12

INTRODUCTION TO N - HALOIMIDES AND GENERAL

CHARACTERISTICS OF N-BROMOSUCCINIMIDE

13

H2C

H2C

CO

CONH

H2C

H2C

CO

CONBr

(1) (2)

CHAPTER ONE

SECTION – I 1.1. INTRODUCTION TO N-HALOIMIDES

The N-haloamides or imides are generally named by putting the prefix, before the name of the parent amide or imide, e.g., N-bromo. Thus in the recent chemical abstracts, N-bromosuccinimide has been listed as a derivative of 2, 5-pyrrolidinedione (1) i.e., 1-bromo-2, 5-pyrrolidinedione (2).

A large number of N-haloimides or amides, including some N-fluoro compounds, have

since been prepared and tested as reagents for allylic bromination and oxidation of organic

compounds. The only reagents which have been found to have as wide acceptability as

NBS for allylic bromination are the N-bromohydantoins. However, some of the reagents

which were found to be poor allylic brominating reagents have proved to be better reagents

in certain other reactions, particularly those involving the use of a polar medium and where

the reaction proceeds by an ionic rather than a free radical mechanism. Although alkali

hypohalites are the most common halogen compounds having halogen in the +1 oxidation

state, the N-haloimides and the alkyl hypohalites are their organic counterparts which have

halogen in +1 oxidation state. While the alkali hypohalites readily undergo

disproportionation into halate and halide ions, the alkyl hypohalites and N-haloimides are

more stable.

The electronegativities of chlorine, bromine, nitrogen and oxygen are 2.83, 2.74,

3.07 and 3.5 respectively, on Pauling’s electronegativity scale. Thus the halogen (except

fluorine) when linked to oxygen or nitrogen acquires a positive oxidation state. The

electronegativity of nitrogen is further enhanced by linking it to certain electron

CHAPTER ONE INTRODUCTION TO N-HALOIMIDES AND GENERAL

CHARACTERISTICS OF N-BROMOSUCCINIMIDE

14

NH

O

O

NH

O

O

NH

O

O

N

O

O

N

O

O

N

O

O

(1.1)

(1.2)

withdrawing groups such as acyl groups. Thus, N-substituted haloimides are referred to as

“positive halogen” compounds.

The N-Br bond in N-bromosuccinimide is essentially covalent. The acidic character

of succinimide (1.1) is accounted for by the stabilization of the anion (1.2) in which charge

dispersal rather than charge separation can take place. Similarly, the contribution of an

ionic form of N-bromosuccinimide particularly in solutions of polar solvents cannot be

ruled out.

The greater the electronegativity of the nitrogen atom, the more positive the halogen which

consequently is a stronger oxidant.

The oxidation potentials of the bromide-hypobromite couple are 0.76 and 1.33 V in

neutral and alkaline media, respectively. No attempt seems to have been made to determine

the oxidation potential of the N-bromoimides. The potentials of the NBS-bromide system

may be expected to be in the same range.

Although most of the N-bromoimides or amides and some chloro and iodo

compounds have been derived from carboxylic acids, some N-chloro or

N-bromosulfonamides are also known, the most important of these being N-chloro-p-

toluenesulfonamide, commonly known as chloramine-T. Chloramine-T has been used

extensively for analytical determinations involving bromination or iodination reactions

15

where the in situ generation of halogen is effected by the addition of bromide or iodide ion.

In certain cases, chloramine-T has been used for direct oxidation of organic and inorganic

species.

SECTION – II

1.2. GENERAL CHARACTERISTICS OF N-BROMOSUCCINIMIDE

1.2.1. Introduction

N-bromosuccinimide was first synthesized by Seliwanow [1] in 1893. The use of N-

bromoacetamide (NBA) as an allylic brominating reagent was reported by Wohl

and Jaschinowski [2]. After more than two decades, Ziegler and co-workers published a

series of papers on their detailed studies of the applications of N-bromosuccinimide for

allylic bromination. Ziegler and co-workers [3] prepared N-bromosuccinimide and eight

other N-bromoimides or bromoamides, but found them to be far less satisfactory than NBS

for allylic bromination. Djerassi [4] has published an excellent review on the allylic

bromination reaction. Under different conditions, this group of N-halogeno compounds

reacts with alkenes to add bromine to the double bond or to act as a source of hypohalous

acid in aqueous solution. They have, therefore, been used extensively as brominating and

oxidizing agents. Other reviews [5-7] on N-haloimides which also include studies on

oxidation have since been published.

1.2.2. Preparation

N-bromosuccinimide is prepared by the bromination of alkaline solution of

succinimide. 50 g (0.5 mole) of succinimide is dissolved in a cold solution of sodium

hydroxide (20 g, 0.5 mole in 100 ml water) in a 1 liter R.B flask and fit it with a dropping

funnel and a mechanical stirrer. Add 100 g finely crushed ice. For larger lots, arrangement

for external cooling may also be necessary. Add 27 ml (84.5 g, 0.5 mole) bromine in one

lot to the mixture with continuous vigorous stirring. The temperature of the reaction

mixture is not allowed to rise above 5 °C. N-bromosuccinimide separates as a thick

crystalline mass. Filter it through a sintered funnel, remove the drained solid and grind it

with a little water in a mortar. Filter again and repeat the operation 2 - 3 times or till the

filtrate is free of bromine and the solid product is pure white with no yellowish tinge. Dry

the product in a desiccator, first over solid potassium hydroxide and then over phosphorus

16

pentoxide. Alternatively, N-bromosuccinimide can be dried rapidly in a drying oven or a

pistol at a temperature not exceeding 50 °C. Yield ~70 g (75 - 80 %); m.p. 174 – 175 °C

(with decomposition).

Pure N-bromosuccinimide, free of traces of sodium bromide may be obtained by

recrystallizing the above product from ten times its weight of water. Dissolve N-

bromosuccinimide portion wise in water warm to 75 – 80 °C. Filter off any insoluble

particles and cool the solution in ice. Some decomposition is unavoidable [3], but 75 – 80

% recovery is possible. The recrystallized product has m.p. 176 – 177 °C. The reactivity of

the recrystallized product is, however, less in allylic bromination reactions [6].

In a modification of the above process, the succinimide is dissolved in a slight

molar excess of sodium hydroxide solution, and the bromine, dissolved in an equal volume

of carbon tetrachloride, is added rapidly with vigorous stirring. A finely crystalline white

product is obtained. This is filtered under suction and dried. The product is known to be

more active for allylic bromination reactions than that obtained above.

Waugh and Waugh [8] have described a method of preparing the N-bromo

compound by the simultaneous use of bromine and either chlorine, sodium hypochlorite or

N-chloro compounds for brominating imides, amides and sulfonamides in an alkaline

solution. The advantage of the method lies in the selective consumption of all the bromine

while the sodium chloride which is formed in the reaction is easily removed.

1.2.3. Properties

Pure NBS (mol. weight, 178) free from sodium bromide and occluded bromine is a

colourless solid melting at 176 – 177 oC. It contains 44.5 % - 44.9 % active bromine

depending upon the purity of the sample. The solubility of NBS in certain solvents is: water

(1.48 g /100 ml), carbon tetrachloride (0.025 g /100 ml), benzene (1.12 g /100 ml) and n-

hexane (0.003 g /100 ml).

17

N-bromosuccnimide is also soluble in chloroform, ethanol, pyridine, glacial acetic

acid and nitromethane. In most of the solvents N-bromosuccinimide undergoes slow

decomposition, particularly in the presence of air, moisture, acids and light. The

decomposition becoming faster at elevated temperatures. However, a well protected

aqueous solution of N-bromosuccinimide can keep its strength for 2 - 3 days if kept

refrigerated at 0 – 3 oC. The decomposition can generally be observed in the solution,

which turns pale yellow because of liberated bromine, and there is also the strong smell of

bromine.

The N-Br bond in N-bromosuccinimide is almost non-polar, although in other

haloimides this bond is generally polar. In contrast to certain other N-bromoimides, N-

bromosuccinimide as well as succinimide molecules are completely planar [9].

1.2.4. Photolysis

Exposure of a chloroform solution of N-bromosuccinimide to light is reported to

produce 3-bromopropionyl isocyanate [10]. The possible mechanism suggested is

represented as follows:

NBr

O

O

N

O

O

H2C CH2 C NCO

NBS

O

NCOBrCH2 CH2C

O

+N

O

O

-Brhv

(1.3)

In many of the reactions N-bromosuccinimide undergoes a two-electron reduction,

producing succinimide and bromide ion according to equation (1.4).

18

NBr H NH2e

O

O

+ +

O

O

+ Br (1.4)

The two-electron reduction of N-bromosuccinimide has been confirmed by polarographic

studies [11].

Recently, the photolysis of aqueous solution of N-bromosuccinimide (NBS) in the

UV region (λ = 2537 Å) has been studied [12]. The rate of photochemical decomposition is

found to be inverse fractional-order with respect to [NBS] and first-order with respect to

intensity of incident light ( Io ). A slight decrease in the rate has been observed upon the

addition of NaBr solution. The quantum yield (φ) for the photolytic decomposition has also

been calculated. Based on the reaction mechanism, the following rate law has been

derived.

]['

'

32

2

RNBrkk

Ikrate o

+= (1.5)

1.2.5. Types of reactions undergone by N-bromosuccinimide

The reactions undergone by N-bromosuccinimide may broadly be classified into the

following types:

(a) Allylic or benzylic bromination reactions

(b) Oxidation reactions

(c) Aromatization reactions

(d) Addition to the olefinic double bond.

(a) Allylic or benzylic bromination reactions

Dauben and McCoy [13] showed that the mechanism of allylic bromination is of the

free radical type since the reaction is very sensitive to free radical initiators and inhibitors

[14]. Indeed, the reaction did not proceed at all if the initiator was completely excluded.

19

These reactions are also catalyzed thermally [3] or by UV radiation [15, 10]. Further, these

reactions are expected to be favoured in non-polar media. Carbon tetrachloride has been the

most widely used solvent.

Allylic bromination reactions are quite specific, so much so that the nature of the

product of bromination with an unsaturated compound can be predicted. It was believed

[6] that the succinimide free radical is the hydrogen abstracting species as represented by

the following scheme:

H2C

H2C

CH2

CH2

CO

CONBr heat

lightor

CO

CON

or

H2C

H2C CO

CONBr NR RBr++

peroxide orinitiators

H2C

H2C

CO

CO

(1.6)

+ Br

Propagation reaction

C C

CO

CONBr C C CHBr

CO

CON

CH + +

Termination reaction

CO

CON X

H2C CO

CO

H2C

H2C

H2C

H2C

H2C

H2C+

NXH2C

(1.9)

(1.10)

or/and

C CC XC C CHX+ (1.11)

H

20

Br

C C CH2

C

C

CH

HBr

CC

CH

Br2

C

C CHBr +

+ +

+

(1.12)

(1.13)

Br

Subsequent work has indicated that, the species which abstracts hydrogen is the

bromine atom. The reaction is initiated by a small amount of Br radical. Once it is formed,

the propagation steps are:

The source of the Br2 is a fast ionic reaction between N-bromosuccinimide and

hydrogen bromide liberated in equation (1.12).

H2C

H2C

CO

CONBr HBr

H2C

H2C CO

CONH Br2+ + (1.14)

N-bromosuccinimide thus serves to provide bromine in a low steady-state

concentration, and to use up hydrogen bromide liberated in step (1.12). This mechanism

was originally suggested by Adam et al [16], but did not win acceptance for a number of

years. There is much evidence now to show that the succinimide radical is not involved in

the reaction, it is not even formed. The main evidence is that N-bromosucinimide and

bromine show similar selectivity [17 - 21]. Hedaya et al [22] and Koenig and Brewer [23]

have shown that the succinimide radical (Y) is much less stable than was originally

thought, since its dimer (X) shows little tendency to dissociate.

CO

COCO

CO CH2

CH2NNN

H2C

H2C

H2C

H2C2

CO

CO(1.15)

(X) (Y)

In the bromination of a double bond, only one atom of attacking bromine molecule

becomes attached to either of the double bonded carbons regardless of whether the addition

is electrophilic or free radical. McGrath and Tedder [24] demonstrated that bromination at

21

the double bond hardly takes place when a very low concentration of bromine is used, and

if the hydrogen bromide is removed as it is formed.

(b) Oxidation reactions

The oxidation reactions of N-bromosuccinimide generally involve the abstraction of

hydrogen from C-H, O-H, N-H, or S-H bonds though the reaction involving addition of

oxygen have also been observed. These reactions have found extensive application in the

determination of a variety of organic compounds.

NBS is relatively more stable in neutral, aqueous or slightly acidic medium (pH 4.5)

and can therefore be used for oxidation at relatively lower pH. NBS serves as a source of

bromonium ion (Br+) or hypobromite of low concentration, and the reaction is free from the

side reactions generally associated with the use of hypobromite solutions. In the oxidation

reactions, NBS undergoes a simple two-electron reduction to give bromide ion and

succinimide as products which do not interfere in the determination of organic compounds.

There is abundant evidence that in polar media the oxidation reactions proceed via a

“positive” halogen which is accepted to be the attacking species. However, NBS may also

be slowly hydrolysed to hypobromite. Even the molecular NBS or molecular bromine may

be the reactive species.

Thiagarajan and Venkatsubramanian [25] carried out extensive kinetic studies of the

oxidation of alcohols with N-bromosuccinimide and allied compounds. A cyclic transition

state was proposed for the oxidation of alcohols with bromine.

Venkatsubramanian and Thiagarajan [26] carried out the oxidation of alcohols with

N-bromosuccinimide in the presence of mercuric acetate, which acts as scavenger for any

bromine formed in the reaction as HgBr42- or Hg(OCOCH3)Br2

2-, thus making sure that

oxidation takes place purely through N-bromosuccinimide. NBS oxidation also involves the

formation of a cyclic transition state [25]. The ease of oxidation of alcohols with N-

bromosuccinimide is in the order: secondary > primary. Tertiary alcohols are more or less

22

resistant to the reagent [7]. One of the most useful applications of N-bromosuccinimide and

allied compounds is in the stereoselective oxidation of steroidal alcohols.

Alkanoic acids except formic acid are generally resistant to oxidation with

N-bromosuccinimide. Aliphatic primary and secondary amines readily undergo N-

brominaton with N-bromosuccinimide, generally followed by elimination of HBr. Tertiary

amines undergo C-N bond fission with the formation of aldehydes and secondary amines.

Hydrazine and its derivatives are readily and quantitatively oxidized by N-

bromosuccinimide and hypohalites at room temperature, yielding nitrogen. The reaction

has been used for the determination of hydrazine by a direct titration [27]. Arylhydrazines

have been reported to be oxidized to nitrogen and hydrazobenzenes [28], but there has been

a controversy over the nature of the oxidation products.

Thiols are oxidized by N-bromosuccinimide in carbon tetrachloride to the

corresponding disulphides [29]. The same oxidation products are formed by oxidation in

aqueous acetic acid medium and the reaction has been used for the determination of thiols

including thiophenols [30]. In aqueous hydrochloric acid medium both thiols and

disulphides are oxidized to the corresponding sulphonic acids, while the thioether group in

methionine is oxidized to the sulphoxide [31].

(c) Aromatization reactions

The ability of N-bromosuccinimide to act as a specific allylic brominating agent has

been used for introducing supplementary double bonds in organic molecules, particularly in

the cyclic systems. The method involves two steps: (i) bromination and (ii)

dehydrobromination. In this way a number of monounsaturated compounds have been

converted into conjugated dienes and trienes. Introduction of additional double bonds in a

cyclic system may eventually lead to aromatization. These have been reviewed by Filler

[7].

(d) Selective peptide bond cleavage reactions

Certain amino acid residues in a peptide chain have unsaturation in a position γ and

δ to the amide bond. Such residues are cleaved selectively by reaction with

N-bromosuccinimide. Unlike the normal hydrolysis of an amide bond by acid- or base-

23

catalyzed nucleophilic attack, the cleavage with N-bromosuccinimide involves

intramolecular nucleophilic assistance from the neighbouring amide group and is thus

limited to certain naturally occurring amino acids. These reactions have been extensively

used for the determination of these amino acids and the site of their bonding in a peptide

chain.

1.2.6. Determination of N-bromosuccinimide The halogen in N-bromosuccinimide is present in the +1 oxidation state. Its

determination has therefore been carried out by a variety of redox reactions. In these

reactions the halogen is reduced to the corresponding halide ion by a reaction involving a

two-electron change.

When N-bromosuccinimide is used as an oxidant for the determination of other

compounds, an excess of the oxidant is usually employed, and after completion of the

reaction, the excess is determined by back-titration. The methods for the determination of

N-bromosuccinimide and other positive halogen compounds are important not only in

determining the purity of the product but also indirectly in the determination of other

organic compounds using an excess of N-bromosuccinimide.

One of the commonly used methods for the determination of N-bromosuccinimide is

described below.

Iodometric Method This is one of the most widely used methods [32]. Since then various modifications

dependent directly or indirectly on the iodometric method have been proposed.

In the direct iodometric method [3, 33] iodine liberated by adding an excess of

potassium iodide to N-bromosuccinimide containing dilute sulphuric acid or acetic acid is

determined by titration with standard sodium thiosulphate using starch as indicator. In the

reaction of N-bromosuccinimide with potassium iodide, two-equivalents of iodine are

produced per active N-halogen atom. The method is applicable to the determination of solid

products as well as solutions of N-bromosuccinimide including those containing excess of

24

N-bromosuccinimide left in a reaction mixture. The reaction probably takes the following

course:

(CH2CO)2 NBr → (CH2CO)2N - + Br + (1.16)

Br+ + 2I - → Br - + I2 (1.17)

(CH2CO)2N - + K + → (CH2CO)2NK (1.18)

(CH2CO)2NK + CH3COOH → (CH2CO)2NH + CH3COOK (1.19)

(CH2CO)2NBr + 2KI + CH3COOH → (CH2CO)2NH + I2 + CH3COOK

+ KBr (1.20)

1.2.7. Quantitative determination of pharmaceuticals using N-bromosuccinimide In recent years there has been growing interest in the role of N-bromosuccinimide

(NBS) as an analytical reagent in the determination of many pharmaceutical compounds.

Determination of ranitidine in pharmaceuticals using NBS as the oxidimetric reagent has

been reported by Somashekar and Basavaiah [34]. Determination of some of the drugs,

viz., tetracycline hydrochloride, nifurtimox, ethionamide, propranolol hydrochloride and

isonicotinic acid hydrazide based on their reactivity with NBS has been investigated by

Sastry et al [35]. Quantification of lamivudine in bulk drug and in tablets using NBS has

been studied [36].

Basavaiah et al [37] have reported the assay of albendazole using NBS as the

reagent. Determination of pantoprazole sodium sesquihydrate in bulk drug and in

formulations using NBS as the oxidimetric reagent has been studied [38]. Micro

determination of salbutamol sulphate with NBS has been reported [39]. Determination of

certain catecholamine derivatives in pharmaceutical preparations using NBS has been

25

investigated by Nagaraja et al [40]. Quantification of salbutamol sulphate using NBS in

acid medium has been reported by Basavaiah et al [41].

Michalowski et al [42] studied the determination of epinephrine in pharmaceutical

preparations using NBS in alkaline medium. Quantification of lisinopril in drug

formulations using NBS has been reported [43]. Barsoum et al [44] have studied the

evaluation of Isoniazid and Rifampicin using NBS. Determination of olanzapine by its

oxidation with NBS in acidic medium has been reported by Anna Krebs et al [45].

Wang et al [46] have investigated the determination of Phenformin in

pharmaceutical formulations using NBS in alkaline medium. Determination of H2-receptor

antagonists: cimetidine, famotidine, nizatidine and ranitidine hydrochloride based on the

reaction of these drugs with NBS has been reported [47]. Alwarthan and Al-Obaid [48]

have studied the quantification of astemizole in bulk and in pharmaceutical dosage forms

using NBS in alkaline medium.

Determination of acetaminophen based on its oxidation using NBS has been

reported by Abdel-Wadood et al [49]. Quantification of metaprolol tartrate in

pharmaceuticals using NBS as the oxidimetric reagent has been investigated by Basavaiah

and Somashekar [50]. Rao et al [51] studied the estimation of betaxolol hydrochloride and

metoprolol tartrate using NBS. Determination of gatifloxacin in pharmaceuticals using

NBS in acid medium has been reported by Basavaiah and Anilkumar [52]. Estimation of

zidovudine using NBS in acid medium has been studied [53].

Determination of tolnaftate using NBS has been reported by Abdelmageed et al

[54]. Quantification of promethazine hydrochloride using NBS has been studied [55].

Determination of diltiazem hydrochloride using NBS has been reported [56]. Srinivas et al

[57] have studied the assay of cefdinir using NBS. Quantification of stavudine using NBS

has been reported by Basavaiah et al [58].

26

SECTION – III

1.3. KINETIC INVESTIGATIONS WITH N-BROMOSUCCINIMIDE: A REVIEW N-bromosuccinimide (NBS) has been used as a brominating agent [4] for a wide

variety of organic compounds, and as an oxidizing agent for the conversion of primary and

secondary aliphatic alcohols to the corresponding aldehydes and ketones. In many cases its

action is highly selective [59, 60].

The kinetics of the oxidation of a number of aliphatic and aromatic secondary

alcohols with NBS has been studied [26]. Kinetics of NBS oxidation of secondary alcohols,

viz. aliphatic, aromatic and alicyclic has been investigated [25]. Kinetics of the oxidation of

methyl n-propyl ketone and methyl isobutyl ketone by NBS have been studied by Singh et

al [61] in perchloric acid medium and in presence of mercuric acetate. A suitable

mechanism in conformity with kinetic results has been proposed.

Gopalakrishnan and Hogg [62] have reported the kinetics of oxidative

decarboxylation of glycine, DL-alanine, and DL-valine promoted by NBS as a function of

pH. A mechanism involving the formation of an acyl hypobromite of glycine, its slow

decomposition to an imine, and subsequent rapid conversion of imine to products is

proposed.

Kinetics of Ru(III)-catalyzed oxidation of diethylene glycol (DG) and ethyl

diethylene glycol(EDG) by NBS have been investigated in perchloric acid medium in the

presence of mercuric acetate [63]. A suitable mechanism in conformity with kinetic results

has been proposed.

Kinetics of oxidation of thiocyanate ion (SCN-) by N-chlorosuccinimide (NCS) and

N-bromosuccinimide (NBS) have been studied in 1:1(v/v) aqueous methanol in the

presence of perchloric acid and in aqueous alkaline medium [64]. Mechanisms consistent

with observed results under different conditions have also been proposed. Kinetics and

mechanism of uncatalyzed and Ir(III) catalyzed oxidation of oxalate ion by NBS in basic

27

medium has been studied [65]. A mechanism involving the hypobromite ion as the reactive

species of the oxidant has been proposed. Karunakaran and Venkatachalapathy [66] have

studied the methoxy bromination of cinnamic acid by NBS in acid medium. Mechanistic

pathways of the reaction are discussed and a rate equation is derived.

Contrastic kinetic behavior of allyl and crotyl alcohols towards NBS in aqueous

methanol medium has been studied by Karunakaran and Ganapathy [67]. Kamble et al [68]

have investigated the kinetics of oxidation of Cr(III) by NBS in aqueous alkaline medium.

A mechanism has been proposed and the reaction constants have been evaluated.

Kinetics and mechanism of uncatalyzed and ruthenium (III) catalyzed oxidation of

allyl alcohol by NBS in aqueous alkaline medium has been studied [69]. A mechanism

involving the hypobromite ion as the reactive species of the oxidant has been proposed. The

reaction constants of individual steps of reaction mechanism have been computed.

The reaction between hexacyanoferrate(II) and NBS in aqueous alkaline medium

has been studied by Kamble et al [70]. A mechanism based on the experimental results is

proposed and the constants involved in the mechanism are evaluated. The osmium (VIII)-

catalyzed oxidation of allyl alcohol by NBS in aqueous alkaline medium has been

investigated by Chougale et al [71]. A mechanism involving hypobromite ion as the

reactive species of the oxidant has been proposed.

Harihar et al [72] have studied the kinetics and mechanism of NBS

oxidation of L-arginine in aqueous acidic medium. A mechanism involving the

unprotonated NBS as the reactive species of the oxidant has been proposed. The kinetics of

oxidation of ethylenediaminetetraacetic acid (EDTA) by NBS in aqueous alkaline medium

was investigated [73] at 25 oC. The proposed mechanism is consistent with the observed

kinetics.

Iridium (III) catalysis of NBS oxidation of reducing sugars in aqueous acid has been

studied by Singh et al [74]. A suitable mechanism conforming to the kinetic results is

28

suggested. Conversion of Mn(VI) to Mn(VII) by NBS in aqueous alkaline medium has

been studied spectrophotometrically [75]. A mechanism involving the HOBr as the reactive

species of the oxidant has been proposed.

Kathari et al [76] have reported the ruthenium (III)-catalyzed oxidation of

manganate(VI) by NBS in aqueous alkaline medium. The kinetics of oxidation of

aminoalcohols (AA) viz., ethanolamine (EA), diethanolamine (DEA) and triethanolamine

(TEA) by NBS in alkaline medium have been investigated in the absence and in the

presence of polyoxyethylene-23 lauryl ether (Brij-35), a non-ionic surfactant [77].

Kinetics and mechanism of the oxidation of chromium (III)-dipicolinic acid complex

by NBS has been reported [78]. It is proposed that electron transfer proceeds through an

inner- sphere mechanism via coordination of [NBS] to Cr(III). Kinetics and mechanism of

oxidation of (ethylenediamine diacetato) chromium (III) by NBS have been studied [79]

spectrophotomerically over the 20 – 40 oC range.

The kinetics of Pd(II)-catalyzed oxidation of D-arabinose, D-xylose and D-

galactose by NBS in acidic medium has been studied using Hg(OAc)2 as a scavenger for

the Br– ion [80]. On the basis of the experimental findings, a suitable mechanism has been

proposed. The kinetics of oxidation of phenylalanine by NBS in HClO4 in the presence of

Ir(III) as a catalyst and Hg(OAc)2 as a scavenger for Br – have been studied in the

temperature range 30 - 40 oC [81]. A suitable reaction mechanism is discussed in terms of

kinetic results.

Photochemistry of vic-diols in the presence of benzoyl peroxide and NBS has been

studied [82]. Kinetics and mechanism of oxidation of aspirin by NBS have been studied

by Ramachandrappa et al [83] in aqueous perchloric acid at 303 K. The proposed reaction

mechanism and the derived rate law are consistent with the observed kinetic data. The

kinetics and mechanism of Ir(III) catalyzed oxidation of cyclopentanol by acidic solution of

NBS has been extensively studied at 35 oC [84]. A suitable mechanism consistent with the

observed kinetic findings has been suggested.

29

Kinetics and mechanism of the oxidation of diaqua(nitrilotriacetato) chromium(III)

complex by NBS has been studied in aqueous solution [85]. The thermodynamic activation

parameters were calculated, and it is proposed that electron transfer proceeds via an inner-

sphere mechanism. Mechanism of Pd(II)-catalyzed oxidation of dimethyl digol and butyl

digol by alkaline solution of NBS in the temperature range 35 – 45 ºC has been reported

[86]. A suitable mechanism in agreement with the observed kinetics has been proposed

and various activation parameters have been computed.

Oxidation of the diaqua (nitrilotriacetato) cobaltate(II) complex, [Co(II)nta(H2O)2]¯

by NBS has been studied in aqueous medium [87]. The thermodynamic activation

parameters were calculated, and proposed that electron transfer proceeds through an inner-

sphere mechanism. The kinetics of oxidation of amino acids, (alanine, phenylalanine and

valine) by NBS has been studied in alkaline medium [88]. A mechanism consistent with

kinetic data has been proposed.

Mavalangi et al [89] have studied the kinetics and mechanism of Pd(II) catalyzed

oxidation of EDTA by NBS in aqueous alkaline medium. The Kinetics of oxidation of 3-

benzolypropionic acid by NBS was studied in acetic acid-water mixture (1:1 v/v) [90].

From the kinetic data obtained, the activation parameters were computed and a suitable

mechanism was proposed.

Singh et al [91] have reported the Pd (II)-catalyzed oxidation of D(-)-fructose and

D(-)- mannose by acidic solution of NBS in the presence of mercuric acetate. A

suitable mechanism in conformity with kinetic results has been proposed. The kinetics of

oxidation of D(-)-glucose and L(-)-sorbose by acidic solution of NBS in the presence of

Pd(II) chloride as homogeneous catalyst and mercuric acetate as scavenger in the

temperature range of 35 – 50 °C has been reported [92]. A suitable mechanism consistent

with the experimental results has been proposed.

30

The kinetics of oxidation of 2-aminomethylpyridine Co (II) complex by NBS has

been studied [93] in aqueous solutions. Ruthenium(III)-catalyzed oxidation of

ethelenediaminetetraacetic acid by NBS in aqueous alkaline medium has been investigated

[94]. A mechanism involving hypobromite ion as the reactive species of the oxidant has

been proposed. Janibai and Vasuki [95] have reported the kinetics of oxidation of

acetophenone oxime and substituted acetophenone oximes by NBS in aqueous acetic acid

medium. A suitable mechanism was proposed.

Kinetics and mechanism of Ir(III)-catalyzed oxidation of aspartic acid by NBS has

been extensively studied under isolation condition at 30 oC [96]. Kinetics and mechanism

of Ru(III)-catalyzed oxidation of butyl digol by NBS has been extensively studied [97] at

35 °C under Ostwald isolation condition. The kinetics of oxidation of a ternary complex

involving nitrilotriacetato cobaltate(II) and succinic acid by NBS in aqueous solution has

been studied spectrophotometrically [98] in the 20 – 40 °C range. It is assumed that

electron transfer takes place via an inner-sphere mechanism.

The kinetics of Ir(III)-catalyzed oxidation of melibiose and cellobiose by NBS in

HClO4 medium in the presence of Hg(OAc)2 as a scavenger for Br – has been investigated

[99]. A mechanism confirming the observed kinetic data has been proposed. The kinetics

and mechanism of oxidation of a ternary complex involving dipicolinatochromium(III) and

DL-aspartic acid by NBS has been investigated in aqueous solution [100].

The kinetics of oxidation of aminoalcohols, viz., ethanolamine (EA),

diethanolamine (DEA) and triethanolamine (TEA) by NBS has been studied in alkaline

medium [101]. Mechanistic study of Ir(III)-catalyzed oxidation of cyclopentanol and

cyclohexanol by NBS has been studied [102] in acidic medium. A suitable mechanism

consistent with the experimental results has been proposed.

Hiran et al [103] have studied the kinetics and mechanism of oxidation of some

substituted benzhydrols by NBS in acidic medium. Two different mechanisms, cyclic

transition state with unprotonated NBS in the absence of acid and non cyclic transition state

31

with protonated NBS in the presence of acid have been suggested. The kinetics of Ru(III)

catalysed and uncatalysed oxidation of ethylamine and benzylamine by NBS in acidic

medium has been studied [104]. Suitable mechanisms and rate laws consistent with the

observed kinetic results are proposed.

Kinetics of oxidation of amino alcohols, viz., ethanolamine, diethanolamine and

triethanolamine by NBS in alkaline medium has been investigated [105] in the absence as

well as in the presence of cetyl trimethyl ammonium bromide (CTAB), a cationic

surfactant. The reaction is strongly catalyzed by CTAB even before the critical micelle

concentration (CMC) of CTAB. However, the observed rate constants attained constancy at

higher [CTAB] (> CMC of CTAB).

The kinetics of oxidation of amino alcohols, viz., ethanolamine, diethanolamine and

triethanolamine by NBS in alkaline medium has been investigated [106] in the presence of

polyoxyethylene (10) octyl phenol (TX-100), a nonionic surfactant. The presence of a small

amount of surfactant (below its CMC), strongly enhanced the rate of oxidation. The

kinetics of oxidation of amino alcohols, viz., ethanolamine, diethanolamine and

triethanolamine by NBS has been investigated in the presence of anionic surfactant, viz.,

sodium lauryl sulfate in alkaline medium [107]. The catalytic influence of anionic micelle

on rate of the reaction has been studied at different temperatures.

The kinetics and mechanism of Ru(III) and Ir (III) catalyzed oxidation of malic acid

by NBS have been studied in acidic medium in the presence of mercuric acetate as a

scavenger in the temperature range of 30 – 45 oC [108]. Ru(III) and Ir(III) catalyzed

reactions follow identical kinetics. A suitable mechanism in conformity with the observed

kinetics was proposed and activation parameters have been calculated. Manivarman et al

[109] have studied the kinetics and mechanism of oxidation of N, a- diphenyl nitrones in

the presence of mercuric acetate in aqueous acetonitrile medium by NBS. The mechanism

proposed and the derived rate laws are in conformity with the observed results.

Kinetics and mechanism of catalyzed and uncatalyzed oxidation of D-glucose by

NBS in aqueous acidic medium have been investigated [110]. Activation parameters have

32

been calculated. A suitable mechanism has been proposed. Kinetics and mechanism of

oxidation of the binary and ternary complexes of Cr(III) involving inosine and glycine by

NBS has been studied by Hassan A Ewais et al [111]. The activation parameters have been

calculated. Electron transfer apparently takes place via an inner sphere mechanism.

Kinetics of oxidation of benzyl ethers by NBS in 80 % aqueous acetic acid was studied

[112]. From the effect of temperature on the reaction rate, the Arrhenius and the activation

parameters were calculated. A suitable mechanism was proposed and a rate law explaining

the experimental results has been derived.

The kinetics of palladium (II) – catalyzed oxidation of EDTA by NBS in acidic as

well as in alkaline medium have been investigated by Rashmi Tripathi et al [113]. The

proposed mechanism involves the formation of [EDTA-Pd (II)] complex which has been

verified spectrophotometrically. Kinetics and mechanism of oxidation of substituted and

unsubstituted 4–oxo acids by NBS in aqueous acetic acid medium has been studied [114]

potentiometrically. Based on the kinetic results and the product analysis, a suitable

mechanism has been proposed for the reaction of NBS with 4-oxoacids.

The kinetics of oxidation of ferrocyanide by NBS has been studied [115]

spectrophotometrically in aqueous acidic medium over temperature range 20 – 35 oC, pH

range 2.8 - 4.3 and ionic strength 0.1 - 0.5 mol dm-3. An outer sphere mechanism has been

proposed for the oxidation pathway of both protonated and deprotonated ferrocyanide

species. The kinetics of oxidation of amino acids and dipeptides by NBS has been studied

in acidic medium spectrophotometrically [116]. The proposed mechanism is consistent with

the experimental results. The kinetics of oxidation of some substituted nitrones by NBS has

been investigated in aqueous alkaline medium [117]. The thermodynamic parameters are

also determined. A suitable mechanism is proposed from the kinetic data.

The kinetics of iridium (III) - catalyzed oxidation of D-mannitol and erythritol by

NBS has been studied in acidic medium [118]. A suitable mechanism was proposed from

the kinetic data. The kinetics of oxidation of tetrapeptides and their constituent amino acids

by NBS has been studied in acidic medium spectrophotometrically [119]. The proposed

mechanism is consistent with the experimental results. Dilip Patil and Sunil [120] have

33

reported the kinetics of oxidation of β-alanine by NBS electrochemically. Surendrakumar

and Aarti have reported the kinetic investigation of uncatalyzed and iridium(III) catalyzed

oxidation of dextrose by NBS in alkaline medium [121]. The kinetics and mechanism of

Ru(III) catalyzed oxidation of amino acids, viz., asparagine and aspartic acid by NBS in

acidic medium has been investigated [122]. The kinetics of oxidation of α-alanine by NBS

in acid medium has been reported [123]. The kinetics and mechanism of Ru(III) catalyzed

oxidative cleavage of thiamine hydrochloride by NBS in acid medium has been

investigated [124]. The kinetics and mechanism of oxidation of 2-hydroxynaphthaldehyde

by NBS in alkaline medium has been reported [125].

Kinetics and mechanism of Ru(III)-catalysed oxidation of some polyhydric alcohols

by NBS in acid medium have been studied by Sharma et al [126]. A suitable mechanism

consistent with the experimental results has been proposed. Kinetics and mechanism of

Ru(III)-catalysed oxidation of glycolic and mandelic acids by NBS have been investigated

[127] in acidic medium. A suitable mechanism in conformity with the kinetic results has

been proposed.

34

SECTION – IV

1.4. INTRODUCTION TO REACTION KINETICS

Chemical kinetics deals with the quantitative study of the rates of a reaction and the

factors upon which they depend. Kinetics is the first step in the study of reaction

mechanisms because of the wealth of information it gives about the nature and course of a

reaction. Besides it assists in the determination of the yields of products, the relative

reactivities of molecules and also the possibility of whether or not a reaction will take place

under certain experimental conditions.

The subject of chemical kinetics covers a wide range. It includes empirical studies

of the effects of various factors such as concentration, temperature, solvent medium,

hydrostatic pressure of the reaction system etc. The aim of the chemical kinetics is two-

fold: To determine the macroscopic rate law of the overall reaction together with the

numerical values of the rate constants and to analyze the mechanism of the reaction.

There are many different types of chemical reactions and wide varieties of

experimental techniques involving both physical and chemical methods are employed to

investigate them. In all these techniques, decreasing concentration of reactants or

increasing concentrations of products or a corresponding response to a physical property is

measured at various time intervals as the reaction proceeds.

For reactions in solution, the mechanism is formulated by the determination of the

different kinetic parameters, the most important being the order of reaction with respect to

the different reactants, effect of concentration of the catalyst (for a catalyzed reaction),

ionic strength [128], solvent [129], dielectric permittivity [130] and the temperature on the

reaction rate. Determination of the stoichiometry of the reaction, detection and estimation

of products and effects of substituents on the reaction rate are also valuable factors which

throw considerable light on the mechanism of the reaction and confirm the rate-determining

step. Further, the isolation and identification of the structure of intermediates and use of

isotopic methods [131] have been proved to be of great value in elucidating reaction

mechanisms. When the reaction has more than one elementary step, the kinetics is limited

35

by the slowest stage which is the rate-determining step. It is known that when a reaction is

completed to only about 10 – 20 % (i.e., considerably smaller than even the first half) the

measured values of x or (a - x) fit in the entire zero, half, first, three halves, second and five

halves order rate laws equally well. Further, a differentiation between a zero-order and

first-order rates can only be affected by observing the reaction rate after the completion of

the second half-life stage. Thus, it is clear that the rate must be pursued till the completion

of at least the second half-life.

1.4.1. Theories of reaction rate

There are two well known theories of reaction kinetics,

1. Collision theory and

2. Activated complex or transition state theory.

According to collision theory, the reactions are regarded as taking place on collision

between the reacting molecules. For a reaction between two identical gaseous molecules,

the rate (v) in molecular unit is given by,

v = ZAAe -Ea/RT molecules cm-3 sec-1 (1.21)

where ZAA is the number of collisions per second between two molecules of A in cm3 of

gas.

The frequency factor or the collision number (A) which determines the rate is given

by:

A = 2n2d2AA M

kTπ (1.22)

where k, is the Boltzmann constant, M is the mass of each molecule and dAA is the average

of the diameter of molecules of A, n is the number of molecules in cm3. The value of

frequency factor was found to be different for those reactions involving complex molecules

than from the value predicted by this theory. When certain shortcomings were noticed in

collision theory, the theory was augmented by the activated complex theory, in which the

reactants are assumed to combine together forming energy rich activated complex, then

36

disproportionates with a certain rate to give products. It is this rate that determines the

overall rate of the reaction. The difference between the energy of the reactant and activated

complex is the “energy of activation” (Ea) for the forward reaction. Three more related

thermodynamic parameters are:

a) Enthalpy of activation: ∆H≠ = Ea – RT (1.23)

b) Entropy of activation:

∆S≠ = ∆H≠ /T − 19.147 log 'k

T − 197.57 JK-1 (1.24)

where k' is the reaction rate constant in sec-1.

c) Gibb’s free energy of activation:

∆G ≠ = ∆H ≠ − T ∆S ≠ (1.25)

The specific reaction rate constant is given as,

ksp = zyx mediumcatalystsubstrate

k

][][][

' (1.26)

where x, y and z are the orders in substrate, catalyst and medium (H+ or OH-), respectively

and k' is the experimental rate constant.

Based on the Arrhenius theory, Ea can be evaluated by determining the rate constant

of the reaction at different temperatures and plotting a graph of log k' vs. 1/T. In most of the

simple cases, the plot will be a straight line with a negative slope. Then,

Ea = − (slope × 2.303 × 8.314) J mol-1 (1.27)

Knowing Ea and ksp, related thermodynamic parameters can be evaluated. The Arrhenius

frequency factor (A) also can be calculated from the relation,

log A = log ksp + Ea / 2.303 RT (1.28)

An expression for the rate constant of a reaction can be formulated by making use

of the change in thermodynamic functions in going from initial state to the activated state.

37

According to the theory of absolute rates, the rate constant is related to the Gibb’s free

energy of activation (∆G ≠) as:

k' =

Nh

RT e-∆G#/RT (1.29)

where N is the Avogadro’s number

Since ∆G ≠ = ∆H ≠ − T ∆S≠, equation (1.29) can be written as

k' =

Nh

RTe∆S≠/R e-∆H≠/RT (1.30)

We know that,

k' = A e∆H≠/RT (1.31)

From equations (1.30) and (1.31) we have,

A =

Nh

RT e∆S≠/R (1.32)

Since,

Nh

RT ≈1013 at room temperature (298 K), one can write A = 1013 e∆S≠/R and hence

∆S≠ = R ln (A × 10-13) (1.33)

Therefore, ∆S≠ = 2.303 R log (A × 10-13) (1.34)

As a result, ∆S≠ may be negative, positive or zero depending on whether A < 1013 or

A > 1013 or A = 1013. Reactions can be classified as normal, fast or slow according to

whether ∆S≠ is zero, positive or negative, respectively. The magnitude of ∆S≠ gives a rough

insight into the nature of reacting species and the structural compactness of the activated

complex.

1.4.2. Effect of dielectric permittivity on rate of reaction

Scatchard [132] has shown that, the reaction rate is influenced by dielectric

permittivity of the medium. According to him, for an ion-ion reaction,

38

log k' = log ko − kDTr

eZZ BA

≠303.2

2

(1.35)

where e = electric charge, k = Boltzmann constant, r≠

= radius of the activated complex (r≠ =

rA + rB), D = dielectric permittivity of the medium.

A plot of log k' versus 1/D must be linear with a slope of − ZAZBe2/ 2.303 r≠ kT.

This is found to be true in a large number of reactions. By allowing a reaction to occur in a

series of mixed solvents of varying dielectric permittivities, it is possible to compare the

values of ‘r≠’ from the observed slopes, and inference can be drawn on the size and charge

of the transition state. For the interaction between an ion and a dipolar molecule, Amis and

Jaffe [133] have derived a relation for the variation of rate constant as a function of the

dielectric permittivity (D) of the medium as,

log k'D = log k'∞ + DkTr

Ze

≠2303.2

µ (1.36)

where Z is the charge on the ion and µ is the dipole moment of the molecule. It is evident

from the equation (1.36) that the rate constant will increase on decreasing D, depending on

whether the transition state bears a negative or positive charge. The treatment adopted for

reactions between dipolar molecules and ions is based on an expression derived by

Kirkwood [134]. Laidler [135], Benson [136], Entelis and Tiger [137] and others have

described the effect of varying solvent composition on the reaction rate in the well-known

monographs. However, it is to be noted that a clear concept of the influence of dielectric

permittivity on the rate of reaction in solution has not emerged so far. It can only be

concluded from these observations as to whether an ion-dipole or dipole-dipole interaction

is involved in the rate-determining step.

1.4.3. Solvent effect on rates of reaction

Solvent effect provide some important information regarding,

1) The nature of the reacting species in the rate determining step, and

2) Structure of the activated complex.

39

For ionic reactions, polar solvents are observed to be the best media. Bronsted [138]

has given the relation between the reaction rate constant, k' and the ionic strength (µ) in an

ionic reaction as:

log k'= log ko + 2 α ZAZB µ (1.37)

Here α is a constant which is ≅ 0.51 for aqueous solution at 298 K and ko is the rate

constant in a medium of infinite dielectric permittivity, ZA and ZB are the charges on the

ions, thus equation (1.37) becomes,

log k' = log ko + 1.02 ZAZB µ (1.38)

According to this equation, a plot of log k' vs. µ will be linear and slope equal to

2αZAZB. The value of slope will be zero, positive or negative depending on the nature of

charges on the reacting species. If one of the reactant is neutral, the slope will be zero,

showing that the rate constant is independent of ionic strength of the medium. However,

more elaborate treatment of the effects of ionic strength on reaction between ions and

neutral molecules indicate that, there is a small ionic strength effect. If the reaction

involves ions of like charges in the rate determining step, the rate constant will increase

with the increase in ionic strength, but will decrease if the ions are of opposite charge. The

extent of variation depends on the magnitude of ZAZB. A study of applicability of equation

(1.37) to reaction between ions by Davies [139] leads to the conclusion that, the equation

holds good in a number of reactions. Some deviations have been observed in more

concentrated solutions where the Debye-Huckel equation breaks down. Huckel explained

the term bµ, in addition to the Debye Huckel term and hence the equation for ion-dipole

reaction can be written as,

k' = ko (1 + bµ) (1.39)

showing that the rate constant varies linearly with ionic strength. When the ion pair

formation is purely an electrostatic phenomenon, the term ‘Bjerrum ion-pair’ is used and

the association product has a definite chemical structure.

40

Ion association affects the rate of reaction in a number of ways. It will result in the

reduction of true ionic strength of the solution. The ion pairing may involve one or both of

the reacting ions. In such cases, there will be change in the electrostatic interaction

between the ions that react with each other. In a reaction between ions of like charges,

association with oppositely charged ions will lead to acceleration by reducing the

electrostatic repulsion.

1.4.4. Isotope effect When an atom is replaced by its isotope, there is no change in potential energy

surface for any reaction that it might undergo, but the rate of reaction changes because there

is change in average vibrational energy of the molecule and that of the activated complex.

For eg., the potential energy curves are identical for species H2, HD and D2, but the zero

point energy (ZPE) levels are different. The values relative to the minimum in the curve

are 6.78, 5.36 and 4.39 k cals mol-1. Thus dissociation of H2 occurs more rapidly than the

dissociation of H-D or D2. The situation is quantitatively similar with more complex

molecules involving C-H bond vibration is greater than that of C-D bond by 1.2 k cals mol-

1. Hence, the activation energy (Ea) for the reaction will be higher for the heavier

compound leading to lower reaction rate or the rate of reaction will thus be relatively

greater for lighter molecule. If the C-H or C-D bond is unaffected when the activated

complex is formed and broken subsequently to products, i.e., if the bond remains intact

during the course of the reaction, the ZPE for the initial state will not be lowered for the

heavier isotope. From Fig.1.1, it is clear that Ea will be the same for both the lighter

molecule and the heavier molecule. Consequently, the rate of reaction will be same for

both the species. Thus the magnitude of the observed isotope effect is a measure of the

degree of bond breaking in the activated complex.

In some cases, due to resonance and other electromeric effects, the bond involving a

hydrogen atom becomes stronger in the activated state. Replacement of H by D will then

lead to a greater decrease in energy in the activated state than in the initial state. As a

result, the activation energy becomes less for the reaction involving the heavy molecule. In

41

other words, isotopic substitution of H by D results in an increase in reaction rate. This is

termed “the inverse isotope effect”.

Many reactions in aqueous medium that are susceptible to acid-base catalysis have

been studied in heavy water after equilibrium. The variation of rates of reaction after the

equilibrium is generally called “solvent isotope effect”. This too affords valuable

information on the type of bond-breaking and bond-making during a chemical reaction.

Most oxidation reactions of organic compound involve the cleavage of C-H bond. Thus

deuterium isotope effect on such reactions gives information concerning the nature of the

rate determining step. One of the first instances of such an application was observed when

Westheimer and Nicoloids [140] reported their mechanistic studies on the oxidation of

isopropyl alcohol by chromic acid. The large isotope effect noted clearly showed that C-H

bond at the α-carbon atom was cleaved in the rate determining step.

42

products

Activated state

Zero-point levels

Zero- point levels

Fig. 1.1

Activation energy for light molecules Activation energy

for heavy molecules

C-H C-D

C-H C-D

Initial state

43

SECTION – V

1.5. SCOPE OF THE PRESENT WORK

N-bromosuccinimide has been extensively used as analytical and oxidizing reagent,

and mechanisms of many of their reactions have been investigated. The reactive species of

NBS in aqueous, acidic and alkaline solutions have been identified, thus making it easy to

understand their oxidative behavior.

The present work is aimed at investigating the kinetics and mechanism of oxidation

of six pharmaceutical compounds with NBS in acidic and alkaline media. The

pharmaceutical compounds chosen for investigation are:

1. 2-Phenylethylamine (PEA).

2. Metronidazole (MTZ).

3. Tinidazole (TNZ).

4. Phenylpropanolamine hydrochloride (PPA).

5. Salbutamol sulphate (SBL).

6. Gabapentin (GBP).

The framework of the investigation is based on the following objectives:

a) To establish the identity of reactive oxidizing species involved in the reaction.

b) To identify and characterize the oxidation products.

c) To ascertain the effects of Cl-, ClO-4, reaction product (succinimide), variation of

ionic strength and dielectric permittivity of the medium on the rate of reaction.

d) To compare the results obtained between acid and alkaline medium wherever

applicable.

e) To propose a suitable mechanism based on the kinetic data obtained.

f) To ascertain the nature of the transition state based on solvent isotope effect and

proton inventory studies using D2O.

g) To ascertain the thermodynamic factors controlling the reactions.

44

The theories discussed in this thesis represent fundamental approaches and these

approaches constitute a valuable tool, which may provide new acceleration to the

investigations in the research field. The study could throw some light on the fate of the

compound in biological system.

45

SECTION - VI

1.6. EXPERIMENTAL

1.6.1. Materials and methods

a) N-bromosuccinimide (NBS): NBS (Merck) was used without further purification.

Aqueous solution was prepared by dissolving required quantity of NBS in warm

water. An approximately 0.1 mol dm-3 solution of NBS was prepared and standardized

by iodometric method. The NBS solution was preserved in brown bottle to arrest its

photochemical deterioration.

b) Succinimide: Succinimide (Merck) was used without further purification. Aqueous

solution was prepared by dissolving required quantity of succinimide in doubly distilled

water.

c) 2-Phenylethylamine (PEA): PEA (Himedia) was used as received. Aqueous solution of

the compound (0.1 mol dm-3) was prepared freshly each time by taking the required

amount of PEA in doubly distilled water. d) Metronidazole (MTZ): Pharmaceutical grade MTZ (supplied by Cipla India Ltd.,

Mumbai) was used as received. A solution of the compound (0.1 mol dm-3) was

prepared by dissolving required quantity of MTZ in doubly distilled water.

e) Tinidazole (TNZ): Pharmaceutical grade TNZ (supplied by Cipla India Ltd., Mumbai)

was used as received. A solution of the compound (0.1 mol dm-3) was prepared by

dissolving required amount of TNZ in doubly distilled water.

f) Phenylpropanolamine hydrochloride (PPA): Pharmaceutical grade PPA (supplied by

Cipla India Ltd., Mumbai) was used as received. A solution of the compound (0.1 mol

dm-3) was prepared by dissolving required quantity of PPA in doubly distilled water.

g) Salbutamol sulphate (SBL): Analar grade SBL (Medrich, India) was used as received. A

solution of the compound (0.1 mol dm-3) was prepared by dissolving required quantity

of SBL in doubly distilled water.

46

h) Gabapentin (GBP): Pharmaceutical grade GBP (Hikal Ltd., India) was used as received.

A solution of the compound (0.1 mol dm-3) was prepared by dissolving required

quantity of GBP in doubly distilled water.

i) Sodium perchlorate: Concentrated (2 M) solution of sodium perchlorate (Riedel) was

used to keep the ionic strength constant at a high value.

j) Other reagents: Hydrochloric acid, perchloric acid, sulphuric acid, sodium thiosulphate,

sodium hydroxide, potassium iodide, mercuric acetate, starch indicator, sodium chloride

and all other chemicals were of accepted grades of purity. Solutions of these

compounds were prepared in doubly distilled water.

k) Reaction Vessel: The reaction was carried out in a glass stopper Pyrex boiling tube (1.5''

× 7'' capacity 200 ml) with a standard B-34 socket carrying B-34 stopper.

l) Thermostat: The kinetics of the reaction was followed between 300 -323 K. For this

purpose, Techno-ST-405 (India) thermostat was used. The temperature maintained with

an accuracy of ± 0.1 oC.

m) FT-IR : IR Spectra were recorded on a JASCO FT-IR spectrometer.

n) NMR : FT-1H NMR spectra were recorded on a BRUKER 400 MHz NMR

spectrometer.

1.6.2. Kinetic procedure All experiments were designed under isolation conditions, where the substrate

concentration was in excess over that of oxidant. In a typical experiment, appropriate

amounts of the substrate, acid /alkali, sodium perchlorate solution, acetonitrile and water

(to keep the total volume constant at 50 ml for all runs) were taken in the reaction vessel

and thermostated at the desired temperature for thermal equilibrium. A measured amount of

the oxidant solution was also thermostated at the same temperature. After attaining thermal

equilibrium, it was rapidly added to the reaction mixture in the reaction vessel. The

progress of the reaction was monitored by iodometric determination of the unreacted

47

oxidant in a measured aliquot of the reaction mixture at different intervals of time. This is

done by pipetting 5 ml aliquots of the reaction mixture at regular intervals and run into

conical flask containing mixture (50 ml ice water, 10 ml of 5 % Kl and 10 ml of 2N

H2SO4). The liberated iodine was then titrated against standard solution of sodium

thiosulphate, using starch as an internal indicator near the end point. The course of the

reaction was followed for two half-lives. The titre at time, t = 0 gives the value of ‘a’ and

titre at any instant denotes (a − x). Plots of log (a − x) or log [NBS] versus time were

plotted and values of pseudo-first-order rate constants were calculated from the slope of the

graphs. Values of k' obtained were reproducible within 3 %.

Regression analysis of the experimental data to obtain regression coefficient (r) of

the points from the regression line was carried out using MS EXCEL.

For investigating the mechanism of the reaction, the experiments were designed to

indicate,

1. The order of the reaction with respect to

a. Oxidant

b. Substrate

c. [H+] or [OH-]

2. The effect of added chloride ion,

3. The effects of varying (a) ionic strength of the medium and (b) dielectric permittivity

of the medium by the addition of acetonitrile into the reaction mixture.

4. The effect of reaction product, succinimide on the rate.

5. The effect of temperature on the rate, so that kinetic and thermodynamic parameters

can be calculated.

6. Solvent isotope effect and proton inventory studies using D2O.

7. The effect of varying mercuric acetate solution.

48

References

1. Seliwanow,T., Ber. Deut. Chem.Ges., 26, 423(1893).

2. Wohl, A. and Jaschinowski, K., Ber. Deut. Chem. Ges., 74, 1243(1941).

3. Ziegler, K., Spath, A., Schaaf, E., Schumann,W. and Winkelmann, E., Justus

Liebigs Ann.Chem., 551, 80(1942).

4. Djerassi, C., Chem. Rev., 43,271(1948).

5. Arapahoe Chem. Inc., Technical Bulletin on “Positive Bromine Compounds”,

Boulder, Colorado, 1962.

6. Horner, L. and Winkelmann, E. H., “Newer Methods of Preparative Organic

Chemistry”, Vol. 3, Academic Press, New York and London, 1964, p.151;

Angew.Chem., 71,349(1959).

7. Filler, R., Chem. Revs., 63, 21(1963).

8. Waugh, T.D. and Waugh, R.C., Brit. Pat., 933, 531(1963); Chem. Abs., 60, 1605b.

9. Buckles, R.E. and Probst, W.J., J. Org. Chem., 22, 1728 (1957).

10. Martin, J.C. and Bartlett, P.D., J. Am. Chem. Soc., 79, 2533(1957).

11. Nagai,Y. and Matsuda,T., Nippon Kagaku Zasshi 88, 66 (1967); Chem. Abs., 66,

111000.

12. Mohana, K. N. and Ramdas Bhandarkar, P.M., Bulg. Chem.Communs., 36, 236

(2004).

13. Dauben, H.J. Jr. and McCoy, L.L., J. Am. Chem. Soc., 81, 4863(1959).

14. Ford, M.C. and Waters, W.A., J. Chem. Soc., 2240(1952).

15. Kharasch, M.S., Malec, R. and Yang, N.C., J. Org. Chem., 22, 1443 (1957).

16. Adam, J. Gosselain, P. A. and Goldfinger, P., Nature, 171, 704 (1953).

17. Walling , C.A. Rieger , A.L. and Tanner, D. D. J. Am. Chem. Soc., 85, 3129 (1963).

18. Russel,G. A., DeBoer, C. and Desmond, K. M., J. Am. Chem. Soc., 85, 365 (1963).

19. Russel, G.A. and Desmond, K.M., J. Am. Chem. Soc., 85, 3139 (1963).

20. Pearson, R.E. and Martin, J.C., J. Am. Chem. Soc., 85, 3142 (1963).

21. Skell, P. S. Tuleen, D. L. and Readio, P. D., J. Am. Chem. Soc., 85, 2850 (1963).

22. Hedaya, E. Hinman, R.L. Kibler, L.M. and Theodoropulos, S., J. Am. Chem. Soc.,

86, 2727(1964).

23. Koenig, T. and Brewer, W., J. Am. Chem. Soc., 86, 2728 (1964).

49

24. McGrath, B. P. and Tedder, J. M., Proc. Chem. Soc., 80 (1961).

25. Thiagarajan, V. and Venkatasubramanyan, N., Indian. J. Chem., 8, 809 (1970).

26. Venkatasubramanyan, N. and Thiagarajan, V., Can. J. Chem., 47, 694 (1969).

27. Barakat, M. Z. and Shaker, M., Analyst, 88, 59(1963).

28. Barakat, M. Z., Wahab, M. F. and El-sadr, M. M., J. Am. Chem. Soc., 77, 1670

(1955).

29. Abdel-Wahab, M. F. and Barakat, M. Z., Monats. Chem., 88, 692 (1957).

30. Bachhawat, J. M., Ramegowda, N. S., Koul, A.K. Narang, C.K. and Mathur, N.K.,

Indian J. Chem., 11, 614 (1973).

31. Schneider, P.O, Thibert, R. J. and Walton, R. J., Mikrochim. Acta, 925 (1972).

32. Biltz, H. and Behrens, O., Ber. 43, 1984 (1910).

33. Takizawa, T. and Hoshiai, K., Mem. Inst. Sci. Ind. Research, Osaka Univ., 7, 136

(1950).

34. Somashekar, B.C. and Basavaiah, K., Bulg. Chem. Communs., 37, 84 (2005).

35. Sastry, C. S. P., Srinivas, K. R. and Krishna prasad, M. M., Mikrochim. Acta, 122,

77 (1996).

36. Basavaiah, K. and Somashekar, B.C., Bulg.Chem.Communs., 38, 145 (2006).

37. Basavaiah, K., Ramakrishna, V. and Somashekar, B.C., The Indian Pharmacist, 5,

129 (2006).

38. Anil kumar, U. R. and Basavaiah, K., Bull.Chem. Soc. Ethiop., 22, 135 (2008).

39. Geeta, N. and Tulsidas, R. B., Mikrochim. Acta, I, 95 (1990).

40. Nagaraja, P., Srinivasa Murthy, K. C., Rangappa, K. S. and Made Gowda, N. M.,

Talanta, 46, 39 (1998).

41. Basavaiah, K., Somashekar, B.C. and Ramakrishna, V., Acta Pharm., 57, 87

(2007).

42. Michalowski, J., Kojlo, A. and Estrela, O.A., Chem. Anal., 47, 267 (2002).

43. Rahman, N., Siddiqui, M. R. and Hejaz Azmi, S. N., Chem. Anal., 52, 465 (2007).

44. Barsoum, N.B., Manal, S.K. and Mohamed Diab, M.A., Research J. Agri. Biol.

Sci., 4, 471 (2008).

45. Anna Krebs., Barbara, S., Helena, P.T. and Joanna, S., Anal. Sci., 22, 829 (2006).

50

46. Wang, Z., Zhang, Z., Zhifeng Fu., Fang, L. and Zhang, X., Anal. Sci., 20, 319

(2004).

47. Ibrahim, A.D., Samiha, A. H., Ashraf, M. M. and Ahmed, I. H., Acta Pharm., 58,

87 (2008).

48. Alwarthan, A. A. and Al-Obaid, A. M., J. Pharm. Biomed. Anal., 14, 579 (1996).

49. Abdel-Wadood, H.M., Niveen, A.M. and Fardous, A.M., Journal of AOAC

International, 88, 1626 (2005).

50. Basavaiah, K. and Somashekar, B.C., E- J. Chem., 04, 117 (2007).

51. Rao, K.V.K., Kumar, B.V.V.R., Rao, M.E.B. and Rao, S.S., Indian J. Pharm. Sci.,

65, 516 (2003).

52. Basavaiah, K. and Anilkumar, U.R., Proc. Indian Natn. Sci. Acad., 72, 225 (2006).

53. Anilkumar,U.R. and Basavaiah,K., Proc. Natn. Acad. Sci., 77(A), 301 (2007).

54. Abdelmageed, O.H., Salem, H., Omar, M.A. and NourEl-din Dina, A.M., Bull.

Faculty Pharm., 45, 177 (2007).

55. Dinesh, N.D., Rangappa, K.S. and Nagaraja, P., Int. J. Chem. Sci., 5, 1311 (2007).

56. El-Didamony Akram, M., Central Euro. J. Chem., 3, 520 (2005).

57. Srinivas, L.D., Prasad Rao, K.V.S. and Sastry, B.S., Int. J. Chem. Sci., 3, 353

(2005).

58. Basavaiah, K., Ramakrishna, V. and Anilkumar, U.R., Indian J. Chem. Tech., 14,

313 (2007).

59. Fieser, L.F. and Rajagopalan, S., J. Am. Chem. Soc., 71, 3938 (1949).

60. Barakat, M.Z. and Mousa.G.M., J. Pharm. Pharmacol., 4, 115 (1952).

61. Bharat Singh., Lalji Pandey., Sharma, J. and Pandey, S.M., Tetrahedron, 38,169.

(1982).

62. Gopalakrishnan, G. and Hogg, J.L., J. Org. Chem., 50, 1206 (1985).

63. Bharat Singh., Singh, A.K., Singh, V.K., Sisodia, A.K. and Singh, M.B.,

J. Mol. Cat., 40, 49 (1987).

64. Thimme Gowda, B. and Ishwara Bhatt, J., Indian J. Chem., 28A, 43 (1989).

65. Saroja, P., Kishore Kumar, B. and Sushama Kandlikar., Indian J. Chem., 28A, 501

(1989).

51

66. Karunakaran, C. and Venkatachalapathy, C., Bull. Chem. Soc. Jpn., 63, 2404

(1990).

67. Karunakaran,C. and Ganapathy, K., J. Phy. Org. Chem., 3, 235 (1990).

68. Kamble, D.L., Hugar, G.H. and Nandibewoor, S.T., Indian J. Chem., 35A, 144

(1996).

69. Kamble, D.L., Chougale, R.B. and Nandibewoor, S.T., Indian J. Chem., 35A, 865

(1996).

70. Kamble, D.L. and Nandibewoor, S.T., Polish J. Chem., 71, 91 (1997)

71. Chougale, R.B., Kamble, D.L. and Nandibewoor, S.T., Polish J. Chem., 71, 986

(1997).

72. Harihar, A.L., Kembhavi, M.R. and Nandibewoor, S.T., J. Indian Chem. Soc., 76,

128 (1999).

73. Mavalangi, S.K., Kembhavi, M. R. and Nandibewoor, S. T., Turk. J. Chem., 25,

355 (2001).

74. Singh, A. K., Rahmani, S., Singh, V. K., Gupta, V., Kesarwani, D. and Bharat

Singh., Indian J. Chem., 40A, 519 (2001).

75. Kathari, C.P., Pol, P.D. and Nandibewoor, S. T., Inorg. React. Mechanism, 3, 213

(2002).

76. Kathari,C.P., Mulla, R.M. and Nandibewoor, S. T., Oxid. Communs., 28, 579

(2005).

77. Shalini Pandey and Santhosh K. Upadhyay., Indian J. Chem. Tech., 11, 35 (2005).

78. Ewais Hassan, A., Transition Met. Chem., 27, 562 (2002).

79. Abdel-Khalek Ahmed, A. and Khaled Eman, S.H., Transition Met. Chem., 24, 189

(1999).

80. Singh, A. K., Rahmani, S., Chopra, D. and Singh,B., Carbohydr.Res., 314,157

(1998).

81. Sahay, V.P., Singh, S.B., Singh,D. and Prasad, J., Oxid. Communs., 21, 390 (1998).

82. Sharma, K.S., Sharda Kumari and Vijender Kumar Goel., J. Indian Chem. Soc., 76,

366 (1999).

83. Ramachandrappa, R., Puttaswamy., Mayanna, S. M. and Made Gowda, N. M., Int.

J. Chem. Kinet., 30, 407 (1998).

52

84. Singh, A. K. and Satyendra Kumar., Asian J. Chem., 10, 250 (1998).

85. Abdul-Khalek, A. A., El-Said, S. M. and Eman, H. K., Transition Met. Chem., 23,

37 (1998).

86. Singh, B., Singh, M. and Kesarwani, D., Oxid. Communs., 20, 475 (1997).

87. Ahmed, A. A. and Eman, S. H., Transition Met. Chem., 23, 201 (1998).

88. Neelu Kamb., Neeti Grover and Santhosh K. Upadhyay., J. Indian Chem. Soc., 79,

939 (2002).

89. Mavalangi, S. K., Desai, S. M. and Nandibewoor, S. T., Oxid. Communs., 23, 617

(2000).

90. Farook Mohammed, N. A., Asian J. Chem., 12, 1113(2000).

91. Singh, A.K., Gupta, Vinodkumar Singh, Deepmala, and Bharat Singh, Oxid.

Communs., 23, 416. (2000).

92. Singh, A. K., Gupta, T., Singh,V. K., Rahmani, S., Kesarwani, D. and Singh, B.,

Oxid. Communs., 23, 609 (2000).

93. Abdel Hady Alaa El-Din, M. and Ayed, S.M., Transition Met. Chem., 26, 417

(2001).

94. Mavalangi, S .K., Nirmala, Halligudi, N. and Nandibewoor, S. T., React. Kinet. Cat.

Lett., 72, 391 (2001).

95. Janibai, T.S. and Vasuki. M., J. Indian Council of Chemists, 21, 60(2004).

96. Singh. A.K., Asian J. Chem., 15, 1313(2003).

97. Singh, A.K., Asian J. Chem., 15, 1307(2003).

98. Abdel-Khalek Ahmed, A., Ewais Hassan, A., Khaled Eman,S.H. and Abdel-Hamied

Anwar. Transition Met. Chem., 28, 635 (2003).

99. Singh, A.K., Rahmani, S., Singh, V., Gupta, V., and Singh, B., Oxid. Communs.,

23, 55 (2000).

100. Ewais Hassan, A., Ahmed, A. E. and Abdel-Khalek Ahmed, A., Int. J. Chem.

Kinet., 36, 394 (2004).

101. Pandey, S., Kambo, N. and Upadhyay, S. K., Oxid. Communs., 27, 821 (2004).

102. Srivastava, S. and Gupta, V., Oxid. Communs., 27, 813 (2004).

103. Hiran, B. L., Malkani, R. K. and Rathore, N., Kinetics and Catalysis, 46,

334 (2005).

53

104. Nadh, R.V., Sundar, B. S. and Radhakrishnamurthi, P.S., Oxid.Communs., 28 , 81

(2005).

105. Shalini Pandey and Santosh K. Upadhyay., J. Colloid Interface Sci., 285, 789

(2005).

106. Pandey, S., Kambo, N. and Upadhyay, S. K., Oxid. Communs ., 29, 328 (2006).

107. Shalini Pandey and Santosh K.Upadhyay., Indian J. Chem., 44A, 1822 (2005).

108. Srivastava, S. and Khare, P., Oxid. Communs., 29, 48 (2006).

109. Manivarman, S., Manikandan, G., Jaya Bharathi, J., Thanikachalam, V. and

Sekar, M., Oxid. Communs., 30, 832 (2007).

110. Surendrakumar, R., Aarti sharma and Priyamvada, C., J. Indian Chem. Soc.,

84, 777 (2007).

111. Hassan A. Ewais, Mohamed A. N. and Abdel Khalek, A.A., J. Coordination

Chem., 60, 2471(2007).

112. Mathiyalagan, N. and Sridharan, R., J. Indian Chem. Soc., 83, 434 (2006).

113. Rashmi Tripathi and Santosh K. Upadhyay., Indian J. Chem. Tech., 4, 64

(2007).

114. Mohamed Farook, N. A., J. Iranian Chem. Soc., 3, 378 (2006).

115. Alaa Eldin Abdel-Hady, M., Transition Met. Chem., 33, 887 (2008).

116. Linge Gowda, N.S., Kumara, M.N., Channe Gowda, D. and Rangappa, K.S., Int.

J. Chem. Kinet ., 38, 376 (2006).

117. Manivarman, S., Manikandan, G., Sekar, M., JayaBharathi, J. and

Thanikachalam, V., Oxid.Communs., 30, 823 (2007).

118. Srivastava Sh and Gupta, V., J. Indian Chem. Soc., 83, 1103 (2006). 119. Linge Gowda, N. S., Kumara, M. N., Channe Gowda, D., Rangappa, K. S.

and Made Gowda, N. M., J. Mol. Cat. A: Chemical, 269, 225 (2007).

120. Dilip Patil, B. and Sunil Chachere, D., Oriental J. Chem., 23, 673 (2007).

121. Surendrakumar, R. and Aarti Sharma., J. Indian Chem. Soc., 85, 71 (2008).

122. Srivastava, S., Khare, P., Srivastava, P. and Shalini, S., J. Saudi Chem. Soc., 12,

211 (2008).

54

123. Dilip Patil, B. and Sunil Chachere, D., Asian J. Chem., 20, 1539 (2008).

124. Mohana, K. N. and Ramya, K. R., J. Mol. Cat. A: Chemical, 302, 80 (2009).

125. Naik, G. T., Angadi, M. A. and Harihar, A. L., J. Indian Chem. Soc., 86, 255

(2009).

126. Sharma, J. P., Singh, R. N. P., Singh, A. K. and Singh B., Tetrahedron, 42, 2739

(1986).

127. Chand, W., Singh, B. and Sharma, J. P., J. Mol. Cat., 60, 49 (1990).

128. Bronsted, J. N., Z. Physik. Chem. Soc., 61, 905 (1939).

129. Amis, E. S., “Solvent effects on reaction rates and Mechanism”, Academic press,

NewYork (1966).

130. Amis, E. S. and Lamer, V.V., J. Am. Chem. Soc., 61, 905 (1939).

131. Mc. Lander, L., “Isotope effect on reaction rates”, The Ranhold Press, Co.,

NewYork (1960).

132. Scatchard, G., Chem. Rev., 10, 229 (1932).

133. Amis, E. S. and Jaffe, G., J. Chem. Phy., 10, 598 (1942).

134. Kirkwood, J. G., J. Chem. Phy., 2, 351 (1934).

135. a. Laidler, K. J. and Eyring, H., Ann., N.Y., Acad, Sci., 9, 303 (1940).

b. Laidler, K. J. and Landskroner, P. A., Trans Faraday Soc., 52, 200

(1957).

c. Laidler, K. J., “Chemical kinetics”, TMH, New Delhi, p. 225 (1965).

136. Benson, S.W., “The Foundations of Chemical Kinetics”, McGraw Hill, New York (1960).

137. Entelis, S.G. and Tiger, R.P., “Reaction Kinetics in the Liquid Phase”, Wiley, NewYork (1976).

138. Bronsted, J. N., Z. Physik. Chem., 102, 169 (1992).

139. Davies, C. W., “Progress in Reaction Kinetics”, Vol. I, p.161, Pergamon Press, Oxford (1961).

140. Westheimer, F. H. and Nicoloids, N., J. Am. Chem. Soc., 71, 25 (1947).