, 61,

9001.

[13] (a) P. A. Grieco, ed. “Organic Synthesis in Water” Blackie, London,

1998; (b) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (c) A.

Lubineau, J. Auge, Y. Queneau, Synthesis, 1994, 741; (d) C. Li, Chem.

Rev., 1993, 93, 2023.

[14] P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice;

Oxford University Press: New York, 1998, 30.

[15] N. Hall, Science, 1994, 266, 32.


28

[16] A. Newman, Environ. Sci. Technol., 1994, 28(11), 463.

[17] R. Wedin, Today's Chemist at Work, 1994 (June), 114.

[18] R. A. Sheldon, Chemtech., 1994 (March), 38.

[19] I. Amato, Science, 1993, 259, 1538.

[20] D. L. Illman, Chem. Eng. News, 1993 (Sept. 6), 26.

[21] R. Wedin, Today's Chemist at Work, 1993 (July/Aug.), 16.

[22] L. Ember, Chemtech, 1993 (June), 3.

[23] P. T. Anastas and T. C. Williamson, Frontiers in green chemistry, Green

Chem. 1998, 1.

[24] P. T. Anastas, M. M. Kirchhoff, Origins, current status, and future

challenges of green chemistry, Acc. Chem. Res., 2002, 35, 686.

[25] D. C. Rideout, R. Breslow, J. Am. Chem. Soc., 1980, 102, 7816.

[26] P. A. Grieco, E. B. Brandes, S. McCann, J. D. Clark, J. Org. Chem.,

1993, 93, 2023.

[27] A. Lubineau, E. Mayer, Tetrahedron, 1988, 44, 6065.

[28] R. Breslow, Acc. Chem. Res., 1991, 24, 159.

[29] C. J. Li, J. Chem. Rev., 1993, 93, 2023.

[30] U. M. Lindatrom, Chem. Rev., 2002, 102, 2751.

[31] T. S. Jin, J. S. Zang, A. Q. Wang, T. S. Li, Synth. Commun., 2004, 34,

2611.

[32] C. Neuberg, Hydrotropy, Biochem. Z., 1916, 76, 107.

[33] (a) P. Ekwall, G. H. Brown (Ed.), Advances in Liquid Crystals,

Academic Press, New York, 1975, 1, 1; (b)Y. P. Koparkar, V. G.

Gaikar, J. Chem. Eng. Data, 2004, 49, 800.

[34] S. E. Friberg, R. V. Lochhead, I. Blute, T. Warnheim, J. Dispers Sci.

Technol., 2004, 25, 243.

[35] B. K. Roy, S. P. Moulik, Curr. Sci., 2003, 85, 1148.

[36] T. K. Hodgdon, E. W. Kaler, Current Option in Colloid & Interface

Science, 2007, 12, 121.

[37] A. Matero, In Handbook of Applied Surface and Colloide Chemistry,

Vol.1, K. Holmberg, Ed., Wiley-VCH, New York, 2002, 407.


29

[38] P. Bauuin, A. Renoncourt, A. Kopf, D. Touraud, W. Kunz, Langmuir,

2005, 21, 6769.

[39] S. E. Friberg, Curr. Opin. Colloid Interface Sci., 1997, 2, 490.

[40] B. Schobert, Naturwissenschaften, 1997, 64, 386.

[41] B. Schobert, H. Tschesche, Biochim. Biophys. Acta, 1978, 541, 270.

[42] P. Mukerjee, J. Pharm.Sci., 1974, 63, 972.

[43] D. Balasubramanian, V. Shrinivas, V. G. Gaikar, M. M. Sharma, J.

Phys. Chem. , 1989, 93, 3865.

[44] (a) A. M. Saleh, L. K. El-khordagui, Int. J. Pharm., 1985, 24, 132; (b) A.

A. Badwan, L. K. El-khordagui, A. M. Saleh, S. A. Khalil, J. Pharm.

Pharmacol, 1980, 32, 74.

[45] (a) V. Srinivas, D. Balasubramanian, Langmuir, 1998, 14, 6658; (b) V.

Srinivas, G. A. Rodley, K. Ravikumar, W. T. Robinson, M. M.

Turnbull, D. Balasubramanian, Langmuir, 1997, 13, 3235; (c) O. R. Pal,

V. G. Gaikar, J. V. Joshi, P. S. Goyal, V. k. Aswal, Pramana-J. Phys.,

2004, 63, 357.

[46] S. Kumar, N. Praveen, Kabir-ud-Din, J. Surfactants Deterg., 2005, 8,

109.

[47] G. Horvath-Szabo, Q. Yin, S. E. Friberg, Colloid Interface Sci., 2001,

236, 52.

[48] G. K. Poochiikian, J. C. Cradock, Pharm. Sci., 1979, 68, 728.

[49] J. C. Eriksson, G. Gillberg, Acta Chem. Scand., 1966, 20, 2019.

[50] R. H. McKee, Use of hydrotropic solutions in industy, Ind. Eng. Chem.,

1946, 38, 382.

[51] S. E. Friberg, I. Blute, In: Lai K-Y, editor. Hydrotropy. In Surfactant

Science Series 129 ( Liquid Detergents , 2 nd Edition), CRC Press LLC,

2006, 19.

[52] S. E. Friberg, C. Brancewicz, D. S. Morrison, Langmuir, 1994, 10,

2945.

[53] S. E Friberg, J. Yang, T. A. Huang, Ind. Eng. Chem. Res., 1996, 35,

2856.


30

[54] Usage of sodium dimethylbenzenesulfonate (mixture of isomers)

according to the National Toxicology Program (US).

[55] V. G. Sadvilkar, S. D. Samant, V. G. Gaikar, J. Chem. Technol.

Biotechnol., 1995, 62, 405.

[56] B. M. Khadilkar, V. R. Madyar, Org. Process Research and

Devlopment., 2001, 5, 452.

[57] S. J. Chandratre, Z. A. Filmwala, J. of Dispersion Science and

Technology, 2007, 28, 279.

[58] B. Janakiraman, M. M. Sharma, Chem. Eng. Sci., 1985, 40, 2156.

[59] X. N. Chen, J. C. Micheau, Colloid Interface Sci., 2002, 249, 172.

[60] G. D. Gupta, S. Jain, N. K. Jain, Pharmazie, 1997, 52, 709.

[61] R. M. Khalil, Pharmazie, 1997, 52, 866.


[63] S. A. ElNahhas, Pharmazie, Pharmazie, 1997, 52, 624.

[64] N. K. Jain, S, Jain, A. K. Singhai, Pharmazie, 1997, 52, 942.

[65] N. S. Tavare, E. J. Colonia, J. Eng. Data, 1997, 42, 631.

[66] J. E. Colonia, A. B. Dixit, N. S. Tavare, Ind. Eng. Chem. Res., 1998, 37,

1956.

[67] G. Horvath-Szabo, J. H. Masliyah, J. J. Czarnecki, J. Colloid Interface

Sci., 2001, 242, 274.

[68] M. J. Lawrence, Chem. Soc. Rev., 1994, 23, 417.

[69] D. Balasubramanian, S. E. Friberg, Suface and Colloid Science, (E.

Matejevic, ed.), Plenum, New York, 1993, 15, 197.

[70] T. Flaim, S. E. Friberg, J. Colloid Interface Sci., 1984, 97, 26.

[71] S. E. Friberg, S. B. Rananavare, W. D. Osborne, J. Colloid Interface

Sci., 1986, 109, 487.

[72] I. A. Darwish, F. A. Ismail, L. K. EI-Koradagui, Alex. J. Pharm. Sci.,

1992, 6, 101.

[73] M. Laxman, M. M. Sharma, Synth. Commun., 1990, 20 (1), 111.

[74] G. Rashinkar, S. Kamble, A. Kumbhar, R. Salunkhe, Transition Met.

Chem., 2010, 35, 185.


31

[75] H. -X. Wang, Y. -J. Li, R. Jin, J. R. Niu, H. -F. Wu, H. -C. Zhou, J. Xu,

R. -Q. Gao, F. -Y. Geng, J. Organomet. Chem., 2006, 691, 987.

[76] Q. Se´bastien, P. Bauduin, D. Touraud,b W. Kunzb and J-M. Aubry,

Green Chem., 2006, 8, 822.

[77] http://www.ehow.com/about_6644358_glycerine-hydrotrope.html

[78] B. S. Furnis, A. J.Hannaford, P. W. G. Smith, A. R. Tatchell, (1996)

Vogel’s textbook of practical organic chemistry. Prentice Hall.

[79] H. Reinke, S. Rudershausen, (1999). Private communication (refcode

HORSUC). CCDC, Cambridge, England.


32

21

Fig 1.10: Sodium salt of p-Toulene Sulphonic Acid

22


23


24

Fig 1.13 Sodium salt of Benzene Sulphonic Acid

25

Fig 1.14: Sodium salt of Benzene Sulphonic Acid

26

Fig 1.15: Sodium salt of Benzene Sulphonic Acid


27

1.3 References

[1] P. Anastas, J. C. Warner, Green Chemistry: Theory and Practice 1998 ,

Oxford University Press.

[2] (a) J. D. Holbrey, K. R. Seddon, J. Chem. Soc. Dalton Trans., 1999,

2133; (b) T. Welton, Chem. Rev. 1999, 99, 2071-2084; (c) M. J. Earle,

P. B. McCormac, K. R. Seddon, Green Chem., 1999, 1, 23. (d) M. T.

Reetz, W. Wiesenhöfer, G. Franciò , W. Leitner, Chem. Commun.,

2002, 992; (e)Y. Gu, C. Ogawa, S. Kobayashi, Org. Lett., 2007, 9, 175;

(f) H. Olivier-Bourbigou, L. Magna, J. Mol. Catal. A: Chem. 2002, 182.

[3] Noyori, R. Super critical fluids. Chem. Rev., 1999, 99, 353.

[4] J. Chen, K. Spear, J. G. Huddleston, R. D. Rogers, Green Chem., 2005,

7, 64.

[5] I. T. Horv´ath, Acc. Chem. Res., 1998, 31, 641.

[6] H. C. Hailes, Org. Process Res. Dev., 2007, 11, 114.

[7] P. Ball, “H2O A Biography of Water” Phoenix, London, 2000.

[8] (a) C. J. Li, T. H. Chang, Organic Reactions in Aqueous Media,Wiley:

New York, 1997; (b) P. A. Grieco, Organic Synthesisin Water; Blackie

Academic and Professional: London,1998.

[9] S. E. Thompson, D. B. Smithrud, Am. Che. Soc., 2002, 124, 442.

[10] S. L. Johnson, Adv. Phys. Org. Chem., 1967, 5, 237.

[11] T. C. Bruice, A. Donzel, R. W. Huffman, A. R. Butler, J. Chem. Soc.,

1967, 89, 2106.

[12] G. K. van der Wel, J. W. Wijnen, J. B. Engberts, J. Org.Chem, 1996, 61,

9001.

[13] (a) P. A. Grieco, ed. “Organic Synthesis in Water” Blackie, London,

1998; (b) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (c) A.

Lubineau, J. Auge, Y. Queneau, Synthesis, 1994, 741; (d) C. Li, Chem.

Rev., 1993, 93, 2023.

[14] P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice;

Oxford University Press: New York, 1998, 30.

[15] N. Hall, Science, 1994, 266, 32.


28

[16] A. Newman, Environ. Sci. Technol., 1994, 28(11), 463.

[17] R. Wedin, Today's Chemist at Work, 1994 (June), 114.

[18] R. A. Sheldon, Chemtech., 1994 (March), 38.

[19] I. Amato, Science, 1993, 259, 1538.

[20] D. L. Illman, Chem. Eng. News, 1993 (Sept. 6), 26.

[21] R. Wedin, Today's Chemist at Work, 1993 (July/Aug.), 16.

[22] L. Ember, Chemtech, 1993 (June), 3.

[23] P. T. Anastas and T. C. Williamson, Frontiers in green chemistry, Green

Chem. 1998, 1.

[24] P. T. Anastas, M. M. Kirchhoff, Origins, current status, and future

challenges of green chemistry, Acc. Chem. Res., 2002, 35, 686.

[25] D. C. Rideout, R. Breslow, J. Am. Chem. Soc., 1980, 102, 7816.

[26] P. A. Grieco, E. B. Brandes, S. McCann, J. D. Clark, J. Org. Chem.,

1993, 93, 2023.

[27] A. Lubineau, E. Mayer, Tetrahedron, 1988, 44, 6065.

[28] R. Breslow, Acc. Chem. Res., 1991, 24, 159.

[29] C. J. Li, J. Chem. Rev., 1993, 93, 2023.

[30] U. M. Lindatrom, Chem. Rev., 2002, 102, 2751.

[31] T. S. Jin, J. S. Zang, A. Q. Wang, T. S. Li, Synth. Commun., 2004, 34,

2611.

[32] C. Neuberg, Hydrotropy, Biochem. Z., 1916, 76, 107.

[33] (a) P. Ekwall, G. H. Brown (Ed.), Advances in Liquid Crystals,

Academic Press, New York, 1975, 1, 1; (b)Y. P. Koparkar, V. G.

Gaikar, J. Chem. Eng. Data, 2004, 49, 800.

[34] S. E. Friberg, R. V. Lochhead, I. Blute, T. Warnheim, J. Dispers Sci.

Technol., 2004, 25, 243.

[35] B. K. Roy, S. P. Moulik, Curr. Sci., 2003, 85, 1148.

[36] T. K. Hodgdon, E. W. Kaler, Current Option in Colloid & Interface

Science, 2007, 12, 121.

[37] A. Matero, In Handbook of Applied Surface and Colloide Chemistry,

Vol.1, K. Holmberg, Ed., Wiley-VCH, New York, 2002, 407.


29

[38] P. Bauuin, A. Renoncourt, A. Kopf, D. Touraud, W. Kunz, Langmuir,

2005, 21, 6769.

[39] S. E. Friberg, Curr. Opin. Colloid Interface Sci., 1997, 2, 490.

[40] B. Schobert, Naturwissenschaften, 1997, 64, 386.

[41] B. Schobert, H. Tschesche, Biochim. Biophys. Acta, 1978, 541, 270.

[42] P. Mukerjee, J. Pharm.Sci., 1974, 63, 972.

[43] D. Balasubramanian, V. Shrinivas, V. G. Gaikar, M. M. Sharma, J.

Phys. Chem. , 1989, 93, 3865.

[44] (a) A. M. Saleh, L. K. El-khordagui, Int. J. Pharm., 1985, 24, 132; (b) A.

A. Badwan, L. K. El-khordagui, A. M. Saleh, S. A. Khalil, J. Pharm.

Pharmacol, 1980, 32, 74.

[45] (a) V. Srinivas, D. Balasubramanian, Langmuir, 1998, 14, 6658; (b) V.

Srinivas, G. A. Rodley, K. Ravikumar, W. T. Robinson, M. M.

Turnbull, D. Balasubramanian, Langmuir, 1997, 13, 3235; (c) O. R. Pal,

V. G. Gaikar, J. V. Joshi, P. S. Goyal, V. k. Aswal, Pramana-J. Phys.,

2004, 63, 357.

[46] S. Kumar, N. Praveen, Kabir-ud-Din, J. Surfactants Deterg., 2005, 8,

109.

[47] G. Horvath-Szabo, Q. Yin, S. E. Friberg, Colloid Interface Sci., 2001,

236, 52.

[48] G. K. Poochiikian, J. C. Cradock, Pharm. Sci., 1979, 68, 728.

[49] J. C. Eriksson, G. Gillberg, Acta Chem. Scand., 1966, 20, 2019.

[50] R. H. McKee, Use of hydrotropic solutions in industy, Ind. Eng. Chem.,

1946, 38, 382.

[51] S. E. Friberg, I. Blute, In: Lai K-Y, editor. Hydrotropy. In Surfactant

Science Series 129 ( Liquid Detergents , 2 nd Edition), CRC Press LLC,

2006, 19.

[52] S. E. Friberg, C. Brancewicz, D. S. Morrison, Langmuir, 1994, 10,

2945.

[53] S. E Friberg, J. Yang, T. A. Huang, Ind. Eng. Chem. Res., 1996, 35,

2856.


30

[54] Usage of sodium dimethylbenzenesulfonate (mixture of isomers)

according to the National Toxicology Program (US).

[55] V. G. Sadvilkar, S. D. Samant, V. G. Gaikar, J. Chem. Technol.

Biotechnol., 1995, 62, 405.

[56] B. M. Khadilkar, V. R. Madyar, Org. Process Research and

Devlopment., 2001, 5, 452.

[57] S. J. Chandratre, Z. A. Filmwala, J. of Dispersion Science and

Technology, 2007, 28, 279.

[58] B. Janakiraman, M. M. Sharma, Chem. Eng. Sci., 1985, 40, 2156.

[59] X. N. Chen, J. C. Micheau, Colloid Interface Sci., 2002, 249, 172.


[61] R. M. Khalil, Pharmazie, 1997, 52, 866.


[63] S. A. ElNahhas, Pharmazie, Pharmazie, 1997, 52, 624.

[64] N. K. Jain, S, Jain, A. K. Singhai, Pharmazie, 1997, 52, 942.

[65] N. S. Tavare, E. J. Colonia, J. Eng. Data, 1997, 42, 631.

[66] J. E. Colonia, A. B. Dixit, N. S. Tavare, Ind. Eng. Chem. Res., 1998, 37,

1956.

[67] G. Horvath-Szabo, J. H. Masliyah, J. J. Czarnecki, J. Colloid Interface

Sci., 2001, 242, 274.

[68] M. J. Lawrence, Chem. Soc. Rev., 1994, 23, 417.

[69] D. Balasubramanian, S. E. Friberg, Suface and Colloid Science, (E.

Matejevic, ed.), Plenum, New York, 1993, 15, 197.

[70] T. Flaim, S. E. Friberg, J. Colloid Interface Sci., 1984, 97, 26.

[71] S. E. Friberg, S. B. Rananavare, W. D. Osborne, J. Colloid Interface

Sci., 1986, 109, 487.

[72] I. A. Darwish, F. A. Ismail, L. K. EI-Koradagui, Alex. J. Pharm. Sci.,

1992, 6, 101.

[73] M. Laxman, M. M. Sharma, Synth. Commun., 1990, 20 (1), 111.

[74] G. Rashinkar, S. Kamble, A. Kumbhar, R. Salunkhe, Transition Met.

Chem., 2010, 35, 185.


31

[75] H. -X. Wang, Y. -J. Li, R. Jin, J. R. Niu, H. -F. Wu, H. -C. Zhou, J. Xu,

R. -Q. Gao, F. -Y. Geng, J. Organomet. Chem., 2006, 691, 987.

[76] Q. Se´bastien, P. Bauduin, D. Touraud,b W. Kunzb and J-M. Aubry,

Green Chem., 2006, 8, 822.

[77] http://www.ehow.com/about_6644358_glycerine-hydrotrope.html

[78] B. S. Furnis, A. J.Hannaford, P. W. G. Smith, A. R. Tatchell, (1996)

Vogel’s textbook of practical organic chemistry. Prentice Hall.

[79] H. Reinke, S. Rudershausen, (1999). Private communication (refcode

HORSUC). CCDC, Cambridge, England.


32

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01 chapter 1shodhganga.inflibnet.ac.in/bitstream/10603/25448/7/07_chapter_01.… · Water is the matrix of life [7], unique extraordinary and safer reaction medium for organic studies