Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
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).