oxidation of some organic substrates by...
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OXIDATION OF SOME ORGANIC SUBSTRATES BY LIPOPATHIC OXIDANTS: KINETIC STUDIES
Thesis
Submitted to Sambalpur University
For the degree of
DOCTOR OF PHILOSOPHY IN
SCIENCE
2013
PRANGYA RANI SAHOO
Centre of Studies in Surface Science and Technology
School of Chemistry, Sambalpur University Jyoti Vihar – 768 019
ODISHA, INDIA
Dedicated to
My Parents
Prof. B. K. Mishra, Ph.D., D.Sc.
Centre of Studies in Surface Science and Technology, School of Chemistry,
Sambalpur University, Jyoti Vihar – 768 019 Phone: 0663-2430093 (Res)-2431078, 2430114(Off.)
FAX: 0663-2430158 E-mail: <[email protected]>
CERTIFICATE
This is to certify that the thesis entitled “Oxidation of some organic
substrates by lipopathic oxidants: kinetic studies” being submitted by Ms.
Prangya Rani Sahoo for the award of Doctor of Philosophy in Science
(Chemistry) of Sambalpur University is a record of bonafide research work
carried out by her under my supervision and guidance. The thesis has
reached the standard fulfilling the requirements of the regulation relating to
the degree. This work has been carried out in the Centre of Studies in Surface
Science and Technology, School of Chemistry, Sambalpur University, Jyoti
Vihar. I further certify that to the best of my knowledge and belief, Ms. Sahoo
bears a good moral character.
(B K Mishra)
ACKNOWLEDGEMENT
I owe my deep sense of gratitude to my esteemed supervisor
Prof. B.K. Mishra, Ph.D., D. Sc., Professor, School of Chemistry,
Sambalpur University, whose splendid guidance, authentic supervision,
meticulous cooperation, invaluable advices and philanthropic attitude
enabled me to make out my research problem in the present form.
I am highly indebted to the Head of the Department and all my
teachers of School of Chemistry, Sambalpur University for their kind
help, valuable suggestions and moral supports.
I convey my sincere gratitude to Dr. (Mrs) Sabita Patel, Lecturer in
Chemistry, NIT, Rourkela; for her immense help and valuable
suggestions during the preparation and revision of the manuscript. I
also express my gratitude to Dr. Sukalyan Dash, Reader in chemistry,
VSSUT, Burla.
I take this opportunity to sincerely thank Dr. H. N. Pati, Scientist,
ADVINUS, Bangalore for his help in spectral analysis.
I record my gratefulness to Dr. Sandhyamayee Sahu, for giving
suggestions and moral supports during my dissertation work.
My heart-felt acknowledgement goes to my fellow labmates Sumi
didi, Mallika didi, Susanta bhaina, Sibani didi, Minati didi, Biswa
dada, Partha, Kabita, Sagarika, Mamta, Sunita, Anuradha, Pratima,
Sweta, Asish, Dipti and Mira for their day to day help and for providing
a stimulating and fun filled environment during my Ph D program.
I also extend my heartiest thanks to my friends, Uma, Poloumi,
Chagala, Chandana for their loving encouragement and co-operation in
every stage of my research work. My thanks are also due to my all
other seniors and loving juniors who helped me in several ways from
the department to hostel.
I am also indebted to some of my good friends Satya, Partha,
Lipika, Kaina, Anju, Pratap, Manoj for their moral support.
Words cannot designate my indebtness to my parents for giving
birth to me and supporting me spiritually throughout my life. The
affection and inspiration of Bhai, Bhauja, my only younger brother Litu
and nephew Dipankar are great support to my career.
It’s my profound pleasure to express my sincere and innermost
sense of gratitude and gratefulness to my respectable parents-in-law for
their blessings, co-operation and suggestion. I am also thankful to my
loving brother and sister-in-laws and nephew Subham for their support.
Last but not the least my regards and deep sense of gratitude
from the core of my heart is for my loving husband Mr. Pradeep Kishore
Sahoo for his unswerving inspiration, multitudinous help and constant
support during my entire research period.
I express my sincere thanks to University Grant Commission
(UGC) and Council of Scientific and Industrial Research (CSIR), India for
providing me junior and senior research fellowships respectively.
(Prangya Rani Sahoo)
Page No.
Preface i
Abbreviations xiv
1. Alkylammonium ions as carriers of metal oxidants 1
1.1 Introduction 1
1.2 Alkylammonium ions as carriers of Cr(VI) oxidants 1
1.2.1 Alkylammonium ions as carriers of chromates 2
1.2.1.1 Tetraalkylammonium chromates 2
1.2.1.2 Trialkylammonium chromates 11
1.2.1.3 Dialkylammonium chromates 13
1.2.1.4 Alkylammonium chromates 14
1.2.2 Alkylammonium ions as carriers of dichromates 15
1.2.2.1 Tetraalkylammonium dichromates 15
1.2.2.2 Cetyltrimethylammonium dichromate 15
1.2.3 1-Butyl-4-aza-1-azoniabicyclo[2.2.2] octane chlorochromate and dichromate
23
1.2.4 Oniums of phosphorus and tellurium with Cr(VI) 24
1.3 Alkylammonium ions as carriers of Mn(VII) oxidants 26
1.3.1 Oxidation of alkenes and their derivatives 27
1.3.2 Oxidation of other functionalities 38
1.4 Alkylammonium ions as carriers of Ce(IV) oxidants 42
1.5 Alkylammonium ions as carriers of Ru(VII) oxidants 44
1.6 Alkylammonium ions as carriers of Tungstate and Molybdate 54
1.7 Conclusion 65
1.8 Scope of the work 65
1.9 References 67
2. Synthesis and characterization of cetyltrimethylammonium ferricyanide, dichromate, permanganate and ceric nitrate
2.1 Introduction 78
2.2 Experimental 80
2.2.1 Materials 80
CONTENTS
2.2.2 Methods 81
2.2.3 Synthesis of cetyltrimethylammonium ferricyanide (CTAFC) 81
2.2.4 Synthesis of cetyltrimethylammonium ceric nitrate (CTACN) 82
2.2.5 Synthesis of cetyltrimethylammonium permanganate (CTAP) 83
2.2.6 Synthesis of cetyltrimethylammonium dichromate (CTADC) 83
2.3 Results and discussion 84
2.3.1 Elemental and spectral analysis 84
2.3.2 Cyclic voltametric analysis of CTAFC 85
2.3.3 Cyclic voltametric analysis of CTACN 87
2.3.4 Cyclic voltametric analysis of CTAP 88
2.3.5 Cyclic voltametric analysis of CTADC 89
2.4 Conclusion 91
2
.5
References 92
3. Oxidation of Phenylthioureas by CTADC and CTAP
3. 1 Oxidation of some Phenylthioureas by CTADC 94
3.1.1 Introduction 94
3.1.2 Experimental 95
3.1.3 Results and discussion 96
3.1.4 References 101
3.2 Oxidation kinetics of Phenylthioureas by CTADC 104
3.2.1 Introduction 104
3.2.2 Experimental 104
3.3.2.1 Materials 104
3.2.2.2 Kinetic measurements 105
3.2.2.3 Product analysis 105
3.2.2.4 Stoichiometry 106
3.2.3 Results and discussion 106
3.2.4 References 114
3.3 Oxidation kinetics of Phenylthioureas by CTAP 115
3.3.1 Introduction 115
3.3.2 Experimental 115
3.3.2.1 Materials 115
3.3.2.2 Kinetic measurements 115
3.3.2.3 Product analysis 116
3.3.2.4 Stoichiometry 116
3.3.3 Results and discussion 117
3.3.4 References 123
4. Oxidation kinetics of Simvastatin by CTADC and CTAP
4.1 Oxidation kinetics of Simvastatin by CTADC 124
4.1.1 Introduction 124
4.1.2 Experimental 127
4.1.2.1 Materials 127
4.12.2 Kinetic measurements 127
4.1.2.3 Product analysis 127
4.1.2.4 Stoichiometry 128
4.1.3 Results and discussion 128
4.1.4 References 137
4.2 Oxidation kinetics of Simvastatin by CTAP 139
4.2.1 Introduction 139
4.2.2 Experimental 139
4.2.2.1 Materials 139
4.22.2 Kinetic measurements 139
4.2.2.3 Product analysis 140
4.2.2.4 Stoichiometry 140
4.2.3 Results and discussion 140
4.2.4 References 145
Publications
OXIDATION OF SOME ORGANIC SUBSTRATES BY LIPOPATHIC
OXIDANTS: KINETIC STUDIES
Search of novel oxidants has been continuing since long due to the advancement
in synthesis of complex organic molecules in different reaction conditions. Most of the
oxidation reactions are due to inorganic oxidants with metal ions of Cr(VI), Mn(VII),
Ce(IV), Fe(III), Ru(IV), V(V) etc. To undertake reactions of organic substrates in organic
homogeneous media, tailor made lipopathic oxidants are of much interest. To convert the
inorganic oxidants lipopathic onium ions having alkyl groups are linked as counterions
and thus help in carrying the oxidant from aqueous medium into organic medium. The
present thesis deals with the synthesis and characterization of some lipopathic oxidants
and their uses in oxidation reactions of some organic substrates like phenylthioureas and
a drug, Simvastatin.
The titled thesis comprises of four chapters. A recent review on alkyl ammonium
ions as carriers of metal oxidants is presented in the Chapter 1 of the thesis. Among the
onium ions like ammonium, phosphonium, tellurium, arsonium, bismuthenium etc.,
ammonium ions are found to be the most stable and extensively used in chemical
laboratories for different purposes. The versatile applications of the oxidants with the
onium ions as carrier are well reflected in the work of Corey on pyridinium
chlorochromate. After its introduction to the novel class of oxidants, a large number of
alkyl ammonium chromate and dichromates have been synthesized, characterized and
applied in organic synthesis. These oxidants can effectively oxidize different organic
substrates e.g. alcohols, carbohydrates, olefinic double bonds, oximes, sulfides to afford
corresponding oxidized products. In most of the cases the reactions do not yield over-
oxidizing products or byproducts. The review includes other oxidants like permanganate,
ferricyanide, ceric nitrate, tungstate, molybdate etc.
Cetyltrimethylammonium (CTA) ion is a magic quaternary ammonium ion due to
its balance hydrophobic and hydrophilic group. It is a typical amphiphile, which can form
various organized assemblies like micelle in water medium, reversed micelle in
nonaqueous medium and microemulsions in water and oil systems. The Chapter 2 of the
PREFACE
ii
thesis deals with the synthesis and characterization of a novel oxidant,
cetyltrimethylammonium ferricyanide, and its physicochemical characteristics have been
compared with those of other analogous oxidants like cetyltrimethylammonium -
permanganate (CTAP), -dichromate (CTADC) and ceric nitrate (CTACN).
The elemental analyses of these compounds reveal that CTAP has a single
cetyltrimethyl ammonium (CTA) ion, while CTACN and CTADC each has two and
CTAFC has three CTA units. The percentage of metal ions, determined from the AAS
studies for CTADC, CTAP and CTAFC also supports the predicted structures of the
oxidants. CTA forms contact ion pair with each of the anionic oxidant. The solubility of
these oxidants increases in organic solvents, and correspondingly, it decreases in aqueous
medium. CTAFC exhibits an absorption band around 420 nm in the visible region in
organic solvents. The chemical shift values of CTAFC at 3.37 and 3.51 are assigned to
the onium methyl and methylene groups of cetyltrimethylammonium ion respectively.
From the studies on the NMR spectral data of CTADC, CTAP, CTACN and CTAB in
CDCl3, it was found that, the protons close to the nitronium ion are affected significantly
compared to other protons with change in the metallic oxidant. This observation also
corroborates the existence of tight ion pair of the oxidants in organic medium.
With a view to investigate the effect of counter ion on the electrochemical
properties of Fe(III), Cr(VI), Mn(VII) and Ce(IV), cyclic voltametric (CV) study of all
these oxidants (CAFC, CTADC, CTAP and CTACN) were carried out by using glassy
carbon electrode and platinum electrode in acetonitrile medium using 0.1M TBAP as
supporting electrolyte within a potential window of -1.0~1.2 V and with a scan rate of 0.2
Vs-1.
Analysis of voltammogram of CTAFC (Figure 1) reveals that, it gives two anodic
peaks. The peaks at 0.67V and -0.45V correspond to the anodic and cathodic peak
volatage of the redox couple Fe(III)/ Fe(II). The presence of the carrier CTA may result
in shifting of the position of peak voltage. The voltage separation between the current
peaks (∆Ep= Epa - Epc) is 1.12V and the ratio of peak current (Ipc / Ipa) is less than unity
(0. 67) which suggest the Fe(III)/Fe(II) redox couple in presence of CTA ion to be a
quasireversible system.
iii
The voltammogram of CTACN, obtained by using platinum disc working
electrode in acetonitrile medium, exhibits one anodic peak around 0.72V and one
cathodic peak about 0.55V. A very small hump in the anodic segment is attributed to the
CTA counter ion. With increase in scan rate the peak current was found to increase
linearly. The peak voltage separation between the current peaks (∆Ep = Epa - Epc) is 0.17
V and the ratio of peak current (Ipc / Ipa) was less than unity (0. 65) indicating the
Ce(IV)/Ce(III) redox couple to be quasireversible system.
Figure 1: Cyclic voltammogram of 0.0005M CTAFC of various scan rates (Vs-1) When scanned in a potential range of -1.0 ~ 2.0V, the cyclic voltamogram of
CTAP at glassy carbon electrode in acetonitrile exhibits two reduction peaks at 0.5V and
0.85V corresponding to a two electron transfer process. A shift in peak voltage towards
more negative potential was observed with increase in scan rate. The redox system is
found to be irreversible. Due to tight ion pair, CTA does not show any isolated peak.
Similarly the voltamogram of CTADC in presence of HCl exhibits a reduction peak at
about -0.14V. The reduction of Cr(VI) to Cr(III) generally occurs at high concentration of
H+ ions. The reduction peak in presence of weak acid like acetic acid was very small. But
in presence of strong acid like 0.1M HCl CTADC gives a very good reduction peak. For
comparative study, the cyclic voltamtric analysis of potassium dichromate in acetonitrile
water mixture (1:1 v/v) in 0.1M HCl was also carried out. The reduction peak of
dichromate was also observed at the same voltage but with less peak current as compared
0.10.20.4
iv
to CTADC. This may be attributed to the existence of tight ion pair in CTADC between
CTA ion and dichromate.
To study the oxidation behavior of CTADC abd CTAP towards multifunctional
groups, phenylthiourea and substituted phenylthioureas have been synthesized and
subjected to oxidation by these two oxidants. The research findings have been reported in
Chapter 3.
When phenylthiourea (PTU) was refluxed with CTADC in acetonitrile without
any acid for more than twelve hours, phenyl isonitrile was obtained, while, in presence of
acid phenyl urea was formed (Scheme 1).
(Scheme 1)
To optimize the oxidation reaction in neutral condition, the phenylthioureas were
subjected to oxidation by CTADC in acetonitrile under microwave irradiation.
Amazingly, the reaction, which required around twelve hours of reflux to yield the
product in solvent medium, needed some seconds to get the products with more yield of
isonitrile without any solvent.
For the acid catalysed oxidation of phenylthiourea with CTADC in dioxan, the
rate was found to increase linearly with increase in [phenylthioura]. From the linear plot
of kobs vs. [PTU], the order was found to be 0.5. The reaction was found to be acid
catalyzed with almost no uncatalytic rate constant. However, with increasing [Acetic
acid], the rate constant increased exponentially with a second order dependency. The
change in substituent on the phenyl ring of the substrate does not have any significant
effect on the rate constant. However, the Hammett equation is found to be
log k = -0.48 - 2.2792 (R2 = 0.95) …1
The negative value of -0.48 suggest the existence a relatively electron deficient
transition state, however, with a low sensitivity.
In organic medium, CTADC may assemble to form a spherical reverse micelle
where the probable localization site of the ionic oxidant is the inner core of the reversed
+CH3CN
CTADC / H+
CH3CNCTADC
N C+ -
C NH2
S
NHNHC
NH2
OC
NH2
O
NH
v
micelle. Phenylthiourea, being soluble in the bulk organic solvent may not be available at
the oxidation site due to the partitioning of the substrate and the ionic oxidant into two
different pseudo phases. The observed oxidation was mostly due to the reaction at the
interface. With increase in [CTADC], the inner nonpolar core may assume a larger
interfacial area so that the substrate can, relatively, be more in contact with the polar
oxidant to facilitate the reaction. This proposition gets further support from the reaction
kinetics monitored in presence of CTAB.
When CTAB was added to the reaction mixture, the rate constant decreased
asymptotically (Figure 2). The decrease in the rate constant may be attributed to the
enhanced reversed micellization in presence of CTAB, which provides a common
counterion with CTADC for the formation of reversed micelle. Further, the interface due
to CTA+ is positively charged, and the rate retardation in presence of CTA+ indicates the
existence of a positively charged transition state during the oxidation process. The rate
enhancement due to the addition of sodium dodecyl sulphate (SDS), an anionic surfactant
also supports the cationic transition state.
The change in rate constant due to change in polarity of the solvent suggests the
existence of a relatively less polar transition state during the oxidation reaction.
Figure 2: Plot of kobs vs. [surfactant] for the oxidation reaction of phenylthiourea with
CTADC at 298K The thermodynamic parameters such as ∆H≠, ∆S≠ and ∆G≠ were determined by
using Arrhenius and Eyring equations for different substituted phenyl thioureas. A high
negative ∆S≠ values (120.2 to 208.8 J mol-1K-1) indicated the existence of a cyclic
transition state during the reaction. The plot of ∆H≠ against ∆S≠ was found to be linear
20
70
120
170
10
15
20
25
30
0 0.0005 0.001 0.0015
104 k
obs
in s
-1
[Surfactant] in M
● [CTAB]▲[SDS]
vi
with an isokinetic temperature of 293.1 K. A reaction mechanism conducive to the above
findings has been proposed as in (Scheme 2).
(Scheme 2)
The rate constant of oxidation of phenylthiourea by CTAP in acetonitrile medium
was found to increase with increase in the concentration of phenylthiourea tending
towards a constancy at higher concentration. The plot of rate constant vs. [substrate] was
found to obey Michaelis-Menten kinetics (Figure 3).
Figure 3: Plot of kobs vs. [PTU] for the oxidation reaction of phenylthiourea with CTAP
at 298 K
The Michaelis-Menten constant, Km was determined to be 1.28 x 10-3M and by
using Line-weaver-Burk type double reciprocal plot (Shown in the inset of Fig 3) the
binding constant K (=k+1/k-1) and k2 were obtained to be 878.33 dm3mol-1 and 15.66 x
CTA+O- Cr O Cr O-CTA+ H+ CTA+ HO Cr O Cr O-CTA+
PhNHC
H2NS H++
PhNH+
CH2N
SH
PhNH+
CH2N
SHPhNH+
CH2N
S Cr
HO OH
OCrO2O-CTA+
PhNH+
CH2N
S Cr
OH OH
OCrO2O-CTA+Cr
OH
OCrO2O-CTA+S
OC
PhNH
NH2
Cr
OH
OCrO2O-CTA+S
OC
PhNH
NH2
Cr OCrO2O-CTA+HOCPhNH
NH2
O S
+ +
+ HO Cr OCrO2O-CTA+
+ +
O O O O
O O
O
O O
O
O O O O
O
00.0020.0040.0060.008
0.010.0120.014
0 0.001 0.002 0.003 0.004
k ob
sin
s-1
[PTU ]in M
vii
10-3 s-1 respectively. With increase in oxidant concentration, the observed rate constant
decreases linearly. However, on addition of CTAB to the reaction mixture, the rate
constant decreases sharply and suffers a transition in the normal linear trend. CTAB
forms reversed micelles and can trap large permanganate ion at its core leading to a
separation of the substrate and the oxidant between the CTA sheaths.
To investigate on the transition state of the reaction, the kinetics of some
substituted phenylthioureas were run at different temperature. The electron donating
substituent retards the rate while the electron withdrawing substituent enhances the rate.
The plot of Hammett substituent constant with logarithm of rate constant is found to be
linear with a positive ρ value of 1.49 (R2 = 0.9571). A relatively high positive ρ value
indicates a negative charged transition state which can be generated by the attack of
manganate ion at the thione carbon leading to a negative charge on the sulfur.
The ∆H≠ values are found to be within 33.3 to 71.47 kJ mol-1 with a decreasing
trend for increasing electron donating substituent. However the change in entropy
increases for these substrates. The entropy values vary from -47.2 to -186.9 J mol-1K-1.
The plot of ∆H≠ against ∆S≠ is found to be linear (R2 = 0.996) with an isokinetic
temperature of 263 K. Considering all the above results a reaction mechanism has been
proposed (Scheme 3).
Simvastatin (SV) is a lactone prodrug used for the treatment of
hypercholesterolemia and conversion of this lactone prodrug to its hydroxyl acid form,
the compound is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA
reductase (HMGCoA), the rate limiting enzyme in cholesterol biosynthesis. The
oxidation behaviour of CTADC and CTAP on this prodrug has been described in
Chapter 4.
The colour of the solution of CTADC and SV in DCM in presence of acetic acid
under reflux condition changed with time and after six hours turned to green indicating
the reduction of Cr(VI) to Cr(III). In presence of acetic acid, the dichromate ion becomes
free from the grasp of the quaternary onium ion due to the change in polarity of the
medium and also the probable substitution of onium ion by proton of acetic acid. On
viii
addition of acrylonitrile to the reaction mixture no turbidity was observed indicating no
free radical mechanism for the reaction.
Ar N CSH
NH2Ar
HN C
S
NH2
fast
ArHN C
S
NH2
+
Mn
O O
O+Q-O
ArHN C
S-
NH2
Mn
O O
OO
Q+
ArHN C
S
NH2
Mn-O
OO
O
Q+
Mn
O O
O-Q+
SArHN C
O
NH2 + +
fast
slow
ArHN C
S
NH2
+
MnO O
+Q-O
ArHN C
S
NH2
Mn-O O
O
Q+
Mn
O O-Q+
SArHN C
O
NH2 + +
Mn (V) + Mn (III) 2 Mn ( IV)
fast
fast
fast
(Scheme 3)
The acid catalysed oxidation of SV with CTADC in DCM was found to increase
linearly with increase in concentration of SV. To obtain a relationship between the rate
constants with the parameters of the reaction condition, i.e. [substrate], [oxidant] and
[acid], log kobs values obtained in different conditions were correlated with the above
three parameters through multiple regression analysis. The regression model, thus
obtained, has been presented in Eq. 2. The orders with respect to [CTADC], [SV] and
[acetic acid] are found to be 0.634, 0.554 and 0.844 respectively.
log kobs = -5.114(±0.321)- 0.634(±0.074)log[CTADC] +0.554(±0.074)log[SV]
+ 0.844±0.107 log[Acetic acid] R2 = 0.964 F = 54 n = 10 …2
The fractional molecularity leads to the proposition of a complex reaction mechanism,
(Scheme 4) resulting in a rate equation 3.
ix
Complex (C)
Q2Cr2O7 + H+ QCr2O7H Q++K1
+SV QCr2O7HK2
k ProductRate determining step
Complex (C)
(Scheme 4)
Rate = − [ ] = k[C] = kK K [ ] [ ] [ ][ ]
…3
Cr(III) is found in the reaction products during the oxidation of various substrates
by CTADC in organic medium. The existence of Cr(III) in the product mixture is well
established from the peak at 580 nm. However, reaction kinetics could not be studied at
this wavelength due to nonreliability and low absorptivity of the spectrum. The formation
of Cr(III) from Cr(VI) due to oxidation seems to be a complex phenomenon as shown
below.
Cr(VI) + 2e → Cr (IV)
Cr(IV) + Cr(VI) → 2Cr(V)
Cr(V) + 2e → Cr(III)
Cr(VI) is initially reduced to Cr(IV), which subsequently changes to Cr(V) with another
Cr(VI). The formation of Cr(III) is a result of two-electron reduction of Cr(V).
The rate constant is found to decrease nonlinearly with increasing [CTADC]
which can be rationalised by the occurrence of a reversed micellar phenomenon during
the oxidation reaction. The decrease in the rate constant with addition of CTAB to the
reaction mixture may be attributed to the enhanced reversed micellization in presence of
CTAB, which provides a common counter ion with CTADC for the formation of reversed
micelle. Further, as the reaction is acid catalysed and the interface due to CTA+ is
positively charged which repels the proton, the rate is retarded. This proposition gets
further support from the rate enhancement due to the addition of sodium dodecyl sulphate
(SDS), an anionic surfactant.
The rate constants obtained in different solvents are found to be highly sensitive
to change in polarity of the solvents. The plots of the rate constants with different
x
polarity parameters delineate scattered relationship, from which the solvents can be
classified into dipolar aprotic solvents (acetonitrile, dioxane, ethyl acetate and acetone)
and non polar solvents (benzene, toluene, carbon tetrachloride, chloroform and
dichloromethane) from the linear relationship of these parameters with the rate constants.
The thermodynamic parameters such as ∆H#, ∆S# and ∆G# were calculated for the
oxidation of SV with CTADC in the presence of 4.86 M acetic acid and are found to be
36.5±1.4 kJmol-1, -181.1±6.9 JK-1 and 91.4±3.5 kJmol-1 respectively. A high negative
value in ∆S# supports the proposal of the involvement of a cyclic transition state (Scheme
5).
Q2Cr2O7 + H+ QCr2O7H Q++K1
O
O
HO O
OK2
Cr O
O
O
Cr
O
O
OH +-OQ+
O
O
O
O
O
O
O
O O
O
Cr O-O
O
O
Q+ Cr
H
Cr O-O
O
O
Q+ CrHO OH
OH+
k
HO OH
O
O
O O
O
Cr O-O
O
O
Q+ Cr
HO
HO OH
O
(Scheme 5)
Attempts have been made to oxidize SV with CTAP in the subsequent section.
Permanganate is well established as an oxidant for oxidizing olefinic double bonds to
corresponding diols. Simvastatin contains two conjugated double bonds and a hydroxyl
group as the reaction centres for permanganate. The oxidation product was found to be
devoid of the hydroxyl group retaining the double bonds, which is clearly evident from
the IR spectra indicating the inertness of the double bonds towards permanganate
oxidation. The lone hydroxyl group present in simvastatin was oxidized to corresponding
carbonyl group leading to the formation of a cyclic dicarbonyl compound. The isolated
product from the reaction mixture exhibits a clear IR spectrum with a characterized band
xi
at 1726cm-1 for an isolated carbonyl group which is nonexistence in the reactant. The
FAB-Mass spectral data also support the formation of the dicarbonyl product.
The fate of Mn(VII) was monitored through electronic spectra. The colour of the
solution of CTAP and SV in acetonitrile changed with time and after twenty four hours
turned to brown indicating the reduction of Mn(VII) to Mn(IV). Mn(III) was found in the
reaction products during the oxidation of various substrates by CTAP in organic medium.
The existence of Mn (III) in the product mixture is ascertained from the peak at 486 nm.
With depletion of the peak at 527 nm, the peak at 486 nm develops concomitantly, albeit
at a different rate. The conversion of Mn(VII) to Mn (IV) is a result of consecutive
reduction of Mn(VII) to Mn(V) and Mn(III) followed by a dispropotionation reaction to
Mn (IV) (Scheme 6)
2(Mn(VII) + 2e → Mn(V)
Mn(V) + 2e → Mn(III)
Mn (V) + Mn(III) → 2 Mn(IV)
2 Mn(VII) + 6e → 2 Mn(IV)
(Scheme 6)
The complex mechanism of the redox reaction of manganese could not be
encountered in the rate equation due to the relatively slow step of conversion of Mn(VII)
to Mn (V) which is the rate determining step in the reaction.
The rate constant of the oxidation of SV with CTAP in acetonitrile was found to
increase with increase in concentration of SV. The plot of observed rate constants against
[substrate] is found to be linear passing through origin. However, the rate constant is
found to decrease nonlinearly with increasing [CTAP] which is attributed to the
aggregation of CTA+ forming small aggregates leading ultimately to the formation of
reversed micelles. The permanganate ions, due to contact ion pair with the CTA unit
partitions away from the substrate, which are solubilized in the bulk solution. With
increasing [CTAP], the formation of reversed micelle increases leading to decrease in
rate.
The log of pseudo-first order rate constants were subjected to multiple regression
analysis and the order of reaction with respect to CTAP and SV are found to be 0.6 and
1.3 respectively. Hence an equation may be proposed vide infra:
xii
log k = 1.321 log [SV] – 0.649 [CTAP] – 3.07 …4
The thermodynamic parameters such as ∆H#, ∆S# and ∆G# were calculated for the
oxidation of SV with CTAP and are found to be 25.16 kJmol-1, -205.01JK-1 and 87.282
kJmol-1 respectively. The high negative entropy, in the present case, suggests a cyclic
transition state during the reaction between the permanganate ion and the substrate.
Accordingly the following mechanism has been proposed for the oxidation of SV by
CTAP (Scheme 7).
O O
O
O
OHH
MnO
O
+Q-O
O
+O O
O
O
OH
MnO
O
-O
O
H
O O
O
O
OH
MnO
-O
+Q-O
O
H
O O
O
O
O
MnOH
-O
HO
OQ+
O O
O
O
OH
MnO
O-
O
+
H
Q+
O O
O
O
O
Mn-O
HO
Q+
+
Mn (V) + Mn (III)
+
2 Mn (IV)fast
fast
Slow
-H2O
MnO-O
OQ+
OH
Mn(V )
Mn (III)
Q+
fast
Slow
k+1
k-1
k2
(Scheme 7)
xiii
The results of the dissertation work have been communicated to different journals
and presented in various Seminars and Conferences. The list of papers published and
communicated is presented below.
1. Oxidation of arylthiourea by cetyltrimethylammonium dichromate. S. Sahu, P.R. Sahoo, S. Patel and B. K. Mishra, Synth. Commun. 2010, 40, 3268-3273.
2. Oxidation kinetics of arylthioureas by cetyltrimethylammonium dichromate. P.R. Sahoo, S. Sahu, S. Patel and B. K. Mishra, Indian J. Chem. 2010, 49A, 1438-1487.
3. Oxidation of thiourea and substituted thioureas: a review. S. Sahu, P. R. Sahoo, S. Patel and B.K. Mishra, J. Sulf. Chem. 2011, 32, 171-197.
4. Oxidation kinetics of Simvastatin using cetyltrimethylammonium dichromate. P. R. Sahoo, S. Patel and B.K. Mishra, Int. J. Chem. Kinet. 2013, 45, 236-242.
5. Oxidation kinetics of Simvastatin by cetyltrimethylammonium permanganate. (Communicated to Int. J. Chem. Kinet.)
6. Oxidation kinetics of arylthioureas by cetyltrimethylammonium permanganate. (Communicated to J. Sulf. Chem.)
7. Synthesis and cyclicvoltametric studies of cetyltrimethylammonium ferricyanide.(Communicated to Electrochim. Acta)
8. Alkyl oniums as carriers of metal oxidants: A review. (Communicated to
Tetrahedron)
xiv
ABBREVIATIONS
ACC Ammonium chlorochromate
BAAO 1-Butyl-4-aza-1-azoniabicyclo[2.2.2] octane
BAAOCC 1-Butyl-4-aza-1-azoniabicyclo[2.2.2] octane chlorochromate
BAAOD 1-Butyl-4-aza-1-azoniabicyclo[2.2.2] octane dichromate
BT Benzothiophene
BTBAD Bis-tetrabutylammonium dichromate
BTEACC Benzyltriethylammonium chlorochromate
BTEAP Benzyltriethylammonium permanganate
BTMAFC Benzyltrimethylammonium fluorochromate
BTPPCC Benzyltriphenyl phosphonium chlorochromate
BTPPD Butyltriphenylphosponium dichromate
CAT Chloramine-T
CDBACN Cetyldimethyl benzyl ammonium cerium nitrate
CTA Cetyltrimethylammonium ion
CTAB Cetyltrimethylammonium bromide
CTABC Cetyltrimethylammonium bromochromate
CTABN Ceric tetrabutylammonium nitrate
CTACN Cetyltrimethylammonium ceric nitrate
CTADC Cetyltrimethylammonium dichromate
CTAFC Cetyltrimethylammonium ferricyanide
CTAP Cetyltrimethylammonium permanganate
CV Cyclic voltametry
DBT Dibenzothiophene
DCM Dichloromethane
DEACC Diethylammonium chlorochromate
DHT Dihydrotestosterone
DMACC Dimethylammonium Chlorochromate
DMDBT 4,6-Dimethyldibenzothiophene
DMF N, N Dimethylformamide
xv
DMSO Dimethylsulfoxide
EBAFC N-ethylbenzylammonium fluorochromate
HLB Hydrophilic–lipophilic balance
MBAFC N-methylbenzylammonium fluorochromate
MBT Methylbenzothiophene
MCC Methylammonium chlorochromate
Met Methionine
MTBAP Methyltributylammonium permanganate
MTPPD Triphenylmethylphosphonium dichromate
NGP Neighbouring group participation
NMO N-methylmorpholine-N-oxide
Ph.TMAP Phenyltrimethylammonium permanganate
PSP Polymer supported perruthenate
PTC Phase transfer catalyst
PTU Phenylthiourea
ROI Reactive oxygen intermediates
SDS Sodium dodecyl sulfate
SV Simvastatin
TBABC Terabutylammonium bromochromate
TBAC Tetrabutylammonium chromate
TBAD Tetrabutylammonium dichromate
TBAFC Tetrabutylammonium fluorochromate
TBAP Tetrabutylammonium perchlorate
TBHP Tert-butyl hydroperoxide
TBPDC Tetrabutylphosphonium dichromate
TEACC Tetraethylammonium chlorochromate
THACC Tetrahexylammonium chlorochromate
THF Tetrahydrofuran
TMACC Tetramethylammonium chlorochromate
TMAFC Tetramethylammonium fluorochromate
TMAO Trimethylamine N-oxide
xvi
TMAXC Tetramethylammonium halochromates
TMEDAD Tetramethylethylenediammonium dichromate
TMTU Trimethyl thiourea
TPABC Tetrapropylammonium bromochromate
TPAP Tetrapropylammonium perruthenate
TriBACC Tributylammonium chlorochromate
TriMAFC Trimethylammoniumfluorochromate
TriPACC Tripropylammonium chlorochromate
TriPAFC Tripropylammonium fluorochromate
TriPAHC Tripropylammonium halochromate
TsOH Toluene-p-sulfonic acid
TU Thiourea
Alkylammonium ions as
carriers of metal oxidants
1.1 INTRODUCTION
Onium ions, as the counter ions for anionic oxidants such as Mn(VII), Cr(VI),
Ce(IV), Ru(VII), Mo(VI), W(VI) etc brings a significant difference in oxidation potential
of the oxidants as well as to the oxidizing system. These ions make the oxidants lipid
soluble, mild and chemoselective. Many tailor-made oniums, such as ammonium,
phosphonium,1 tellurium,2 arsonium,3 bismuthenium4 etc. have been used as the counter
ions of the anionic oxidants. In different reaction conditions, sometimes these oxidants
show biomimetic characteristics, due to the counter ions, providing a micro-
heterogeneous environment with different solubilization pockets for the substrates as in
case of micelles, reversed micelles, microemulsions, vesicles for artificial systems, and
proteins and lipid membranes in living systems.5 The onium counter ions contribute
significantly to the solubility of the oxidants in the reaction media. A great deal of efforts
in research is directed to the development of new oxidants with these onium ions.
With the aim to develop new efficient oxidation protocol, a number of symmetric
and asymmetric tetraalkylammonium ions with varying alkyl chain length have been
synthesized in different research schools to serve as carriers of the oxidants and to deal
with organic substrates in organic medium. Some of them have been used in solid state,
in solvent free conditions and by microwave irradiation. The effect of
tetraalkylammonium ions on the change in water structure is ambiguous. With large alkyl
groups the structuredness of water increases6 while with relatively small alkyl groups and
more exposed charge on the onium ion, the water structure breaks.7
1.2 ALKYL AMMONIUM IONS AS CARRIERS OF Cr(VI) OXIDANTS
Water-soluble potassium or sodium dichromates are the common laboratory
oxidants to oxidize organic substrates and are effective in presence of strong acid. With
the advent of organic phase transferring agent, an attempt was made by Sarett School of
research, who used pyridine to form salt with CrO3, a Lewis acid, to oxidize some
steroidal alcohols in organic solvents.8 This reagent was subsequently used by other
workers without analyzing the structure of the oxidant.9 Corey, in his novel attempt in
establishing pyridinium chlorochromate10 as a versatile oxidant, revisited the Sarett’s
reagent and discovered it to be pyridinium dichromate.11 Later on many heterocyclic
2
ammonium ion based Cr(VI) oxidants were synthesized and their oxidation potential
towards various substrates were investigated. An extensive review on these oxidants has
been published.12
Many oxidative reagents have been developed in recent years with some
success.13 In particular; there is continued interest in the development of new chromium
(VI) reagents for the effective and selective oxidation of organic substrates, under mild
conditions.14 Significant improvement has been achieved by the use of new oxidizing
agents with tetralkylammonium ion like tetrahexylammonium, tetrabutylammonium
tetrapropylammo-nium, tetraethylammonium tetramethylammonium as counter ions and
chlorochromate, fluorochromate, bromochromate and dichromate as oxidants.
1.2.1 Alkyl ammonium ions as carriers of chromates
1.2.1.1 Tetraalkylammonium chromates
Tetrabutylammonium ion has been extensively used as an additive in various
water-lipid systems due to its balanced amphiphilic characteristics. Various oxidants
developed with tetrabuylammonium ion include tetrabutylammonium -chlorochromate
(TBACC),15 fluorochromate (TBAFC)16 and chromate (TBAC).17 TBAFC
(C4H9)4NCrO3F) has been used for the effective and selective oxidation of alcohols,
under mild conditions. The reagent can be synthesized by the reaction of
tetrabutylammonium fluoride with CrO3 in a 1:1 mole ratio. The simplistic oxidation of
triphenylphosphine to corresponding oxide by TBAFC in acetonitrile provides a clear
evidence for the involvement of an oxygen-transfer reaction in the oxidation process.16
Two versatile reagents of this category are tetrabutylammonium bromochromate
(TBABC : (Bu)4NCrO3Br) and tetrapropylammonium bromochromate (TPABC :
(Pr)4NCrO3Br)18 which can efficiently oxidize alcohols to corresponding carbonyl
compounds under mild conditions (Scheme 1.1).
(Scheme 1.1)
R'
R''
OHR'
R''
OCH2Cl2
NCrO3Br( 4R ) )R = Pr, Bu(
3
Pourali et al.17 reported the conversion of oximes into the corresponding carbonyl
compounds by using tetrabutylammonium chromate (TBAC) under homogeneous,
aprotic and moderately acidic conditions. Recently TBAC has been used for the nitration
of phenolic compounds in presence of sodium nitrite and oxidation of hydroquinones to
quinones in dichloromethane.19 The same reaction can also take place in the presence of
tetrabutylammonium dichromate (TBAD) under neutral aprotic conditions using CH2Cl2
(Scheme 1.2). OH
R
OH
H
NO2
TBAD or TBACNaNO2
CH2Cl2/ Reflux
OH
OH
O
O
CH2Cl2/ RefluxTBAD or TBAC
(Scheme 1.2)
Tetraethylammonium chlorochromate (TEACC) is one of the versatile reagents
for efficient and selective oxidation of organic substrates like crotonaldehyde in acetic
acid.20 Using TEACC Tomar and Kumar investigated the kinetics of oxidation of
aldohexose like, D-mannose, D-fructose, D-glucose and D-galactose.21-24 All these
reactions were carried out in 50% aqueous acetic acid in presence of perchloric acid with
constant ionic strength. In case of D-mannose and D-glucose the oxidation products were
found to be arabinose and formic acid and for D-fructose the products were identified to
be D-erythrose and glycollic acid. Similar kinetics observations were reported for all the
aldoses. In each case, a first order dependency was followed by the reaction with respect
to both the [oxidant] and the [substrate]. The reaction was catalyzed by [H+] and a
hydride ion transfer mechanism was proposed for each case.
4
TEACC was synthesized by using a direct reaction of chromium (VI) oxide and
tetraethylammonium chloride (Scheme 1.3). The crystal structure of TEACC was
ascertained by X-ray diffraction studies.25
Et4NCl CrO3 Et4N [ ]CrO3Cl+
(Scheme 1.3)
The X-ray diffraction analysis revealed that the tetraethylammonium (TEA)
cations are located in two different symmetry environments (Figure 1.1). The cation and
anion moieties are separated from each other and arranged in a C-centered lattice with the
TEA cation located at the midpoint of the edges of the unit cell. Geometry about the Cr is
a distorted tetrahedron with six unique bond angles around this atom. X-ray data clearly
demonstrate inequality between the Cr–O and the Cr–Cl bond length that is responsible
for the higher reactivity of this compound over similar oxidizing agents in terms of the
amount of oxidant and solvent required, short reaction times and high yields. The reason
for this inequality in bond length is due to the CH…..O hydrogen bond that forms
between the ethyl hydrogen of the cation and oxygen of the anion.
Figure 1.1: ORTEP diagram of [Et4 N(CrO3Cl)]
5
Recently Sharma and coworkers studied the oxidation kinetics of some α-hydroxy
acids like glycolic, lactic, malic, and a few substituted mandelic acids with TEACC in
dimethylsulfoxide (DMSO).26 Each reaction is first order with respect to both TEACC
and hydroxy acids. The reaction is catalyzed by hydrogen ion with an appreciable
uncatalytic rate suggesting the occurrence of two mechanistic pathways for acid
independent and acid dependent reactions (Scheme 1.4). The acid catalysis was attributed
to the protonation of TEACC to give a stronger oxidant and electrophile. Further the
oxidation kinetics of α-deuteriomandelic acid exhibited the presence of a primary kinetic
isotope effect (kH/kD = 5.63 at 298 K), which suggests the cleavage of the C-H bond in
the rate-determining step.
CrO
O ONEt4
Cl
+
CO H
H
HOOC
Ar+ Ar
H
C O
COOH
Cr
O
HO Cl
O NEt 4+
HO
Cr
O
Cl
ONEt4+
CO OH
OCAr
H
Slow
(A)
+ArCOC OOH+
(OH)2CrClONEt 4
#
Acid independent path
#
+(A ) H + +Ar
H
C O
COOH
CrHO Cl
ONEt4 +OH
Sl ow
HO
Cr
OH
Cl
ON Et4+
COO H
OC Ar
H
+ArCOCOOH+
(O H)2CrCl O NEt 4 + H2O
Acid dependent path
(Scheme 1.4)
6
Similar reaction kinetics was obtained while oxidizing some lower oxyacids of
phosphorus to corresponding oxyacids with phosphorus in higher oxidation state.27 The
reaction was first order with respect to both the [oxidant] and [substrate]. The presence of
a substantial primary kinetics isotope effect envisages the cleavage of a P - H bond in the
rate determining step. In accordance with the kinetic results a mechanism involving
hydride transfer in the rate determining step was proposed (Scheme 1.5).
P OH
H
R
O
P OHR
O
RP(O)(OH)2
CrO
O
O-N+Et4
ClCr
HO
O
O-N+Et4
Cl
CrO
Cl
O-N+Et4
++Slow
Fast
+
+
(Scheme 1.5)
Pohani et al. reported the kinetics of oxidation of some diols and their monoethers
to corresponding hydroxycarbonyl compounds by using TEACC as the oxidant in DMSO
medium.28 A first order dependency was found with respect to both TEACC and diols.
The oxidation of organic sulfides by TEACC resulting in the formation of the
corresponding sulfoxides was reported by Sharma et al.29 The toluene-p-sulfonic acid
(TsOH) catalyzed reaction of sulphides was first order with respect to both TEACC and
sulphide. The reaction followed two mechanistic pathways, one TsOH-catalyzed and the
other uncatalyzed. The small magnitudes of the contribution of steric constants are in
consistent with the acyclic mechanism accounting the rate determining electrophilic
oxygen transfer from TEACC to the sulphide (Scheme 1.6).
The oxidation of aliphatic primary alcohols to corresponding aldehydes30 and
aliphatic aldehydes to corresponding carboxylic acids31 by TEACC in DMSO were found
to be first order with respect to TEACC and the substrates and a reaction mechanism
involving the hydride ion transfer was proposed for each reaction. Oxidation of
monosubstituted benzaldehydes by this reagent resulted in the formation of
7
corresponding benzoic acids and a substantial primary kinetic isotope effect was
exhibited in duteriated benzaldehyde.32 From linear regression analysis it was observed
that the oxidation of para-substituted benzaldehydes is more susceptible to the
delocalized effect than that of ortho- and meta- substituted ones, which display a greater
dependence on the field effect.
S
R'
R
CrO
O
O-N+Et4
Cl+ Cr
O
O-N+Et4
ClOS
R'
R
SR R'
O
CrOClO-N+Et4+
#
. .
Acid Independent Path
SR R'
O
SR R' +
+
HCr+O2ClO-N+Et4
HCr+OClO-N+Et4
Cr
HO
O-N+Et4
Cl
+OS
R
R'
O2CrClO-N+Et4 + TsOH [OCr(OH)ClO-N+Et4]+[ TsO]-
Acid dependent Path
(Scheme 1.6)
The oxidative deoximination of several aldo- and keto-oximes by TEACC in
DMSO, exhibited a first order dependence on both the oxime and TEACC. The oxidation
of ketoximes was slower than that of aldoximes.33 From the results of the reaction
kinetics a mechanism involving the formation of a cyclic intermediate in the rate-
determining step was proposed. Further, the observed rate retardation for ketoximes in
the oxidation process was attributed to the steric hindrance by the alkyl groups.
Recently the kinetics of oxidation of methionine (Met) by TEACC in DMSO
leading to the formation of the corresponding sulfoxide was proposed by Mansoor et al.34
8
The reaction was first order each in Met and TEACC and is catalyzed by hydrogen ions.
Chouhan et al. reported the oxidation of formic and oxalic acids to yield CO235 and
aliphatic aldehydes to carboxylic acid36 by using benzyltriethylammonium
chlorochromate (BTEACC) in DMSO. The reagent BTEACC was also used in oxidation
of aliphatic primary alcohols to corresponding aldehydes.37
Tetramethylammonium fluorochromate (TMAFC: (CH3)4N[CrO3]F) and
chlorochromate (TMACC: (CH3)4N[CrO3]Cl) constitute another class of Cr(VI)
oxidants. The reagents were prepared by the reaction of the corresponding quaternary
ammonium salts with CrO3 in a 1:1 ratio in acetonitrile medium.38 TMACC was used to
carry out oxidative deprotection of trimethylsilyl and tetrahydropyranyl ethers or ethylene
acetals and ketals to the corresponding carbonyls (Scheme 1.7).39 The reagent was also
used to oxidize aromatic and aliphatic thiols to corresponding disulfides.40
R', R'' = H, Alkyl, Aryl
(Scheme 1.7)
The crystal and molecular structures of TMAFC were determined at 130K by X-
ray diffraction. As in case of TEACC25b in TMAFC also the X-ray data demonstrate
inequality between the Cr-O and the Cr-F bonds, which can be attributed to the CH….F
hydrogen bond that forms between the methyl hydrogen of the cation and the fluoride
atom of the anion. 41
TMAFC can effectively bring oxidation of isopropyl, benzyl, and n-butyl alcohols
to corresponding aldehydes.38b The kinetics of the oxidation reaction was investigated in
the presence of p-toluenesulfonic acid. Michaelis-Menten kinetics with respect to
alcohols was proposed, demonstrating the quasi-equilibrium formation of an oxidizing
agent-alcohol complex. The kinetic isotope effect for benzyl alcohol suggested the
cleavage of the C-H bond at the C atom linked to the OH group. A mechanism involving
hydride transfer was proposed for the oxidation reaction (Scheme 1. 8). Oxidations of a
R'
R'' O
OTMACC+
MeCN reflux conditions
AlCl3, 0.3 molar ratio( ) R'
R''
O
9
number of aliphatic, aromatic and allylic thiols to the corresponding disulfide were
reported by Imanieh et al.42 Each reaction proceeds with a two electron reduction of
TMAFC without any detectable amounts of sulphones or sulphonic acids.
CrO3FNMe4
H+
( HOCrO2FNMe4)+
2
R CH2OH R C+HOH R CHO
R CHO( HOCrO2FNMe4)+
R CH2OH
H+
H+
+
++
+
( HOCrO2FNMe4)+
H+
(Scheme 1. 8)
The identification of reduced chromium product in the oxidation of some alcohols
(Scheme 1.9) and triphenylphosphine by using TMAFC (Scheme 1.10) was attempted by
using cyclic voltametry.43 The reduced chromium compound exhibited quasi-reversible
behavior, which changed to higher oxidative states such as Cr(VI) by increasing the
potential, and reduced to lower oxidative species such as Cr(III) state by decreasing the
potential. Further, the appearance of IR band at 945 cm-1, 900 cm-1and 645 cm-1 assigned
to s (Cr–O), as (Cr–O) and (Cr–F) modes, and the 2.91BM confirmed the reduced
chromium compound to be (CH3)4N[CrO2F].
(Scheme 1.9)
C OR
H
HCr
O
O F
-N CH3)( 4+OH
H
CrO
F
-N CH3)( 4+OH
O
C OR
H
+ H2O+RCHO CrO2FN( )CH3 4
C OHR
H
H
CrO
O F
-N CH3)( 4+O
+
10
(Scheme 1.10)
Recently, Ghammamy et al.44 carried out the oxidation of primary and secondary
alcohols using tetramethylammonium halochromates (TMAXC) (X=Cl, Br) and obtained
corresponding carbonyl compounds. These halo chromates were also used for oxidation
of carbohydrates such as 1,2: 5,6 -di-O- isopropylidine –-D-glucofuranose to its
corresponding keto sugar in high yield using equimolar ratio of the reagents (Scheme
1.11).
O
OH
CH2Cl2, rt
O
O
MeMe
O
O
MeMe
O
O
O
MeMe
O
O
MeMe
(CH3)4N+[CrO3X-]
O
(Scheme 1.11)
Benzyltrimethylammonium fluorochromate (BTMAFC), which was synthesized
by reacting benzyltrimethylammonium bromide with an aqueous solution of CrO3 and
HF, was used by Kassaee et al. for conversion of oximes into the parent ketones or
aldehydes.45 This reagent was found to be fruitful for selective oxidation of primary,
secondary, allylic and benzylic alcohols to their corresponding carbonyl compounds,
under mild and neutral conditions (Scheme 1.12). Similarly the reagent,
dodecyltrimethylammonium bromochromate46 ((C12H25)N(CH3)3[CrO3Br]), was found to
be an effective oxidant for the selective oxidation of primary and secondary alcohols to
the corresponding carbonyls, carbohydrate to ketosugar, anthracene and phenanthrene to
anthraquinone and phenanthraquinone, respectively.
N( )CH3 4 CrO3FP + CrO2FN( )CH3 4 + P
O
11
R
H
OH
R
H
R
H
NO OHBTMAFC
CH2Cl2rt /rt / CH2Cl2
BTMAFC
(Scheme 1.12)
Ghammamy and his co-workers used tetrahexylammonium chlorochromate
(THACC) for oxidation of various primary and secondary alcohols to their corresponding
carbonyl compounds.47 In presence of equimolar amounts of 2-phenylethyl alcohol and
benzyl alcohol, the product was found to be benzaldehyde with 96% yield with no further
oxidation of aldehyde to corresponding acid.
Tetraethylammonium, tetrahexylammonium and tetraheptyl ammonium
bromochromate are some novel reagents used for almost quantitative conversion of
alcohols into the corresponding aldehydes and ketones (Scheme 1.13).48
(Et)4/(Hex)4/(Hept)4NCrO3Br
CH2Cl2R1 R2 R1 R2
OH O
(Scheme 1.13)
1.2.1.2 Trialkylammonium chromates
A valuable addition to the prolific oxidant family is the trialkylammonium
halochromates (R3NH [CrO3X]) (R= CH3, C2H5, C3H7 and C4H9, X= Cl, F). These
reagents are of low cost, readily available and capable of oxidizing numerous organic
substrates. A mild and efficient method for the oxidation of diols to the corresponding
hydroxy aldehydes with trialkylammonium fluorochromates (R3NH[CrO3F]) (R= CH3,
C2H5, C3H7 and C4H9) in solution at room temperature, and under microwave radiation
was reported by Ghammamy et al.49
Tributylammonium chlorochromate (TriBACC) was used for the oxidation of
primary and secondary alcohols in dichloromethane to afford corresponding aldehydes
and ketones in high yields.50 The reagent was prepared by the interaction of tributylamine
with CrO3 and hydrochloric acid in a 1:2:2 mole ratio. Recently, Mansoor et al. studied
the oxidation kinetics of benzhydrols to the corresponding benzophenones by TriBACC.
The reaction was first order each in the concentration of TriBACC, benzhydrol and H+.51
12
The order of the reactivity for substituted benzhydrol was found to be p-OCH3 > p-CH3 >
p-H >> p-Cl > p-NO2 benzhydrol. A mechanism involving hydride transfer was proposed
(Scheme 1.14) for the reaction.
Cr
O
O
Cl O-TriBNH+ + H+k1
k-1
Cr(IV) Cr(VI)
Cr(V)
fast
slow
H2O(HO)Cr+ClOTriBNH+
Product
Cr
O
OH
Cl O-TriBNH+
CHOHC6H5
C6H5
k2
k-2+
k3
Cr
O
HO Cl
O-TriBNH+
CC6H5
C6H5
+
CrO
HO Cl
O-TriBNH+
H
OH
CC6H5
C6H5
CrO
O Cl
O-TriBNH+
H
OH
H
CC6H5
C6H5
O +Cr(IV)
+fast
2 Cr(V)
Reductantfast
Cr(III)+ + (Scheme 1.14)
Oxidation of alcohols to aldehydes or ketones, anthracene and phenanthrene to
anthraquinone and phenanthraquinone respectively were achieved by
tripropylammonium fluorochromate (TriPAFC).52 Tripropylammonium chlorochromate
(TriPACC) was used for oxidative coupling of thiols to corresponding disulfides both in
solution and under microwave irradiation (Scheme 1.15).53 Both the reagents TriPAFC
and TriPACC adsorbed on alumina in solution were also used for the oxidation of thiols
to corresponding disulphides.54
RSH TriPACCA or B
RSSR
A: CH2Cl2, rtB: CH2Cl2, rt, microwave
(Scheme 1.15)
Triethylammonium fluorochromate (Et3NHCrO3F) oxidizes primary alcohols,
anthracene and naphthalcene, and carbohydrates to corresponding oxo derivatives in
13
dichloromethane with high yields (Scheme 1.16).55 Conversion of various aliphatic and
aromatic thiols into the corresponding disulfides by triethylammonium fluorochromate or
triethylammonium chlorochromate supported on silica gel were carried out by
Ghammamy et al.56
O
OHCH2Cl2
O
O
Me
Me
O
O
MeMe
O
O
O
Me
Me
O
O
MeMe
Et3HNCrO3F
O
(Scheme 1.16)
Trimethylammoniumfluorochromate (TriMAFC), which was synthesized from
CrO3, trimethylamine and aqueous 40%HF in a molar ratio of 1:1:2 was used for
oxidation of alcohols to corresponding carbonyl compounds in dichloromethane.57
1.2.1.3 Dialkylammonium chromates
Diethylammonium chlorochromate (DEACC), a dialkylammonium chromate, was
used for the oxidation of primary and secondary alcohols to corresponding carbonyl
compounds in aqueous-acetic acid medium.58 The reaction was found to be first order in
DEACC and H+ and followed Michaelis-Menten type kinetics.
Chemisorbed on alumina and silica, dimethylammonium chlorochromate
(DMACC) was found to be effective for oxidation of alcohols,59 benzoins60 and
R'OH
R"
R'
R"
OEt3NHCrO3F CH2Cl2,room temp
Et3NHCrO3F CH2Cl2,room temp
O
O
14
regeneration of carbonyl compounds by oxidative cleavage of C=N under non-aqueous
condition.61, 62
Sayyed-Alangi and his co-workers utilized N-methylbenzylammonium
fluorochromate (MBAFC)63 and N-ethylbenzylammonium fluorochromate (EBAFC)64
for selective oxidation of alcohols to their corresponding carbonyls. The effectiveness of
MBAFC and EBAFC was considerably increased upon its adsorption on silica gel. Many
functional groups are inert towards this oxidizing agent, including thiols, sulfides and
phenols, enhancing the usefulness as chemoselective of these oxidants and the oxidation
conditions for the synthesis of highly functionalized molecules. The MBAFC and
EBAFC were synthesized by treating CrO3 with aqueous HF and N-methylbenzylamine/
N-ethylbenzylamine in the molar ratio of 1:1.5:1.
1.2.1.4 Alkylammonium chromates
Regeneration of carbonyl compounds from their nitrogen containing derivatives
(oximes. p-nitrophenylhydrazones, 4-phenylsemicarbazones and semicarbazones) was
achieved using methylammonium chlorochromate adsorbed on silica gel(MCC/SiO2)
with good yields.65 The compound was also used for the oxidation of hydroxyl groups on
silica to corresponding carbonyl compounds.66
The kinetics of oxidation of phenols to quinones by ammonium chlorochromate
(ACC) in aqueous acetic acid medium was carried out by Patwari et al.67 The reaction
was first order with respect to both phenol and ACC and catalyzed by hydrogen ion. The
rate of oxidation decreased with increase in dielectric constant of solvent indicating the
existence of ion-dipole interaction in the oxidation process. The decrease in rate of
oxidation with increase in concentration of KCl, was attributed to the formation of a
reactive species by interaction of Cl- and protonated ACC. Oxidation of some
hydrobenzoins to corresponding benzils by ACC supported on montmorillonite K10 in
dichloromethane was reported by Li et al.68
15
1.2.2 Alkyl ammonium ions as carriers of dichromates
1.2.2.1 Tetraalkylammonium dichromates
A study of the literature indicated that benzyl bromides could be converted to the
corresponding carbonyl compounds by bis-tetrabutylammonium dichromate (BTBAD).69
Under microwave conditions deprotection of oximes by BTBAD was successfully
achieved by Murugan and Reddy.70 By employing BTBAD, 1,4-diacylbenzenes was
synthesized in good yield. 71
As the oxidant was found to be more efficient in the solid state, the investigation
on the crystal structures of alkylammonium dichromate has been of current interest.
Fosse et al. determined the structures of tetramethylammonium dichromate and
trichromate from X-Ray diffraction study. These compounds crystallize in an
orthorhombic system.72 However, bis-dihexadecyldimethyl ammonium dichromate
exhibits a lamellar structure73 and ethylenediammonium dichromate crystalises in the
monoclinic form.74 The crystal structure of the anhydrous bisoctyltrimethylammonium
dichromate, (C18H37(CH3)3N)2 Cr2O7, was found to be in the triclinic form.75 The
dichromate anions were found to stack up in a layer, separated by a double layer of
octyltrimethylammonium surfactant chains lying in parallel. The interlayer spacing of
43.4 Ao, smaller than the expected value for the fully extended molecular model, was
achieved through a tilting of the surfactant chains of about 37.5° from the normal to the
(Cr2O7)2-plane. Tetramethylethylenediammonium dichromate(TMEDADC) obtained
from CrO3 and TMEDA was utilized for selective oxidation of benzylic and allylic
alcohols.76
1.2.2.2 Cetyltrimethylammonium dichromate
The use of cetyltrimethylammonium ion (CTA) as the counterion has opened up a
new vista to the ongoing oxidizing system. CTA ion is well known for its amphipathicity,
which is having the characteristics of being solubilized in both aqueous and nonaqueous
media. Unlike other quaternary ammonium ions (tetrabutyl or octyl ammonium ions),
CTA has a relatively small head group with more exposed charge and a well-balanced
hydrophobic group to carry the ion to both water and organic media and thus is a magic
amphiphile. CTA with its counter ion forms tight ion pair in organic solvents, whereas in
16
aqueous medium it dissociates.77 Cetyltrimethylammonium (CTA) ion has a balanced
amphiphilic system, capable of forming various organized assemblies like micelle in
aqueous medium, reversed micelles in organic solvents,78 microemulsion in aquo-organic
medium79and even hemimicelles on solid matrix.80
A number of oxidants such as cetyltrimethylammonium –permanganate
(CTAP),81 -ceric ammonium nitrate (CTACN),82 -bromochromate (CTABC),83 etc. were
synthesized with CTA as the carrier. Among these oxidants, CTA dichromate (CTADC),
first reported in 2004, is still in its infancy. Its mildness and chemoselectivity have been
observed in various mono and bifunctional groups.
Cetyltrimethylammonium dichromate (CTADC) can be synthesized by a simple
ion exchange method. Addition of potassium dichromate solution to
cetyltrimethylammonium bromide (CTAB) in aqueous solution gives the water-insoluble
yellowish-orange salt, CTADC (Scheme 1.17).84 The elemental analysis clearly
envisages the presence of two CTA units per molecule of dichromate. A comparison of
spectral study and solubility of other such oxidants(CTAP and CTACN) suggests the
existence of a tight ion pair in CTADC in organic media. In most of the organic solvents,
the compound absorbs at around 353–383 nm. CTADC is stable in these solvents at
reflux temperature and for an appreciable time period. On water surface, it assumes an
area of 51 A°2/ molecule at a temperature of 298 K.85
2C16H33N+(CH3)3Br + K2Cr2O7 → [C16H33N+(CH3)3]2Cr2O7 + 2KBr
(Scheme 1.17)
CTADC has shown its effectiveness in oxidation of various functional groups like
alcohols, aldehydes, hydroxyquinones, cinnamic acid etc.84 The oxidised products of
alcohols and hydroxyquinones were found to be the corresponding carbonyl compounds
and benzoquinones, respectively (Scheme 1.18). In the same way, oxidation of aromatic
aldehydes led to the formation of substituted benzoic acids, and cinnamic acid afforded
benzoic acid (Scheme 1.19).
17
R=Ph, NO2Ph, C7H15, R’=H R=Me, R’=Me
R=Ph, R’=PhCO R=Ph, R’=PhCO RCR’= c-C6H10
(Scheme 1.18)
X=H, CH3, Cl, OCH3
(Scheme 1.19)
Thiols and aromatic amines on oxidation with CTADC produced oxidative
coupled disulfides and diazo compounds, respectively (Scheme 1.20).86
R= Bu, Ph, o-MePh, p-MePh, Bn, benzothiazole
NH2X
CTADCN
XN
X
X= H, o-OH, p-OH, p-OMe, p-Cl
(Scheme 1.20)
CTADC R CR'
OR CHR'
OH
CTADC
OH
OH
O
O
CHO COOHCTADC
XX
COOHCOOH
CTADC
R SHCTADC
R S S R
18
Oxidation of cholesterol with CTADC in DCM resulted in the formation of 7-
dehydrocholesterol, which was characterized from its 13C NMR, 1H NMR, and FABMS
spectral characteristics.87 For this dehydrogenation, a remote-functionalization
mechanism analogous to that reported by Breslow et al.88 was proposed. The
dehydrogenation occurs through a seven-membered cyclic transition state involving a
change of oxidation state of Cr(VI) to Cr(IV) (Scheme 1.21). But, 5-cholesten 3-one was
found to be the oxidised product of cholesterol with CTADC in presence of 20% acetic
acid in DCM.
(Scheme 1.21)
Easy deprotection of oximes by CTADC in the presence of a trace amount of
acetic acid in dichloromethane reveals the mildness of CTADC in oxidation reactions
(Scheme 1.22).89 When the reaction was performed in the absence of acetic acid,
however, the corresponding nitrile derivatives was obtained. Under these reaction
conditions ketoximes did not react.
Q+Cr O
O
O
O
O-CrO
O- +12N
HH
OH
HO
CTADC
CH2Cl2
CH2Cl2/CH3COOH
O N+12O
HO- Cr O
O
OO-Cr
OH
OH
HO
Q+
19
(Scheme 1.22)
From the investigation of oxidation kinetics of a series of aliphatic primary and
secondary alcohols and cyclohexanol it was found that, the reaction kinetics obey the
Michaelis–Menten equation with respect to [alcohol], due to the formation of a complex
between the oxidant and substrate prior to the rate-determining step. The complex
subsequently decomposes into the products.5
Further, the solvent kinetic isotope effect, k(H2O)/k(D2O) was found to be 0.76. The
reverse isotope effect was attributed to the involvement of a pre-equilibrium protonation
in the reaction mechanism. The kinetic isotope effect of 2.81 obtained by using methanol-
d4 as the substrate supports the involvement of -C–H bond breaking in the rate-
determining step. Accordingly, a mechanism was proposed where the dichromate ion
forms an ester intermediate with the alcohol, which subsequently decomposes by -
hydrogen abstraction to the corresponding aldehyde or ketone (Scheme1.23).
(Scheme1.23)
R2
R1
NOHR2
R1
O R2 CNNH2OH
CTADC/H+
CTADC
R2 = Aryl group, R1 = H, Me, C6H5CH(OH), R1CR2 = Cyclohexane
R1=H
k2 RC
ROC
H
O CrOCrO2O-CTA+
OHO
O-
R
R
CH OR
RCH OH
R
R
+
K
OCr
O
OCrO2O-CTA+
O-CTA++ H+
OCr
OCrO2O-CTA+
O OH(CTADC)
+
Complex (C)
OCr
OCrO2O-CTA+
O OH
OCr
OCrO2O-CTA+
OHO-CTA+
CrOCrO2O-CTA+
O- OH
HO
CTA+
CTA+
CTA++
''
''
20
With increasing concentrations of CTADC, the rate constant decreased
nonlinearly with concavity, which was attributed to the formation of a reversed micelle in
which the dichromate ion is enveloped by CTA+. At a cationic CTAB-reversed micellar
interface, a proton may not be available for the dichromate leading to a decrease in the
rate. Further with increasing [CTADC], there may be an increase in reverse micelle
formation and, thus, a negative trend is inevitable. The formation of reversed
micellization also gets support from the asymptotic rate fall due to an increase in [CTAB]
(Figure 1.2). Similar kinetics was obtained for oxidation of benzyl alcohol by CTADC in
various organic solvents and in surfactant systems.90 Benzaldehyde was found to be the
only oxidation product without any further oxidation. The variation in rate constants with
change in [acid], [substrate], [oxidant], and [surfactant] led to the proposal that the
reaction occurs in a reversed micellar system produced by the oxidant, similar to an
enzymatic environment. The changes in the rate constant with variations in [surfactant]
and the solvent isotope effect suggest the path of the reaction to be through the formation
of an ester complex, the decomposition of which is the rate-determining step.
Figure 1.2: Schematic representation of the aggregation of CTADC in non-polar solvents
The proposal of formation of reversed micelle in CTADC solutions was further
supplemented by the oxidation of cholesterol. Oxidation of cholesterol by CTADC in
DCM in the presence of acetic acid to 5-cholesten-3-one was found to obey Michaelis–
Menten type kinetics.87 From the inverse solvent isotope effect (k(D2O)/k(H2O)=0.72) and
HO
HO
OH
OH
CH3OH
CH3COOH
CTADC
CTAB
21
other kinetic parameters, it was proposed that the reaction occurs in a reversed micellar
system, and the reaction path involves the intermediate formation of an ester complex,
which undergoes decomposition to give the product (Scheme 1.24).
CrO OCrO2O-CTA+
O-CTA+O + H+ CTA+CrO
OCrO2O-CTA+
OHO+
CrHO
CTA+O-O2CrO
+ K
HO
O-
OO
HCTA+
CrO OCrO2O-CTA+
OHO CrHO
CTA+O-O2CrO
O-
O
OH
CTA+
k2
OCr
HO OCrO2O-CTA+
OHCTA+O-+
(Scheme 1.24)
From the deoximation kinetics of some oximes by CTADC in presence of acetic
acid it was found that the rate of reaction was found to be highly sensitive to the change
in [CTADC], [oxime], [acid], [surfactant], polarity of the solvents and reaction
temperature. 91 The reaction was found to be catalyzed by acid with an appreciable
uncatalytic rate and was first order with respect to substrate. A decrease in rate constant
with increase in CTADC concentration was observed and accordingly, a mechanism was
proposed in which the substrate forms a complex with CTADC in the rate determining
step followed by decomposition with a fast process to yield corresponding carbonyl
compounds (Scheme 1.25).
22
(Scheme 1.25)
The product analysis of the oxidation of benzoin oxime, which has two reaction
centers for oxidation, a secondary hydroxyl group and an oxime, revealed a selective
oxidation to benzoin by CTADC. The exorbitant kobs for benzoin oxime was explained
through a neighbouring group participation by the hydroxyl group through the formation
of cyclic intermediate (Scheme 1.26).
(Scheme 1.26)
CTADC was also proved to be effective for deoximation as well as for oxidation
of alcohols to aldehydes and ketones in the absence of organic solvents.92 Double bonds
present in some of the oximes are not affected further by CTADC.
Recently the oxidation kinetics of some alkyl phenyl sulfides93 with CTADC was
investigated in dichloromethane-acetic acid (80:20, V/V) and in aqueous acetic
acid(60:40,50:50,V/V). The oxidation of alkyl phenyl sulfides followed an overall second
order kinetics, first order each with respect to substrate and CTADC. It was found that
+k2
Fast HNO2OCR1
R2
H ++K+ CTA+ HCr2O7CTACTA2Cr2O7
+ k1
Slow
ONC
HR1
R2
O
O
NCH
OCr
R1
R2
OO H
HCr2O7CTA
CTAOO2Cr
O
O
NCH
O
Cr
R1
R2
OO HCTAOO2Cr
CrOO HCTAOO2Cr
OO
CHPh C N OH
O PhH H
CHPh C N OH
O Ph
O O
CTAOO2Cr HO OCr
CHPh C N OH
O Ph
O O
CTAOO2Cr HO OCr
H+
23
the rate of reaction increases with increasing electron donating power of the alkyl groups.
A possible mechanism was also proposed for the oxidation process (Scheme 1.27).
+
CrO
O
OCTA-
O
+2H+
+
CrO
O
OCTA-
O Cr O
O
OCTA-
CrO
OH
OCTA-
O Cr O
OH
OCTA-
CrO
OH
OCTA-
O Cr O
OH
OCTA-
SR R
S O
R
R
CrOH
OCTA-
H2OSR R
O
H2CrO3 CTA
+
+
Slow
..
....
(Scheme 1.27)
1.2.3 1-Butyl-4-aza-1-azoniabicyclo[2.2.2]octane chlorochromate and dichromate
1-Butyl-4-aza-1-azoniabicyclo[2.2.2] octane (BAAO) was used as a carrier of
Cr(VI) in both chromate and dichromate forms. BAAO chlorochromate (BAAOCC) in
presence of AlCl3 was found to be an effective oxidizing system for oxidation of a variety
of alcohols to corresponding carbonyls in acetonitrile medium.94
Hajipour et al. have reported the oxidation of sulfides to sulfoxides and
thioacetals to corresponding parent carbonyls with BAAO dichromate (BAAOD) in
nonaqueous medium (Scheme1.28).95 Another oxidant, 1-benzyl-4-aza-1-
azoniabicyclo[2.2.2]octane dichromate was used for the oxidative cleavage of the C=N
bond of oximes and semicarbazones to carbonyl compounds in the presence of
aluminium chloride in solvent free conditions.96 This reagent was prepared by treating the
aqueous solution of 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride with CrO3 in
3N HCl at room temperature (Scheme1.29).
24
SR1 R2
+N+
N
Bu 2
Cr2O72- CH3CN
RefluxS
R1 R2
O
(Scheme1.28)
N
N
N
N
PhPhCl
CrO3 / 3N HCl
2
Cr2O72-
(Scheme1.29)
1.2.4 Oniums of phosphorus and tellurium with Cr(VI)
Some chromates and dichromates with other than nitrogen oniums like
phosphonium and telluronium were synthesized for specific oxidation reactions.
Benzyltriphenyl phosphonium chlorochromate (BTPPCC) prepared from aqueous
solution of chromium trioxide in 6N HCl and benzyl triphenyl phosphonium chloride97 is
insoluble in aqueous medium and soluble in organic solvents like acetonitrile, chloroform
and dichloromethane. It can selectively oxidize benzyl alcohol in presence of phenyl
ethanol, benzhydrol or methyl phenyl sulfide. The reactivity of this reagent in organic
solvent and under microwave irradiation without solvent was compared separately for the
oxidation of alcohol to corresponding aldehyde. The reagent was found to be suitable for
oxidation of sulfides to corresponding sulfoxides.98 Butyltriphenyl phosphonium
chlorochromate prepared as its chloro counter part was used for the transformation of
alcohol to corresponding carbonyl compounds.99
Mahammadpour-Baltrok et al. prepared butyltriphenylphosponium dichromate
(BTPPD) and applied this reagent for the oxidation of some hydroxy groups to
corresponding carbonyl compounds in homogeneous solution,100 thiones to
corresponding carbonyl compounds by microwave irradiation without any solvent,101
thiols to corresponding disulfides under microwave irradiation102 and sulfides to
25
sulfoxides and sulfones in presence of aluminium chloride in solution and under
microwave irradiation.103
The oxidation kinetics of substituted benzyl alcohols, -hydroxy acids and
aliphatic aldehydes by BTPPD were repoted by different workers.104,105 The kinetics of
oxidation of aliphatic aldehydes by BTPPD to corresponding carboxylic acid in DMSO
was found to be first order with respect to BTPPD and a Michaelis-Menten type kinetics
was observed with respect to the aldehyde.105 The oxidation of a series of nine α-amino
acids by BTPPD in glacial acetic acid in the presence of toluene p-sulphonic acid
(TsOH), resulted in the formation of corresponding aldimines.106 The reactions were of
first order with respect to BTPPD whereas the second order dependence was observed
with respect to each of the amino acids and hydrogen ion. The oxidation of
perdeuterioglycine exhibited the absence of a kinetic isotope effect (kH/kD = 1.01 at 308
K) indicating noninvolvement of C-H bond in the rate determining step. Recently the
kinetics of oxidation of some organic sulfides to corresponding sulfoxides107 and diols to
corresponding hydroxyaldehydes108 by BTPPD were reported. In both the cases the
reaction was found to be acid catalysed and first order with respect to BTPPD and second
order with respect to substrates and hydrogen ion. In oxidation of diols a substantial
kinetic isotope effect ( kH / kD > 6.0) supporting the reaction mechanism with breaking of
C-H bond in a slow step was observed.
Tetrabutylphosphonium dichromate (TBPDC) was found to be an efficient
oxidizing agent for the aromatization of various 1,4-dihydropyridines to corresponding
pyridine derivatives in acetonitrile and also under microwave irradiation.109 Similarly a
solid phase oxidation of benzylic alcohols to the corresponding aldehydes and ketones
was accomplished using triphenylmethylphosphonium dichromate (MTPPD) under
solvent-free conditions with high chemoselectivity.1(c)
Song2 prepared a novel oxidant i.e. benzyldimethyltelluronium dichromate by
adding an aqueous solution of potassium dichromate to an aqueous solution of
benzyldimethyltelluronium bromide at room temperature. The reagent is slightly soluble
in acetonitrile or dimethylformamide, air stable and effective after long storage times.
Oxidation of benzyl alcohol with benzyldimethyltelluronium dichromate in acetonitrile
26
affords benzaldehyde in high yield. The chemoselectivity of the oxidant is well evident
from the oxidation of 1-phenyl-1,3-propandiol (1.1) having a benzylic and a saturated
primary hydroxyl group to yield 3-hydroxy-1-phenyl-1 propanone (1.2) in 75% yield
without affecting the saturated primary hydroxy group (Scheme 1.30). Similarly,
compound (1.3) was also transformed into the corresponding hydroxy ketone (1.4) by the
same oxidant with 67% yield (Scheme 1.31).
HO OH HO O
[C6H5CH2Te(CH3)2]2Cr2O7
CH3CN, Reflux
1.1 1.2 (Scheme 1.30)
OH
OH
CH3CN, Reflux
[C6H5CH2Te(CH3)2]2Cr2O7 OH
O
1.41.3 (Scheme 1.31)
1.3 ALKYL AMMONIUM IONS AS CARRIERS OF Mn(VII) OXIDANTS
For the use of Mn(VII) as the oxidant for organic substrates in organic solvents,
crown ethers and onium ions as the carrier of oxidants have wide applications as phase
transfer catalysts.110 In nonpolar solvents, due to the amphipathic nature of the
tetraalkylammonium ions, quarternary ammonium permanganates are effective reagents
for the oxidation of organic substrates.111-13 However, many organic solvents are highly
sensitive to the oxidation potential of Mn(VII) and thus have limited use as solvents for
oxidation reaction.114-15 At high temperature, some quaternary salts explode due to self
oxidation. Mishra and Dash reported an appreciable rate of autooxidation of some
qutarenary ammonium permanganate in organic solvents.116
Tetraalkylammonium permanganates were formed by simple ion exchange in
tetraalkylammonium bromides and potassium permanganate in aqueous medium. These
reagents act as excellent phase-transfer oxidants for organic substrates in completely non-
27
polar organic solvents, such as benzene, dichloromethane, chloroform, carbon
tetrachloride, toluene, etc., and in completely anhydrous conditions. In some experiments,
the soluble permanganate salts were formed in phase-transfer processes and are utilized
in situ without isolation114,117 while, in other cases, the salts were first isolated and were
then dissolved in the desired solvents.111,118-121
Quaternary ammonium salts in aqueous medium dissociate to constituting ions,
while in organic solvents the salts exist in ion pairs.122 The probability of salts existing as
ion pairs is inversely dependent upon the distance between the centers of the two ions and
the dielectric constant of the solvents.77 From the 1H NMR spectral data, Lee et al.123
demonstrated that most quaternary ammonium permanganates exist as ion pairs in all
solvents, except in water. In less polar solvents, where theory predicts tighter ion pairs,77
the ions must be intimately associated, either in the ground state or in the transition state.
Moreover, close contact within the ion pair seems to increase the rate of reaction. For
example, the rate constants for the oxidation of methyl cinnamate by methyltri-n-
octylammonium permanganate are greater than that for tetra-n-octylammonium
permanganate, because the former allows a greater penetration of the anion into the
structure of the cation.122,124 It, therefore, appears that quaternary ammonium
permanganates may exist as solvent-separated ion pairs in acetone, but as intimate ion
pairs in toluene and dichloromethane.125
1.3.1 Oxidation of alkenes and their derivatives
In the advent of lipophilic characteristics of onium permanganate, the oxidation of
water insoluble organic substrates by Mn(VII) can be carried out smoothly in organic
solvents. Permanganate ion solubilized in benzene or dichloromethane by the use of
quaternary ammonium salts,126,127-29 dimethylpolyethylene glycol130 or cryptates131 was
successfully used for the oxidation in anhydrous conditions and, in some cases,132 no
precipitate of manganese dioxide was formed (e.g., reduction of permanganate). A
striking example is ‘purple benzene’, in which crown ethers can dissolve up to 0.06 M
KMnO4 in benzene.127 ‘Purple benzene’ can also be readily prepared by using
tetrabutylammonium bromide as the lipopathic carrier.133
28
In the pioneering work in phase transfer oxidation by Mn(VII), Weber and
Shepherd134 oxidized cyclohexene, cis-cyclooctene and trans-cyclooctene
stereospecifically to vicinal cis-diols by cold, dilute alkaline potassium permanganate in
the presence of a catalytic quantity of benzyltriethylammonium chloride in water-
dichloromethane mixture. Subsequently, Ogino and Mochizuki132 reported that KMnO4
solubilized in dichloromethane in the presence of an equimolar amount of
benzyltriethylammonium chloride readily oxidizes alkenes under anhydrous conditions.
Either 1,2-diols or aldehydes are obtained directly in good yields or by decomposition of
the reaction intermediates with an aqueous solution, depending upon pH without any
over-oxidation.
In an oxidation reaction of methyl (E)-cinnamate with quaternary ammonium
permanganates in methylene chloride solutions, Lee and Brown135 proposed that the
counter ion has a substantial effect on the rate of reaction i.e. the rate of reaction is fastest
for those in which the inter ionic distance in the quaternary ammonium ion pair is
minimum. This observation also supports the existence of ion pairs in nonaqueous
solution.77 For symmetrical tetraalkylammonium ions, there is an inverse relationship
between the second-order rate constants and the radius of the cation.124 Since the ion-
pairing stability is inversely dependent upon the inter ionic distance between the centers
of positive and negative charge, the transition state must form a tighter ion pair than the
ground state, i.e., the transition state must derive more stability from close association
with the cation than does the ground state. This observation is in consistent with the
proposed mechanism ( Scheme 1.32) where, in the ground state, the charge is spread over
the four permanganate oxygens including the oxygen atoms of the ,β-unsaturated
carbonyl groups of the substrate, while the transition state is a more localized enolate ion.
Since the interaction with the quaternary ammonium ion would be stronger for the
structure in which there is greater localization of the negative charge, it follows that the
transition state would benefit more from an interaction with the cation. Hence, smaller
cations would promote a faster reaction.
29
Ph
C
O
OMe
MnO4-
+ Ph
C
O
OMe
MnOO
O-
Oslow
C
O-
OMe
MnO
O
Ph
O
O
C
O
OMe
MnO
O
Ph
O
O O OMn
O-O
Ph C
O
OMe
(Scheme 1.32)
The introduction of substituents into the aromatic ring of the substrate also causes
marked changes in the rate of reaction with the Hammett p value being 0.95. The
Hammett plot for the oxidation of a series of substituted stilbenes reported earlier136 was
found to be concave upward. A positive slope is observed when electron-withdrawing
substituents are present and a negative slope for electron-donating substituents. A
concave upward Hammett plot for the oxidation of methyl cinnamates by
tetrabutylammonium permanganate in dichloromethane is indicative of a change in
reaction mechanism.137 Apparently the reaction can proceed via an electron-deficient or
an electron-rich transition state, depending on the demand of the substituents. With
electron-withdrawing substituents the reaction proceeds (Scheme 1.32) along a profile
that takes advantage of the ability of these groups to delocalize negative charges.
Conversely, when electron-donating substituents are present, carbocation-like transition
states can be stabilized (Scheme 1.33).
R
O Me
MnO4-
+ R
O Me
MnOO
O-
Oslow
O Me
MnO
O
R
-O
O-
O Me
MnO
O
R
-O
O- O OMn
O-O
R O Me
1.5
(Scheme 1.33)
30
A comparison of Schemes 1.32 and 1.33 indicates that both reactions proceed
through the same organometallic intermediate, but via different transition states, to the
cyclic diester (1.5). The principal difference in the transition states is associated with the
timing of the reduction of Mn(VII); in Scheme 1.32 the reduction occurs after the
transition state is achieved, while, in Scheme 1.33 the reduction occurs during the
formation of the transition state. When styrene derivatives were oxidized by quaternary
ammonium or phosphonium permanganates in a polar organic solvent, such as acetone,
the substituents have little or no effect on the rate of reaction.123 In less polar solvents,
such as dichloromethane or toluene, the rates of the reaction are, however, dependent
upon the nature of the quaternary ammonium or phosphonium ions.
Lee and Perez-Benito138 detected autocatalysis during the reaction of methyltributylammonium permanganate with 1-tetradecene in dichloromethane (Scheme 1.34).
C C C C C COHHO
+ Q+MnO4-
O OMn
O O-Q+
H+ + MnO2
(Scheme 1.34)
Manganate(V) diesters formed during the reaction is reduced to colloidal MnO2,
which was supported from the linear plot of the logarithm of the absorption of the
product against the logarithm of the wavelength.139 The autocatalytic nature of the
reaction was also attributed to the colloidal MnO2, that provides a surface on which the
catalyzed reaction takes place. Many workers have previously detected soluble colloidal
MnO2 as the inorganic product during the oxidation of alkenes.140-142
A self-oxidation process was proposed by Dash and Mishra116 in case of
cetyltrimethyl-ammonium permanganate(CTAP) used in a chloroform medium. Since
CTAP exists as a tight ion pair in chloroform medium, the permanganate ion easily
abstracts a proton from the β-carbon atom of the cetyl chain, thereby producing
pentadecanal. The mechanism of the self-oxidation process was proposed with supporting
31
evidences (Scheme 1.35). It was observed that with an increase in the polarity of the
solvent medium, the rate of self-oxidation increases.
Additional evidence in support of the existence of ion pairs was obtained from a
consideration of the effect of substituents on the rate of reaction.143 The Hammett ρ value
for the oxidation of substituted methyl cinnamates by tetrabutylammonium permanganate
is greater in acetone (ρ=1.43) than in dichloromethane (ρ=0.95). Since the ρ values are
positive, the reaction centre has more electron density in the transition state than the
ground state.
MnO
O
O
O-
Me (CH2)13 C C N Me
Me
Me
H
H
H
H
MnO
O
O
O
H NMe3:
Me (CH2)13 CH
CH2
Me (CH2)13 CH
CH2
slow
O OMn
-O O
Me (CH2)13 CHO +MnO2- HNMe3
+ CH2O++
HNMe3
(Scheme 1.35)
This indication of an electron-rich transition state leads to a reasonable
proposition that the rate limiting step may involve a heterolytic cleavage of the carbon–
manganese bond to give an enolate-like transition state (Scheme 1.36). It is assumed that
the proximity of the quaternary ammonium ion would increase the stability of the
32
transition state in non-polar solvents, but that this effect would be less in more polar
solvents (such as acetone), where the cation could have a conducive solvation cell.
C CC OMe
O
+Q+MnO4
-
C CC OMe
O
MnO
OO
OQ
C CC OMe
O
O MnQ+O-
O
O
C CC OMe
O Mn
O
OO
O
Q+C CC OMe
O O
O
Mn
O-Q+O 1.6
(Scheme 1.36)
Although there is good evidence that 1.6 is an intermediate in these reactions, the
yellow-brown product contains manganese in the +4 and not in the +5 oxidation state.
Hence, 1.6 appears to be a very reactive intermediate, rapidly undergoing a one-electron
reduction, possibly by abstraction of a hydrogen atom from a molecule of solvent
(Scheme 1.37). The product of this reaction would be a manganese(IV) cyclic diester 1.7,
which would decompose to a diol anion and manganese dioxide.
C C C COQHOO O
MnHO OQ
CH2Cl2 + MnO2C CO O
MnO OQ
1.7 (Scheme 1.37)
Oxidation of unsaturated carboxylic acids in non-aqueous solvents by
methyltributylammonium permanganate144 differs, in several ways, both from the
corresponding aqueous-phase oxidations145 and from the oxidation of unsaturated
esters.146 A Mn(III) species is found to be the final product of the reduction of
33
permanganate by unsaturated acids in dichloromethane. The second-order rate constants
for the oxidation of a series of meta- and para-substituted cinnamic acids exhibit a linear
Hammett correlation with a positive slope, indicative of an electron-rich transition state.
A similar result was previously reported for the oxidation of the corresponding methyl
esters under comparable conditions.135 In these reports, the authors suggested a reaction
sequence where the cleavage of a carbon–manganese bond is rate limiting. Since the
Hammett ρ value is positive, it is apparent that the rate-limiting step must proceed with
the development of a negative charge on the -carbon (Scheme 1.38).
HO Mn
OQO
H
Ph
O
O
OHH
OMn
O
H
Ph
O
O
OH
QO
HO
Mn
O
H
Ph
O
OH
QO
#
O
(Scheme 1.38)
The catalytic activity is due to the formation of a powerful oxidant HMnO4
(Scheme 1.39) .147
QMnO4 + RCOOH HMnO4 + RCOO-Q+
(Scheme 1.39)
The involvement of the reaction sequence shown in Scheme 1.40 accounts for the
decrease in the rate observed, when tetrabutylammonium acetate is added to the reaction
mixture while other quaternary ammonium salts such as tetrabutylammonium perchlorate
do not affect the rate, thus eliminating the possibility of ascribing the suppression in rate
caused by the quaternary ammonium acetate to a salt effect.
HO Mn
OQO
H
Ph
O
O
OHH
O Mn
OQO
H
Ph
O
OH
OH+ RCO2H + RCO2
-
(Scheme 1.40)
In this study, the formation of free radicals has been proposed for the reduction of
the reactive manganese(V) diester to manganese(III) (Scheme 1.41).
34
2CH2Cl2
C CO O
MnO OQ
+ MnO2QC C
OH OH
2 CHCl2+.
+
(Scheme 1.41)
Oxidations of some monochromophoric styrylpyridinium dyes were carried out in
chloroform medium using CTAP and the results were compared with the oxidation of the
same substrate using KMnO4 in acid medium.81 CTAP forms a tight ion pair in non-polar
medium and, because the substrate is also charged, both hydrophobic interaction and
electrostatic effect bring the reactant and the substrate into proximity, thereby facilitating
the reaction. A negative ρ value (-0.21) indicates the presence of an electron-deficient
center in the substrate. A mechanism consistent with these observations was proposed
(Scheme 1.42).
NBr-
R
X MnO O-
O O
NBr-
R
XMn
O O-
O O
NBr-
R
XMn
O O-
O ON
X
CHO
R
CHO
MnO2
Br-
++
(Scheme 1.42)
The oxidation of some substituted alkyl cinnamates148 containing trans-double
bonds was carried out using CTAP in chloroform medium. Electron-donating groups
retard the rate of reaction, whereas the electron-withdrawing groups enhance the rate. The
Hammett plot was found to be non-linear with a positive deviation from linearity. Due to
the presence of the CTA+ ion, the transition state with a negative charge was found to be
more approprite (Scheme 1.43).
During the oxidation of styrylpyridinium dyes and alkyl cinnamates, which
contain trans-double bonds, bond breaking was observed, leading to the formation of
35
carbonyl compounds. In the case of some compounds containing cis-double bonds, e.g.,
cyclohexene, maleic anhydride and cholesterol149 the products were found to be
corresponding diols (Schemes 1.44–1.46)
X
COOR
H
+
MnO
O
O-
OX
COOR
H
H
MnO
O
O
OX
COOR
H
H
MnO
O
O
OX
COOR
H
H CTA+ CTA+
Mn
-O
O
O
OX
COOR
H
H
XCHO
+ + MnO2- + CTA+
2 1CTA+MnO4-
OHC-COOR
. (Scheme 1.43)
CHOCHO
OH
OH
Mn
O
MnO2MnO2
-+ +
O
OMn
-O
O
OO
O-Mn
OO
O-O+
(Scheme 1.44)
OO
MnO
O
O
O
O
O-
OH
OH
O
O
MnO2-O
O
O
MnO
O-
O
O+ +
(Scheme 1.45)
36
HO HO HOOH
OHOO
MnO-O
MnO2-+
(Scheme 1.46)
CTAP was used successfully for the cis dihydroxylation of the spiro fused
dihydropyran ring of 1.8 to afford 1.9, an analog of antibiotic, griseusin A (Scheme
1.47).150
O
O
OO
O
O
Me
O
HO
HO
Me
1.8 1.9 (Scheme 1.47)
Treatment of a tricyclic rigid diene (1.10) with one equivalent of
triethylbenzylamm onium permanganate at low temperature (-50oC) followed by
quenching with aqueous sodium hydroxide afforded the diol 1.11 (70%) together with the
diol epoxide 1.12 (20%).151 With increase in temperature, yield of diol decreases with
formation of dialdehyde. The unexpect- ed formation of 1.12 can be rationalized by a
mechanism depicted in (Scheme 1.48). The cyclic manganese (V) diester 1.13, formed by
the attack of the permanganate on the most reactive double bond, decomposes into diol
1.14 or epoxy-diol 1.12 through two different reduction processes: one electron reduction
by reaction with the solvent to give the Mn(IV) diester 1.14 (path a) or an intramolecular
oxygen transfer to the other double bond which lies in close proximity to the manganese
centre (path b).
From CPK models and molecular minimization of the intermediate 1.13, it was
found that the tetrahedral manganese (V) centre places the metal oxo double bond nearly
parallel to the isopropylidene group making unlikely an orthogonal approach of both
centres to form a charge-transfer complex or to produce a concerted “oxene” insertion.
On the other hand, the parallel orientation of both oxo-metal double bond and alkene
37
favours the reversible formation of a highly strained metallooxetane intermediate 1.15,
which irreversibly rearranges to the epoxide following two possible different routes: (i)
direct carbon migration from manganese to oxygen atom, or (ii) homolytic cleavage of
the manganese-carbon bond to give the stabilized radical intermediate 1.16 which
collapses to the epoxide. Basic hydrolysis of the epoxide–manganese (III) diester 1.17
affords the epoxide-diol 1.12. The absence of rearrangement compounds supports the
idea of a direct rearrangement but the other possibility cannot be excluded.
RR
PGO
O
HOHO
PGOR= OH
OO
MnO
QOO
OMn
HO
QO
OO
MnO
QO OO
MnO
QO
OO
QOMn
O
+
a
b
NaOH
1.11 1.12
1.13 1.14
ii
1.15 1.16
i
1.17
1.12
PGO= OSiMe2tBu
1.10
1.11
..
(Scheme 1.48)
The oxidation of polypropylene homopolymer film and powder (film grade) in
presence of an aqueous solution of phenyltrimethylammonium permanganate (Ph.TMAP)
at room temperature resulted in the formation of polar groups (such as, alcoholic,
38
hydroperoxide, etc.) like carboxylate ions and quaternary ammonium hydroxides
liberating MnO2 as a by-product.152
Unsaturated methyl esters of Blighia unijugata which had previously been
subjected to urea adduct complexation was used to synthesize methyl 9, 10-
dihydroxyoctadecanoate via hydroxylation in the presence of cetyltrimethylammonium
permanganate (CTAP) in solvent free condition.153
1.3.2 Oxidation of other functionalities
Permanganate has been widely used as a strong, easily handled, readily available
and versatile oxidant that reacts with alcohols, alkenes, aldehydes, saturated C–H bonds
and other functionalities. 154-58 The lack of selectivity of permanganate is due, at least in
part, to its ability to react readily by either one- or two electron pathways, and its
conversion into even stronger oxidants such as MnO3+.158c The reaction pathway is
influenced by solvent, pH, substrate and other variables, thus complicating the
mechanistic understanding.
The use of organic solvents allows the substrate and solvent to be in the same
phase and avoids some of the complications of aqueous permanganate reactions, such as
decomposition at high pH,159 autocatalysis at low pH,160 involvement of water in the rate
determining step161 and limited solubility of the organic substrates of interest.162
Permanganate can be solubilised in organic solvents in presence of phase transferring
agents like quaternary ammonium ions.
Alkylammonium permanganates have been found to oxidize C-H bonds in
organic solvents.111,118,120 Tetraethyl, tetrabuty and benzyl(triethyl)ammonium
permanganate and methyl-(triphenyl) phosphonium permanganate are found to be about
equally effective as oxidants for the conversion of alkanes into alcohol and ketones.120
In the oxidation of aryl alkanes such as toluene, ethylbenzene, diphenylmethane,
triphenylmethane, 9,10-dihydroanthracene, xanthenes and fluorene by tetrabutyl
ammonium permanganate, toluene is oxidized to benzoic acid and a small amount of
benzaldehyde where as other substrates give carbonyl compounds and/or dehydrogenated
products.163 The manganese product of all of the reactions is colloidal MnO2. The
39
reactions of toluene and dihydroanthracene exhibit primary isotope effects: kC7H8/kC7D8 =
6.0 (±1.0) at 45 °C and kC14H12/kC14D12 = 3.0 (±0.6) at 25 °C indicating the first step in
these reactions to be the abstraction of a hydrogen atom by permanganate (Scheme 1.49).
The occurrence of these reactions is a direct result of the strength of the O–H bond
formed on addition of a hydrogen atom to the oxidant.161,164
CH3 C CH2H
HH
O MnO3-
HOMnO3-MnO4
- + +
#.
(Scheme 1.49)
Holba et al. reported the oxidation kinetics of C4–C10 aliphatic aldehydes by
quaternary ammonium permanganates, R4NMnO4 (R=Et, Bu, Oct), in DCM with special
regard to the colloidal Mn (IV) intermediate.165 Dynamic light scattering measurements
showed that colloidal particles appeared at the beginning of the reactions, their
dimensions being around 250 nm and having differing polydispersity, which was the
largest for the reaction mixture with tetraethylammonium permanganate. The stability of
the systems was directly proportional to the alkyl chain length of the tetraalkylammonium
permanganate used. The absorption spectrum recorded at the end of the reactions (after
complete permanganate consumption) showed a uniform increase of absorbance with
decreasing wavelength, which is consistent with the Rayleigh law for light scattering.139-
40
Additional evidence for the colloidal nature of the brown-yellow intermediate of
the permanganate reduction was obtained from simultaneous monitoring of the reacting
solution at two wavelengths, 418 and 526 nm. Permanganate exhibits its highest
absorbance peak at 526 nm, whereas it is almost transparent at 418 nm. As a result it has
been shown that the relationship presented in Eq. 1.1 is valid:145, 166,143
A(526) = εR526pCo – [(εR
526 – εP526) / εP
418]A(418) (1.1)
where p is the optical pathlength, Co is the initial permanganate concentration and εR and
εP are the extinction coefficients of the reactant (permanganate) and the product (colloidal
MnO2), respectively.
40
The A(526) versus A(418) plots based on Eq. 1.1 are very useful in kinetic
experiments when colloidal MnO2 is (i) behaving as a stable species, (ii) being reduced to
Mn(II) and (iii) coagulating.167 In the case of (i), Eq. 1.1 leads to a linear relationship
between A(526) and A(418), in the case (ii) it provides a plot showing a concave-
downward curvature and in the case (iii), the A(526) versus A(418) relationship leads to a
plot showing a concave-upward curvature.
In the oxidation of benzaldehyde by quaternary ammonium permanganates in
dichloromethane,168 the rate of the oxidation by CTAP was found to be much greater than
the rates of the oxidation with other ammonium permanganates (ethyl, 1-propyl, 1-butyl,
1-pentyl, 1-octyl) which may be rationalised to its self oxidation as reported earlier.116
Oxidation of 4-halo-2-nitrotoluene with tetrabutylammonium permanganate in
pyridine was found to be an efficient method to synthesize 4-halo-2-nitrobenzoic acid.169
A significant induction period was observed at room temperature, the cause of which is
unclear, and the vigorous exothermic reaction leads to the risk of a run-away reaction.
But by control feeding cold tetrabutylammonium permanganate into the reaction mixture
at 60oC, the initiation process is managed and the reaction is safely performed on a
multigram scale (Scheme 1.50).
NO2 X NO2
OH
O
XX= Br, I
[Ox]
(Scheme 1.50)
Srinivasan and Ramadas170 synthesized trisubstituted guanidines in excellent
yields from 1,3-diarylthioureas using quaternaryammonium permanganates in the
presence of an amine in THF (Scheme 1.51). This proposed scheme was preferred since
the sulfonyl group is reported to be displaced about 15 times faster than the
corresponding S-alkylated species in the case of monosubstituted thioureas.171 From a
comparative study using benzyltriethylammonium permanganate(BTEAP), CTAP and
tetrabutylammonium permanganate on several thioureas and amines it was found that
BTEAP is better oxidant than the other two oxidants because of its stability, shock-
resistant and decomposition above 100°C. CTAP furnished poor results and the product
41
isolation was rendered difficult due to foaming during the follow-up action in aqueous
medium.
RHN
HN
RR
HN N
R RHN N
R
SSOxH N
R1 R2
R1R2NHTHF / PhCH2N+(C2H5)3MnO4- ,
(5-10oC), 30 min.
R1R2NH
( x= 2 or 3)(oxidised thiourea)
(Scheme 1.51)
Recently oxidation of olefifns to diols and regeneration of aldehydes and ketones
from oximes using CTAP in solvent free condition was reported by Vimala and
Nagendrappa.92 The oxidation was achieved in solvent-free processes without using any
eco-risky organic solvents. An important observation that is worth noting was that the
success of the CTAP reaction depends on the presence of a little water which seems to be
required for the hydrolysis of the intermediate olefin– MnO4 adduct (Scheme 1.52).
+ +
MnOOOO-
nn
OHHO
n
MnO4- H2O MnO3
-
NOH + O
MnO
OOO-
MnO4- N OH
H2OHNO2 MnO2++
(Scheme 1.52)
While investigating the kinetics of oxidation of substituted benzylamines to
corresponding aldimines by CTAP Shukla et al. observed that the reaction was first order
with respect to both amine and CTAP. Oxidation of deuteriated benzylamine
(PhCD2NH2) exhibited a substantial kinetic isotope effect (kH/kD = 5.60 at 293 K)
confirming the cleavage of an -C–H bond in the rate determining step. The oxidation
exhibited an extensive cross-conjugation, in the transition state, between the electron-
donating substituents and the reaction centre. A mechanism involving a hydride-ion
transfer from the amine to CTAP in the rate-determining step has been proposed
(Scheme 1.53).172
42
(Scheme 1.53)
Octahedral MnO nanocrystals and carbon core–shell nanoparticles coated MnO
(MnO–C) can be synthesized by a single-step direct pyrolysis of CTAP in specially
made Let-lock union cells.173 The core–shell particles were observed only when the core
size is smaller than 150 nm. The shape of the nanocrystals was controlled by varying
reaction temperature and duration. When the temperature was increased from 600 to
800oC, the octahedral MnO crystals without any carbon shell were obtained. By
controlling the reaction parameters, it was possible to obtain naked MnO octahedral
shapes and also core-shell nanoparticles exclusively. The electrocatalytic activities of the
MnO nanocrystals for the oxygen reduction reaction in an aqueous basic medium were
found to be higher than that of bulk MnO.
1.4 ALKYL AMMONIUM IONS AS CARRIERS OF Ce(IV) OXIDANTS Literature on onium ions with ceric ammonium nitrate (CAN) as the counterion is
sparse. Dehmlow, is probably, the pioneer in this area by synthesizing tetrabutyl
ammonium cerate to be used in oxidation of organic substrates.174 This onium is
incapable of forming micellar aggregation. As cetyltrimethylammonium ion has a
balanced hydrophilicity and lipophilicity and can form various organized assemblies like
micelles, reversed micelles, microemulsions etc., it has been used as the counterion of
cerric nitrate. The oxidant cetyltrimethylammonium ceric nitrate (CTACN), was
synthesized by stirring CTAB with cerricammonium nitrate in aqueous medium82 and
used for the oxidation of alcohols.175 CTACN is sparingly soluble in water and in many
polar organic solvents, and insoluble in non-polar solvents like hexane, benzene and
toluene. Above critical concentration it forms micelle in aqueous medium. The change in
CMC due to temperature monitored by conductance method supports a temperature
induced micellization.176 CTACN exists as tight ion pairs forming stable monolayer at the
43
air-water interface and the monolayer spreading of CTACN at air/ water interface gives a
surface area/molecule value of 45Ao2.85 The products of oxidation of alcohols with
CTACN were found to be the corresponding carbonyl compounds. The stoichiometry of
the reaction was found to be 2:1 for Ce(IV) and substrate. The decrease in the rate of
oxidation with increased concentration of CTACN in organic media was attributed to the
formation of reversed micelles by the oxidant in organic medium. An asymptotic
decrease in rate with increase in [CTAB] supports the reversed micellization. The plots of
rate constants with [substrate] reflect the partitioning of the substrate into the reversed
micellar system of CTACN. The kinetic isotope effect (kH/kD) of 1.97 was attributed to
the dehydrogenation mechanism for the oxidation of alcohols.175
Cetyldimethylbenzylammonium ceric nitrate (CDBACN) which was synthesized
from cetyldimethylbenzylammonium chloride and ammonium ceric nitrate was used for
the oxidation of different alcohols.177 It was found to be soluble in water, polar and
nonpolar organic solvents like benzene. CTACN and CDBACN were also used for
oxidative deoximation of oximes to corresponding carbonyl compounds.178 Of the two
phase transfer oxidants CTACN was found to be more efficient than that of CDBACN in
their reactivities. Further the presence of other functional groups influences the reaction
rate. In case of benzophenone oximes the substrates bearing electron withdrawing groups
require longer reaction time than those bearing electron donating groups (Scheme 1.54).
C N C OR1
R2
R1
R2
OH
CDBACN/Solvent
CTACN/Solvent
(Scheme 1.54) From the rate constant values of oxidation of methyl acetoacetate, 1,3-
cyclohexanedione and (trimethylsiloxyl)-3-pentene-2-one by CAN and ceric
tetrabutylammonium nitrate (CTABN) Zhang and Flowers observed that the silyl enol
ether and the 1,3-diketone are oxidized by Ce4+ at a significantly faster rate than the -
keto ester.179 Enols and enol ethers are known to be oxidized more readily than the
corresponding -dicarbonyls. 180 Interestingly, the rates of oxidation of substrates by
CAN and CTBAN are different even though their thermodynamic redox potentials are the
44
same. The bimolecular rate constants for the oxidation of all substrates by CAN are
approximately 2 to 3 times faster than oxidation by CTBAN. This finding suggests that
the relatively large tetrabutylammonium counterion of CTBAN may be associated with
the cerium complex to some extent, thus affecting the oxidation of substrates through
steric interactions. The replacement of the ammonium cation of CAN with
tetrabutylammonium has a modest impact on the rate of oxidation of all substrates
examined in this study.
1.5 ALKYL AMMONIUM IONS AS CARRIERS OF Ru(VII) OXIDANTS
Tetrapropylammonium (TPA) ion seems to be the only quaternary ammonium salt
reported till date, for the use of Ru(VII) as the oxidant in organic solvents. Griffith and
co-workers are the pioneers in the synthesis and use of quarternary ammonium
perruthenate as oxidant.181-183 They prepared the oxidant by dissolution of K[RuO4] in
water at low temperature followed by addition of tetra-alkyl ammonium hydroxide in
aqueous solution. In an alternative method hydrated ruthenium trichloride and sodium
periodate were stirred overnight in water generating RuO4 in situ, which were transferred
in an oxygen atmosphere into an aqueous solution of tetra-n-propylammonium
hydroxide in presence of sodium hydroxide at 0-5oC. In a one pot synthesis, RuCl3 nH2O
was oxidized with excess sodium bromate (NaBrO3) in molar aqueous carbonate to
[RuO4]–, followed by addition of (Pr4N)OH to afford TPAP as dark green crystals. The
catalytic and chemoselective reagent TPAP is highly effective with N-methylmorpholine-
N-oxide (NMO) as a cooxidant. The oxidations using this reagent proceed rapidly (0.2-6
h) at room temperature in dichloromethane using less than 0.5 mole % of catalyst. The
chemoselectivity is well-judged from the oxidation reactions of alcohols with other easily
oxidizable functional groups like epoxides, tetrahydropyranyl ethers, silyl ethers, esters,
double bonds, indoles, amides, lactones, amines, etc. The alcohols are oxidized to
corresponding carbonyl compounds, while the other groups remain unaffected. Further,
the chiral groups adjacent to reaction centres are also found to be unchanged. Primary
alcohols are more readily oxidized by TPAP than secondary alcohols, although the latter
can be selectively oxidized in the presence of other functionalities. 182
45
For example, the alcohol function of decaline 1.18 was chemoselectively oxidized
in the presence of a double bond and of a silyl protecting group (Scheme 1.55). 184 The
open-chain alcohol 1.20 was chemoselectively oxidized in the presence of an epoxide.185
Alcohol 1.22 was oxidized in good yield in the presence of a highly unsaturated ester and
an epoxide function.185 Both the primary and the secondary alcohol groups of steroid 1.24
were oxidized by TPAP.186
The use of the finely ground version of molecular sieves (4 Å) greatly improves
the rate and the efficiency of the oxidation reactions181 and dichoromethane is mostly
used as the solvent. However, in some cases better catalytic turnovers are observed when
acetonitrile or acetonitrile / dichloromethane mixtures are used. The efficient aerobic
oxidation of primary and secondary alcohols using catalytic amounts of TPAP was also
reported.187
O
OH
HO
O
TPAP55%
1.24 1.25
O CO2CHPh2O
HO CO2CHPh2O
TPAP78%
1.22
1.23
OH
OTBDSO TPAP
70%
O
OTBDSO
1.20 1.21
H
R
OSDBTOH
H
R
OSDBTO
Pr4NRuO4(TPAP)85%
1.18 1.19
(Scheme 1.55)
A polymer supported perruthenate (PSP) used as a reusable oxidant for alcohols
as the substrate was obtained by adding Amberlyst anion exchange resin (IR 27)
46
containing quaternary ammonium groups, to an aqueous solution of powdered potassium
perruthenate under ultrasonic condition. 188 The reagent was used in a stoichiometric
amount of 20 mol% for the oxidation of primary and secondary alcohols using NMO or
trimethylamine N-oxide (TMAO) as the co-oxidant. (Scheme 1.56).189
R OH R OR = aryl, alkyl, alkenyl
(PSP)
O2, 75-85 oC, 0.5-8 hToluene, 56-95 %
PSP= Polymer- supported Perruthanate
NMe3+RuO4
-
(Scheme 1.56)
During the synthesis of isoxazolines, PSP was used for the synthesis of the
precursors by oxidizing alcohols to the corresponding aldehydes, which were further
converted to corresponding hydroxylamines (Scheme 1.57). This hydroxylamine was
oxidized by PSP into the nitrone, which on subsequent [3+2] cycloaddition reaction led
to obtain the desired product.190 The use of polymer-supported reagents helped in
obtaining the products in pure form. Owing to the high chemoselectivity of the
perruthenate oxidant the transformations are possible in the presence of other functional
groups. For example, the tertiary amine functionality and the pyridine moiety in a
piperazine derivative were inert under the reaction conditions (Scheme 1.58).
Ar OH Ar ONMe3
+RuO4-
CHCl3NMe3
+OAc-
MeNHOH.HCl
NMe3+RuO4
-
CHCl3Ar N
OH
CH3
Ar NO-
CH3
60oC, CHCl3(one-pot)
(55-91 %)N
O
CO2Me
H3C ArCO2Me
(Scheme 1.57)
47
N N
N
CHCl389%
1) PSP, CHCl32) H2C=CHCO2Me
F3C Cl
OH
N N
N
F3C Cl
CO2MeO
(Scheme 1.58)
During the synthesis of 5-dihydrotestosterone (DHT) starting from 3β-hydroxy-
5-androstan -17-one, TPAP/NMO was used as a mild oxidizing agent in the synthesis
of a key intermediate, 17β-[(tert-butyldimethylsilyl)oxy]-5-androstan-3-one.191
It was reported that organically modified silica gels doped with TPAP are
recyclable heterogeneous catalysts for the aerobic oxidation of alcohols with a
remarkable hydrophobic effect.192 Similarly the use of tetraalkylammonium salts or
imidazolium ionic liquids in catalytic oxidations of alcohols with TPAP allows recovery
and reuse of the oxidant.193 Both tetraethylammonium bromide and 1-ethyl-3-methyl-
1H-imidazolium hexafluorophosphate [emim][PF6] can be used to enable the recovery
and reuse of TPAP in oxidation of benzyl alcohol.
TPAP- doped organically modified silica gels are effective catalysts for the
oxidation of alcohols by hydrogen peroxide at room temperature, provided that the
oxidant H2O2 solution is added slowly.194 The effect of the surface catalyst polarity is the
opposite of that found in aerobic alcohols oxidation and is consistent with the polar
nature of the H2O2 primary oxidant.
A convenient sequential TPAP oxidation–Wittig olefination protocol using
phosphonium salts as olefin source was proved to be efficient for a wide range of
alcohols, including aromatic, aliphatic, heterocyclic, secondary, and chiral alcohols, with
both stabilised and nonstabilized Wittig reagents to synthesize methylenes, ethylenes,
vinyl halides and esters (Scheme 1.59).195
R OH RR'
1) TPAP, NMO, CH2Cl2, 4 AMS
R' = H, Me, Cl, Br, CO2EtX = Cl, Br
, n BuLi, THFX-Ph3P+
R'
2)
(Scheme 1.59)
48
Chandler et al.196 carried out the oxidation kinetics of 2-propanol by TPAP in a
reaction that is second order in TPAP and first order in 2-propanol. The reaction was
found to be autocatalytic due to the generation of ruthenium dioxide. Substituents do not
have any effect on the rate of oxidation. Primary kinetic deuterium isotope effects were
observed when either the hydroxyl or the α hydrogen was replaced by deuterium. The
authors proposed a reaction mechanism wherein a perruthenate ester was formed at the
initial step (Scheme 1.60).
C
R
H
R O
H
Ru
O
OO OQ
: :k1
k2
k3
k-2
k-1C
R
H
R O Ru
O
OO OQ
H
Ru
O
O O
H
Ru
O
OO OQ
: :
O OQC
R
R
H
Ru
O
O O Ru
O
OO OQO OQ
C
R
R
H
H
Ru
O
O O Ru
O
OO OQO OQ
C
R
R
H
H
Ru
O
O O Ru
O
OO OQO OQ
C
R
R
H
H
+
(Scheme 1.60)
A mobile microreactor system for the catalytic oxidation of benzyl alcohol to
benzaldehyde by TPAP with NMO in the liquid phase under stop-flow mode and on
supported TPAP with oxygen under continuous flow mode was reported by Cao et al.197
(Scheme 1.61). The benefits of the technique include flow and reaction temperature
control to suit the different requirements of synthetic reactions and safe operation of
reactions involving oxygen at elevated reaction temperatures.
OH O
H
TPAP / NMOAcetonitrile, rt
OH O
H
TPAP / Al2O3
Mesitylene, 75oC
(Scheme 1.61)
49
Fluorinated organo-silica gels doped with TPAP are excellent catalysts for the
aerobic oxidative dehydrogenation of alcohols in supercritical CO2 (scCO2).198 It was
found that the hydrophilic–lipophilic balance (HLB) of the sol–gel matrices is a true
structural parameter, dictating reactivity for the oxidative dehydrogenation taking place
within the sol–gel cages. The reagents are polar and activity increases with increasing
HLB. For reactions in scCO2 within very hydrophobic matrices, diffusion is a very fast
process and the reaction, which occurs due to reagents-matrix interaction at the pores’
surface (the sol–gel cages) becomes the controlling step.
Recently, Schmidt and Stark developed a mild protocol for the TPAP catalyzed
direct oxidation of primary alcohols to carboxylic acids with excess of NMO.H2O.199 The
reaction pathway involves two oxidative steps proceeding via similar intermediates,
Ru(VII) esters A and B (Scheme 1.62). The key feature of this method is the stabilization
of the intermediate aldehyde hydrate which was accomplished by using an excess of
NMO containing one equivalent of water of crystallization. The hydration experiments
support the assumption that NMO.H2O not only serves as the co-oxidant but also, and
uniquely, stabilizes the aldehyde hydrate. This stabilization occurs through hydrogen-
bonding between the geminal diol and the Lewis basic oxygen of the N-oxide (Figure
1.3).200
OH
HHR
N+O
H2O
RuO4-
-OH-
-RuO3-H
HR
RuO
O
OO
A B-RuO3
-
HHR
RuO
O
OO
-OH-
HO
OH
HRO-
O
HR
O
OHR
(Scheme 1.62)
N+O
O
OR
O-H
H
N+O
O
OR
O-H
H N+
O
O-
Figure 1.3: Possible models of hydrate stabilization by NMO
50
On the basis of these findings authors subsequently investigated the potential of
TPAP and the hydrate of stabilisation concept for direct conversion of vicinal diols to
corresponding (di) acids or keto acids.201 The same effect was found to be operative in
converting initial shunt products such as hydroxyl ketones or diketones to the desired
acids. The protocol for diol oxidation was most operative in solvent like acetonitrile or
dichloromethane. The products were obtained as free acids or after treatment with TMS-
diazomethane as the resulting methyl esters. This mild reaction protocol is applicable to a
wide range of substrates providing the respective acids, diacids (or diesters), or keto acids
in good to high yields. Under the standard conditions many functional as well as
protecting groups such as ethers, silyl ethers, ketals, esters, and remote tertiary alcohols
are tolerated and potentially labile stereocenters remain intact.
The proposed mechanism involves initial formation of a cyclic perruthenate
diester (C)202 which then dissipates to give the corresponding carbonyl compounds
(Scheme 1.62). Hydration of the latter and subsequent oxidation give the desired
carboxylic acid (or diacid). Alternatively, the diol is first oxidized to the hydroxy ketone
(or diketone) which, after hydration, could also form a cyclic perruthenate diester (D).
The oxidative fragmentation of this Ru(VII) diester would result in a carboxylic acid (two
carboxylic acids in the case of a diketone precursor) and an aldehyde which could then be
oxidized further.199 In any of the cases, the success of the overall process is strongly
dependent on the efficiency of the hydrate formation. Both the tertiary hydroxy ketone
1.26 and the diketone 1.27 underwent smooth conversion to the corresponding acids
(Scheme 1.64).
51
R'
HO OH
R
HO OH
R H
HO O
R'R
O O
R'R
R H
O
RuO O-O
H R'
ORuO4
-
H2O
(D)
R'
O O
R
RuO O-O
R'
O O
ROH
RuO4-
RuO4-
H2O
HO OH
H R'
R H
O
HO R'
O
H R'
O+
+
+
+
or
R'
HO OH
ROH
R OH
O
RuO4-
H2O,
(C)
(Scheme 1.63)
O
O
CO2H TPAP (20 mol % )NMO.H2O ( 20 equiv)
CH2Cl2 ( 0.1 M) 0 oC-rt
77%
65%
TPAP (20 mol % )NMO.H2O ( 20 equiv)
CH2Cl2 ( 0.1 M) 0 oC-rt
OHO
OH
OO
1.26
1.27 (Scheme 1.64)
Goti and Romani reported the oxidative conversion of secondary amines to
corresponding imines by TPAP/NMO in high yield (Scheme1.65).203 The reagent was
found to be useful for in situ generation of nitrones from hydroxyl amines in presence of
dipolarophiles in acetonitrile (Scheme 1.66).204 In the oxidation condition, isoxalidines
1.30 was obtained in good yield from hydroxylamine 1.28 and ethyl fumarate 1.29
(Scheme 1.67). Successively an aerobic oxidation of hydroxylamines to nitrones
catalyzed by TPAP was also carried out.205 Complete conversions and good yields were
obtained for cyclic hydroxylamines.
R1 NH
R2
Yield 62-95%
R1 NR2TPAP (0.05eq)
NMO (1.5 eq)CH3CN rt,
(Scheme1.65)
52
R1 NR2
OH Yield 92-100%
R1 NR2
O-
TPAP (0.05eq)NMO (1.5 eq)CH3CN rt,
(Scheme1.66)
NN
O
EtOOC
COOEtOH
H COOEt
COOEt+
TPAP (0.05eq)NMO (1.5 eq)
CH3CN rt 3.5 h
1.28 1.291.30Yield 68%
,,
(Scheme 1.67)
An easy oxidation of dihydroxyimidazolidine derivatives to nitronyl nitroxide
radicals (NNRs) was achieved using the TPAP/NMO system (Scheme 1.68).206
.
N N
R
OHHO
TPAP / NMOCH2Cl2 , rt, 1-12h, 44-90%
R= electron-rich and electron-poor aromatics, heteroaromatics, aliphatics
N N
R
OO
(Scheme 1.68)
Recently, biologically important pyrazolylpyridine derivatives were synthesized
in excellent yield by the oxidation of pyrazolyl 1,4-dihydropyridines (pyrazolyl 1,4-
DHPs) using TPAP/NMO under mild conditions at 0oC (Scheme 1.69).207 The catalytic
activity of TPAP/NMO was found to vary with different solvents. Dichloromethane
/acetonitrile were found to give maximum yield followed by acetonitrile alone. The
catalyst was found to be mildly effective in toluene. The effect of an ionic liquid on the
TPAP/NMO catalyzed reaction was also favorable and gave good yield (89-94%). In the
case of 1.31, both DHP and 4-substituted methylsufanyl groups were oxidized under the
identical reaction conditions, yielding 1.32 with good yield. Thus 1.32 was the common
oxidised product of pyrazolyl 1,4-DHPs 1.31 and 1.33 (Scheme 1.70).
53
R2R3
R4NN
NH
Me Me
CO2R1R1O2C
TPAP/NMODCM: Acetonitrile, 0oC
R2R3
R4NN
NMe Me
CO2R1R1O2C
(Scheme 1.69)
The reagent TPAP/NMO was also found to be fruitful in oxidative dimerization of
4-oxotetrahydrothiophene-3-carboxylates to bi(4-methoxycarbonyl-3-oxothiolan-2-
ylidene) derivatives (Scheme 1.71).208
SNN
NH
Me Me
CO2EtEtO2C
TPAP/NMODCM: Acetonitrile, 0oC
1.31 1.32
SNN
NMe Me
CO2EtEtO2C
TPAP/NMODCM: Acetonitrile, 0oC
O
O
SNN
NH
Me Me
CO2EtEtO2C
O
O
1.33
(Scheme 1.70)
S
S
S
O
R
CO2Me
RMeO2C
O
O R
CO2Me3 equiv. NMO, 0.05 equiv. TPAP, mol. sieves 4Ao
CH3CN, 15h, 40oC
R = Me, Bn, Allyl (Scheme 1.71)
54
In the development of a catalytic asymmetric oxidative iminium cascade, TPAP
was used as a substrate-selective redox catalyst, well tolerated by the amine catalyst and
provides an opportunity to form the , β-unsaturated aldehydes in situ for further
transformations.209
1.6 ALKYL AMMONIUM IONS AS CARRIERS OF TUNGSTATE AND MOLYBDATE
As important classes of reactive intermediates in catalytic oxidation reactions,
peroxomolybadates and peroxotungstates have attracted the attention of chemists since
long. These are found to be effective catalysts to activate hydrogen peroxide in selective
oxidation reactions, such as epoxidation of olefin,210 cleavage of double bonds211 and
conversion of primary and secondary alcohols to carbonyl compounds under moderate
condition.212 Peroxo complexes of molybdate and tungstate include mononuclear anion
[M(O2)4]2−, binuclear anion [M2O3(O)4]2−, mononuclear anion formed from molybdenum
or tungsten and organic ligands, heteropolyperoxo-tungstate anion {PO4[W(O)(O2)4]4}3−
and Keggin unit [PW12O40]3−.213
Quaternaryammoniums linked with molybdate have also played important roles in
catalytic oxidation reactions. X-ray diffraction study of bis(tetramethylammonium)
hexamolybdate(VI)214 and bis(tetramethylammonium) pentachlorooxomolybdate(V)-
acetonitrile(1:1),215 showed the crystal structure of the compounds to be trigonal and
monoclinic respectively. In case of bis(tetramethylammonium) hexamolybdate(VI), each
Mo atom is coordinated by six O atoms in a distorted octahedral arrangement. The six
MoO6 coordination octahedra in each anion share a common vertex at the central O atom.
Each octahedron shares four edges with adjacent octahedra (Figure1.4).
55
Figure 1.4: The ORTEP diagram of the only one independent [Mo6O19]2-anion in the
structure and the numbering system
In the pentachlorooxomolybdate anion, the planar chlorines are bent away from
the axial oxygen ligand. The Mo-O bond length is 1.6620(18) Ao indicating significant
double bond character. The oxygen trans Mo-Cl bond is longer than the planar Mo-Cl
bonds. The Clcis-Mo-O bond angles drop below the center of the molybdenum atom and
are slightly larger than 90° (figure 1.5). The overall geometry of the [MoOCl5]-2 anion is
Cs symmetrical octahedral structure.
Figure 1.5: The ORTEP diagram of the two [(CH3)4N]2[MoOCl5], CH3CN molecules
and the numbering system
A novel diammonium Gemini surfactant phase transfer catalyst, diethyl-ether-
,ω-bis-dimethyldodecylammonium molybdate (12-EO-12-Mo), was found to enable the
56
dark singlet oxygenation of organic substrates by chemically generated 1O2.216 The
peroxidation of two typical organic substrates: -terpinene, which reacts with 1O2
according to a [4+2] cycloaddition(Scheme 1.72) and the less reactive β-citronellol,
which provides two hydroperoxides according to the ene-reaction were demonstrated
using this catalyst. 12-EO-12-Mo provides a simple reaction medium with only three
components for the preparative peroxidation of hydrophobic substrates by chemically
generated singlet oxygen.
(Scheme 1.72)
Anderson type polyoxomolybdates with mixed-valence molybdenum ions,
[(C18H37)2N(CH3)2]3Co(OH)6Mo6O18 can aerobically oxidize sulfur-containing
compounds in decalin to corresponding sulfones under mild conditions.217 The quaternary
ammonium cations in the catalysts play a vital role in the aerobic oxidative
desulfurization system. The catalytic activity for the oxidation of sulfur-containing
compounds decreases in the order of 4,6-DMDBT > DBT > BT. A mechanism is
proposed as shown in Scheme 1.73. The polyoxometalate reacts with dioxygen leading to
the oxidation of Mo5+ to Mo6+ and then the coordination of DBT with the oxidized
polyoxometalate. This activated DBT is oxidized to the corresponding sulfone and the
catalyst is reduced. The reduced catalyst is oxidized in presence of dioxygen to start
another catalytic cycle.
57
MoO
O
OO O
O2 MoO
O
OO O
v VIOO
S
MoO
O
OO O
O
MoO
O
OO O
VIO
S
S
MoO
O
OO OH
vO
VI
O
O
SO
O
S
S
O
+
+
O2
(Scheme 1.73)
With the flow of time some emerging multi-site phase transfer catalysts (PTC)
were developed and proved to be more efficient than that of single site PTC. Bis-
quaternary salts are particularly attractive because of an enhanced thermal stability and
easy recovery from the reaction mixture. This generation of surfactants was demonstrated
to possess unique properties, such as lower critical micelle concentration (cmc), greater
efficiency in lowering the surface tension and better solubilization, in comparison with
the conventional surfactants, which is due to a great difference of molecular structures
between bis-quaternary and conventional surfactants. Some novel bis-quaternary
ammonium salts of binuclear peroxotungstate and peroxomolybdate complexes in which
the cation and counteranion are all bivalent:PhCH2N(CH2CH2)3NCH2Ph[W2O3(O2)4],
PhCH2N(CH2CH2)3NCH2Ph[Mo2O3 (O2)4], [PhCH2(CH3)2NCH2]2[W2O3(O2)4] and
[PhCH2(CH3)2NCH2]2[Mo2O3(O2)4] were synthesized by Shi and Wei.218 The catalytic
properties of these bis-quaternary ammonium peroxo complexes were examined for the
oxidation of benzyl alcohol and its ring-substituted derivations under mild conditions
without organic solvents and halide (Scheme 1.74).
R
CH2OH CHO COOH
RR
+ H2O2Cat. or
(Scheme 1.74)
58
A possible catalytic cycle was proposed (Scheme 1.75), for the biphasic
oxidation. Because of the different interactions in the complexes, such as ionic
interaction, intramolecular and intermolecular hydrogen bonding,219 a close ion pair was
formed between bis-quaternary ammonium bivalent cation (Q2+ ) and peroxo metal
dianion [W(O2)]2−. The close ion pair 1.34 partitioned between the aqueous phase and
organic phase and the anion [W(O2)]2− in the organic phase transferred its active oxygen
to organic reactant and generated oxidant product. During the transfer of active oxygen,
the deperoxotungstate [W(O)]2− was produced. At the same time, the close ion pair 1.35,
which was also partitioned between the aqueous phase and organic phase, was formed
from Q2+ and the anion of deperoxotungstate [W(O)]2−. In the aqueous phase, the H2O2
and deperoxotungstate anion [W(O)]2− were combined to produce 1.34. The transfer of
active oxygen took place once more after 1.34 entered the organic phase exhibiting a
catalytic cycle. In this way, bis-quaternary ammonium cation can extract peroxo Mo (VI)
and W(VI) dianion carrying active oxygen into organic phase, where the oxidation
reaction can take place effectively.
Organic phase
Aqueous phase
Q22+[M(O2)]2-
Q22+[M(O)]2-
1.34 1.35active oxygen transfer
organic reactant oxidised product
1.34 1.35
Q22+[M(O)]2-
Q22+[M(O2)]2-
H2O2
(Scheme 1.75)
Recently surfactant-type polyoxometalate-based ionic liquids (SPILs), such as
[(n-C8H17)3NCH3]3{PO4[MoO(O2)2]4}(1.36), [(n-C12H25)3NCH3]3{PO4[MoO(O2)2]4}
(1.37), [(n-C8H17)3NCH3]3{PO4[WO(O2)2]4}(1.38) and [(n-C12H25)3NCH3]3-
{PO4[WO(O2)2]4} (1.39) were found to be very efficient extractants and catalysts for
oxidative desulfurization of dibenzothiophene(DBT) to sulfone using H2O2 as the
oxidant.220 The oxidative desulfurization of some organosulfur compounds like BT, DBT,
and 4,6-DMDBT using 1.36 as the catalyst was found to be pseudo first-order. The trend
of catalytic activity is in the order BT < 4, 6-DMDBT < DBT, which was ascribed to the
electron density on the sulphur atom and steric hindrance. The catalyst 1.36 can be
59
recycled for 8 times effectively and accordingly a reaction mechanism (Scheme 1.76)
was proposed revealing its catalytic role.
(Scheme 1.76)
Step (1): The active peroxo species (II) was regenerated from the reaction of (I), when 1.36 reacting with excess H2O2. Step (2): An Oxygen transfers from the active Mo-peroxo species (II) to the sulphide with the formation of a transition state. Step (3): A complete O-transfer to the sulfide takes places affording the sulfoxide and the Mo(O) species (I).Step (4): The active species (II) takes part in the oxidative desulfurization leading to the corresponding sulfone and the regeneration of the Mo(O) species (I).
Quaternary ammonium ions were used as carriers for various oxometallates
including tungstates. The reaction between tetramethylammonium fluoride (CH3)4NF and
WO3 in a 1: 1 molar ratio in dry acetonitrile afforded tetramethylammonium trioxofluoro
tungstate(VI)[(CH3)4NWO3F] in high yield.221 The oxidation of cyclohexane by
hydrogen peroxide in presence of catalytic amount of the Keggin-type
tetrabutylammonium heteropolytungstate, hydrated [(TBA)4Hx[PW11M(L)O39], M=
Mn(II), Fe(III), Co(II), Ni(II), Cu(II), L=H2O] was found to produce cyclohexanol,
cyclohexanone and in certain cases, cyclohexyl hydroperoxide.222 Sugahra et al. have
60
reported the use of tertabutylammonium salt of gamma-Keggin germanodecatungstate as
a homogeneous catalyst in Knoevenagel condensation reaction.223
Zhang et al. reported the solvent-free oxidation of secondary alcohols to
corresponding ketones in presence of hexadecyltrimethylammonium
heteropolyphosphato tungstate ((n-C16H33N(CH3)3)3[PW4O16]) with aqueous hydrogen
peroxide as oxidant.224 When hydrogen peroxide was 200 times more than the catalyst
better selectivity, yield and catalyst recovery efficiency were obtained for oxidation of
alcohols. The secondary alcohols were preferentially oxidized faster than the primary
alcohols. The catalyst can be reused without any loss of selectivity.
Hexadecyltrimethylammonium 12-phosphotungstate(PW12), [n-C16H33N(CH3)3]3
PW12 O40 has been employed for catalysed oxidation of alcohols to carbonyls with 27.5%
aqueous hydrogen peroxide under solvent-free conditions.225 In this catalytic system,
PW12 species was partially degraded to the PW4 ((PO4[WO(O2)2]4)3− ) species by its
reaction with hydrogen peroxide, which was the active species for catalyzing alcohol
oxidation. Initially the PW12 and PW4 species exist in equilibrium during the oxidation
process and with time most of the PW4 species are transformed to the PW12 species
(Scheme 1.77).
PW12
H2O2
P
alcohol ketone
WOO W
OO O
W 44
H2O2
+ P
(Scheme 1.77)
The catalytic complex [Bun4N]3{PO4[WO(O2)2]4}was found to provide higher
yields of mono- and dicarbonic acids in oxidation of alcohols and cyclic alkenes with
hydrogen peroxide in two phase systems with no additional organic solvents.226 The
complex was synthesized by stirring an aqueous mixture of H2O2, and H3PW12O40.6H2O
followed by addition of tetarbutylammonium chloride.
Ma et al. have reported a tri-vanadium-substituted phosphotungstate, [n-
Bu4N]3H3[PW9V3O40], as efficient homogeneous catalyst for direct oxidation of C- H
bonds of toluene and substituted toluene to corresponding aldehyde in high yields, with
61
tert-butyl hydroperoxide (TBHP) as an oxidant under solvent-free conditions.227
Increasing the reaction temperature resulted in the oxidation of toluene faster, while the
selectivity of aldehyde decreased and the selectivity to benzyl alcohol increased. It was
found that the ring-substituent group could affect the reactivity. For the toluene
derivatives containing electron donating group, the reaction rate was faster than that of
toluene. Another toluene derivative of p-methoxy-toluene containing the electron
donating group of methoxy also showed the similar high reaction rate and conversion
except for a relative lower selectivity to 4-methoxybenzaldehyde (73%). The reason was
ascribed to the high reactivity of electron donating group. Thus, the substrates were
oxidized to some other products (alcohol and carboxylic acid) besides 4-
methoxybenzaldehyde. For ethyl benzene, the methyl group could not be oxygenated;
only benzylic C-H bonds were oxidized to the carbonyl compound with high yield (95%)
and selectivity (96%) to acetophenone. On the otherhand, toluene derivatives containing
electron-withdrawing group, the activity was less than that of the ones having electron
donating groups. The electron withdrawing group made the benzene ring electron
deficient and inactivate. So, it was harder for them to be oxidized. p-Chlorotoluene gave
a 89% selectivity to 4-chlorobenzaldehyde and a 52% yield. The toluene derivative of o-
nitrotoluene which has a stronger electron withdrawing group gave a poor reactivity; a
92% selectivity to 2-nitrobenzaldehyde and a 23% yield were obtained after 6 h.
In recent past, polyoxometalates(POMs), such as a quaternary ammonium
polytungsto-phosphate catalyst assembled at the interface of the emulsion droplets, were
used for the oxidation of sulfur-containing compounds presented in fuel oils.228-231
The catalyst, [(C18H37)2N+(CH3)2]3[PW12O40] in emulsion of diesel is very active
and selective in the oxidation of 4,6-dimethyldibenzothiophene (4,6-DMDBT) into
sulfones with stoichiometric amounts of H2O2 under mild conditions.232 The sulfones can
easily be separated from the diesel and the catalyst can be recycled. The strategy of the
oxidation and extraction process has been described in Scheme 1.78.
62
Scheme 1.78: Catalytic oxidation and extraction of sulfur-containing molecules present in real diesel: A) before oxidation; B) during oxidation; C) catalytic oxidation of sulfur-containing molecules in emulsion droplets; D) after oxidation; E) extraction with a polar extractant.
Subsequently Li and his coworkers used another amphiphilic catalyst
[C18H37N(CH3)3]4[H2NaPW10O36] for oxidation of benzothiophene, dibenzothiophene,
and their derivatives into their corresponding sulfones using hydrogen peroxide as an
oxidant in emulsion oxidative system.233 The reactivity of sulfur-containing compounds
was found to have a trend, BT < MBT < DBT < 4,6-DMBT. Although BT is relatively
difficult to oxidize by conventional medium, it can be efficiently oxidized in the emulsion
system using this catalyst.
Zhang et al.234 developed a quarternary ammonium polytungstophosphate
[C18H37N(CH3)3]5Na2[PW11O39] (PW11) with lacunary Keggin-structures, and used it for
oxidative desulfurization in emulsion system. It was found that the amphiphilic catalyst
PW11 exhibits high catalytic activity towards the oxidation of BT to corresponding
sulfone under mild conditions with H2O2 as oxidant in emulsion system. On the other
hand, the catalytic activity of PW11 can be largely blocked by the coordination of
transition metals like Ti, Mn, Fe, Co, Ni and Cu, implying that the mono-lacunary POMs
63
are propitious to the oxidation of BT. The amphiphilic catalyst PW11 is assembled at the
interface of the emulsion droplets (Scheme 1.79).
(Scheme 1.79)
Peroxo-POMs have been proved to be the active intermediates in many reactions.
The (PO4[WO(O2)2]4)3−, one of the most active POMs for H2O2-based oxidations, is the
real active species in the Keggin-type H3PW12O40/H2O2 system.235,236 It has been
recognized that [PW12O40]3− and [PW11O39]3−, which can rapidly convert into
polyperoxometalate (PO4[WO(O2)2]4)3−, are the effective species for the epoxidation of
the terminal alkenes .236 Zhang’s group237 reported that a tungsten peroxo complex rather
than a high valent transition–metal oxo species operates as the key intermediate in the
sandwich-type POM-catalyzed epoxidations of chiral allylic alcohols. The similar
phenomenon was imagined with PW11 as catalyst.
64
Recenly, oxidation of SCN- by O2 as the oxidant in a micellar system, where
amphiphilic catalysts [CH3(CH2)15N(CH3)3]5[PW11(TiO2)O39] (1.40),
[CH3(CH2)15N(CH3)3]7 [PW10(TiO2)2O38] (1.41), and [CH3(CH2)15N(CH3)3]9
[PW9(TiO2)3O37] (1.42) act as the surfactant and the catalysts, leading to simple inorganic
species SO42-, HCO 3
- and NO3- under extremely mild conditions was reported by Wei et
a.l (Scheme 1.80). These catalysts exhibit high efficiency of oxidation, ease of
separation, long lifetime, and regenerability. The number of peroxo-titanium influences
the catalytic activity, which shows the active range: 1.40<1.42<1.41. This result could
provide information on designing catalyst in oxidation reactions.238
(Scheme 1.80)
Mukherjee et al. have synthesized and characterised double tailed alkyl (C10–C18)
trimethylammonium dichromate, (C12–C16) tungstate and (C12–C16) molybdate
complexes239 and characterised physicochemically. The water solubility of the molybdate
complexes was higher than the tungstate complexes. These compounds aggregate in
water which can be revealed from the conductometric, tensiometric and
microcalorimetric studies. The aggregation process was exothermic in nature. The release
of solvent molecules surrounding the amphiphilic tails and their free motion in the oily
interior of the aggregates largely contribute to the positive entropy change outweighing
the entropy decrease by the way of hydration of the amphiphile head group in the
palisade layer of the aggregates. The size and the zeta potential of the aggregates of
65
synthesized tungstate and molybdate complexes increased with the increase in length of
the hydrophobic tail of the complexes.
1.7 CONCLUSION
Onium ions are charged molecules susceptible for acquiring hydrophobic
characteristics though carboneous groups present in the molecule. Variation of these
groups, which are mostly due to methylene units, can tune the hydrophobicity of the
oniums; thereby these molecules can acquire amphipathic characteristics and are able to
carry anionic metal oxidants to organic domains. Oxidations by these oxidants can be
carried out both in aqueous and organic media as well as in heterogeneous and solvent-
free conditions. Due to amphipathic characteristics of these oxidants and resultant ion
pair characteristics in different solvents, the redox potentials vary for different substrates.
Accordingly, these reagents are found to be mild, chemoselective and regioselective. The
catalytic activity of these reagents has been exhibited in many redox reactions like
oxidation reactions using H2O2 under biphasic condition. A large number technological
applications such as synthesis of nano particles, fabrication of tailor made nano tubes,
asymmetry synthesis etc can be explored by using these reagents.
1.8 SCOPE OF THE WORK
Literature studies, as mentioned earlier, envisage the scope of wide applications
of anionic oxidants with quaternary ammonium as the counter ion in oxidation reactions
of substrates in both aqueous and nonaqueous medium. The interactions of oxidants,
quaternary ammonium ions and the solvents in a reaction system lead to a differently
behaving reaction condition, wherein, a strong oxidant can be mild, and a weak oxidant
can have enhanced oxidation potential. Till now lot of attempts have been made to
convert the water soluble Cr(VI), Mn(VII), Ce(IV), Ru(VII), W(VI), Mo(VI) salts to
lipopathic with the help of phase transferring quaternary ammonium salts. With
appropriate alkyl groups in the quaternary ammonium groups, the salts assemble in both
aqueous and nonaqueous media to form organized assemblies mimicking bioaggregates
like protein, lipids, nucleic acids. Cetyltrimethylammonium (CTA) ion is a typical
66
compound of this class, which can form micelles in aqueous medium, while it can form
reversed micelle in organic solvent and microemulsion in presence of oil and water.
Earlier CTA has been used to synthesize corresponding dichromate (CTADC),
permanganate (CTAP), ceric nitrate (CTACN) to establish as suitable oxidants for
organic substrates in both water and oil.
Fe (III) has been extensively used as an oxidant for oxidizing phenols, amines,
alcohols, aldehydes in aqueous medium as well as in solvent free condition. Its oxidation
behaviour also provides a scope for its analytical application in both chemical and
biological sciences. Literature study reveals that till date no attempt has yet been made to
convert Fe(III) lipopathic with quaternary ammonium as the carrier. In the subsequent
chapter attempt has been made to synthesize cetyltrimethyl ammonium ferricyanide
(CTAFC). To compare the physico-chemical characteristics of CTAFC with other
reagents, CTADC, CTACN and CTAP have also been synthesized.
Further to investigate the applications of the lipopathic oxidants, oxidations of
substituted phenylthioureas and a drug, simvastatin, by CTADC and CTAP have been
studied and presented in Chapter 3 and 4.
67
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Synthesis and characterization cetyltrimethylammonium ferricyanide, dichromate, permanganate and ceric
ammonium nitrate
78
2. 1 INTRODUCTION
Search of novel reagents has been continuing since long due to the advancement
in synthesis of complex organic molecules. Most of the oxidation reactions are due to
inorganic oxidants. To undertake reactions of organic substrates in homogeneous media,
tailor made lipopathic reagents are of much interest. To convert the inorganic oxidants
lipopathic, onium ions having alkyl groups are linked as counterions and thus help in
carrying the oxidants into organic media. An onium ion, as the counter ion for anionic
oxidants such as Mn(VII), Cr(VI), Ce(IV), Ru(VII) etc. makes a significant difference in
oxidation potential of the oxidant as well as to the oxidizing system. It makes the oxidant
lipid soluble, mild, and many a times, chemoselective. Tailor-made oniums have been
used as the counter ions, wherein heterocyclic bases like pyridine, quinoline, caffeine,
imidazole and nicotine units become a part of the oxidant.1 In different reaction
conditions, these oxidants may show biomimetic characteristics due to the counter ions,
providing micro-heterogeneous environment having different solubilization pockets for
the substrates as in case of micelles, reversed micelles, micro-emulsions and vesicles for
artificial systems, and proteins and lipid membranes in living systems. Among these
oxidants, Mn(VII)2 and Cr(VI)1 have been studied extensively. The applications of
lipopathic oxidants containing alkylammonium as the counter ions are well documented
in Chapter 1.
Symmetrical tetraalkylammonium ions are mostly used as lipopathic carriers of
the lipophobic counterions.3 Cetyltrimethylammonium ion (CTA) having a point charge
and capable of forming organized assemblies in both aqueos and nonaqueous media has
also been used for converting the oxidants to lipopathic.4 Dash and Mishra5 have reported
the product specificity of cetyltrimethylammonium permanganate (CTAP) in chloroform
medium for olefinic double bonds. The cis compounds are converted to the
corresponding diols where as trans compounds lead to cleavage of double bond. They
have proposed a mechanism for the self-oxidation of CTAP in chloroform akin to -
oxidation of fatty acids by corresponding dehydrogenase.6 This mechanism is based on
the existence of tight ion pair in CTAP in organic solvents. Patel et al.7 have synthesized
a lipopathic oxidant, cetyltrimethylammonium dichromate (CTADC), and have
79
investigated the oxidation behavior towards various organic substrates. CTADC is found
to be milder than other Cr(VI) oxidants. In the absence of acid, CTADC exhibits some
bizarre reactions with nonconventional products. Aromatic amines are found to yield the
corresponding diazo compounds, while aryldoximes yield the corresponding nitriles.8,9
Further, in an oxidation reaction of cholesterol with CTADC, Patel and Mishra10 have
observed the formation of 7-dehydrocholesterol instead of cholestenone. This,
dehydrogenation is a rare event in Cr(VI) oxidation studies, and is explained through a
remote functionalization mechanism. In this mechanism, the CTA ion provides a
conducive environment for proper orientation of the oxochromium group, which is also
due to the existence of tight ion pair of dichromate and onium ion, so that the removal of
hydrogen becomes easier. Further the protonated dichromate oxidizes the secondary
hydroxyl group of cholesterol to the corresponding ketone on the addition of acid. The
reaction system resembles that of the cholesterol oxidase, which carries FAD as the
dehydrogenating agent in the enzyme and oxidizes cholesterol to the corresponding
cholestenone. In an analogy to this system, CTADC in an organic solvent like DCM
forms reversed micelles where the dichromate is encapsulated by the cationic oniums and
cholesterol is partitioned into the mesophase. The variation in oxidizing activity of these
anionic oxidants having long chain CTA counterion is attributed to the formation of tight
ion pair due to which, these oxidants provide microheterogeneous phase for the
encapsulation of the organic substrates.11 The lipopathicity of Ce(IV) could also be
obtained by using CTA as the carrier of ceric nitrate. Mishra et al. have prepared
cetyltrimethylammonium cerric nitrate (CTACN)12 and investigated its oxidation
behavior with different alcohols in organic medium.13
Tight ion pairs play a key role in anion and ion-pair receptor chemistry14 and in
general, in the functional behavior of most of the anionic cofactors and substrates
involved in biological transformations.15 For the transportation of potassium through
biological membrane, the role of tight ion pair is well established.16 The formation of
tight ion pairs depends on head group structure (e.g. size), counter type, and the stability
of the hydrated tight ion pair.17 The existence of tight ion pair of CTA ion and the counter
ions in CTAP, CTADC and CTACN has been reported by Mishra et al.18
80
Ferricyanide is a versatile oxidizing agent and is used in oxidation of many
organic substrates like amines,19 pyridinium salts,20 aldehydes,21 thiols,22 phenols23 etc. in
aqueos media. In histology, potassium ferricyanide is used to detect ferrous iron in
biological tissues.24 Hexacyanoferrate(III) has been used in the determination of
tranquillizers like 2,10-disubstituted phenothiazines,25 perphenazine26 and isoniazid27.
Biomimetic oxidation of Quercetin with potassium ferricyanide under alkaline
conditions28 affords a heterodimer, which occurs in onion skins. The levels of tannin in
tea can be measured by amperometry of ferricyanide pre-reaction with a sample in a
flow-injection system.29 A new mediator method for BOD measurement under aerated
condition utilizing ferricyanide as electron acceptor has been proposed.30 The versatile
applications of ferricyanide ion in electroanalytical study include (i) biosensor based on
covalent immobilization of glucose oxidase (GOx) on multiwalled carbon nanotubes
(MWCNTs)31 (ii) probing electrode with thin films of polysaccharide and
poly(allylamine)32 and (iii) electrocatalytic reduction of nitrite33. Till date, there is no
report on lipopathic Fe(III) oxidants in chemical literature.
In order to make ferricyanide ion lipid soluble, which may find wide applications
as an analytical tool in biological system, in the present work, an attempt has been made
for the synthesis and characterization of cetyltrimethylammonium ferricyanide (CTAFC)
and to compare its various analytical data with those of such other
cetyltrimethylammonium oxidants like CTAP, CTADC and CTACN.
2.2 EXPERIMENTAL
2.2.1 Materials
The experimental section deals with the synthesis of cetyltrimethylammonium
ferricyanide (CTAFC), permanganate (CTAP), dichromate (CTADC), and ceric nitrate
(CTACN) and characterization of these oxidants by elemental analysis, spectral studies
and electroanalysis. The chemicals used for the synthesis, in the present study were of
high purity and were obtained from E-Merck, Spectrochem, Mumbai, India. The solvent,
acetonitrile, was distilled before use. Tetrabutylammonium perchlorate (TBAP) for the
use as supporting electrolyte was synthesized from tetrabutylammonium bromide and
81
perchloric acid. It was recrystallized from acetonitrile. Milipore water was used
throughout the study.
2.2.2 Methods
The melting points of the compounds were recorded in open capillary in a sulfuric
acid bath. The NMR spectra were run on Brucker Ultra Shield 400MHz NMR
Spectrometer in DMSO-d6 and CDCl3; and IR spectra on Perkin Elmer Spectrometer in
KBr. The UV spectra were recorded on Hitachi (U-3010) UV-Visible Spectrophotometer.
Metal ions were estimated using Varian AA240 Atomic Absorption Spectrophotometer.
Electrochemical measurements were made using a computerized CH Instrument
model 600C Electrochemical Analyzer. A three-electrode system was used with a glassy
carbon (3mm diameter) or platinum disc (2mm diameter) as working electrode,
Ag/AgNO3 as reference electrode and a platinum wire as the counter electrode. Before
each experiment the working electrode was mechanically polished to mirror finish using
0.05 γ-alumina powder and then cleaned in Millipore water followed by rinsing with the
solvent used for the experiment. All electrochemical experiments were performed under
atmospheric pressure and in room temperature. Tetrabutylammonium perchlorate
(TBAP) of 0.1M was used as supporting electrolyte in all electroanalytical studies in
organic solvents.
2.2.3 Synthesis of cetyltrimethylammonium ferricyanide (CTAFC)
Potassium ferricyanide (3.29g, 0.01mol) in 10 ml of water was added slowly to an
aqueous solution of cetyltrimethylammonium bromide (10.93g, 0.03mol) with continuous
stirring using a Teflon-coated magnetic bar at room temperature. A light green colored
compound appeared immediately (Scheme 2.1). Stirring was continued for 15 minutes
more after completion of the addition of the ferricyanide solution. The resulting light
green product was then filtered off and washed with water several times till no bromide
and ferricyanide were detected in the filtrate. It was then vacuum dried and kept in a
desiccator.
82
3C16H33N+(CH3)3Br- + K3Fe(CN)6 [C16H33N+(CH3)3]3Fe(CN)63- + 3KBr
(Scheme 2.1)
Melting point : 220 oC (decomposed)
Yield : 98 %
Elemental analysis : Fe: 5.21 %; C63H126N9Fe requires Fe 5.26%
IR (cm–1) : 3036 ( N-CH3 str), 2916 (C-H str of CH3), 2849 (C-H str
of CH2), 2104 (CN), 1468 (C-H def) and 721 (Fe-CN
str). (Chart 2.1)
NMR (δ in ppm) in
CDCl3
: 0.87 (3H, t), 1.25 (24H, distorted singlet), 1.75 (4H, m),
3.37 (9H, s), 3.51 (2H, t) (Chart 2.2)
2.2.4 Synthesis of cetyltrimethylammonium ceric nitrate (CTACN)
CTACN was synthesized as shown in Scheme 2.2.12 A saturated solution of ceric
(IV) ammonium nitrate (CAN: 5.48 g, 0.01mol) in 10 ml water was added to an aqueous
solution of CTAB (10.93 g, 0.03mol) with continuous stirring on a magnetic stirrer. A
yellow coloured compound appeared slowly. Stirring was continued for 30 minutes after
completion of CAN addition. The yellow coloured compound was filtered off and
washed with distilled water for several times till no trace of bromide (Br -) was detected
in the filtrate. It was vacuum dried and kept in a desiccator.
Melting point : 910C
Yield : 90 %
Elemental analysis : C, 42.17; H, 7.52; N, 14.0 %; C38H84N8O18Ce requires
C: 42.22, H: 7.77, N: 13.73%
IR (cm–1) : 3014 ( N-CH3 str), 2918 (C-H str of CH3), 2850 (C-H str
of CH2), 1465 (C-H def), 950, 900, and 722 (Ce-N str).
2C16H33N+(CH3)3Br- + (NH4)2Ce(NO3)6
[C16H33N+(CH3)3]2Ce(NO3)6 + 2NH4Br
(Scheme 2.2)
500
750
1000
1250
1500
1750
2000
2500
3000
3500
4000
4500
1/cm
0153045607590 %T
4438.214393.844376.48
4320.554251.114189.394135.384110.31
4044.734015.793942.503913.573807.48
3485.373429.43
3390.863307.923300.20
3132.403035.96
2916.372848.86
2684.912657.912636.69
2590.402561.472515.182490.10
2426.452411.022364.732331.94
2173.782152.56
2104.342065.76
2021.401944.251919.171894.10
1666.50
1467.831419.61
1398.391379.10
1300.021274.95
1242.161219.01
1195.871165.00
1141.861122.57
1089.781058.92
1029.991012.63
960.55912.33
883.40835.18
796.60721.38
613.36599.86538.14
501.49455.20
383.83345.26
CTA
FC
Cha
rt 2
.1: I
R sp
ectra
of C
etyl
trim
ethy
lam
mon
ium
ferr
icya
nide
(CTA
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Cha
rt 2
.2: N
MR
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f Cet
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83
2.2.5 Synthesis of cetyltrimethylammonium permanganate (CTAP)
Cetyltrimrthylammonium permanganate6 was prepared by stirring
cetyltrimethylammonium bromide (3.64g, 0.01mol) with an equivalent amount of
potassium permanganate (1.58g, 0.01mol) in distilled water (Scheme 2.3). A dark
compound separated out immediately, which was washed with water several times. The
yield was found to be 92%. The compound decomposed at 98oC inside a capillary tube
and exploded violently in the temperature range of 115-120oC when heated on a wider
surface. It was vacuum dried and kept in a dark bottle in a refrigerator, (Yield: 92%).
C16H33N+(CH3)3Br- + KMnO4 [C16H33N+(CH3)3]MnO4- + KBr
(Scheme 2.3)
2.2.6 Synthesis of cetyltrimethylammonium dichromate (CTADC)
Cetyltrimethylammonium dichromate8 was synthesized by treating potassium
dichromate (2.94 g, 0.01mol) with an aqueous solution of cetyltrimethylammonium
bromide (7.38 g, 0.02 mol) (Scheme 2.4). The resulting yellow colored insoluble salt was
isolated, and washed with water several times till no bromide and dichromate were
detected in the filtrate. It was vacuum dried and kept in a desiccator.
Melting point : 212 oC (decomposed)
Yield : 98%
Elemental analysis : C, 58.14; H, 10.65; N 3.54; Cr 13.11%; C38H84O7N2Cr2
requires C 58.16, H 10.71, N 3.57, Cr 13.26%.
IR (cm–1) : 771, 879, 933, 1467, 2850, 2921, 3028, 3471.
2C16H33N+(CH3)3Br- + K2Cr2O7 [C16H33N+(CH3)3]2Cr2O7 + 2KBr
(Scheme 2.4)
84
2.3 RESULTS AND DISCUSSION
The counterions contribute significantly to the solubility of ionic amphiphiles.
Quaternary ammonium ions form contact ion pairs with the counter ions3d and
consequently their solubility increases in organic solvents with concomitant decrease of
solubility in aqueous medium. The extent of solubilization contributes to the partitioning
of the molecules between surface and bulk. With a view to study the effect of counter
ions on the oxidation potential of metal oxidants, bromide of CTAB was exchanged with
large metallic oxidants such as ferricyanide, dichromate, permanganate and ceric nitrate.
The exchange of counter ions in the present study was found to obeys simple ion
exchange mechanism and it changes the solubility of the oxidants significantly. CTAFC
is insoluble in water, whereas CTACN is sparingly soluble in water. Both the reagents are
soluble in polar organic solvents like, methanol, ethanol, acetonitrile, dimethylsulfoxide
but insoluble in nonpolar organic solvents like hexane, benzene, toluene, chloroform etc.
CTADC and CTAP were found to be almost insoluble in water but soluble in all organic
solvents.
2.3.1 Elemental and spectral analysis
The elemental analyses of the synthesized compounds mentioned above reveal
that CTAP has a single cetyltrimethyl ammonium (CTA) unit, while CTACN and
CTADC each has two and CTAFC has three CTA units. The percentage of metal ions,
determined from the AAS studies for CTADC, CTAP and CTAFC also supports the
predicted structures of the oxidants. CTAFC exhibits an absorption band around 420 nm
in the visible region in organic solvents. An absorption band at 2104 cm-1 in the IR
spectra of CTAFC indicates the existence of –CN group in the molecule. The appearance
of a band at 721 cm-1 also supports the presence of Fe-CN bond. The chemical shift
values of CTAFC at 3.37 and 3.51 are assigned to the onium methyl and methylene
groups of cetyltrimethylammonium ion respectively. Thus, the IR and NMR spectral data
(Chart 2.1-2.2) support the presence of CTA in the oxidant and the proposed structure of
CTAFC to be as shown in Scheme 2.1. From the earlier studies on the NMR spectral data
of CTADC, CTAP, CTACN and CTAB (Table 2.1) in CDCl3, it is found that, the
85
protons close to the nitronium ion are affected significantly compared to other protons
with change in the metallic oxidant.18 While comparing the solubility in water, which
relates to the dissociation of ions, CTAB is highly soluble in water, but CTAFC is water
insoluble, indicating the formation of a tight ion pair in the later. The up-field shifts of
NMR spectral data of CTAFC in DMSO-d6 and CDCl3 compared to that of CTAB in
CDCl3 also corroborate the existence of the tight ion pair in CTAFC. There is a
significant change in the chemical shift of hydrogen atoms around nitronium ion in
CTAFC with change in polarity of the solvent (CDCl3 and DMSO-d6), while the
chemical shifts of other hydrogen atoms are found to be unaltered (Table 2.1).
Table 2.1: Chemical shift value (δ) of different protons of CTAFC, CTAB, CTACN,
CTADC and CTAP in CDCl3 (δ in DMSO-d6)
Oxidants Chemical Shift(δ)
-N(CH3)3 -CH2- β-CH2- -(CH2)13 ω-CH3
CTAFC 3.37 (3.1) 3.51 (2.79) 1.75 (1.63) 1.25 (1.25) 0.87 (0.86)
CTAB 3.49 3.58 1.76 1.27 0.90
CTACN 3.33 3.50 1.72 1.26 0.88
CTADC 3.42 3.51 1.77 1.26 0.90
CTAP 3.11 3.30 1.75 1.28 0.89
2.3.2 Cyclic voltametric analysis of CTAFC
With a view to investigate the effect of counter ion on the electrochemical
properties of Fe(III), Cr(VI), Mn(VII) and Ce(IV), cyclic voltametric (CV) study of all
these oxidants (CTAFC, CTADC, CTAP and CTACN) has been carried out. The CV
behavior of CTAFC was studied in acetonitrile medium using 0.1M TBAP as supporting
electrolyte at glassy carbon electrode(GCE). A potential window of -1.0~1.2 V has been
employed for the CV analysis with a scan rate of 0.2 Vs-1. Typical cyclic voltammogram
of CTAFC in two different concentrations and CTAB are shown in Figure 2.1.
86
Figure 2.1: Cyclic voltammograms of CTAFC and CTAB at a scan rate of 0.2Vs-1
Analysis of voltammogram of CTAFC reveals that, it gives two anodic peaks
around 0.46V and 0.67V and one cathodic peak at about -0.45V. The peak at 0.0.46V is
attributed to the CTA counter ion, which gets support from the appearance of anodic peak
in the voltammogram of CTAB at 0.40 V for CTA. The peaks at 0.67V and -0.45V
correspond to the anodic and cathodic peak volatage of the redox couple Fe(III)/ Fe(II).
The reversibility of the Fe(III)/Fe(II) redox couple has been investigated in terms of the
separation of peak potentials and the ratio of cathodic to anodic peak currents. The
presence of the carrier CTA may result in shifting of the position of peak voltage. The
voltage separation between the current peaks (∆Ep = Epa - Epc) is 1.12V and the ratio of
peak current (Ipc / Ipa) is less than unity (0. 67). The wide separation of peak potentials
may be attributed to the presence of the carrier ion, CTA+, which decreases the
reversibility of redox reaction due to strong binding with ferricyanide. Cyclic
voltammogram of 0.0005M CTAFC with different scan rate is shown in Figure 2.2.
Since the separation of the peak potentials is more than 0.059V and the ratio of the peak
currents is less than unity, the Fe(III)/Fe(II) redox couple in presence of CTA ion can be
considered as a quasireversible system with a slow electron transfer process.34
0.001M CTAB0.0005M CTAFC0.001M CTAFC
87
Figure 2.2: Cyclic voltammogram of 0.0005M CTAFC of various scan rates (Vs-1)
2.3.3 Cyclic voltametric analysis of CTACN
Analysis of voltammogram of CTACN at platinum disc working electrode in
acetonitrile medium in a potential window of 0 ~ -1.2 V (Figure 2.3) exhibits, one anodic
peak around 0.72V and one cathodic peak at about 0.55V. A small hump in the anodic
segment is attributed to the CTA counter ion. The reversibility of the Ce(IV)/Ce(III)
redox couple has been investigated in terms of the separation of peak potentials and the
ratio of cathodic to anodic peak currents. With increase in scan rate the peak current was
found to increase linearly. The peak voltage separation between the current peaks (∆Ep =
Epa - Epc) is 0.17 V and the ratio of peak current (Ipc / Ipa) is less than unity (0. 65).
Cyclic voltammogram of 0.002M CTACN with different scan rates exhibit a significant
separation of the peak potential (Figure 2.3). Since the separation of the peak potentials
in each scan is more than 0.059V and the ratio of the peak currents is less than unity, the
Ce(IV)/Ce(III) redox couple in presence of CTA ion can be considered as a
quasireversible system.35
0.10.20.4
88
Figure 2.3: Cyclic voltammogram of 0.002M CTACN of various scan rates (Vs-1)
2.3.4 Cyclic voltametric analysis of CTAP
Cyclic voltammogram of CTAP at GCE in acetonitrile exhibits two reduction
peaks when scanned in a potential range of -1.0 ~ 2.0V. Figure 2.4 represents the CV of
0.001M CTAP with different scan rate. The two reduction peaks at 0.5V and 0.85V
correspond to a two-electron transfer process. A shift in peak voltage towards more
negative potential has been observed with increase in scan rate. The redox system is
found to be irreversible. No isolated peak for CTA is observed, which may be attributed
to the existence of tight ion pair of CTA in CTAP.
0.10.20.5
89
Figure 2.4: Cyclic voltammogram of 0.001M CTAP of different scan rate (Vs-1)
2.3.5 Cyclic voltametric analysis of CTADC
Cyclic voltametry study of CTADC has been carried out in acetonitrile water
mixture (1:1 v/v) in 0.1M HCl at glassy carbon electrode in a potential range of 0.6~1.2
V. (Figure 2.5).
Figure 2.5: CV of CTADC of different concentrations with a scan rate of 0.1Vs-1at GCE
0.10.20.4
0.001M0.002M0.003M
90
The reduction of Cr(VI) generally occurs at high concentration of H+ ions. In
presence of weak acid like acetic acid the voltammogram of CTADC exhibits an
insignificant reduction peak. Whereas, in presence of strong acid like 0.1M HCl, CTADC
gives a significant reduction peak at -0.14 V. During the study on the reduction of toxic
hexavalent chromium ion to the less toxic trivalent species at the GC-MWCNT electrode,
Garry et al. have detected a shift in the peak potential, Ep, from 0.105 V at pH of 5.0 to
0.639 at a pH of 2.0 V against saturated Calomel electrode.36 Shaikh et al. have also
observed a shifting of the peak potential for reduction of Cr(VI) from 0.24 V in K2Cr2O7
to 0.34 V in thiaminium dichromate at GCE in 0.2M HCl. This has been explained by the
proposition that the adsorbed thiaminium cation on the electrode surface may inhibit the
reduction process.37
For comparative study, the cyclic voltamtric analysis of potassium dichromate in
acetonitrile water mixture (1:1 v/v) in 0.1M HCl has also been carried out. The reduction
peak of dichromate appears at the same voltage (-0.14 V) but with less peak current as
compared to CTADC. This may be explained by the existence of tight ion pair in
CTADC between CTA ion and dichromate. The reduction peak experiences a shift
towards negative potential with increase in scan rate (Figure 2.6).
Figure 2.6: CV of 0.002M CTADC with of various scan rates (Vs-1) at GCE
0.10.2
0.05
0.4
increasing
91
2.4 CONCLUSION
The solution behavior of cetyltrimethylammonium salts varies with variation of
counterion attached. The naked anions e.g. bromide, pernamgamate, ferricyanide, ceric
nitrate and dichromate, are soluble in water but the corresponding CTA salts differ in
solubility in aqueous and organic solvents. This observation refers to the ionpair
formation of the species in their solution. The interactions of these ion pairs have been
monitored from the NMR and cyclic voltammetry studies. CTADC and CTAP are found
to form strong tight ion pairs when compared to CTAFC, while CTAB remains as loose
ion pairs. Accordingly these compounds can be used as oxidants in organic medium to
oxidize various organic substrates with different potential.
The oxidation behaviors of CTADC and CTAP on substituted phenyl thioureas
and a prodrug, Simvastatin, are presented in Chapter 3 and 4 respectively.
92
2.5 REFERENCES
1. Patel, S.; Mishra, B. K. Tetrahedron 2007, 63, 4367.
2. Dash, S.; Patel, S.; Mishra, B. K. Tetrahedron 2009, 65, 707. 3. (a) Okimoto, T.; Swern, D. J. Am. Oil. Chem. Soc. 1977, 54, 862A; (b) Sala, T.;
Sergent, M. V. J. Chem. Soc., Chem. Commun. 1978, 253; (c) Lee, D. G.; Brown, K. C. J. Am. Chem. Soc. 1982, 104, 5076; (d) Karaman, H.; Barton, R. J.; Robertson, B. E.; Lee, D. G. J. Org. Chem. 1984, 49, 4509 (e) Murugan, R.; Reddy, B.S.R. Chem. Lett. 2004, 33, 1038.
4. (a) Lee, D. G.; Brown, K. C.; Karaman, H. Can. J. Chem. 1986, 64, 1054; (b) Shukla, R.; Sharma, P. K.; Kotai, L.; Banerji, K. K. Proc Indian Acad. Sci. (Chem Sci) 2003, 115, 129.
5. Dash, S.; Mishra, B. K. Indian J. Chem. 1997, 36A, 662. 6. Dash, S. Mishra, B. K. Int. J. Chem. Kinet. 1995, 27, 627.
7. Patel, S.; Kuanar, M.; Nayak, B. B.; Banichul, H.; Mishra, B. K. Synth. Commun. 2005, 35, 1033.
8. Patel, S.; Mishra, B. K. Tetrahedron Lett. 2004, 45, 1371. 9. Sahu, S.; Patel, S.; Mishra, B. K. Synth. Commun. 2005, 35, 3123.
10. Patel, S.; Mishra, B. K. J. Org. Chem. 2006, 71, 3522. 11. Patel, S.; Mishra, B. K. J. Org. Chem. 2006, 71, 6759.
12. Mishra, B. K.; Kuanar, M.; Sharma, A.; Nayak, B. B. Indian J. Chem. 2001, 40B, 724.
13. Nayak, B. B.; Sahu, S.; Patel, S.; Dash, S; Mishra, B. K. Indian J. Chem. 2008, 47A, 1486.
14. (a) Beer, P. D.; Gale P. A. Angew Chem. Int. Etd. 2001, 40, 486; (b) Gale, P. A. Coord. Chem. Rev. 2003, 240, 191.
15. Yoon, D-W.; Gross, D. E.; Lynch, V. M.; Lee, C. H.; Bennett, P. C.; Sessler, J. L. Chem. Commun. 2009, 1109.
16. (a) Gadsb, D. C. Nature 2004, 427, 795; (b) Noskov, S. Y.; Berneche, S.; Roux, B. Nature 2004, 431, 830.
17. Soldi, V.; Keiper, J.; Romsted, L. S.; Cuccovia, I. M.; Chaimovich, H. Langmuir 2000, 16, 59.
18. Mishra, B. K. ; Sahu, S.; Padhan, S.; Patel, S. Indian J. Chem. 2009, 48A, 1527. 19. (a) N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the
USSR, Moscow. Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 12, pp. 2758-2762, December, 1982, G. I. Nikishin, E.I. Troyanskii and V. A. Ioffe. (b) Zourab Shehata, M.; Ezzo Essam, M.; El-Aila Hisham, J.; Salem Jamil, K. J. J. Surf. Deterg. 2005, 8,83.
93
20. (a) Fujii, T.; Hiraga, T.; Ohba, M. Chem. Pharm. Bull. 1981, 29, 2503. (b) Terán, J. L.; Gnecco, D.; Galindo, A.; Juárez, J. R.; Enríquez, R. G.; Soriano, M.; Reynolds, W.F. Molecules 2000, 5, 1175.
21. Singh, V. N.; Gangwar, M .C.; Saxena, B. B. L. ; Singh, M. P. Can. J. Chem. 1969, 47, 1051.
22. Kapoor, R. C.; Chohan, R. K.; Sinha, B. P. J. Phys.Chem.1971, 75, 2036.
23. Manda, E. Bull. Chem. Soc. Jpn. 1973, 46, 2160. 24. Carson, F. L.; (1997). Histotechnology: A Self-Instructional Text (2nd ed.), pp.
209-211. Chicago: American Society of Clinical Pathologists. 25. Puzanowska-Tarasiewicz, H.; Karpinska, J.; Kuzmicka, L. Int. J. Anal. Chem.
Volume 2009, Article ID 302696, 8 pages. 26. Guo, L.; Zhang, Y.; Li, Q. Spectrochim. Acta Part A: Mol. and Biomol. Spectrosc.
2009, 74, 307. 27. Zhang, H.; Wu, L.; Li, Q. Du, X. Anal. Chim. Acta 2008, 628,67.
28. Gulşen, A.; Makris, D. P.; Kefalas, P. Food Res. Int. 2007, 40, 7. 29. Hung, Y-T.; Chen, P-C; Chen, R. L.C.; Cheng, T. Sens. and Actuators B: Chem.
2008, 130, 135. 30. Liu, L.; Shang, L.; Liu, C.; Liu, C.; Zhang, B.; Dong, S. Talanta 2010, 81, 1170.
31. Chen, Y.; Huang, J.; Chuang, C. Carbon 2009, 47, 3106. 32. Noguchi, T.; Anzai, J. Langmuir 2006, 22, 2870.
33. Ojani, R.; Raoof, J-B.; Zarei, E. Electrochim. Acta 2006, 52, 753. 34. Przyojski, J. A.; Arman, H. D.; Tonzetich, Z. J. Organometallics 2012, 31, 3264.
35. Leung, P.K.; Leon, C. P. ; Low, C.T.J.; Walsh, F.C. Electrochim. Acta 2011, 56, 2145.
36. Garry, L. M.; Alcock, B. E.; Breslin, C. B. ECS Transactions 2012, 41, 1. 37. Shaikh, A. A.; Akter, S.; Rahman M. S.; Bakshi, P. K. J. Bangladesh Acad. Sci.
2011, 35, 51.
Oxidation of phenylthioureas by CTADC and CTAP
94
3.1 OXIDATION OF SOME PHENYLTHIOUREAS BY CTADC
3.1.1 INTRODUCTION
Albeit, thiourea and substituted thioureas are not natural occurring substances,
these are found to have wide applications in industrial domain. Reaction of thiourea with
hydrogen peroxide under certain conditions produces a powerful reductive bleaching
agent which is routinely used in textile industry.1,2 Some other applications of thiourea
and its derivatives include inhibition of corrosion,3,4,5,6 in spectrophotometric
determination of several metals,7 as a non-specific indicator of cancer,8,9 effective
scavengers of reactive oxygen intermediates (ROI),10-14 preventing ROI-induced lung
injury in vitro and in vivo,15,16 having antioxidant17 and potent anti-HIV18,19 activities.
These compounds are hazardous, while the corresponding oxidized products,
ureas are nontoxic and useful for the natural habitats. Further, these compounds can be
oxidized to various nitrogenous heterocyclic compounds having pharmaceutical
activities. Thiourea can be oxidized by a wide variety of oxidizing agents.20-30 The
reaction pathways and the final products of the oxidation reaction depend on the reagents
used and reaction condition. The oxidation products may be urea, disulphide,
formamidine sulfanic acid20 and in some cases, it may undergo either oxidative cleavage
or cyclization.31,32 During the oxidation of thiourea by Cr(VI) to urea, corresponding
disulfide is proposed to be an intermediate.33 The other oxidants for transurifications are
hypervalent iron,34 potassium monopersulfate and peroxodisulfate,35-37 bromate38 and
chlorite.39,40 The oxidation, sometimes, occurs via free radical mechanism. However, in
most cases, thioureas form complexes with the oxidants in the first step, which is
followed by decomposition to the oxidized products.
Fell et al. reported the oxidative degradation of thioureas with potassium
monopersulfate37 in neutral medium to give the corresponding desulfurized ureas,
whereas in acidic medium the products were thiourea disulfides. With sodium
peroxydisulfate and hydrogen peroxide, the oxidized products of thiourea were found to
be NH4+, sulfur, SO4
2-, and CO2 under acidic conditions and in excess of the oxidants.21
But in excess thiourea, the formamidine disulfide was formed at low pH, and thiourea
95
dioxide is produced under neutral conditions.1,23 Oxidation of thiourea by bromate in
acidic medium produced HO(NH)SCNH2, HO2SC(NH)NH2, HO3SC(NH)NH2, and SO42-
with variation in stoichiometry.41 Use of peroxide as oxidant in aqueous medium at
different pH led to the oxidative degradation of thiourea derivatives to corresponding
sulfenic, sulfinic, sulfonic acids and some other products.42
Among other oxidized products, formamidine disulfide was also obtained from
the oxidation of thiourea by various oxidants43 which include iridium hexachloride,44
hexacyanoferrate (III),45 permanganate,46 sodium N-chloro-p-toluenesulfonamide or
chloramine-T (CAT).47
Advancement in specific and selective oxidation of organic compounds under
nonaqueous conditions is a thrust area of many research schools. For this, a variety of
onium ions have been engaged with inorganic oxidants likes Cr(VI), Mn(VII), Ce(IV)
etc. These oxidants with onium counter ions become lipopathic, sometimes amphipathic,
chemoselective, mild and many a time lead to bizarre products. Among quaternary
ammonium ions, CTA+ has a relatively small head group with more exposed charge and a
well-balanced hydrophobic group to carry the ion to both water and organic medium. It
can form a variety of aggregates in different conditions e.g. micelles in aqueous medium,
reversed micelles in organic solvents, microemulsions in aquo-organic systems etc.
To study the oxidation behavior of CTADC towards multifunctional groups,
phenylthiourea and substituted phenylthioureas are synthesized and subjected to
oxidation by CTADC.
3.1.2 EXPERIMENTAL
General method for oxidation of pheylthioureas with CTADC in acetonitrile:
A solution of (0.002mol) of pheylthiourea and CTADC (0.00066mol) in
acetonitrile was refluxed for 12-15 hours. The progress of reaction was monitored by
TLC. After completion of the reaction the green precipitate was filtered off and the
filtrate was reduced to a paste under low pressure. The product was separated from its
mixture by column chromatography using a mixture of ethyl acetate and toluene in
96
different proportions. The reaction was also carried out in presence of acetic acid, in the
above manner with addition of extra 20% acetic acid to the reaction mixture.
General method for oxidation of pheylthioureas with CTADC in microwave condition:
A mixture of phenylylthiourea and CTADC in 3:1 molar ratio was thoroughly
ground in a mortar. The mixture was irradiated in LG cooking microwave oven (Little
Chef- MS194A) at 800W till the reaction mixture turned green. The reaction mixture was
cooled to room temperature and the products were separated by column chromatography
on silica gel eluted with toluene-ethyl acetate mixture.
3.1.3 RESULTS AND DISCUSSION
In order to explore the chemoselectivity of CTADC, a series of substituted
phenylthioureas were synthesized to be used as the substrates.48 These were characterized
from their IR spectral data and melting points, which were compared with that of the
authentic samples. The oxidation was carried out both in neutral and acidic conditions.
Earlier, it was observed that CTADC can dehydrogenate amines and thiols to
oxidative coupled products like diazo and disulfide compounds respectively49 and
cholesterol is dehydrogenated to corresponding cholestenone.50 Thus the possible
products of phenylthiourea may be corresponding diazo, disulfide compound and
benzothiazole (Scheme 3.1).
(Scheme 3.1)
NCS
NH2
HN
CS
NH2
H S
NNH2
N N CS
NHCS
NH S S CNH2
NCNH2
N
97
When phenylthiourea was refluxed with CTADC in acetonitrile without any acid
for more than twelve hours, the colour the of solution turned green indicating the
reduction of Cr(VI) to Cr (III). The product, isolated by removal of acetonitrile under low
pressure, was a pasty mass with mal-odor. The tlc of the product mixture on silica sheet
exhibited two spots, when separated by column chromatography in a silica column. The
major product (60% of the yield) was found to be phenyl urea. The IR and NMR spectra
of some representative compounds are given in Charts 3.1 to 3.3. The minor product
(40% of the yield) was found to be a liquid retaining the mal-odor. Elemental analysis
does not show the presence of sulphur in this product. The IR spectra exhibit
characteristic bands at 2126-2130 cm-1 for isonitrile group (Chart 3.4). The NMR peaks
are found to be in the aromatic region only (Chart 3.5 and 3.6: 1H and 13C NMR of p-
chlorophenyl isonitrile). Accordingly, the product is characterized to be phenyl isonitrile.
When the reaction was carried out in presence of acetic acid (20%), and the pasty
mass was subjected to column chromatography, a white solid mass was obtained, which
was characterized to be phenyl urea. No trace of corresponding isonitrile was detected in
the product. The same product was also obtained, when phenylthiourea was oxidized by
potassium dichromate in presence of sulfuric acid in water medium by using standard
method.51
To generalize the reaction, substituted phenyl thioureas (Table 3.1) were
subjected to oxidation in neutral condition as well as in presence of acetic acid. In all the
cases the products were found to be corresponding ureas and isonitriles in neutral
condition and corresponding ureas only in acidic condition (Scheme 3.2).
(Scheme 3.2)
Oxidation of thiourea to corresponding urea has also been reported earlier.52 In a
mixture of phenylthiourea and diphenyl thioketone in acetonitrile medium,
phenylthiourea was selectively oxidized to phenylurea by quinolinium fluorochromate.53
+CH3CN
CTADC / H+
CH3CNCTADC
N C+ -
C NH2
S
NHNHC
NH2
OC
NH2
O
NH
Cha
rt 3
.1: I
R sp
ectra
of p
-eth
oxyp
heny
lure
a
Cha
rt 3
.2: 1 H
NM
R sp
ectra
of p
-eth
oxyp
heny
lure
a
Cha
rt 3
.3: 1 H
NM
R sp
ectra
of p
-chl
orop
heny
lure
a
O
H2N
HN
Cl
Cha
rt 3
.4:
IR sp
ectra
of p
-chl
orop
heny
lison
itrile
Cha
rt 3
.5: 1 H
NM
R sp
ectra
of p
-chl
orop
heny
lison
itrile
Cha
rt 3
.6: 13
C N
MR
spec
tra o
f p-c
hlor
ophe
nylis
onitr
ile
98
In the formation of isonitrile from phenylthiourea, a plausible mechanism involves the
coupling of –NH2 and –SH of one molecule with the –NH2 and –SH of another molecule
following removal of nitrogen and sulfur (Scheme 3.3).
To optimize the oxidation reaction in neutral condition, the phenylthioureas were
subjected to oxidation by CTADC in acetonitrile under microwave irradiation.
Amazingly, the reaction, which required around twelve hours of reflux to yield the
product in solvent medium, needed some seconds to get the products with more yield of
isonitrile without any solvent. The application of microwave offers a very quick and
clean method for the oxidation reaction. The reaction time and the yield of the products
are given in (Table 3.1and 3.2). The elemental analysis, NMR (13C and 1H) and IR and
Mass spectral data of some representative isonitriles are given in Table 3.3.
(Scheme 3.3)
CS
NH
NH2 N NH2C
SHCTADC
Acetonitrile
SS
N NNN
CN-+
Phenylisocyanide
99
Table 3.1: Yield and melting point of pheylthioureas (X-C6H4NHCSNH2) and the products of oxidation by CTADC in acetonitrile (neutral and in presence of acetic acid) and in solid phase (microwave). The yields are on isolation basis.
Table 3.2: Reaction time for the oxidation of arylthiourea (X- C6H4NHCSNH2) by CTADC under reflux condition and microwave irradiation
Sl. No.
X
Time Reflux condition
(in hours) Microwave irradiation (in second)
1 H 14 100
2 p-Chloro 14 16
3 m-Chloro 16 60
4 o-Chloro 16 39
5 p-Methyl 16 114
6 p-Ethoxy 14 52
7 p-Nitro 16 450
Sl. No.
X M. Pt. (oC)
Yield (%)
Urea Isonitrile
M.Pt. (oC)
Yield(in %) M.Pt. (oC)
Yield Reflux Micro
Wave Reflux Micro
wave Without acid
With acid
1 H 152 65 147 48 85 32 Pale yellow oil
24 56
2 o-Chloro 147 45 152 51 78 34 Yellow oil
29 55
3 m-Chloro 144 72 156 46 80 25 pale yellow oil
30 43
4 p-Chloro 176 70 212 34 85 34 73 20 47
5 p-Methyl 190 70 186 48 80 48 Yellow oil
32 48
6 p-Ethoxy 170 68 173 52 75 52 49 36 44
7 p-Nitro 198 50 228 47 70 47 110 35 35
100
Table 3.3: Physical and spectral characteristics of some representative compounds:
Phenyl isonitrile
Elemental analysis: Found; C,81.37 ; H,5.01; N,13.64. C7H5N requires C, 81.53 ; H,4.89; N,13.58.
1H NMR (CDCl3) ; 7.37(br s,5H) 13C NMR (CDCl3,) : 126, 129, 164;
MS: m/z: 103 ( M+), 76, 50.
IR: in cm-1 (Nujol): 2128, 1589, 1487, 1456, 756, 685.
3-Chlorophenyl isonitrile.
Elemental analysis: Found C, 60.94; H,2.86 ; N,10.03. C7H4ClN requires ; C,61.12 ; H,2.92 ; N,10.18;
1H NMR (CDCl3) 7.25-7.42 (m,4H); 13C NMR (CDCl3); 124, 126, 130, 135, 166.
MS: m/z : 139(M++2), 137(M+), 102, 75, 50.
IR: in cm-1 (Nujol) 2129, 1594, 1584, 1575, 1472, 852, 784, 675.
4-Chlorophenyl
isonitrile
Elemental analysis: Found C, 61.17; H, 3.00; N, 10.01, C7H4ClN requires; C,61.12;H, 2.93;N, 10.18
1H NMR(CDCl3); 7.32(d,2H, J 8.9Hz), 7.35(d,2H, J 8.9Hz) 13C NMR (CDCl3) ; 124, 127, 129, 135,166.
MS m/z : 137(M+),102,75, 50
IR: in cm-1 (Nujol); 2126, 1487,1092, 1017, 829 cm-1
4-Nitrophenyl isonitrile
Elemental analysis: Found C, 56.21; H, 2.78; N, 18.88, C7H4N2O2 requires; C, 56.75; H, 2.70; N, 18.92
1H NMR(CDCl3); 7.57(d,2H, J 8.7Hz), 8.30 (d,2H, J8.8Hz) 13C NMR (CDCl3) ; 125, 127, 131, 147,170.
MS m/z : 148 (M+)
IR: in cm-1 (Nujol) 3108, 3077, 2130, 1610, 1595, 1489, 1531, 1348, 860, 747.
101
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1992, 119, 508. 14. Kelner, M. J.; Bagnell, R.; Welch, K. J. J. Biol. Chem. 1990, 265, 1306.
15. Fox, R. B. J. Clin. Invest. 1984, 74, 1456. 16. Lai, Y. L.; Wu, H. D.; Chen, C. F. J. Card. Pharm. 1998, 32,714.
17. Dong, Y.; Venkatachalam, T. K.; Narla, R. K.; Trieu, V. N.; Sudbeck, E. A.; Uckun, F. M. Bioorg. Med. Chem. Lett. 2000, 10, 87.
18. Vig, R.; Mao, C.; Venkatachalam, T. K.; Tuel-Ahlgren, L.; Sudbeck, E. A.; Uckun, F. M. Bioorg. Med. Chem. 1998, 6, 1789.
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19. Mao, C.; Vig, R.; Venkatachalam, T. K.; Sudbeck, E. A.; Uckun, F. M. Bioorg. Med. Chem. Lett. 1998, 8, 2213.
20. Simoyi, R. H.; Epstein, I. R. J. Phys. Chem. 1987, 91, 5124. 21. Vaidya, V. K.; Pitlia, R. L.; Kabra, B. V.; Mali, S. L. J. Photochem. Photobiol. A
Chem. 1991, 60, 47. 22. Rabai, G.; Wang, R. T.; Kustin. K. Int. J. Chem. Kinet. 1993, 26, 53.
23. Saradamba, G. V.; Ramakrishna, K.; Raju, K. N. Rev. Roum. Chim. 1988, 33, 547. 24. Hoffmann, M.; Edwards, J. O. Inorg. Chem. 1977, 16, 3333.
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1729. 29. El-Wassimy, M. T. M.; Jorgensen, K. A.; Lawesson, S. O. Chem. Scr. 1984, 24, 80.
30. Hu, N. X.; Aso, Yo.; Otsubo, T.; Ogura, F. Bull. Chem. Soc. Jpn. 1986, 59, 879. 31. Bondock, S.; Fadaly, W.; Metwally, M. A. J. Sulf. Chem. 2009, 30, 74.
32. Kidwai, M.; Bhatnagar, D.; Mothsra, P.; Singh, A. K.; Dey, S. J. Sulf. Chem. 2009, 30, 29.
33. Thomas, A.; Maxcy, G.; Willhite, P.; Green, D. W.; James, K. B. J. Petro. Sc. Eng. 1998, 19, 253.
34. Sharma, V.; Joshi, W. V.; Millero, F. J.; Connor, D. Environ. Sci. Tech. 1999, 33, 2645.
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38. Chikwana, E.; Otoikhian, A.; Simoyi, R. H. J. Phys. Chem. A 2004, 108, 1159. 39. Chigwada, T. R.; Simoyi, R. H. J. Phys. Chem. A 2005, 109, 1094.
40. Chigwada, T. R.; Edward, C.; Simoyi, R. H. J. Phys. Chem. A 2005, 109, 1081. 41. Simoyi, R.H.; Epstein, I.R.; Kustin, K. J. Phys. Chem. 1994, 98, 551.
42. James, J. P.; Quistad, G. B.; Casida, J. E. J. Agric. Food. Chem. 1995, 43, 2530. 43. Zatko, D. A.; Kratochvil, B. Anal. Chem. 1968, 40, 2120.
44. Henry, N. P. O.; Harutyuneran, K. Y.; Byrd, J. E. Inorg. Chem. 1979, 18, 197. 45. Lilani, M. D.; Sharma, G. K.; Shanker, R. Indian J. Chem. 1986, 25, 370.
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46. Khan, S. A.; Kumar, P.; Saleem, K.; Khan, Z. Colloids Surf. A: Physicochem. Eng. Asp. 2007, 302, 102.
47. Shubha, J. P.; Puttaswamy J. Sulf. Chem. 2009, 30, 490. 48. Rasmussen, C. R.; Villani, F. J.; Weaner, L. E.; Reynolds, B. E.; Hood, A. R.;
Hecker, L. R.; Nortey, S. O.; Hanflin, A.; Constanzo, M. J.; Powell, E. T.; Milinari, A. J. Synthesis 1988, 456.
49. Patel, S.; Mishra, B. K. Tetrahedron Lett. 2004, 45, 1371. 50. Patel, S.; Mishra, B. K. J. Org. Chem. 2006, 71, 3522.
51. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. in VOGEL’s Textbook of Practical Organic Chemistry, Pearson Education Pt. Ltd., Singapore, 2005 pp. 609.
52. Corsaro, A.; Pistara, V. Tetrahedron 1998, 54, 15027.
53. Tajbakhsh, M.; Mohammadpoor, I.; Alimohammadi, S. K. Indian J. Chem. 2003, 42B, 2638.
104
3.2 OXIDATION KINETICS OF PHENYLTHIOUREAS BY CTADC
3.2.1 INTRODUCTION
Oxidation of thiourea containg multiple functional groups presents a situation
where there is posiibility of the oxidation of thio group to oxo derivative and formation of
disulphide and cyclized products by different reagents. The reaction pathways and the
final products of the oxidation reaction depend on the reagents used and condition of the
reaction. The conversion of thioureas into ureas has attracted the interest of chemists
since long.1 However, a study of the metabolism of thioureas showed that while
substituted naphthylthiourea is a toxin, it’s oxidation product, corresponding urea, is
nontoxic.2 Further, due to the multiple functional groups in thiourea, it has become an
interesting candidate for selective oxidation reaction. The oxidation product are found to
be corresponding urea, disulphide and in some cases, it undergoes either oxidative
cleavage or cyclization.3
In the present section, an attempt has been made to look into the mechanism of
the oxidation of phenylthioureas by CTADC through kinetics study. Conventional
spectrophotometric technique has been used to study the oxidation process. The rate of
reaction has been investigated by varying [CTADC], [phenylthiourea], [acid],
[surfactant], polarity of the solvents and the reaction temperature.
3.2.2 EXPERIMENTAL
3.2.2.1 Materials
The organic solvents mentioned in Table 3.7 were obtained from Merck and
purified by the standard methods.4 Phenylthioureas were prepared by standard method as
mentioned in Section 3.1 and were characterized from the melting point, IR and NMR
spectral data recorded on Shimadzu-FTIR 8400S and Brucker AMX 500FT respectively.
Cetyltrimethylammonium bromide (CTAB) and sodium dodecylsulfate (SDS) were
obtained from Spectrochem, Mumbai and purified by recrystallisation.
105
3.2.2.2 Kinetic Measurements
The oxidation kinetics of phenylthioureas (PTU) by CTADC in presence of
acetic acid were monitored in different solvents and surfactant system
spectrophotometrically at an analytical wavelength of 350 nm using Hitachi U3010
spectrophotometer with a thermostatic cell holder attached to a water bath. The
successive scans of the absorption spectra of CTADC with time are shown in Figure 3.1.
The effects of variation of [CTADC], [PTU], [acid], [CTAB] and [SDS] on the rate
constant were investigated by varying the concentration of the desired constituent in the
reaction mixture. The values of given rate constants are the average of duplicate runs and
were reproducible within ±6% error. Solvent used for the kinetic study was dioxan,
unless mentioned otherwise.
Figure 3.1: Successive scans of the spectra of CTADC with PTU in dioxan /acetic acid medium per minute.
3.2.2.3 Product Analysis
After completion of the reaction (keeping the reaction mixture for 72 hours) the
green precipitate was filtered off and the filtrate was reduced to a paste under low
pressure. The products were separated from its mixture by column chromatography using
mixture of ethyl acetate and toluene in different proportions. By comparing the tlc of the
isolated products with that of the phenyl urea, the molecular structure of the product was
300 400 500nm0.0
0.10.20.30.40.50.60.70.80.9
Abs
106
ascertained to be phenylurea. The melting point, IR and NMR spectral data of the product
were found to match well with those of phenylurea.
3.2.2.4 Stoichiometry
The stoichiometry of the reaction was determined by performing the experiment
at 303 K, under the condition of [CTADC] ≈ [PTU] at various concentrations. The
disappearance of Cr(VI) was followed, until the absorbance values become constant. The
[CTADC] was estimated after 48h from the preparation of the reaction mixture. A
stoichiometry ratio, Δ [CTADC]/ Δ [PTU] ≈ 1.5 was observed, which confirmed a 3:2
CTADC/ PTU relationship.
3.2.3 RESULTS AND DISCUSSION
The reaction kinetics of the oxidation reaction has been monitored in presence of
acetic acid and the kinetic data are tabulated in Table 3.4. For the acid catalysed
oxidation of phenylthiourea with CTADC in dioxan, the rate increases linearly with
increase in [PTU] (Figure 3.2).
Figure 3.2: Plot of 104kobs versus [PTU] for the oxidation reaction of PTU with CTADC at 298 K
From the linear plot of kobs vs. [PTU], the order is found to be 0.5. In an earlier
report on oxidation of alcohols, nonlinearity with Michaelis-Menten relationship of
substrates with the kobs was experienced indicating a complex mechanism for the
oxidation reaction.5 The reaction is found to be acid catalyzed with almost no uncatalytic
0
20
40
60
80
100
120
0 0.02 0.04 0.06
104
k obs
in s
-1
[Phenylthiourea] in M
107
rate constant. However, with increasing [Acetic acid], the rate constant increases
exponentially with a second order dependency (Figure 3.3).
Table 3.4: Rate constant of oxidation of PTU by CTADC at 298 K in dioxan
The change in substituent on the phenyl ring of the substrate does not have any
significant effect on the rate constant (Table 3.5). The plot of Hammett substituent
constant () with log kobs (at 308K) is found to be linear (Eq. 3.1) with a value -0.48.
The rate enhancement due to electron donating substituent indicates a relatively electron
deficient transition state, however, with a low sensitivity.
[CTADC]× 104M [PTU] M [Acetic acid] M kobs× 104 in s-1
1.5 0.01 3.24 43.83
2.02 0.01 3.24 38.38
2.52 0.01 3.24 31.82
3.03 0.01 3.24 25.95
3.53 0.01 3.24 20.92
4.04 0.01 3.24 20.00
4.54 0.01 3.24 17.73
5.05 0.01 3.24 15.28
4 0.005 3.24 15.55
2 0.005 3.24 26.04
2 0.02 3.24 52.28
2 0.03 3.24 63.03
2 0.04 3.24 79.49
2 0.05 3.24 94.00
2 0.01 0.81 1.02
2 0.01 1.62 5.99
2 0.01 2.43 14.43
2 0.01 4.05 49.9
2 0.01 4.86 77.03
108
log k = -0.48 - 2.2792 (R2 = 0.95) (3.1)
Figure 3.3: Plot of 104kobs versus [Acid] for the oxidation reaction of PTU with
CTADC at 298K.
Table 3.5: Rate constants of oxidation of different substituted phenylthioureas at four different temperatures in dioxan
The plot of rate constant against [CTADC] is bilinear with a transition point at 3.5
x 10-4 M (Figure 3.4). Before the transition point the decreasing trend in the rate constant
is higher when compared to the rate constant after the transition point. While
0102030405060708090
0% 5% 10% 15% 20% 25% 30% 35%
[Acid]in Percentage
104 k
obs
in s
-1
Arylthiourea
kobs× 10-4 in s-1 Ea kJ mol-1
∆H
kJ mol-1 ∆S J mol-1 K-1
∆G kJmol-1 293K 298K 303K 308K
Phenylthiourea 26.98 38.38 40.76 48.55 27.44 24.96 -207 86.77
P-Chloro Phenylthiourea
20.26 33.65 37.08 41.76 34.21 31.73 -186 87.09
m-Chloro Phenylthiourea
26.1 32.62 52.01 60.07 44.56 42.08 -151 87.17
o-Chloro Phenylthiourea
23.03 28.21 34.93 39.73 27.79 25.311 -209 87.53
p-Methyl Phenylthiourea
25.16 40.1 58.03 63.64 47.50 45.02 -140 86.66
p-Methoxy phenylthiourea
25.04 38.92 56.73 72.18 53.41 50.93 -120 86.73
109
investigating the kinetic behavior of CTADC on alcohols it is observed that the rate
constant decreases with a concavity due to formation of reversed micelles by CTADC in
organic medium.5 In the present study, a significant bilinearity may lead to the
proposition of change in structure of the reversed micelle with increase in [CTADC].
Figure 3.4: Plot of 104kobs versus [CTADC] for the oxidation reaction of PTU with
CTADC at 298 K. In organic medium, CTADC may assemble to form a spherical reverse micelle
where the probable localization site of the ionic oxidant is the inner core of the reversed
micelle. Phenylthiourea, being soluble in the bulk organic solvent may not be available at
the oxidation site due to the partitioning of the substrate and the ionic oxidant into two
different pseudo phases. The observed oxidation is mostly due to the reaction at the
interface. With increase in [CTADC], the inner nonpolar core may assume a larger
interfacial area so that the substrate can, relatively, be more in contact with the polar
oxidant to facilitate the reaction.
When cetyltrimethylammonium bromide (CTAB) was added to the reaction
mixture, the rate constant decreased asymptotically (Figure 3.5).
05
101520253035404550
0 1 2 3 4 5 6
10-4[CTADC] in M
104
k obs
s-1
110
Figure 3.5: Plot of kobs vs. [surfactant] for the oxidation reaction of PTU with CTADC at
298K The decrease in the rate constant may be attributed to the enhanced reversed
micellization in presence of CTAB, which provides a common counterion with CTADC
for the formation of reversed micelle. Further, the interface due to CTA+ is positively
charged, and the rate retardation in presence of CTA+ indicates the existence of a
positively charged transition state during the oxidation process. This proposition also gets
further support from the rate enhancement due to the addition of sodium dodecyl sulphate
(SDS), an anionic surfactant (Table 3.6). SDS is inert towards CTADC and provided an
anionic environment to the reactant either through mixed micellization or through a
reversed micellar aggregate which can provide an anionic interface for the interaction
between the proton, dichromate and PTU.
Table 3.6: Rate constants of oxidation PTU at different [CTAB] and [SDS] concentration at 298K in dioxan
20
70
120
170
10
15
20
25
30
0 0.0005 0.001 0.0015
104 k
obs
in s
-1
[Surfactant] in M
● [CTAB] ▲[SDS]
[CTAB] kobs× 10-4 in s-1 [SDS] kobs× 10-4 in s-1
1x10-3 13.47 1x10-3 161.63 5x10-4 18.58 5x10-4 134.61 1x10-4 25.03 1x10-4 54.35 5x10-5 28.56 5x10-5 52.59
1x10-5 37.69 - -
111
From the observed data the rate equation was found to be
Rate = k [CTADC]a [thiourea]b [acetic acid]c (3.2)
where k is the rate constant of the reaction and a, b and c represents the order of
the reaction with respect to CTADC, thiourea and acetic acid and are found to be -0.9, 0.5
and 2 respectively.
To investigate the effect of environment on the reaction mechanism, nine organic
solvents with different polarity were used as reaction medium (Table 3.7). CTADC was
found to be stable in all these solvents in presence of acetic acid for more than twenty
four hours. When various solvent parameters like acity (A), basity (B),6 cation () and
anion () solvating ability, Taft polarity scale (*), dielectric constant () and dipole
moment ()7 have been correlated with kobs values, the correlation coefficient is found to
be poor. However, in most cases scattered plots are obtained with a few outliers. The rate
constant is found to be highly sensitive to change in polarity. With increasing dielectric
constant or dipole moment of the solvent, the rate constant decreases steeply. When the
rate constants are plotted against logP as the hydrophobic parameter8, an increasing trend
is observed with a good correlationship (Eq. 3.3).
log kobs = 54.368 logP + 29.406, R2 = 0.9816 (3.3) These observations also support the existence of a relatively less polar transition
state during the oxidation reaction.
Table 3.7: Rate constant of oxidation of PTU in different solvents at 298K
Solvent kobs× 10-4 in s-1 Solvent kobs× 10-4 in s-1
Dioxane 15.55 Benzene 142.75
Acetone 21.57 Dichloromethane 97.61
Acetonitrile 51.47 Chloroform 121.83
Ethyl Acetate 65.52 Carbon tetrachloride 1358.77
Toluene 189.81 - -
112
The thermodynamic parameters such as ∆H≠, ∆S≠ and ∆G≠ have been determined
by using Arrhenius and Eyring equations for different substituted phenyl thioureas
(Table 3.5). The ∆H≠ values are found to be within 25.0 to 50.9 kJ mol-1 with an
increasing trend for increasing electron donating ability of the substituent. With
phenylthiourea as an outlier, for the rest three substrates, ∆H≠ values are found to have
excellent correlationship (R2 = 1) with Hammett substituent constant. A high negative
∆S≠ values(120.2 to 208.8 J mol-1K-1) indicate the existence of a cyclic transition state
during the reaction. The ∆G≠ values are found to be almost constant i.e. 87.1±0.4 kJmol-1.
The plot of ∆H≠ against ∆S≠ is linear (R2 = 0.999) (Eq. 3.4) with an isokinetic
temperature of 293.1 K. At this temperature all the substituted phenyl thioureas undergo
oxidation reaction by CTADC with a common mechanism. The excellent linear
compensation effect of enthalpy and entropy may be attributed to a simple reaction
mechanism.
∆H≠ = 293.11∆S≠ + 86168, R2 = 0.9993 (3.4)
From the above results a step wise reaction mechanism (Scheme 3.4) has been
proposed, wherein the initiation of the reaction is due to protonation of CTADC. The
protonated dichromate reacts with phenyl thiourea to yield a four membered cyclic
transition state, which then decomposes to phenyl urea with the involvement of a proton.
The involvement of two protons in the reaction mechanism was also supported from the
plot of the rate constant against [acetic acid]. Similar observation was made by
Maxcy et al., who have reported the involvement of two protons during the oxidation of
thiourea by Cr (VI) to corresponding urea via a disulfide.9 The existence of the less polar
transition state was evidenced from the investigation of the effect of additives like CTAB
and SDS, and solvent on the kobs.
Thus, CTADC is proved to be a mild oxidizing agent, capable of oxidizing
substituted thioureas to corresponding ureas through an electron deficient intermediate. In
organic media, CTADC aggregates to form reversed micelles and the reaction occurs at
the interface. The effect of charge at the interface could be visualized from the change in
the rate constants.
113
(Scheme 3.4)
CTA+O- Cr O Cr O-CTA+ H+ CTA+ HO Cr O Cr O-CTA+
PhNHC
H2NS H++
PhNH+
CH2N
SH
PhNH+
CH2N
SHPhNH+
CH2N
S Cr
HO OH
OCrO2O-CTA+
PhNH+
CH2N
S Cr
OH OH
OCrO2O-CTA+Cr
OH
OCrO2O-CTA+S
OC
PhNH
NH2
Cr
OH
OCrO2O-CTA+S
OC
PhNH
NH2
Cr OCrO2O-CTA+HOCPhNH
NH2
O S
+ +
+ HO Cr OCrO2O-CTA+
+ +
O O O O
O O
O
O O
O
O O O O
O
114
3.2.4 REFERENCES 1. (a) Chigwada, T. R.; Chikwana, E.; Simoyi, R. H. J. Phys. Chem. A 2005, 109,
1081 (b) Sharma, V. K.; Ivera, W.; Joshi, V. N.; Millero, F. J.; Connor, D. O.
Environ. Sci. Techn. 1999, 33, 2645 (c) Khan, S. A.; Kumar, P.; Saleem, K.;
Khan, Z. Colloids Surf. A: Physicochem. Eng. Asp. 2007, 302, 102 (d)
Alexandrova, P. V.; Neicheva, A.; Nikolova, M. Anal Lab 1996, 5, 19 (e) Joshua,
C. P.; Sujatha, T. S. Indian J. Chem. 1991, 30B, 600.
2. Miller, A. E.; Bischoff, J. J.; Pae, K. Chem. Res. Toxicol. 1988, 1, 169.
3. Corsaro, A.; Pistara, V. Tetrahedron 1998, 54, 15027.
4. Riddick, J. A.; Bunger, W. B. Organic Solvent Techniques of Chemistry, Vol II,
Wiley- Interscience, New York, 1970.
5. Patel, S.; Mishra, B. K. J. Org. Chem. 2006, 71, 6759.
6. Swain, C. G.; Swain, M. S.; Powel, A. L.; Alunni, S. J. Am. Chem. Soc. 1983,
105, 502.
7. Taft, R. W.; Abboud, J. L. M.; Kamlet, M. J. J. Org. Chem. 1984, 49, 2001.
8. Katritzky, A. R.; Fara, D. C.; Kuanar, M.; Hur, E.; Karelson, M. J. Phys. Chem.
A 2005, 109, 10323.
9. Maxcy, T. A.; Willhite, G. P.; Green, D. W.; James, K. B. J. Petroleum Sc. Eng.
1998, 19, 253.
115
3.3 OXIDATION KINETICS OF PHENYLTHIOUREAS BY CTAP
3.3.1 INTRODUCTION
Cetyltrimethylammonium permanganate (CTAP) has been reported as a synthetic
reagent for the oxidation of various substrates in organic solvents.1 Due to its self
oxidizing characteristics2 studies on its reaction kinetics need a strategic approach.3 Even
in synthetic applications of CTAP, main importance has been given to solvent free
reaction.4 Banerji and his co-workers have reported the oxidation kinetics of oximes5 and
benzylamines6 by CTAP. In each case the reaction was found to be first order with
respect to both substrate and CTAP. The oxidation of benzylamines by CTAP to the
corresponding aldimines proceeds through the formation of a carbocationic activated
complex in the rate-determining step. As thiourea derivatives can produce different
oxidized products in presence of different oxidants and reaction conditions, it is
worthwhile to investigate the oxidation of phenylthioureas (PTU) by the lipopathic
oxidant CTAP in organic medium.
This section deals with the kinetics of oxidation of phenylthioureas by CTAP in
acetonitrile medium.
3.3.2 EXPERIMENTAL
3.3.2.1 Materials
Arylthioureas were prepared and characterized as described in Section 3.1.
Solvent acetonitrile used in the kinetic study was distilled before use. CTAP was
prepared by the method described in Chapter 2.
3.3.2.2 Kinetic Measurements
The reactions have been studied under pseudo-first-order conditions by keeping
an excess (x 10 or greater) of the phenylthiourea over CTAP at constant temperature (±
0.1K) and have been followed by monitoring the decrease in the [CTAP]
spectrophotometrically at 527nm for upto 75% reaction (Figure 3.6). Beer,s law is found
to be valid within the concentration range used in the experiment. The first-order rate
constant, kobs is obtained from the linear (r = 0.99) plot of log of change in [CTAP]
against time. The rate constants reported are the mean values of duplicate runs and were
116
reproducible within ±6% error. All the observed rate constants determined by the above
method are tabulated in Tables 3.8 to 3.10.
400 500 600nm0.0
0.10.20.30.40.50.60.70.80.91.0Abs
Figure 3.6: Successive scans of the spectra of CTAP with PTU in acetonitrile per minute.
3.3.2.3 Product Analysis
After keeping the reaction mixture of CTAP and PTU in proper composition for
24h in acetonitrile, the mixture was filtered and the volume of filtrate was reduced under
low pressure. Then the organic compounds were extracted by using diethylether in
excess. On evaporation of the ether the products were subjected to column
chromatographic separation by using a mixture of ethyl acetate and toluene (1:3 v/v).
After chromatographic separation with a single spot in TLC, the isolated compound was
subjected to NMR analysis. From the melting point (147oC) and spectral data (Chart
3.3), the product is found to be phenyl urea.
3.3.2.4 Stoichiometry
The stoichiometry of the reaction was determined by performing the experiment
at 298K, under the conditions with fixed [Oxidant] and varying [PTU]. The
disappearance of Mn(VII) was followed until the absorbance values became constant and
then CTAP was estimated after 24 h. The stoichiometry ratios are found to be 2:3 for
CTAP/PTU.
117
3.3.3 RESULTS AND DISCUSSION
Thiourea remains in its tautomeric form as thioenol and on oxidation by
permanganate in aqueous medium yields corresponding disulfide in presence of acid.7
The mechanism is reported to be through free radical generation by one electron transfer
from Mn(VII). However, in the present study the oxidation reactions of phenylthioureas
are carried out in organic solvent by Mn(VII) without the presence of any acid. The
absence of acid in the reaction medium drives the phenyl thiourea to its thione form
rather than the thiol form. From the reaction mixture, corresponding phenylureas are
obtained as the products, which is evident from their analytical data. The conversion of
thione to corresponding carbonyl can be achieved by using mercuric acetate8, alkaline
peroxide,9 1,2-dibromotetrachloroethane10 etc. Thus the probability of oxidative coupling
of thiol group during the oxidation process is ruled out. Further, addition of acrylonitrile
to the reaction mixture does not lead to polymerization product indicating absence of any
free radical during the oxidation process.
CTAP is unstable in many of the organic solvents, while it is relatively stable in
acetonitrile exhibiting four peaks at 486, 527, 548 and 571nm in the visible range. During
reduction of CTAP the later three peaks suffer hypochromism, while the peak at 486
experiences a hyperchromism. Due to significant change in the peak at 527nm the optical
density at this wave length has been monitored with time and the corresponding rate
constants were determined in pseudo-unimolecular condition with high concentration of
the substrate.
In the present work the reaction kinetics of the oxidation of phenylthiourea by
CTAP in acetonitrile medium in different reaction parametric conditions have been
investigated and the observed kinetic data is given in Table 3.8.
118
Table 3.8: Rate constants of oxidation of PTU by CTAP at 298 K in acetonitrile
The rate constants are found to increase with increase in the concentration of
phenylthiourea tending towards a constancy at higher concentration. The plot of rate
constant vs. [substrate] obey Michaelis-Menten equation which refers to the following
reaction mechanism.
PTU + CTAP [Complex] (3.5)
[Complex] Product (3.6)
Thus by applying the steady-state approximation11
][1]][[][ 2
PTUKCTAPPTUKk
dtComplexdRate
(3.7)
][1][
][1][ 2
PTUKPTUKkk
CTAPdtComplexd
obs (3.8)
22
1][
11kPTUKkkobs
(3.9)
[CTAP]× 104M [PTU] M kobs× 104 in s-1
0.5 0.002 101.6
1.0 0.002 89.43
1.5 0.002 72.62
2.0 0.002 51.93
1.0 0.001 31.93
1.0 0.0015 62.95
1.0 0.0025 107.86
1.0 0.003 112.85
1.0 0.0035 118.6
k+1
-1k
k2
119
Figure 3.7: Plot of kobs vs. [PTU] for the oxidation reaction of phenylthiourea with CTAP at 298 K.
By using Line-weaver-Burk type double reciprocal equation (Eq. 3.9) the binding
constant K (=k+1/k-1) and k2 are obtained to be 878.33 dm3mol-1 and 15.66 x 10-3 s-1
respectively. Further from Figure 3.7 the steady-state dissociation constant of the oxidant
–substrate complex known as, Michaelis-Menten constant, Km (= (k-1 + k2)/ k+1) is
determined to be 1.28 x 10-3M. The corresponding double reciprocal curve is shown in
the inset of Figure 3.7. Considering k2, K and Km values k+1 and k-1 are determined and
found to be 6971 s-1 and 0.126 s-1 respectively.
With increase in oxidant concentration the observed rate constant decreases
linearly (Figure 3.8). Earlier, Dash and Mishra12 have reported similar trend for the
oxidation of various substrates with CTAP and they have proposed a partition of
permanganate from the substrate due to the cetyl chain without involving formation of
micelles. Generally, micelle formation is indicated from the change in linearity due to
change in micelle forming reagent. In the present case CTA is the micelle forming
reagent, but due to large permanganate ion at the core it may not be forming a micellar
type aggregate. However, on addition of CTAB to the reaction mixture, the rate constant
decreases sharply and suffers a transition in the normal linear trend (Figure 3.9). CTAB
forms reversed micelles and can trap large permanganate ion at its core leading to a
separation of the substrate and the oxidant between the CTA sheaths. Similar
0
0.002
0.004
0.006
0.008
0.01
0.012
0.014
0 0.001 0.002 0.003 0.004
k ob
sin
s-1
[PTU ]in M
y = 0.072x + 63.85R² = 0.98880
84889296
250 350 450
1/ k
obs
1/ [PTU]
120
observations have been reported by Patel and Mishra during oxidation of different
substrates by CTADC.13
Figure 3.8: Plot of kobs vs. [CTAP] for the oxidation reaction of PTU with CTAP at 298K
Figure 3.9: Plot of kobs vs. [CTAB] for the oxidation reaction of PTU with CTAP at 298K
To investigate the transition state of the reaction, the kinetics of some substituted
phenyl thioureas were run at different temperatures. The electron donating substituents
retard the rate while the electron withdrawing substituents enhance the rate (Table 3.10).
The plot of Hammett substituent constant with logarithm of rate constant is linear with a
positive ρ value of 1.49 (R2 = 0.9571). A relatively high positive ρ value indicates a
negative charged transition state which can be generated by the attack of manganate ion
at the thione carbon leading to a negative charge on the sulfur.
0
0.002
0.004
0.006
0.008
0.01
0.012
0 1 2 3
k obs
in s
-1
[CTAP ] x104 M
0
0.001
0.002
0.003
0.004
0.005
0.006
0 5 10 15 20
k obs
in s
-1
[CTAB] x104 M
121
The thermodynamic parameters such as ∆H≠, ∆S≠ and ∆G≠ have been determined
by using Arrhenius and Eyring equations for different substituted phenyl thioureas. The
∆H≠ values are found to be within 33.3 to 71.47 kJ mol-1 with a decreasing trend for
increasing electron donating substituent. However the change in entropy increases for
these substrates. The entropy values vary from -47.2 to -186.9 J mol-1K-1. The ∆G≠ values
are found to be within the range of 83.6 to 89.1 kJ mol-1K-1 and obey Hammett equation
(R2 = 0.93). The plot of ∆H≠ against ∆S≠ is found to be linear (R2 = 0.996) with an
isokinetic temperature of 263 K. At this temperature all the substituted phenyl thioureas
undergo oxidation reaction by CTAP with a common mechanism. The excellent linear
compensation effect of enthalpy and entropy may be attributed to a simple reaction
mechanism.
∆H≠ = 263 ∆S≠ + 82893 , R2 = 0.996 (3.10)
Table 3.9: Rate constants of oxidation of PTU at different [CTAB] concentration at 298K in acetonitrile
Table 3.10: Rate constants of oxidation of different substituted phenylthioureas at four different temperatures in acetonitrile
[CTAB] 1.5x10-3 1x10-3 5x10-4 2.5x10-4 1x10-4
kobs× 10-4 in s-1 26.41 27.52 30.21 39.23 50.17
Arylthiourea
kobs× 104 in s-1 Ea kJ mol-1
∆H
kJ mol-1 ∆S
J mol-1 K-1 ∆G
kJmol-1 288K 293K 298K 303K
Phenylthiourea 22.99 40.23 62.95 108.28 73.95 71.47 -47.20 85.54
P-Chloro Phenylthiourea
45.79 59.84 136.34 165.43 67.89 65.41 -61.13 83.63
p-Methyl Phenylthiourea
09.98 12.17 17.81 27.67 49.79 47.31 -138.78 88.67
p-Methoxy phenylthiourea
11.98 12.94 15.16 21.05 35.83 33.35 -186.95 89.07
122
Considering all the above results a reaction mechanism may be proposed
(Scheme 3.5). The permanganate ion attacks the sp2 carbon of the thiourea to form a
complex (3.1). The resultant sulfide attacks the electron deficient Mn to form a four
membered cyclic ester which, with a loss of two electrons, dissipates to corresponding
carbonyl compound, sulfur and Mn(V). The reactive Mn(V) again reacts with another
phenylthiourea in the similar manner to yield phenylurea, sulfur and Mn(III). The
unstable Mn(III) undergoes disporopotionation reaction with Mn(V) to yield two Mn(IV).
In this complex mechanism, the dissipation of the complex of Mn(VII) to Mn(V) is the
rate determining step.
Ar N CSH
NH2Ar
HN C
NH2
ArHN C
S
NH2+
Mn
O OO
+Q-O
ArHN C
S
NH2
Mn-O
OO
O
Q+
Mn
O O
O-Q+
SArHN C
O
NH2 + +
fast
slow
ArHN C
S
NH2
+
MnO O
+Q-O
ArHN C
S
NH2
Mn-O O
O
Q+
Mn
O O-Q+
SArHN C
O
NH2 + +
Mn (V) + Mn (III) 2 Mn ( IV)
fast
fast
fast
S
(3.1)
Mn(V)
Mn(III)
(Scheme 3.5)
123
3.3.4 REFERENCES 1. (a) Bhushan, V.; Rathore, R.; Chandrasekaran, S. Synthesis 1984, 431. (b)Vanker,
P.; Rathore, R.; Chandrasekaran, S. J. Org. Chem. 1986, 51, 3063. (c) Dash, S.; Patel, S.; Mishra, B. K. Tetrahedron 2009, 65, 707.
2. Mishra, B. K.; Dash, S. Int. J. Chem. Kinet. 1995, 27, 627.
3. Sumichrast, R.; Holba, V. React. Kinet. Catal. Lett. 1992, 48, 93.
4. Adewuyi, A.; Oderinde, R. A.; Rao, B.V.S.K.; Prasad, R.B.N.; Nalla, M. Chem. Central Journal 2011, 5, 79.
5. Sankhla, R.; Kothari, S.; Kotai, L.; Banerji, K. K. J. Chem. Res. (S), 2001, 127.
6. Shukla, R.; Sharma, P. K.; Kotai, L.; Banerji, K. K Proc. Indian Acad. Sci. (Chem. Sci.) 2003, 115, 129.
7. AL-Thabaiti, S. A.; Al-Nowaiser, F. M.; Obaid, A. Y.; Al-Youbi, A. O.; Khan, Z. Colloid Polym Sci 2007, 285, 1479.
8. Bryce, M. R.; Johnston, B.; Kataky, R.; Toth, K . Analyst 2000, 125, 861.
9. Clezy, P. S.; Smythe, G.A. Aust. J. Chem. 1969, 22, 239.
10. Barton, D.H.R.; Ley, S.V.; Meerholz, C.A. Tetrahedron Lett. 1980, 21, 1757.
11. Laidler, K. J. in Chemical Kinetics McGraw Hill: New York, 1968, 2nd edition, p.327.
12. Mishra, B. K.; Dash, S. Indian J. Chem. A 2001, 40, 159.
13. Patel, S.; Mishra, B. K. J. Org. Chem. 2006, 71, 6759.
Oxidation kinetics of Simvastatin by CTADC and
CTAP
124
4.1 OXIDATION KINETICS OF SIMVASTATIN BY CTADC
4.1.1 INTRODUCTION
Simvastatin (SV) is a lactone prodrug used for the treatment of
hypercholesterolemia1 and is chemically designated as [(1S, 3R, 7R, 8S, 8aR)-8-[2-[(2R,
4R)-4-hydroxy-6-oxo-oxan-2-y1l]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-
1-y1]2,2- dimethylbutano- ate (Figure 4.1). Following conversion of this lactone prodrug
to its hydroxyl acid form, the compound is a potent competitive inhibitor of 3-hydroxy-3-
methylglutaryl-CoA reductase (HMGCoA), the rate limiting enzyme in cholesterol
biosynthesis.2 The oxidative biotransformation of SV takes place at the heptanoic acid
side chain.3 In vitro formation of a β-oxidation product of simvastatin hydroxy acid and
its intermediates in mouse livers has been reported. SV inhibits the oxidation of low-
density lipoproteins4 and also decreases aldehyde production derived from lipoprotein
oxidation.5 It acts as an antioxidant in lipoprotein particles and together with its lipid-
lowering properties, plays an important role in preventing atherosclerosis. SV treatment
induces an increase in autoantibodies against specific oxidized LDL antigens.6
The electrochemical detection of SV in the form of drugs stems on its oxidation
behaviour in presence of a multi-walled carbon nanotubes-dihexadecyl hydrogen
phosphate composite modified glassy carbon electrode.7
It is expected that SV, as lactone, is very susceptible to hydrolysis (Figure 4.1).
Investigation of SV stability after various stress tests, such as: acid and base hydrolysis,
oxidation, and heat has been carried out.8
In order to make definite conclusions about SV degradation behavior and profile,
reaction kinetics have been investigated. The primary aim of performing these studies for
pharmaceutical compounds is to predict the rate of degradation reaction and to
understand the mechanism of the reaction.9 Furthermore, understanding of these reactions
provides valuable information as to which degradation products or by-products are likely
to constitute significant impurities that need to be monitored. The majority of degradation
reactions of pharmaceutical compounds in solution occurs at a finite rate and is affected
by solvent type, concentration of reactants, temperature, pH of the medium, etc. The
degradation of the majority of drugs can be classified as zero, first or pseudo first order,
125
even though they may degrade by more complex mechanisms and the true expression
may be of higher order.
O O
CH3H3C
CH3
CH3H
H
H
CH3H H
O
O
HOH
HO O
CH3H3C
CH3
CH3H
H
H
CH3H H
COOHOHH
OH
H
O O
CH3H3C
CH3
CH3H
H
H
CH3H H
O
O
H
hydrolysis
simvastatin acidsimvastatin
anhydrosimvastatin
hydrolysis
Figure 4.1: Possible degradation path-ways of simvastatin.
The acid degradation of SV was found to be second order whereas the oxidative
degradation was proved to be the first order reaction for which the rate constant and half-
life were determined.9 The oxidative decomposition of SV was faster than the acid
degradation.
Oxidation of this diene containing drug by tert-butoxyl and 1,1-diphenyl-2-
picrylhydrazyl radicals was reported by Karki et al.10 A competitive kinetic method was
used to determine the relative rate of hydrogen atom abstraction by tertbutoxyl radical to
β-scission.
In the kinetics study of oxidation of SV in aqueous surfactant solution a thermally
labile free radical initiator was used to attain measurable reaction rates, and the rate
constants were determined by measuring oxygen consumption using an oxygen
126
electrode.11 The addition of butylated hydroxyanisole(BHA) was found to stabilize the
drug.
In the efforts of exploring some biomimetic oxidants to oxidize organic substrates
in organic solvents, the oxidation behaviour of cetyltrimethylammonium permanganate
(CTAP), 12-15 cerate (CTACN),16 and dichromate (CTADC)17 towards various organic
substrates have been reported from our research school. These are inorganic oxidants
with an organic amphipathic carrier, cetyltrimethylammonium (CTA+) ion, to carry the
oxidants into the organic (lipid) phase. However, these oxidants are hydrophobic and thus
support the existence of a tight ion pair between the cationic carrier and the anionic
oxidant in nonpolar medium.18 In organic solvents, CTAP oxidizes its carrier, CTA+, in a
manner similar to β-oxidation of fatty acids.12 Other aforesaid oxidants are found to be
inert toward their carrier. CTAP and CTADC have been used for oxidation of cholesterol
to yield a diol at the double bond15 and 7-dehydrocholesterol17 respectively, while with
addition of acetic acid to CTADC in dichloromethane (DCM) the product was found to
be 5-cholesten-3-one. CTADC is devoid of an acidic proton and thus is relatively milder
than other Cr(VI) oxidants.19 In the absence of acid, CTADC exhibits some bizarre
reactions with nonconventional products. Aromatic amines are found to yield
corresponding diazo compounds,20 and arylaldoximes yielded corresponding nitriles.21
In this section, an attempt has been made to investigate the oxidation behavior of
CTADC towards the prodrug, SV in organic solvents. To achieve the objective, the
oxidation product was characterized, and kinetics were run in different media with varied
polarities and also in microheterogeneous systems, generated due to the presence of a
cationic surfactant, (CTAB: cetyltrimethylammonium bromide) and anionic surfactant
(SDS: sodium dodecyl sulfate) at different concentrations. By analyzing the rate
constants determined by varying [substrate], [acid], and [CTADC] in the reaction
process, a suitable mechanism for the reaction has been proposed. Earlier, SV was
subjected to oxidative degradation by using hydrogen peroxide to yield a variety of
products through a free radical mechanism.22 Cr(VI) oxidation of many biological
substrates also encountered free radical intermediate and the reactions become
127
complicated. In most of the oxidations by CTADC, no free radical mechanism has been
proposed. Thus the present study highlights the effect of Cr(VI) oxidant on SV to get a
clear picture of the oxidative stress on SV.
4.1.2 EXPERIMENTAL
4.1.2.1 Materials
CTADC was prepared by the method reported earlier (Chapter 2). SV (4.1)
obtained from Aldrich was used without further purification. Glacial acetic acid was used
as a source of hydrogen ion and was used without further purification. The organic
solvents used were purified by standard methods.23 The surfactants,
cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS) were
obtained from Spectrochem, Mumbai and were purified by recrystallization from ethanol
solution.
4.1.2.2 Kinetic Measurements
The oxidation kinetics of SV by CTADC in the presence of acetic acid were
monitored in different solvents and surfactant systems spectrophotometrically at the
absorption maxima of CTADC ( 350 nm) by using Hitachi U3010 spectrophotometer
with a thermostatic cell holder attached to a water bath. The first-order rate constant, kobs
was obtained from the linear (r = 0.99) plot of log[oxidant] against time upto 75%
completion of the reaction in a pseudounimolecular condition by keeping a large excess
of SV. The values reported are the average of triplicate runs and are reproducible within
±4% error.
4.1.2.3 Product Analysis
After keeping the reaction mixture of CTADC and SV in proper composition for
24h in DCM and acetic acid, the volume of the reaction mixture was reduced to a pasty
mass under low pressure. Then the organic compounds from pasty mass were extracted
by using diethyl ether in excess. On evaporation of the ether the products were subjected
to column chromatographic separation by using a mixture of ethyl acetate and toluene
(1:2 v/v). On evaporation of the eluents collected from the column and having a single
spot in TLC, the isolated compound was subjected to IR, NMR and FABMS analyses
128
(Charts 4.1-4.2). The compound was found to be the corresponding carbonyl compound
(4.3) (Scheme 4.2).
4.1.2.4 Stoichiometry
The stoichiometry of the reaction was determined by performing the experiments
at 303 K, under the conditions with fixed [Oxidant] and varying [SV]. The disappearance
of Cr (VI) was followed until the absorbance values became constant and then CTADC
was estimated after 48 h. The stoichiometry ratios are found to be 1:2 for CTADC/SV.
4.1.3 RESULT AND DISCUSSION
The colour of the solution of CTADC and SV in DCM in presence of acetic acid
under reflux condition changes with time and after six hours turns to green indicating the
reduction of Cr(VI) to Cr(III). From the area per molecule of CTADC on water surface
determined from the surface pressure/ area isotherm, it is found that CTADC exists as
contact ion pair in aqueous medium as well as in organic solvents. 18 In presence of acetic
acid, the dichromate ion becomes free from the grasp of the quaternary onium ion due to
the change in polarity of the medium and also the probable substitution of onium ion by
proton of acetic acid. Further, when acrylonitrile is added to the reaction mixture during
the reaction process, no turbidity of the medium in the reaction mixture is observed. This
observation rules out the possibility of free radical mechanism. The reaction kinetics of
the oxidation reaction has been monitored in the presence of acid, and the kinetic data are
tabulated in Table 4.1.
The acid catalysed oxidation of SV with CTADC in DCM is found to increase
linearly with increase in concentration of SV (Figure 4.2). To obtain a relationship
between the rate constants with the parameters of the reaction condition, i.e. [substrate],
[oxidant] and [acid], log kobs values obtained in different conditions have been correlated
with the above three parameters through multiple regression analysis. The regression
model, thus obtained, is presented in Eq. 4.1. The orders with respect to [CTADC], [SV]
and [acetic acid] are found to be 0.634, 0.554 and 0.844 respectively.
500
750
1000
1250
1500
1750
2000
2500
3000
3500
4000
1/cm
6065707580859095 %T
3847.993784.34
3535.523510.45
3456.443429.43
3406.293381.21
3346.503325.28
3305.993286.703265.49
3248.133207.62
3109.253088.033066.82
2964.592927.94
2877.792854.65
2738.922603.90
2194.992156.422123.632102.412077.332052.262029.112002.11
1955.821942.321896.031880.601851.66
1724.361654.92
1624.061577.77
1406.111311.59
1246.021153.43
1039.631016.49
968.27
866.04817.82
771.53725.23
657.73613.36
580.57553.57
532.35486.06
470.63432.05
406.98
PS
1
Cha
rt 4
.1: I
R sp
ectra
of o
xidi
zed
prod
uct o
f Sim
vast
atin
with
CTA
DC
Cha
rt 4
.2: 1 H
NM
R sp
ectra
of o
xidi
zed
prod
uct o
f Sim
vast
atin
with
CTA
DC
129
Table 4.1: Effect of [SV], [CTADC], and [Acetic Acid] on the rate constant of oxidation
of SV by CTADC at 303K in DCM
log kobs = -5.114(±0.321)- 0.634(±0.074)log[CTADC] +0.554(±0.074)log[SV]
+ 0.844±0.107 log[Acetic acid] R2 = 0.964 F = 54 n = 10 ( 4.1)
Figure 4.2: Plot of 104kobs vs. [SV] in the oxidation reaction of CTADC with SV at 303K
0
5
10
15
20
0 0.02 0.04 0.06
104 k
obs
in s
-1
[SV] in M
[CTADC]×104(M) [SV](M) [Acetic acid](M) kobs× 104 (s-1) Rate x107 (mol l-1s-1)b
0.5 0.02 4.86 17.27 0.86
1 0.02 4.86 11.13a 1.11
2 0.02 4.86 9.21 1.84
4 0.02 4.86 4.22 1.69
1 .005 4.86 5.76 0.58
1 0.01 4.86 6.91 0.69
1 0.04 4.86 17.27 1.73
1 0.02 6.48 14.97 1.50
1 0.02 3.24 8.06 0.81
1 0.02 1.62 4.61 0.46 a104kobs at 293, 298 and 308 were found to be 6.53, 9.98 and 14.97s-1 respectively. brate = kobs x [CTADC]
130
Using the regression model, the logkobs values have been calculated and plotted
against the observed values (Figure 4.3). A linear plot without any outlier supports the
validity of the regression model.
Figure 4.3: Plot of observed logk vs calculated logk using the regression model eq. 4.1
Without acid, the reaction became too slow to measure. With increasing [Acetic acid], the
rate constant increases linearly (Figure 4.4). The reaction is found to be acid catalyzed
with an uncatalyzed rate of 1.15 x 10-4 s-1.
Figure 4.4: Plot of 104kobs vs [acetic acid] in the oxidation reaction of SV with
CTADC at 303K
In an earlier report on oxidation of cholesterol, nonlinearity with Michaelis-
Menten relationship of substrate with the kobs was observed indicating a complex
mechanism for the oxidation reaction.17 In the present study the molecularity is found to
-3.5
-3.3
-3.1
-2.9
-2.7
-2.5
-3.5 -3 -2.5
Cal
cula
ted
logk
Observed logk
0
5
10
15
20
0 2 4 6 8
104 k
obs
in s
-1
[Acetic acid] in M
131
be in fraction (eq. 4.1) indicating the occurrence of a complex reaction mechanism, which
may be proposed vide in fra (Scheme 4.1: where Q refers to CTA).
Complex (C)
Q2Cr2O7 + H+ QCr2O7H Q++K1
+SV QCr2O7HK2
k ProductRate determining step
Complex (C)
(Scheme 4.1)
The above scheme can lead to the derivation of a rate equation (eq. 4.2).
Rate = − [ ] = k[C] = kK K [ ] [ ] [ ][ ]
(4.2)
Cr(III) is found in the reaction products during the oxidation of various substrates
by CTADC in organic medium.17 The existence of Cr(III) in the product mixture is well
established from the peak at 580 nm. However, reaction kinetics could not be studied at
this wavelength due to nonreliability and low absorptivity of the spectrum. The formation
of Cr(III) from Cr(VI) due to reduction seems to be a complex phenomenon as shown
below.
Cr(VI) + 2e → Cr (IV)
Cr(IV) + Cr(VI) → 2Cr(V)
Cr(V) + 2e → Cr(III)
Cr(VI) is initially reduced to Cr(IV), which subsequently changes to Cr(V) with
another Cr(VI). The formation of Cr(III) is a result of two-electron reduction of Cr(V).
The existence of Cr(IV) as the reduced state in oxidation of benzyl alcohol by
quinolinium fluorochromate has also been reported by Dave et al.24
132
Figure 4.5: Plot of 104 kobs vs [CTADC] in the oxidation of SV at 303 K in DCM
The rate constant is found to decrease nonlinearly with increasing [CTADC].
(Figure 4.5) Similar observations have been made for oxidation reaction of different
substrates by CTADC in organic solvents. Earlier, it has been rationalised by proposing
the occurrence of a reversed micellar phenomenon during the oxidation reaction.17 This
proposition was further supported by drastic decrease in the rate constant with addition of
CTAB (Table 4.2), a reversed micelle forming surfactant. The spherical reversed micelle
has various localization sites, including the polar inner core, where the ionic polar
oxidant is partitioned more. Substrate, being nonpolar in characteristics, partitions to the
bulk and remains away from the reactive oxidant. With increase in [CTADC], the inner
polar core may assume a larger interfacial area so that the substrate can, relatively, be
more in contact with the polar oxidant to facilitate the complexation of the SV and
Cr(VI). Due to decrease in the polarity of the complex compared to the reactants, it is
partitioned to the nonpolar bulk and, therein, dissociates to the product. The larger the
interfacial area, the less will be the partitioning leading to decrease in the rate. CTAB can
form spherical micelle in aqueous medium and reversed micelle in nonaqueous
medium.25 The decrease in the rate constant may be attributed to the enhanced reversed
micellization in presence of CTAB, which provides a common counter ion with CTADC
for the formation of reversed micelle.
0
5
10
15
20
0 2 4 610
4 kob
sin
s -1
[CTADC] x104 in M
133
Table 4.2: Rate constant of oxidation of SV at different [CTAB] and [SDS] at 303K in
Dichloromethane. ([CTADC] =1x10-4M, [SV] = 0.02M, [Acetic Acid] = 4.86M)
[CTAB]x104 M kobs× 104 s-1 [SDS]x104M kobs× 104 s-1
1 9.6 1 17.66
5 5.76 5 36.08
10 3.45 10 46.06
20 2.30 15 58.73
- - 50 74.46
Further, as the reaction is acid catalysed and the interface due to CTA+ is
positively charged which repels the proton, the rate is retarded. This proposition gets
further support from the rate enhancement due to the addition of sodium dodecyl sulphate
(SDS), an anionic surfactant(Figure 4.6). SDS is inert towards CTADC and provides an
anionic environment to the reactant either through mixed micellization or through a
reversed micellar aggregate, which can provide an anionic interface for the interaction
between the proton, dichromate and SV.
The rate law as derived in eq. 4.2 gets support from the above observations. With
increasing [CTADC], [acetic acid] and [substrate] the rates of reaction (Table 4.1)
increase linearly. Similarly, the rate of reaction decreases with increasing [CTA]. The
plot of rate vs. 1/ [CTA] is also found to be linear (R2=0.99).
Figure 4.6: Plot of 104kobs vs [surfactant] for the oxidation reaction of SV with CTADC at 303K
01020304050607080
0 0.002 0.004 0.006
104 k
obs
in s
-1
[ surfactant]M
SDS
CTAB
134
To investigate the effect of environment on the reaction mechanism, nine organic
solvents (Table 4.3) with different polarity were used as reaction medium. CTADC was
found to be stable in all these solvents in presence of acetic acid for more than 24hr. The
rate constant is found to be highly sensitive to change in polarity of the solvents (Table
4.3). To elucidate the characteristics of the transition state of the reaction, the rate
constants were plotted against various solvent parameters like cation binding (A) and
anion binding (B) capacity, dielectric constant, π, dipole moment and logP (P being the
partition coefficient of the substrate between octanol and water indicating the nonpolar
characteristics of the solvents). The plots of the rate constants with all the polarity
parameters delineate scattered relationship indicating the transition state to be sensitive to
polarity without any specific trend. However, from the linear relationship of these
parameters with the rate constants, the solvents can be classified into dipolar aprotic
solvents (acetonitrile, dioxane, ethyl acetate and acetone) and non polar solvents
(benzene, toluene, carbon tetrachloride, chloroform and dichloromethane). With
increasing dipole moment or dielectric constant of the solvent, in most of the cases, the
rate constant decreases. In cognizance to this, the rate constant increases with increasing
logP value of the solvent (Figure 4.7). These observations support the formation of a
relatively less polar transition state compared to the polarity of the reactants.
Table 4.3: Observed rate constants for the oxidation reaction of SV in various organic solvents at 303K, [CTADC]=1x10-4M, [SV]=0.02M and [Acetic Acid]=4.86M.
Sl No. Solvent kobs x 104(s-1)
1 Dioxan 6.91 2 Ethyl acetate 8.44
3 Acetone 8.06
4 Acetonitrile 5.76
5 Benzene 13.43
6 Toluene 15.74
7 Dichloromethane 11.13
8 Chloroform 17.66
9 Carbontetrachloride 19.96
135
The thermodynamic parameters such as ∆H#, ∆S# and ∆G# were calculated for the
oxidation of SV with CTADC in the presence of 4.86 M acetic acid by using Arrhenius
and Eyring equation and are found to be 36.5±1.4 kJmol-1, -181.1±6.9 JK-1 and 91.4±3.5
kJmol-1 respectively. A high negative value in ∆S# supports the proposal of the
involvement of a cyclic transition state (4.2).26
Figure 4.7: Plot of 104kobs vs Log P for the oxidation of SV with CTADC at 303K
From the above findings a tentative mechanism has been proposed (Scheme 4.2),
wherein, the CTADC equilibrates with acetic acid to form the protonated dichromate,
which subsequently reacts with SV giving rise to a dichromate ester. The complex
decomposes to the reduced Cr(IV), which further disproportionates to stable Cr(III); and
corresponding carbonyl compound by -hydrogen abstraction from the substrate. The
FABMS results of the carbonyl compound with a (M-H)/z peak at 415.3 corroborate the
structure of the product. The appearance of characteristic IR band at 1577 cm-1 for β-
diketone and disappearance of 3549 and 1265 cm-1 for –OH substantiate the oxidation of
secondary –OH to corresponding carbonyl one. Further the disappearance of NMR peak
at 1.568 δ in the product is also an indicator of conversion of hydroxyl group to
corresponding carbonyl group.
Thus, SV an established prodrug, when interacts with CTADC, leads to the
formation of the corresponding carbonyl compounds catalyzed by an acid through an
ionic intermediate. The non free-radical reaction leads to a mechanism with less number
or almost no side products. Further, the reaction is proposed to occur in an organized
media where the partition of substrates and oxidants into different domains, retards the
123
4
5
6
7
8
0
5
10
15
20
25
-1 0 1 2 3
104 k
obs
in s
-1
LogP
136
rate of the reaction. The use of amphiphilic compounds like CTAB and SDS in the
reaction media provides a biomimetic environment to understand the reaction process.
Thus CTADC is found to be an excellent model-oxidant to unveil the oxidative
degradation of different substrates in biological membranes.
Q2Cr2O7 + H+ QCr2O7H Q++K1
O
O
HO O
OK2
Cr O
O
O
Cr
O
O
OH +-OQ+
(4.1)
O
O
O
O
O
O
O
O O
O
Cr O-O
O
O
Q+ Cr
H
Cr O-O
O
O
Q+ CrHO OH
OH+
k
(4.3)
HO OH
O
O
O O
O
Cr O-O
O
O
Q+ Cr
HO
HO OH
O
(4.2)
(Scheme 4.2)
137
4.1.4 REFERENCES
1. Mauro, V.F. Clin. Pharmacokinet. 1993, 24, 195.
2. Alberts, A.W.; Chen, J.; Kuron, G.; Hunt, V.; Huff, J.; Hoffman, C.; Rothrock, J.; Lopez, M.; Joshua, H.; Harris, E.; Patchett, A.; Monaghan, R.; Currie, S.; Stapley, E.; Albers-Schonberg, G.; Hensens, O.; Hirshfield, J.; Hoogsteen, K.; Liesch, J.; Springer, J. Proc. Natl. Acad. Sci. USA 1980, 77, 3957.
3. Prueksaritanont, T.; Ma, B.; Fang, X.; Subramanian, R.; Yu, J.; Lin, J. Drug Metabolism Disposition 2001, 29, 1251.
4. Giroux, L.M.; Davignon, J.; Naruszewicz, M. Biochim. Biophys. Acta. 1993, 1165, 335.
5. Girona, J.; La Ville, A.E.; Sola, R.; Plana, N.; Masana, L. Am. J. Cardiol. 1999, 83, 846.
6. Gonçalves, I.; Cherfan, P.; Söderberg, I.; Fredrikson, G. N.; Jonasson, L. Autoimmunity 2009, 42, 203.
7. Zhang, H.; Hu, C.; Wu, S.; Hu, S. Electroanalysis 2005, 17, 749.
8. Malenovic, A.; Jančic-Stojanovic, B.; Ivanovic, D.; Medenica, M. J. Liq. Chromat. Relat. Techn. 2010, 33, 536.
9. Ahuja, S. Impurities Evaluation of Pharmaceuticals; Marcel Dekker Inc.: New York, USA, 1998.
10. Karki, S.B.; Treemaneekarn, V.; Kaufman, M.J. J. Pharm. Sci. 2000, 89, 1518.
11. Kaufman, M.J. Pharm. Res. 1990, 7, 289.
12. Mishra, B. K.; Dash, S. Int. J. Chem. Kinet. 1995, 27, 627.
13. Mishra, B. K.; Dash, S. Bull. Chem. Soc. Jpn. 1994, 67, 673.
14. Mishra, B. K.; Dash, S. Indian J. Chem. A 1997, 36, 662.
15. Mishra, B. K.; Dash, S. Indian J. Chem. A 2001, 40, 159.
16. Nayak, B. B.; Sahu, S.; Patel, S.; Dash, S.; Mishra, B. K. Indian J. Chem. A 2008, 47, 1486.
17. Patel, S.; Mishra, B. K. J. Org. Chem. 2006, 71, 3522.
18. Mishra, B K; Sahu, S.; Padhan, S.; Patel, S. Indian J. Chem. A 2009, 48, 1527.
19. Patel, S.; and Mishra, B. K. Tetrahedron 2007, 63, 4367.
20. Patel, S.; Mishra, B. K. Tetrahedron Lett. 2004, 45, 1371.
21. Sahu, S.; Patel, S.; Mishra, B. K. Synth. Commun. 2005, 35, 3123.
138
22. Razavi, B.; Song, W.; Santoke, H.; Cooper, W. J. Rad. Phys. Chem. 2011, 80, 453.
23. Riddick, J. A.; Bunger , W. B.; Organic Solvent Techniques of Chemistry, Vol. II, Wiley-Interscience; New York, 1970.
24. Dave, I.; Sharma, V.; Banerji, K. K. Indian J. Chem. A 2002, 41, 493.
25. Senapati, S.; Dash, P. K.; Mishra, B. K.; Behera, G. B. Indian J. Chem. 1995, 34A, 227.
26. Freeman, F.; Kappos, J. C. J. Am. Chem. Soc. 1985, 107, 6628.
139
4.2 OXIDATION KINETICS OF SIMVASTATIN BY CTAP
4.2.1 INTRODUCTION
Due to the multifunctional groups in Simvastatin (SV), it has become an
interesting candidate to investigate on selective oxidation reaction. The reaction pathways
and the final products of the oxidation reaction depend on the reagents used and condition
of the reaction. In previous Chapter 3 cetyltrimethylammonium permanganate (CTAP)
has been used for oxidation of phenyl thiourea in organic medium. Earlier CTAP has
been used for oxidation of olefinic double bonds, trans olefinic double bonds cleave to
corresponding carbonyl comounds1,2 whereas cis-olefinic double bonds result in the
formation of diols.3 Recently the selective oxidation of benzylalcohol to benzaldehyde
was obtained with KMnO4 using 18-crown-6 as passé transfer catalyst.4 Cholesterol
contains both an cis-olefinic double bond and hydroxyl group. However, oxidation of
cholesterol by CTAP afforded corresponding diol.3
The present section deals with the oxidation kinetics of SV, bearing multiple
functional groups by using CTAP as the oxidant in organic solvent. By analyzing the rate
constants determined by varying [substrate], [CTAP], and the reaction temperature in the
oxidation process, a suitable mechanism for the reaction has been proposed.
4.2.2 EXPERIMENTAL
4.2.2.1 Materials
CTAP was obtained by precipitation from an aqueous mixture of
cetyltrimethylammonium bromide and potassium permanganate as reported earlier
(Chapter 2). SV was used without further purification. The solvent acetonitrile used was
purified by standard method. 5
4.2.2.2 Kinetic Measurements
Kinetic measurements were carried out using a Hitachi U3010 spectrophotometer
with a thermostatic cell holder attached to a water bath. The rates of the oxidation were
determined by monitoring the disappearance of permanganate ion at 527nm. All the
solution were prepared afresh for each experiment using acetonitrile as the solvent. The
first-order rate constant, kobs was obtained from the linear (r = 0.99) plot of log of change
140
in [CTAP] against time upto 75% completion of the reaction in a pseudounimolecular
condition by keeping a large excess of SV. The rate constants reported were the mean
values of duplicate runs and were reproducible within ±6% error.
4.2.2.3 Product Analysis
After keeping the reaction mixture of CTAP and SV in proper composition for
24h in acetonitrile, the mixture was filtered and the volume of filtrate was reduced under
low pressure. Then the organic compounds were extracted by using diethylether in
excess. On evaporation of the ether the products were subjected to column
chromatographic separation by using a mixture of ethyl acetate and toluene (1:2 v/v). On
evaporation of the eluent with single spot in TLC, the isolated compound was subjected
to FABMS, and IR analysis (Charts 4.3-4.4). The compound is proposed to be the
corresponding carbonyl compound (4.3).
4.2.2.4 Stoichiometry
The stoichiometry of the reaction was determined by performing the experiment
at 303 K, under the conditions with fixed [Oxidant] and varying [SV]. The disappearance
of Mn(VII) was followed until the absorbance values became constant and then CTAP
was estimated after 24 h. The stoichiometry ratios are found to be 2:3 for CTAP/SV.
4.2.3 RESULT AND DISCUSSION
Permanganate is well established as an oxidant for oxidizing olefinic double
bonds to corresponding diols. Simvastatin contains two conjugated double bonds and a
hydroxyl group as the reaction centres for permanganate. The oxidation product is found
to be devoid of the hydroxyl group retaining the double bonds, which is clearly evident
from the IR spectra indicating the inertness of the double bonds towards permanganate
oxidation. The lone hydroxyl group present in simvastatin is oxidized to corresponding
carbonyl group leading to the formation of a cyclic dicarbonyl compound. The isolated
product from the reaction mixture exhibits a clear IR spectrum with a characterized band
at 1726cm-1 for an isolated carbonyl group which is nonexistence in the reactant. The
FAB-Mass spectral data also support the formation of the dicarbonyl product (Chart
4.4).
500
750
1000
1250
1500
1750
2000
2500
3000
3500
4000
1/cm
707580859095100
%T
3786.273462.223444.87
3427.513406.293385.073367.713346.50
3327.213307.92
3290.563267.41
3250.053230.77
3211.483192.19
3111.183091.893070.68
3014.742966.52
2929.872875.86
2736.992607.76
2534.462497.822480.462463.10
2409.092364.73
2077.332050.332029.11
1957.751903.74
1722.431660.711627.921583.56
1456.261386.82
1311.591253.73
1219.011157.29
1124.501055.06
1014.56889.18
864.11817.82
767.67663.51
605.65580.57
557.43538.14
482.20432.05
364.55
PS
2
Cha
rt 4
.3: I
R sp
ectra
of o
xidi
zed
prod
uct o
f Sim
vast
atin
with
CTA
P
Cha
rt 4
.4: F
AB
MS
spec
tra o
f oxi
dize
d pr
oduc
t of S
imva
stat
in w
ith C
TAP
141
The fate of Mn(VII) has been monitored through electronic spectra. The colour of
the solution of CTAP and SV in acetonitrile changes with time and after twenty four
hours turned to brown indicating the reduction of Mn(VII) to Mn(IV). Mn(III) is obtained
in the reaction products during the oxidation of various substrates by CTAP in organic
medium.3 The existence of Mn (III) in the product mixture is ascertained from the peak at
486 nm.6 With depletion of the peak at 527 nm, the peak at 486 nm develops
concomitantly, albeit at a different rate. The conversion of Mn(VII) to Mn (IV) is a result
of consecutive reduction of Mn(VII) to Mn(V) and Mn(III) followed by a
dispropotionation reaction to Mn (IV) (Scheme 4.3)
2(Mn(VII) + 2e → Mn(V))
Mn(V) + 2e → Mn(III)
Mn (V) + Mn(III) → 2 Mn(IV)
2 Mn(VII) + 6e → 2 Mn(IV)
(Scheme 4.3)
The complex mechanism of the redox reaction of manganese could not be encountered in
the rate equation due to the relatively slow step of conversion of Mn(VII) to Mn (V)
which is the rate determining step in the reaction. The kinetic data of the oxidation
reaction are tabulated in Table 4.4.
Table 4.4: Rate constants of oxidation of SV by CTAP at 303K in Acetonitrile at 527nm
[CTAP]×104(M ) [DG] (M) kobs× 104 (s-1) 2 0.02 10.75 2 0.015 7.29 2 0.01 4.22 2 0.0075 3.07 2 0.005 2.31 4 0.02 7.68 6 0.02 7.29 1 0.02 19.58
0.5 0.02 34.55 1 0.01 6.91a
a104kobs at 293 and 313K were found to be 5.37 and 11.13s-1 respectively.
142
The rate constant of the oxidation of SV with CTAP in acetonitrile is found to
increase with increase in concentration of SV (Figure 4.8). The plot of observed rate
constants against [substrate] is found to be linear passing through origin. While
investigating the oxidation of some cyanines with CTAP in dichloromethane, Dash and
Mishra have also observed similar trend with respect to [substrate] variation.1 However,
the rate constant is found to decrease nonlinearly with increasing [CTAP] (Figure 4.9).
Similar observations have been made during the kinetic study of cinnamic acid by
tetrabutylammonium permanganate.6 When tetrabutylammonium acetate was added to
the reaction mixture, the rate retards gradually. This phenomenon has been attributed to
the role of acetate ion in rate determining step. But in the present study the rate
retardation due to increase in CTAP concentration has been attributed to the aggregation
of CTA+ forming small aggregates leading ultimately to the formation of reversed
micelles. A reversed micelle is characterized by the self assembly of surfactant in organic
solvents and with structural artifact opposite to micelle in aqueous medium. In reversed
micelle, the polar head groups assemble due to the lipophobic interaction forming the
core of the aggregate and the hydrophobic tails ripple around the core. The permanganate
ions, due to contact ion pair with the CTA unit7 partitions away from the substrate, which
are solubilized in the bulk solution. With increasing [CTAP], the formation of reversed
micelle increases leading to decrease in rate.
Figure 4.8: Plot of 104kobs vs. [SV] in the oxidation of SV at 303K
With the addition of CTAB, which forms reversed micelles in most of the organic
solvents, the rate of reaction is found to be unaltered. Earlier, a rate retardation of
0
2
4
6
8
10
12
0 0.01 0.02 0.03
104 k
obs
in s
-1
[SV] in M
143
oxidation by CTADC with increase [CTAB] has been reported in section 4.1. In the
present case, the inertness of the [CTAB] on the rate constant may be attributed to the
inertness of the effect of CTAB on the micellization of CTAP. It can happen only when
CTAP does not form mixed micelles with CTAB in presence of SV. As SV is a large
hydrophobic molecule, and as micellization is an entropy driven process, the mixed
micellization due to CTAP and CTAB is hindered by the presence of SV.
Figure 4.9: Plot of 104 kobs vs [CTAP] in the oxidation of SV at 303 K
The log of pseudo-first order rate constants have been subjected to multiple
regression analysis and the order of reaction with respect to CTAP and SV are found to
be 0.6 and 1.3 respectively. Hence an equation may be proposed vide in fra:
log k = 1.321 log [SV] – 0.649 [CTAP] – 3.07 (4.3)
The thermodynamic parameters such as ∆H#, ∆S# and ∆G# have been calculated
for the oxidation of SV with CTAP by using Arrhenius and Eyring equation and are
found to be 25.16 kJmol-1, -205.01JK-1 and 87.282 kJmol-1 respectively. The high
negative value in ∆S# supports the proposition made by Stewart and co-workers8,9 for
ionic transition state. It is of interest that the entropy of activation, ∆S# is negative for the
group of Mn(VII) reactions for which the investigators either present direct evidence or
postulate complex formation between Mn(VII) and the reductant species.8,9 The high
negative entropy, in the present case, suggests a cyclic transition state during the reaction
05
10152025303540
0 2 4 6 8
104 k
obs
in s
-1
[CTAP] x 104 in M
144
between the permanganate ion and the substrate.8,10 Accordingly the following
mechanism has been proposed for the oxidation of SV by CTAP (Scheme 4.4). The
interaction of permanganate with the substrate initiates with the entrapment of -proton
of the hydroxyl group by the permanganate ion with concomitant transfer of the hydroxyl
hydride to the oxo group resulting in loss of two electrons from Mn. The normal attack of
manganate to double bond is found to be formidable due to the thermodynamic stable
conjugated system. The further interaction of MnO3- with another SV in the same
manner finally leads to MnO2-. The disproportionation reaction of MnO3
- and MnO2-
affords MnO2.
O O
O
O
OHH
MnO
O
+Q-O
O
+O O
O
O
OH
MnO
O
-O
O
H
O O
O
O
OH
MnO
-O
+Q-O
O
H
O O
O
O
OMn
OH
-O
HO
OQ+
O O
O
O
OH
MnO
O-
O
+
H
Q+
O O
O
O
O
Mn-O
HO
Q+
+
Mn (V) + Mn (III)
+
2 Mn (IV)fast
fast
slow
fast
-H2O
MnO
-O
OQ+
OH
Mn(V )
Mn (III)
Q+
k+1
k-1
k2
slow
(Scheme 4.4)
145
4.2.4 REFERENCES
1. Mishra, B. K.; Dash, S. Bull. Chem. Soc. Jpn. 1994, 67, 3289.
2. Mishra, B. K.; Dash, S. Indian J. Chem. A 1997, 36, 662.
3. Mishra, B. K.; Dash, S. Indian J. Chem. A 2001, 40, 159.
4. Jose, N.; Sengupta, S.; Basu, J.K.; J. Mol. Catal. A 2009, 309, 153.
5. Riddick, J. A.; Bunger , W. B.; Organic Solvent Techniques of Chemistry, Vol. II, Wiley-Interscience; New York, 1970.
6. Perez-Benito J. F.; Lee D. G. J. Org. Chem. 1987, 52, 3239.
7. Mishra, B. K.; Sahu, S.; Padhan, S.; Patel, S. Indian J. Chem. A 2009, 48, 1527.
8. Stewart, R. Oxidation in organic chemistry part A, edited by K B Wiberg (Academic Press, New York) 1985, vol 1, 48.
9. Stewart, R.; Maden R. V. Discuss Faraday Soc. 1980, 211.
10. Freeman, F. Rev. React. Species Chem. React. 1976, 1, 179.
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Synthetic CommunicationsPublication details, including instructions for authors and subscription information:http://www.informaworld.com/smpp/title~content=t713597304
Oxidation of Arylthiourea by Cetyltrimethylammonium DichromateSandhyamayee Sahua; Prangya Rani Sahooa; Sabita Patelb; B. K. Mishraa
a Center of Studies in Surface Science and Technology, Department of Chemistry, SambalpurUniversity, Jyoti Vihar, India b Department of Chemistry, National Institute of Technology, Rourkela,India
Online publication date: 04 October 2010
To cite this Article Sahu, Sandhyamayee , Sahoo, Prangya Rani , Patel, Sabita and Mishra, B. K.(2010) 'Oxidation ofArylthiourea by Cetyltrimethylammonium Dichromate', Synthetic Communications, 40: 21, 3268 — 3273To link to this Article: DOI: 10.1080/00397910903398684URL: http://dx.doi.org/10.1080/00397910903398684
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OXIDATION OF ARYLTHIOUREA BYCETYLTRIMETHYLAMMONIUM DICHROMATE
Sandhyamayee Sahu,1 Prangya Rani Sahoo,1 Sabita Patel,2
and B. K. Mishra11Center of Studies in Surface Science and Technology, Department ofChemistry, Sambalpur University, Jyoti Vihar, India2Department of Chemistry, National Institute of Technology, Rourkela, India
With a view to investigate the oxidation behaviors of cetyltrimethylammonium dichromate
on multifunctional groups, some arylthioureas were subjected to oxidation, both in neutral
and in acidic conditions. In neutral conditions, the products were found to be a mixture of
corresponding urea and isonitrile. In acidic conditions, the products were corresponding
ureas only. A probable mechanism was proposed for the formation of the product, wherein
the first step involves coupling of –NH2 and –SH of one molecule to the –NH2 and –SH
of another molecule, respectively, which is followed by removal of nitrogen and sulfur.
The microwave irradiation resulted in great yield of isonitrile than urea in neutral conditions.
Supplemental materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 to view the free supplemental file.
Keywords: Cetyltrimethylammonium dichromate; isonitrile; thiourea
INTRODUCTION
Chromium(VI) oxidants with inorganic counterions are well established asstrong oxidants for many substrates, ranging from metal ions to naturally occurringorganic compounds. These oxidants are mostly water soluble and, because of theirhigh redox potential, are nonspecific. The thrust to make these oxidants lipopathicand chemoselective has generated several onium ions as the counterion of thechromates or dichromates. The pioneering work of Corey and coworkers gave birthto the first reagent of this type (i.e., pyridinium chlorochromate)[1] and subsequentlymany such other oxidants were established by various workers.[2] In our laboratory,we have synthesized cetyltrimethylammonium dichromate (CTADC) and studiedthe oxidation behavior of the oxidant toward various organic substrates.[3–7] Inthe absence of acid, CTADC exhibits some bizarre reactions, leading to nonconven-tional products.[3–5] The reagent is insoluble in water, which reduces contaminationof Cr(VI) in aqueous medium, and thus it can be used as a green reagent.
Received August 4, 2009.
Address correspondence to B. K. Mishra, Center of Studies in Surface Science and Technology,
Department of Chemistry, Sambalpur University, Jyoti Vihar 768019, India. E-mail: bijaym@
hotmail.com
Synthetic Communications1, 40: 3268–3273, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903398684
3268
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Table
1.Yield
andmeltingpointofarylthioureas(X
-C6H
4NHCSNH
2)andtheproducts(X
-C6H
4NHCONH
2andX-C
6H
4NC)ofoxidationbyCTADC
inthe
acetonitrile
(neutralandin
thepresence
ofaceticacid)andin
solidphase
(microwave)
Phenylurea
Yield
(%)
Phenylisonitrile
Phenylthiourea
Reflux
Yield
(%)
No.
XMp(�C)
Yield
(%)
Mp(�C)
Withoutacid
Withacid
Microwave
Mp(�C)
Reflux
Micowave
1H
152
65
147
48
85
32
Pale
yellow
oil
24
56
2o-C
hloro
147
45
152
51
78
34
Yellow
oil
29
55
3m-C
hloro
144
72
156
46
80
25
Pale
yellow
oil
30
43
4p-C
hloro
176
70
212
34
85
34
73
20
47
5p-M
ethyl
190
70
186
48
80
48
Yellow
oil
32
48
6p-Ethoxy
170
68
173
52
75
52
49
36
44
7p-N
itro
198
50
228
47
70
47
110
35
35
Note.Theyieldsare
onisolationbasis.
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To explore the chemoselectivity of CTADC, a series of substitutedphenylthioureas have been synthesized to be used as the substrates (Table 1).[8]
These were characterized from their infrared (IR) spectral data and melting points,which were compared with those of authentic samples. The oxidation was carriedout both in neutral and acidic conditions.
RESULTS AND DISCUSSION
CTADC was found to be a dehydrogenating agent in the oxidation of amine,thiol, and cholesterol, and thus the products of phenylthiourea are the correspondingdiazo compound, disulfide, and benzothiazole (Scheme 1).
When phenylthiourea was refluxed with CTADC in acetonitrile without anyacid for more than 12 h, the appearance of an insoluble green material in the reactionmixture indicated the formation of Cr(III). On washing the residue by ether withmechanical agitation, no organic compound was obtained in the ether medium.The product was isolated by removal of acetonitrile under low pressure as a pastymass with malodor. The thin-layer chromatography (TLC) on silica sheets exhibitedtwo spots, which necessitated a separation of these two species. Among these, themajor product (60% of the yield) was phenyl urea, which was confirmed from itsIR and NMR spectral characteristics. The minor product (40% of the yield) was aliquid retaining the malodor. The elemental analysis does not show the presenceof sulfur in the product. The IR spectra exhibit characteristic bands at2126–2130 cm�1 for the isonitrile group. The NMR peaks are in the aromatic regiononly. Thus, the product was characterized as phenyl isonitrile.
When the reaction was undertaken in the presence of acetic acid (20%) and thepasty mass was subjected to column chromatography, a white solid mass wasobtained, which was characterized as phenyl urea. No trace of the correspondingisonitrile was detected in the product. The same product was also obtained whenphenylthiourea was oxidized in aqueous medium by potassium dichromate insulfuric acid by a standard method.[9]
To generalize the reaction, substituted phenyl thioureas were subjected tooxidation in neutral conditions as well as in the presence of acetic acid. In all the
Scheme 1.
3270 S. SAHU ET AL.
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cases, the products were found to be corresponding ureas and isonitriles in neutralconditions and corresponding ureas only in the acidic conditions (Scheme 2).
Formation of urea as the oxidation product of corresponding thiourea isnot new.[10] Tajbakhsh et al.[11] selectively obtained phenyl urea from a mixture ofphenylthiourea and diphenyl thioketone by using quinolinium fluorochromate inacetonitrile. Further, Puri et al.[12] reported the formation of corresponding disulfidefrom the oxidation of thiourea by K2Cr2O7 in the presence of bromoaceticacid. For the formation of isonitrile, a probable mechanism has been proposedwherein the first step involves the coupling of –NH2 and –SH of one moleculewith the –NH2 and –SH of another molecule, respectively, followed by removal ofnitrogen and sulfur (Scheme 3).
To optimize the oxidation reaction in neutral conditions, the phenylthioureaswere subjected to oxidation by CTADC under microwave irradiation. Surprisingly,the reaction, which had required around 12 h of reflux to yield the product, nowneeded only seconds to get the products with greater yield of isonitrile (see theSupplementary Materials, available online). The application of microwaves offersa very quick and clean method for the oxidation reaction. The reaction time andthe yield of the products are given in Table 1.
Scheme 3.
Scheme 2.
OXIDATION OF ARYLTHIOUREA BY CTADC 3271
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In conclusion, dichromate with amphiphilic counterion, such as cetyltrimethy-lammonium ion, becomes mild and on oxidation of arylthiourea yields arylisonitrilein nonpolar organic solvent and arylurea in the presence of acetic acid.
EXPERIMENTAL
General Method for Oxidation of Arylthioureas withCTADC in Acetonitrile
A solution of (0.002mol) of arylthiourea and CTADC (0.00066mol) inacetonitrile was refluxed for 12–15 h. The reaction was monitored by TLC. Aftercompletion of the reaction, the green precipitate was filtered off, and the filtratewas reduced to a paste under low pressure. The products were separated from themixture by column chromatography using a mixture of ethyl acetate and toluenein different proportions.
For the reaction in the presence of acetic acid, it was mixed in the reactionsystem with acetonitrile to obtain a 20% solution.
General Method for Oxidation of Arylthioureas withCTADC in Microwave Conditions
A mixture of arylthiourea and CTADC in a 3:1 molar ratio was thoroughlyground in a mortar. The mixture was irradiated at 800W until the reactionmixture turned green. The reaction mixture was cooled to room temperature, andthe products were separated by column chromatography on silica gel eluted with atoluene–ethyl acetate mixture.
ACKNOWLEDGMENTS
B. K. M. thanks the University Grants Commission, New Delhi, for financialassistance through a research project. S. S. thanks the Council of Scientific andIndustrial Research, New Delhi, for a senior research fellowship.
REFERENCES
1. Corey, E. J.; Suggs, J. W. Pyridinium chlorochromate: An efficient reagent for oxidationof primary and secondary alcohols to carbonyl compounds. Tetrahedron Lett. 1975, 16,2647.
2. Patel, S.; Mishra, B. K. Chromium(VI) oxidants having quaternary ammonium ions:Studies on synthetic applications and oxidation kinetics. Tetrahedron 2007, 63, 4367.
3. Patel, S.; Mishra, B. K. Cetyltrimethylammonium dichromate: A mild oxidant forcoupling amines and thiols. Tetrahedron Lett. 2004, 45, 1371.
4. Sahu, S.; Patel, S.; Mishra, B. K. Selective oxidation of arylaldoximes by cetyltrimethy-lammonium dichromate to arylaldehydes and arylnitriles. Synth. Commun. 2005, 35, 3123.
5. Patel, S.; Mishra, B. K. Oxidation of cholesterol by a biomimetic oxidant, cetyltrimethy-lammonium dichromate. J. Org. Chem. 2006, 71, 3522.
6. Patel, S.; Kuanar, M.; Nayak, B. B.; Banichul, H.; Mishra, B. K. Cetyltrimethylammo-nium dichromate: A phase-transferring oxidant. Synth. Commun. 2005, 35, 1033.
3272 S. SAHU ET AL.
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7. Patel, S.; Mishra, B. K. Oxidation of alcohol by lipopathic Cr(VI): A mechanistic study.J. Org. Chem. 2006, 71, 6759.
8. Rasmussen, C. R.; Villani, F. J.; Weaner, L. E.; Reynolds, B. E.; Hood, A. R.; Hecker,L. R.; Nortey, S. O.; Hanflin, A.; Constanzo, M. J.; Powell, E. T.; Milinari, A. J.Improved procedures for the preparation of cycloalkyl-, arylalkyl-, and arylthioureas.Synthesis 1988, 456.
9. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. In Vogel’s Textbookof Practical Organic Chemistry; Pearson Education: Singapore, 2005; p. 609.
10. Corsaro, A.; Pistara, V. Conversion of the thiocarbonyl group into the carbonyl group.Tetrahedron 1998, 54, 15027.
11. Tajbakhsh, M.; Mohammadpoor, I.; Alimohammadi, S. K. Selective conversion ofthioamides and thioureas to their oxygen analogues using quinolinium fluorochromate.Indian J. Chem. 2003, 42B, 2638.
12. Puri, J. K.; Vats, V. K.; Sharma, V. Oxidation–reduction reactions and analysis ofthiourea, hydrazine, and ascorbic acid in monobromoacetic acid. Indian J. Chem. 1986,25A, 565.
OXIDATION OF ARYLTHIOUREA BY CTADC 3273
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giving rise to various products including ureas, suldes, oxides of sulfur, and nitrogen. Some novel
thiourea; oxidation; thiazole; disulde; urea
Oxidation Kinetics ofSimvastatin UsingCetyltrimethylammoniumDichromatePRANGYA RANI SAHOO,1 SABITA PATEL,2 B. K. MISHRA1
1Center of Studies in Surface Science and Technology, School of Chemistry, Sambalpur University, Jyoti Vihar 768 019, India
2Department of Chemistry, National Institute of Technology, Rourkela 769 008, India
Received 5 May 2012; revised 22 August 2012; 13 September 2012; accepted 18 September 2012
DOI 10.1002/kin.20759Published online 5 December 2012 in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: This article reports an attempt on the studies on resistance of oxidative stressby the prodrug, simvastatin (SV). Cetyltrimethylammonium dichromate has been used as alipid compatible oxidant to study the oxidation kinetics of SV in organic media. The reactionundergoes via an ionic mechanism without any side product. The reaction is found to be acidcatalyzed and sensitive to solvent polarity. The increase in the rate constant due to an increasein hydrophobicity (apolarity) of the solvent indicates the existence of a less polar transitionstate. Furthermore, the decrease in the rate constant due to an increase in [CTAB] suggestspartitioning of the substrates and the oxidants into two different domains with different polarcharacteristics akin to a reversed micellar aggregates. Considering the above results and thethermodynamic parameters, a reaction mechanism has been proposed, wherein a complexformed at the interface of the two domains due to the reactant and the oxidant in a fast processdecomposes to the products in a slow process in the nonpolar bulk. C© 2012 Wiley Periodicals,Inc. Int J Chem Kinet 45: 236–242, 2013
INTRODUCTION
Simvastatin (SV) is a lactone prodrug used for thetreatment of hypercholesterolemia [1]. Following con-version of this lactone prodrug to its hydroxyl acidform, the compound is a potent competitive inhibitorof HMGCoA reductase, the rate-limiting enzyme incholesterol biosynthesis [2]. The oxidative biotrans-
Correspondence to: B. K. Mishra; e-mail: [email protected] Information is available in the online issue at
www.wileyonlinelibrary.com.C© 2012 Wiley Periodicals, Inc.
formation of SV takes place at the heptanoic acid sidechain. It acts as an antioxidant and inhibits the oxi-dation of low-density lipoproteins (LDL) [3] and alsodecreases aldehyde production derived from lipopro-tein oxidation [4]. SV treatment induced an increasein autoantibodies against specific oxidized LDL anti-gens [5].
The electrochemical detection of SV in the formof drugs stems on its oxidation behavior in the pres-ence of a multiwalled carbon nanotubes–dihexadecylhydrogen phosphate composite modified glassy carbonelectrode [6]. SV, on various stress degradation, suchas acid and base hydrolysis, oxidation by hydrogen
OXIDATION KINETICS OF SIMVASTATIN 237
peroxide led to the formation of simvastatin acid anddehydrated products, respectively [7].
An onium ion, as the counterion for anionic oxi-dants, makes a lot of difference in oxidation poten-tial of the oxidant as well as to the oxidizing system.It makes the oxidant lipid soluble, mild, and many atime chemoselective [8,9]. Tailor-made oniums havebeen used as the counterions, wherein heterocyclicbases such as pyridine, quinoline, caffeine, imidazole,and nicotine units become a part of the oxidant [8].In different reaction conditions, these oxidants oftenshow biomimetic characteristics due to the counteri-ons, which help in providing a microheterogeneous en-vironment with different solubilization pockets for thesubstrates as in the case of micelles, reversed micelles,microemulsions, vesicles for artificial systems, andproteins and lipid membranes in living systems [10].Among these oxidants, Cr(VI) has been studied exten-sively.
In our efforts in exploring some biomimetic ox-idants to oxidize organic substrates in organic sol-vents, we have reported the oxidation behavior ofcetyltrimethylammonium permanganate (CTAP) [11–14], cerate (CTACN) [15], and dichromate (CTADC)[10,16] toward various organic substrates. These areinorganic oxidants with an organic amphipathic car-rier, cetyltrimethylammonium (CTA+) ion, to carrythe oxidants into the organic (lipid) phase. However,these oxidants are hydrophobic and thus support the ex-istence of a tight ion pair of the cationic carrier and theanionic oxidant in nonpolar medium [17]. In organicsolvents, CTAP oxidizes its carrier, CTA+, in a man-ner similar to β-oxidation of fatty acids [11]. Otheraforesaid oxidants are found to be inert toward theircarrier. We have used CTAP and CTADC for oxidationof cholesterol to yield a diol at the double bond [14]and 7-dehydrocholesterol [10], respectively, while withaddition of acetic acid to CTADC in dichloromethane(DCM) the product was found to be 5-cholesten-3-one.CTADC is devoid of an acidic proton and thus is rela-tively milder than other Cr(VI) oxidants [8]. In the ab-sence of acid, CTADC exhibits some bizarre reactionswith nonconventional products. Aromatic amines arefound to yield corresponding diazo compounds [18],and arylaldoximes yielded corresponding nitriles [19].
In this paper, we have made an attempt to inves-tigate the oxidation behavior of CTADC toward theprodrug, SV, in organic solvents. To follow up the ob-jectives, the oxidation product was characterized andkinetics were run in different media with varied polar-ities and also in microheterogeneous systems, gener-ated due to the presence of a cationic surfactant (CTAB:cetyltrimethylammonium bromide) and anionic surfac-tant (SDS: sodium dodecyl sulfate) at different concen-
trations. By analyzing the rate constants determined byvarying [substrate], [acid], and [CTADC] in the reac-tion process, a suitable mechanism for the reaction hasbeen proposed. Earlier, SV was subjected to oxidativedegradation by using hydrogen peroxide to yield a vari-ety of products through a free radical mechanism [20].Cr(VI) oxidation of many biological substrates alsoencountered free radical intermediate, and the reac-tions become complicated. In most of the oxidationsby CTADC, no free radical mechanism has been pro-posed. Thus the present study highlights the effect ofCr(VI) oxidant on SV to get a clear picture of the ox-idative stress on SV.
EXPERIMENTAL
Materials
CTADC was prepared by the method reported ear-lier [21]. SV(I) was used without further purification.Glacial acetic acid was used as a source of hydrogen ionand was used without further purification. The organicsolvents used were purified by standard methods [22].The surfactants, CTAB and SDS, were obtained fromSpectrochem (Mumbai, India) and were purified byrecrystallization from ethanol solution.
Kinetic Measurements
The oxidation kinetics of SV by CTADC in the pres-ence of acetic acid was monitored in different solventsand surfactant systems spectrophotometrically at theabsorption maxima of CTADC (350 nm) by using aHitachi U3010 spectrophotometer with a thermostaticcell holder attached to a water bath. The first-order rateconstant, kobs, was obtained from the linear (r = 0.99)plot of log[oxidant] against time upto 75% completionof the reaction in a pseudo-unimolecular condition bykeeping a large excess of SV. The values reported arethe average of triplicate runs and were reproduciblewithin ±4% error.
Product Analysis
After keeping the reaction mixture of CTADC and SVin proper composition for 24 h in DCM, the volumeof the reaction mixture was reduced to a pasty massunder low pressure. Acetic acid was added to the re-action mixture with CTADC as the oxidant. Then theorganic compounds from the pasty mass were extractedby using diethylether in excess. On evaporation of theether, the products were subjected to column chromato-graphic separation by using a mixture of ethyl acetate
International Journal of Chemical Kinetics DOI 10.1002/kin.20759
238 SAHOO, PATEL, AND MISHRA
and toluene (1:2 v/v). On evaporation of the eluentswith a single spot in TLC, the isolated compound wassubjected to fast atom bombardment mass spectrom-etry (FABMS), nuclear magnetic resonance (NMR),and infrared (IR) analyses. The compound is proposedto be the corresponding carbonyl compound (II).
Stoichiometry
The stoichiometry of the reaction was determined byperforming the experiment at 303 K, under the con-ditions with fixed [Oxidant] and varying [SV]. Thedisappearance of Cr(VI) was followed until the ab-sorbance values became constant, and then CTADCwas estimated after 48 h. The stoichiometry ratios arefound to be 1:2 for CTADC/SV.
RESULTS AND DISCUSSION
Under reflux conditions, the solution of CTADC andSV in DCM in the presence of acetic acid becamegreen, indicating the reduction of Cr(VI) to Cr(III). Thecompletion of the reaction was ascertained by moni-toring the TLC of the reaction mixture. CTADC existsas a contact ion pair in aqueous medium as well as inorganic solvents [17]. In the presence of acetic acid,the dichromate ion becomes free from the grasp of thequaternary onium ion due to the change in polarity ofthe medium and also the probable substitution of theonium ion by proton of acetic acid. Furthermore, acry-lonitrile was added to the reaction mixture during thereaction process. As no turbidity of the medium in thereaction mixture was observed, the possibility of thefree radical mechanism was ruled out. The reaction ki-netics of the oxidation reaction was monitored in thepresence of acid, and the kinetic data are presented inTable I.
The acid-catalyzed oxidation of SV with CTADC inDCM was found to increase linearly with an increase inthe concentration of SV (Fig. 1). To obtain a relation-ship between the rate constants with the parametersof the reaction condition, i.e., [substrate], [oxidant],and [acid], log kobs values obtained in different condi-tions were correlated with the above three parametersthrough multiple regression analysis. The regressionmodel, thus obtained, is given by Eq. (1). The orderswith respect to [CTADC], [SV], and [acetic acid] arefound to be 0.634, 0.554, and 0.844, respectively:
log kobs = −5.114 (±0.321) − 0.634(±0.074)
× log[CTADC] + 0.554(±0.074)log[SV]
+ 0.844 ± 0.107 log[acetic acid]
Table I Effect of [SV], [CTADC], and [Acetic Acid] onthe Oxidation of SV by CTADC at 303 K in DCM
[CTADC]× 104 (M)
[SV](M)
[AceticAcid] (M)
kobs × 104
(s−1)Rate × 107
(mol L−1 s−1)a
0.5 0.02 4.86 17.27 0.861 0.02 4.86 11.13b 1.112 0.02 4.86 9.21 1.844 0.02 4.86 4.22 1.691 .005 4.86 5.76 0.581 0.01 4.86 6.91 0.691 0.04 4.86 17.27 1.731 0.02 6.48 14.97 1.501 0.02 3.24 8.06 0.811 0.02 1.62 4.61 0.46
aRate = kobs × [CTADC].b104 kobs at 293, 298, and 308 K were found to be 6.53, 9.98, and
14.97 s−1, respectively.
R2 = 0.964, F = 54, n = 10 (1)
Using the regression model, the log kobs valueswere calculated and plotted against the observed values(Fig. 2). A linear plot without any outlier supports thevalidity of the regression model.
Without acid, the reaction became too slow to mea-sure. With increasing [acetic acid], the rate constantincreases linearly (Fig. 3). The reaction is found toacid catalyzed with an uncatalyzed rate of 1.15 ×10−4 s−1.
In an earlier report on oxidation of cholesterol, non-linearity with the Michaelis–Menten relationship ofthe substrate with the kobs was observed, indicating acomplex mechanism for the oxidation reaction [10]. Inthe present study, the molecularity was found to be indecimal (Eq. (1)), indicating an occurrence of a com-plex reaction mechanism, which may be proposed videinfra (Scheme 1, where Q refers to CTA).
Figure 1 Plot of 104 kobs vs. [SV] in the oxidation reactionof CTADC with SV at 303 K.
International Journal of Chemical Kinetics DOI 10.1002/kin.20759
OXIDATION KINETICS OF SIMVASTATIN 239
Figure 2 Plot of observed log k vs. calculated log k usingthe regression model equation (1).
Figure 3 Plot of 104 kobs vs. [acetic acid] in the oxidationreaction of SV with CTADC at 303 K.
Scheme 1 can lead to the derivation of a rate equa-tion (Eq. (2)):
Rate = −d[C]
dt=k[C] = kK1K2
[Q2Cr2O7][H+][SV]
Q+(2)
Cr(III) is found in the reaction products during theoxidation of various substrates by CTADC in organicmedium [10]. The existence of Cr(III) in the productmixture is well established from the peak at 580 nm.However, reaction kinetics could not be studied at thiswavelength due to nonreliability and low absorptivityof the spectrum. The formation of Cr(III) from Cr(VI)
Complex (C)
Q2Cr2O7 + H+ QCr2O7H Q++K1
+SV QCr2O7HK2
kProduct
Rate-determining step
Complex (C)
Scheme 1
Figure 4 Plot of 104 kobs vs. [CTADC] in the oxidation ofSV at 303 K in DCM.
due to oxidation seems to be a complex phenomenonas shown below:
Cr(VI) + 2e → Cr (IV)
Cr(IV) + Cr(VI) → 2Cr(V)
Cr(V) + 2e → Cr(III)
Cr(VI) is initially reduced to Cr(IV), which sub-sequently changes to Cr(V) with another Cr(VI). Theformation of Cr(III) is a result of two-electron reduc-tion of Cr(V). The existence of Cr(IV) as the reducedstate in oxidation of benzyl alcohol by quinolinium flu-orochromate has also been reported by Dave et al. [23]
The rate constant is found to decrease nonlinearlywith increasing [CTADC] (Fig. 4). Similar observa-tions have been made for the oxidation reaction ofdifferent substrates by CTADC in organic solvents.Earlier, it has been rationalized by proposing the oc-currence of a reversed micellar phenomenon duringthe oxidation reaction [10]. This proposition was fur-ther supported by a drastic decrease in the rate con-stant with addition of CTAB (Table II), a reversed
Table II Rate Constant of Oxidation of SV at Different[CTAB] and [SDS] at 303 K in DCM ([CTADC] = 1 × 10−4
M, [SV] = 0.02 M, [Acetic Acid] = 4.86 M)
[CTAB] ×104 (M)
kobs × 104
(s−1)[SDS] ×104 (M)
kobs× 104
(s−1)
1 9.6 1 17.665 5.76 5 36.0810 3.45 10 46.0620 2.30 15 58.73– – 50 74.46
International Journal of Chemical Kinetics DOI 10.1002/kin.20759
240 SAHOO, PATEL, AND MISHRA
micelle-forming surfactant. The spherical reversed mi-celle has various localization sites, including the po-lar inner core, where the ionic oxidant is partitionedmore. Substrate, being nonpolar in characteristics, par-titioned to the bulk and remains away from the reactiveoxidant. With an increase in [CTADC], the inner po-lar core may assume a larger interfacial area so thatthe substrate can, relatively, be more in contact withthe polar oxidant to facilitate the complexation of theSV and Cr(VI). Owing to the decrease in the polarityof the complex compared to the reactants, it is parti-tioned to nonpolar bulk and, therein, dissociates to theproduct. The larger the interfacial area, the less will bethe partitioning leading to decrease in the rate. CTABcan form spherical micelle in aqueous medium and re-versed micelle in nonaqueous medium. The decreasein the rate constant may be attributed to the enhancedreversed micellization in the presence of CTAB, whichprovides a common counterion with CTADC for theformation of reversed micelle.
Furthermore, as the reaction is acid catalyzed andthe interface due to CTA+ is positively charged whichrepels the proton, the rate is retarded. This propositiongets further support from the rate enhancement dueto the addition of SDS, an anionic surfactant (Fig. 5).SDS is inert toward CTADC and provides an anionicenvironment to the reactant either through mixed mi-cellization or through a reversed micellar aggregate,which can provide an anionic interface for the interac-tion between the proton, dichromate, and SV.
The rate law as derived in Eq. (2) gets support fromthe above observations. With increasing [CTADC],[acetic acid], and [substrate], the rates of the reaction(as mentioned in Table I) increase linearly. Similarly,the rate of reaction decreases with increasing [CTA].The plot of rate vs. 1/[CTA] is also found to be linear(R2 = 0.99).
Figure 5 Plot of 104 kobs vs. [surfactant] for the oxidationreaction of SV with CTADC at 303 K.
Table III Observed Rate Constants for the OxidationReaction of SV in Various Organic Solvents at 303 K,[CTADC] = 1 × 10−4M, [SV] = 0.02 M, and [Acetic Acid]= 4.86 M
S. No. Solvent kobs × 104 (s−1)
1 Dioxan 6.912 Ethyl acetate 8.443 Acetone 8.064 Acetonitrile 5.765 Benzene 13.436 Toluene 15.747 Dichloromethane 11.138 Chloroform 17.669 Carbon tetra chloride 19.96
To investigate the effect of environment on the re-action mechanism, nine organic solvents with differentpolarities were used as reaction medium. CTADC wasfound to be stable in all these solvents in the presenceof acetic acid for more than 24 h. The rate constantis found to be highly sensitive to change in polarityof the solvents (Table III). To elucidate the character-istics of the transition state of the reaction, the rateconstants were plotted against various solvent param-eters such as cation-binding (A) and anionic-binding(B) capacity, dielectric constant, π*, dipole moment,and log P (where P being the partition coefficient ofthe substrate between octanol and water indicating thenonpolar characteristics of the solvents). The plots ofthe rate constants with all the polarity parameters de-lineate scattered relationship indicating the transitionstate to be sensitive to polarity without any specifictrend. However, from the linear relationship of theseparameters with the rate constants, the solvents canbe classified into dipolar aprotic solvents (acetonitrile,dioxane, ethyl acetate, and acetone) and nonpolar sol-vents (benzene, toluene, carbon tetrachloride, chloro-form, and DCM). In some corelationships, DCM isfound to be in the boarder line of the classification.With the increasing dipole moment or dielectric con-stant of the solvent, in most of the cases, the rate con-stant decreases. In cognizance of this, the rate constantincreases with increasing log P value of the solvent(Fig. 6). These observations support the formation ofa relatively less polar transition state compared to thepolarity of the reactants.
The thermodynamic parameters such as �H#, �S#,and �G# were calculated for the oxidation of SV withCTADC in the presence of 4.86 M acetic acid by usingArrhenius and Eyring equations and are found to be36.5 ± 1.4 kJ mol−1, –181.1 ± 6.9 J K−1, and 91.4± 3.5 kJ mol−1, respectively. A high negative value
International Journal of Chemical Kinetics DOI 10.1002/kin.20759
OXIDATION KINETICS OF SIMVASTATIN 241
Figure 6 Plot of 104 kobs vs. log P for the oxidation reactionof SV with CTADC at 303 K .
of �S# supports the proposal of the involvement of acyclic transition state [24].
From the above findings, a tentative mechanism hasbeen proposed (Scheme 2), wherein the CTADC equi-librates with acetic acid to form the protonated dichro-mate, which subsequently reacts with SV, giving riseto a dichromate ester. The complex decomposes to thereduced Cr(IV), which on further disproportionationgives rise to stable Cr(III), and corresponding carbonylcompound by α-hydrogen abstraction from the sub-
strate. The FABMS results of the carbonyl compoundwith a (M – H)/z peak at 415.3 corroborate the struc-ture of the product. The appearance of characteristicsIR band at 1577 cm−1 for β-diketone and disappear-ance of 3549 and 1265 cm−1 for –OH substantiate theoxidation of secondary –OH to corresponding carbonylone. Furthermore, the disappearance of the NMR peakat 1.568 δ in the product is also an indicator of con-version of the hydroxyl group to a corresponding car-bonyl group. (The spectra of the reactant and productare available as Supporting Information.)
CONCLUSION
SV is an established prodrug used in increasing thelevel of high-density lipoproteins and acts at cellularsurface exposed to various oxidants. SV undergoes ox-idative degradation by hydrogen peroxide through afree radical mechanism. In the lipid system, metallicoxidants like Cr(VI) can act to different substrates withthe help of an amphiphilic carrier. SV when interactswith CTADC, Cr(VI) carried by cetyltrimethylammo-nium ion, leads to the formation of the correspond-ing carbonyl compounds catalyzed by an acid throughan ionic intermediate. The non–free radical reactionleads to a mechanism with fewer or almost no side
k
k
k
Scheme 2
International Journal of Chemical Kinetics DOI 10.1002/kin.20759
242 SAHOO, PATEL, AND MISHRA
products. Furthermore, the reaction is proposed to oc-cur in an organized media where the partition of sub-strates and oxidants into different domains retard therate of the reaction. The use of amphiphilic compoundssuch as CTAB and SDS in the reaction media provides abiomimic environment to understand the reaction pro-cess. Thus CTADC is found to be an excellent modeloxidant to study the oxidative degradation of differentsubstrates in biological membranes.
The authors thank the University Grants Commissionand Department of Science and Technology, New Delhi,for financial assistance through the DRS and FIST pro-grams. Financial assistance by CSIR, New Delhi, througha major research project (no. 02(0030)/11/EMR-II) is alsoacknowledged.
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