Chapter-1
Introduction
1.1
Halogenation
2
1.2
Chemical bromination
7
1.2.1
Use of molecular Bromine
7
1.2.2
In situ generation of bromine
7
1.2.3
N-bromosuccinimide
8
1.2.4
Combined bromide – H202
8
1.3
Advantages of Electrochemical method
1.3.1
Electrochemical bromination
9
11
1.4
Mechanistic pathways of electrochemical bromination
24
1.5
Future work
26
1.5.1
Side chain bromination
28
1.5.2
Nuclear bromination
28
1.5.3
α-Bromination of alkyl aryl ketones
29
1.5.4
α,α- Dibromination of alkyl aromatic compounds
29
1.5.5
Hydrolysis of benzylic bromides
30
1.5.6 Conversion of benzylic bromides to the corresponding
aldehydes using sodium nitrate as a mild oxidant
32
1.6
References
33
1
Introduction
1.1 Halogenation
Organohalogen compounds due to their distinctive properties
have widespread use in a range of applications, serving as valuable
intermediates in organic synthesis, as radiolabelled markers in medical
diagnostics and as an active substance in the pharmaceutical industry.
Halogenated organics are also utilized as agrochemicals, pigments and
photographic materials.
Consequently, their related chemistry has
received a wealth of attention [1 - 8]. There is a considerable variation
in the properties of the halogens (X= F, Cl, Br, I) with fluorine
occupying one extreme and iodine the other, resulting in a marked
difference in reactivity of the C-X bond and consequently, in the
corresponding synthetic routes that are available for forming carbonhalogen bonds.
To illustrate this, it is sufficient to point out that fluorine is the
smallest halogen, it is highly electronegative, least polarizable and
forms the strongest C-X bond, while for iodine, the opposite
characteristics hold true.
2
Table 1.1
Atomic properties of halogens [5,9] and comparison with other
elements
Atom
αv (A3)
γv (A)
IP
EA
Kcal/mole
K cal/mol
H
313.6
17.7
0.667
1.20
2.20
O
310.4
33.7
0.82
1.52
3.5
C
240.5
29
1.76
1.70
2.55
F
401.8
79.5
0.557
1.47
3.98
115.7
Cl
299
83.3
2.18
1.75
3.16
77.2
Br
272.4
72.6
3.0
1.85
2.96
64.3
I
241.2
70.6
4.7
1.98
2.66
50.7
Xp
E c-x
K cal/mol
IP = ionization potential; EA = electron affinity
αv = atomic polarisability γv = Van der waals radius
E c-x = bond energy. xp = Pauling electronegativity
Whereas elemental fluorine is too reactive / poorly selective,
requiring special handling and safety precaution, elemental iodine is
scarcely reactive enough to be effectively introduced into the organic
molecules.
Therefore
numerous
approaches
and
reagents
were
developed for efficient and selective halogenation. The progress and
3
outcomes of halaotransformations proved to be crucially dependent
upon the substrate structure, reagent structure, and other reaction
conditions such as solvent properties, reaction time, source of energy
(Heat, Microwave and Pressure), presence of promoters and catalyst.
Among these halogenation processes, bromination is considered as an
important one. The Bromine substituted organic compound gives
increase of product yield as the bromide is a better leaving group
than other halides like fluoride, chloride. Bromination is involved in the
synthesis of many important drug molecules (fig.1.1). Benzylic
bromides are used to prepare a variety of different molecules (fig.1.2).
The chemical bromination was carried out using different types of
brominating agents and its advantages, disadvantages are discussed in
detail in this chapter. The present chapter outlines about both the
electrophilic and side chain bromination process in general.
OH
HO
O
Eugenol
Obovatrol (Antitumor, Antiinflammatory)
4
Br
C H3
O
Br2
O
COO H
H3CO
H3CO
H3CO
Naproxen (Anti-inflammatory)
Br
Br
NC
Mesitylene
CN
N
N
N
Anastrozole (cancer treatment)
Figure 1.1 Some important drug molecules whose preparation involves
bromination step
5
Figure 1.2 Functionalisation of benzylic bromides into other
useful products.
6
1.2 Chemical Bromination
1.2.1
The
Use of molecular bromine
direct
bromination
of
aromatic
compounds
using
generates toxic and corrosive HBr along with product.
bromine
The product
may also include mono and polybrominated compounds which require
the separation of unwanted product. Molecular bromine itself is very
difficult to handle as it is highly dense (density =3.11) and corrosive
liquid. Consequently various brominating agents have been developed
1.2.2
In-Situ generation of Bromine
Alkali metal bromide or HBr is taken along with an oxidizing
agent such as KMnO4, sodium bromate or Hydrogen peroxide to
oxidize the metal bromide to generate bromine molecule. During the
course of reaction, one, out of two bromine atoms in a bromine
molecule becomes part of the product, the other atom released as
corrosive HBr. This has to be neutralized before discharge. Hence this
reaction is environmental unfriendly. This reaction gives low atomic
yield, as part of the bromine formed the unwanted Hydrobromic acid.
C - H of alkyl benzenes and alkanes are brominated in excellent yield
using NaIO4 in 10% H2SO4 and LiBr as reagents in methanolic medium
at 110oC [10].
In this case though the yield is satisfactory, but the
chemicals involved in this reaction are very costly.
1.2.3
N-bromosuccinimide
7
N-bromosuccinimide is one of the reagents often used for
introduction of bromine into organic molecules. Because of ease of
handling and availability N-bromosuccinimide is generally used for the
bromination
of
aromatic
compounds
instead
of
corrosive
liquid
bromine. However the disadvantages of this reagent include (i) high
temperature reaction (ii) and after completion of reaction, the side
product succinimide formed has to be either disposed off or recycled
[11]. In some cases unsatisfactory yields are also observed [12 ].
1.2.4
Combined bromide – H2O2
Recently, combined bromide – H2O2 is used for benzylic
bromination of aromatic compounds. Though this brominating system
works at room temperature it uses 3 equivalents of hydrogen
peroxide, and 3 equivalents of acid and in the presence of UV
irradiation.
Excess H2O2 has to be removed by washing with 40%
NaHSO3 solution.
The product yield falls at a range of 40-80% with
bye-product formation (Selectivity is not very high) [13 ].
8
1.3 Advantages of Electrochemical method
Electrochemical methods have received significant research
interest from both academia and industry, over regular chemical
methods because they serve as environmentally benign process for
organic synthesis [14-34]. It is particularly noteworthy that the
electrochemical reactions serve as excellent method for the generation
of reactive species under mild conditions [35-42] which do not require
large quantities of noxious or corrosive reagents. It has been widely
used in many areas such as synthesis of pharmaceutical drugs, amino
acids, dye stuff, speciery and organic reagents. It has received much
attention in recent years [43].
Electrochemical method is very simple and does not require
complex and expensive equipment. The commercially available other
brominating agents are irritant and sensitive.
Their storage and
handling requires serious caution. The main advantage of the present
electrochemical method is that these reactive species could be formed
in situ, avoiding the above mentioned problems. In this case, it is an
excellent dosage control (by simple current control) what is not easy in
many classical methods when a solid should be gradually introduced
into the reaction mixture, this procedure might be recommended as a
superior one.
9
Electrohalogenation is one of the general class of electro organic
synthetic process, which has been studied several years. Among these
electrochemical
halogenation
processes,
electro
bromination
is
considered as an important one.
Electrohalogenation
processes
have
been
reviewed
systematically at regular intervals [44-47]. These reviews cover the
types of electrobromination reactions and mechanisms involved in
detail.
In addition electrobromination reactions have been appeared
from time to time over the past years. The objective here would be to
present
a
general
outlines
of
recent
trends
in
this
field
of
electrobromination with special focus on the two-phase electrolysis
which are presently being actively pursued.
Towards these ends a fairly detailed outline of these distinct
types of electrobromination process is presented in Section 1.3.1. This
is followed by the presentation of broad outline of the mechanistic
pathways in the electrobromination in the next section (Section 1.4).
Finally the field of two-phase electrobromination that has been
selected
for
evaluation
in
the present
specifically brought out (Section 1.5).
10
research
programme
is
1.3.1 Electrochemical bromination
Due to the commercial and synthetic importance of the product
N-bromosuccinimide, succinimide was one of the earliest reactant
considered for electrobromination [48]. A fairly good yield of 54% was
obtained.
The products formed during the anodic bromination of ethyl
benzene were similar to the products formed in daylight reactions
suggesting radical mechanism [49].
Ortho and para - bromophenols were formed as products when
phenol underwent bromination reaction [50].
However formation of
mono and dibromo phenol formation can be controlled by the amount
of charge passed for electrolysis [51].
The electrochemical process
has been proposed through adsorbed bromide atoms. Acetanilide also
undergoes
bromination
under
controlled
conditions
to
yield
predominantly p-bromoacetanilide [52]. Electrochemical bromination
of anthracene and naphthalene also received considerable attention.
By controlling the potential in dry acetonitrile medium one may get 9bromo anthracene (at 1.2V) or 9, 10-dibromo anthracene (at 1.6V)
along with 9-bromo anthracene [53]. Similar selectivity was achieved
in
the
bromination
of
naphthalene
11
[54].
Some
voltammetric
investigations on the mechanism of bromination of toluene and pxylene in anhydrous acetic acid were also reported [55].
Carbon tetra bromide was prepared by continuous electrochemical
bromination of bromoform until a product containing 70% carbon tetra
bromide and 30% bromoform was obtained followed by separation of
the product by cooling to -5 to -7
o
C and centrifuging. In an example
the electrolysis of 350 gpl sodium bromide and 20gpl sodium
hydroxide with 75 gram of bromoform was carried out using graphite
anode and stainless steel cathodes at 25 -30 oC and anode current
density of 0.45 A cm-2 with vigorous stirring for 4.5 hours. 84.6 gram
of a mixture of products were obtained containing 70% carbon tetra
bromide and 35% bromoform. This mixture was separated by
centrifuging at -5oC and 6000 rpm into carbon tetra bromide and a
mixture containing 55% CBr4 and 45% bromoform which was
recirculated. The purity of the carbon tetra bromide obtained was 96%
[56].
In acetonitrile media anodic bromination of anisole exhibits
excellent regioselectivity. At anode potentials of 1.3 to 1.8 V Vs
Ag/Ag+ the para to ortho ratio was found to be more than 12 [57].
12
The electrochemical bromination of cyclohexene on a pt electrode
in nitro methane solution was studied by C. S. Visy & M. Novak and in
this process a complex intermediate forms between the olefin and Br2
evolved and it transforms to dibromo cyclohexane. At higher potential
values the electrochemical oxidation of this complex results bromocyclohexanol, the formation of which is hindered by oxide layer on the
electrode surface [58].
Electrochemical bromination of DMSO in alkaline media was carried
out by V. A. Ilyushin using diaphragm less electrochemical cell,
Ruthenium oxide coated over Titanium anode, SS cathode and 10%
KBr
as
electrolyte.
The
author
have
concluded
that
the
electrochemical bromination of DMSO in alkaline media lead to the
formation of (CBr3)2SO2 (in the presence of Na2CO3) or CBr3SO2CH3 (in
the presence of NaHCO3).The use of sodium carbonate instead of alkali
in the electrosynthesis permitted an increase in the yield of product
up to 50% [59].
A novel and straightforward method to accomplish regioselective
α-bromination of α, β-unsaturated ketones was reported by Mtani et al
in which a substrate – CF3CO2H – CuBr – Et4NOTs – MeCN system was
subjected to electrolysis with variable current density [60].
13
Electrosynthesis of eosin [61] was carried out by brominating
fluorescein in different media such as NaHCO3, CH3COONa, NH3, etc.,
and also in several binary electrolyte mixtures at stationary/rotating
anodes at different current densities and temperatures. The yield of
eosin
was
extremely
sensitive
to
electrolyte
pH.
NaHCO3
and
CH3COONa were found to be suitable media. Ti/TiO2, RuO2 electrodes
were found to be most suitable in the production of eosin.
Kinetics of the electrochemical bromination of some unsaturated
fatty acids was studied by Jan Malyszko et.al using rotating ring–disc
electrode technique. A platinum ring–disc electrode was used to
investigate the kinetics of the bromination of oleic and linoleic acid.
Bromine was generated by constant current at the disc. The
bromination was studied in a mixed solvent which contained 90 vol%
acetic acid and 10 vol % acetonitrile. The influence of concentration of
the background electrolyte on the bromination kinetics of oleic acid
was investigated. Conclusions were drawn concerning the use of the
reactions studied to the determination of the iodine value of oils by
coulometric titration [62].
The electrochemical dibromination of the chiral building block
followed by a dehydrobromination step allowed the preparation of a
14
bromopiperidin. The stereo selective addition of nucleophiles onto this
key intermediate permitted the synthesis of various 4-substituted
piperidine derivatives (fig.1.3) [63].
Ph
Ph
NC
2
(i) Br- N C
O
N
6
Ph
O
N
(i) Na
NC
N
Lewis acid
Bu3 salt, AIBN
(ii) DBU, THF
Reflux
4
Br
Nu
Figure 1.3 Electrochemical bromination of Piperidine
Compounds
containing
active
electrochemical bromination.
methylene
groups
may
undergo
Acetoacetic ester and diethyl malonate
were selectively brominated in bromide containing methylene chloride
media [64].
Electrogenerated bromine molecules were readily trapped by
cyclohexene leading to the formation of 1,2-dibromocyclohexane[65].
Olefinic compounds however yielded the corresponding dibromo
compound and bromohydrin [66]. Under optimum experimental
conditions the bromohydrin pathway leads to epoxidation (fig.1.4)
[67]. The epoxidation of olefin to epoxide was achieved by constant
current electrolysis of NaBr in the presence of olefin in an undivided
electrochemical cell with graphite felt electrodes in a MeCN / H2O 3:2
solvent system.
15
O
Epoxide was formed cleanly and crystallized directly from the
solution (86% yield) after simple filtration.
The epoxide is made
possible by the different local environments provided by the anode and
cathode in the reaction vessel.
Ph
Ph
OH
N
O
N
Br
NBS
O
IPAC, H2O
NaHCO3
O
Electricity
H2 O, NaBr
NaOMe
Ph
O
N
Figure 1.4 Electrochemical Epoxidation
16
O
O
O
At the cathode the formation of base allows for the closure of
bromohydrin to the epoxide with the concomitant regeneration of the
bromide. Since NaBr is regenerated at the closure of bromohydrin to
epoxide, the electrochemical epopxidation is expected to be catalytic in
NaBr. Indeed 0.5 equivalent of NaBr effects complete conversion.
At the anode the hypohalous acid, HOBr generated and added
efficiently to the olefin to form bromohydrin. The generation of HOBr
was confirmed by getting the same product in 84% yield using
chemically generated HOBr using Br2 and HgO.
At Anode :
2Br -
At Cathode :
2H2 O + 2e-
In solution:
CH3 CH= CH2 + Br2 + HO -
Br2 + 2e-
H2 + 2HO -
R-CH-CH2 Br + BrOH
Electrochemical oxidation of iodide and bromide in the presence of
dimedone in acetic acid/water mixture was studied by Nematallahi etal
using cyclic voltammetry and controlled potential coulometry. The
results showed that, dimedone reacted with resulting iodine or
bromine to form the halogen derivatives of 2-iodo, 2-bromo and 2,2-
17
dibromodimedone at constant current, in an undivided cell in good
yield [68].
Regioselective electrobromination of benzofuran [69] was achieved
successfully by an adequate choice of solvents and bromide salts to
afford
5-bromobenzofuran,
dibromobenzofuran respectively.
5,7-dibromobenzofuran
and
2,3-
Upon electrolysis of benzofuran in
AcOH / H2O (100/1) containing NH4Br, substitution at the C-5 position
of benzofuran proceeded smoothly to afford 5-bromobenzofuran. After
passage of totally 4 F/mol of electricity in a similar medium 5,7dibromobenzofuran was obtained as a sole product (fig.1.5). On the
other hand, the electrolysis of benzofuran in CH2Cl2/H2O (1/1) and / or
AcOH / H2O (10/1) in the presence of either NaBr or NH4Br afforded 2,
3-dibromo-2, 3-dihydro benzofuran exclusively.
Br
Br
O
-e
NaBr
CH2Cl2/H2O 1:1
or
NH4Br
AcOH/H2O
Br
-e
O
NH4Br
AcOH/H2O
100:1
O
-e
Br
Figure 1.5 Electrochemical bromination of benzofuran
O
Br
18
The electrochemical oxidation of bromide in the presence of 1,3indandione [70] in water/acetic acid and methanol/acetic acid mixtures
was
studied
by
cyclic
voltammetry
and
controlled-potential
coulometry. The results indicated the participation of 1,3-indandione in
the bromination reaction. On the basis of the electro analytical and
preparative results a reaction mechanism including electron transfer,
chemical reaction and regeneration of bromide was discussed. The
electrochemical synthesis of bromo derivatives of 1,3-indandione was
successfully performed at constant current, in an undivided cell, in
good yield and purity.
Electrochemical
Halogenation
of
4-Hydroximino-2,2,6,6-
tetramethylpiperidine [71] was halogenated by V.P. Kashparova et al.
and they found that in the electrochemical chlorination of 4hydroximino-2,2,6,6-tetramethylpiperidine in acidic solution (pH 4 - 5)
yielded 4-nitro-4-chloro-2,2,6,6-tetramethyl piperidinehydrochloride in
70%
yield,
whereas
in
the
electrochemical
bromination
of
4-
hydroximino-2,2,6,6-tetramethylpiperidine in neutral solution yielded
4-bromo-4-nitro-2,2,6,6-tetramethyl piperidine in 60% yield.
19
Electrochemical bromination of germacrene- D and geranial [72]
carrying plural olefinic bonds provided the corresponding brominated
products (fig.1.6). The bicyclic derivative was preferentially produced,
while chemical bromination provided no clear selectivity of its product
distribution. Influence of the parameters of the electrochemical
reaction
conditions
were
evaluated,
aiming
at
improvement
regioselectivity and yields of the brominated products.
Br
H
MeO
Figure 1.6 Bromination of Germacrene-D
20
of
An electrochemical method was described in US patent 6827836
about the preparation of brominated hydroxy aromatic compounds
[73].
Direct
bromination
of
hydroxy
aromatic
compounds
by
electrolysis of mixtures comprising the aromatic compound, a source
of bromide ion, and an organic solvent provided brominated hydroxy
aromatic compounds at synthetically useful rates with high paraselectivity
Cholest-5-enes was [74] electrochemically
et al. and
brominated by Smiljka
showed that 5,6-unsaturated steroids can be smoothly
brominated by electrochemically-generated bromine derived from
bromides in a divided cell. This methodology allowed for the
preparation of the corresponding 5α,6β-dibromosteroids in good to
high yields when aprotic solvents were used. The process compared
yield and ease of operation with the classic bromination reaction but
avoided
the
use
of
hazardous
brominating
reagents.
Bromomethoxylation also yielded solely 5α,6β-products. In contrast,
electrolytical experiments in an undivided cell gave only complex
mixtures.
A–ring bromination of estrogen [75] has been achieved by
constant current electrolysis of the solutions of these substrates and
Et4NBr in appropriate solvent. Thus the electrolysis consuming 2 Fmol-1
charge gave mixtures of 2 and 4-estrogens (1:1-1:2.5) up to 97%
21
yield, whereas 4 Fmol-1 charge experiments yielded 2,4-dibromo
estrogens as the sole product.
Electrochemical Bromination of per acetylated glycals [76] was
studied by Marija Colovic et al. Bromination of glycals with tribromides
formed
in
situ
from
bromine
and
different
bromide
salts
in
dichloromethane or acetonitrile was found to give predominantly the
products of anti addition of bromine from the C-6 side in high yields.
The same selectivity, which was much higher compared to bromination
with bromine alone, was achieved in bromination of these substrates
by anodic generation of bromine from the same salts. The main
advantages of the present electrochemical method were that the
reactive species could be formed in-situ, avoiding the handling of
noxious and corrosive bromine molecule.
OAc
Br
O
AcO
Br
Figure 1.7 Electrobromination of glycals
22
Halogenation and thiocyanation of the univalent anion of dodecahydro7,8-dicarbanido-undecaborate in a diaphragm electrochemical cell was
studied
by
D.
A.
Rudakov
et
al.[77].
Chemical
methods
for
synthesizing B (9)- monohalo derivatives of the dodecahydro-7,8dicarbanido-undecaborate (–1) anion K were known for the chloro ,
bromo, and iodo derivatives. The dichloro, dibromo, and diiodo
derivatives containing halogens at atoms B (9,11) was obtained via a
chemical route. Halogenation reactions were studied for a number of
C-substituted
derivatives
of
dodecahydro-7,8-dicarbanido-
undecaborate (–1) anions, as well as reactions leading to B(9)monosubstituted or B (9,11)-disubstituted dicarbanido undecaborate.
Elemental halogens were usually used as the halogenating agents
although halosuccinimides were also used occasionally. In previous
experiments the electrochemical halogenation of the potassium salt
during diaphragm less electrolysis was studied. Halogenation occurred
at position 9 of the carborane skeleton and led to the monohalosubstituted
compounds
K+.
The
processes
of
electrochemical
functionalization can differ in diaphragm less and diaphragm cells.
Therefore, in this investigation the author studied electrochemical
halogenation and thiocyanation of the potassium salt with separate
anode
and
electrochemical
cathode
synthetic
compartments.
routes
23
for
The
development
ortho-carborane
of
derivatives
provided an extremely convenient means for introducing substituents
such as the halogens since the halogen is generated from halide ions.
The corresponding metal salts served as sources for these ions and
thus are more accessible than and preferable to the hazardous
elemental halogens. In addition, the halogens were recycled during
electrolysis. From these considerations the electrochemical method of
synthesis is better ecologically and technologically than chemical
methods.
1.4 Mechanistic pathways of Electro bromination Reactions.
Anodic brominations can proceed in at least four distinct
pathways.
1. In the first mechanistic pathway the substrate molecule (AH) may
get oxidized at the electrode surface. The cation radical (AH+) thus
formed then undergo nucleophilic attack by bromide ion (Br-) and
further oxidises subsequently.
AH
AH + Br
AHBr o
AH
………………………
(1.1)
AHBr. …………….. ………(1.2)
ABr + H+ + e- ………….
24
(1.3)
2. In the second mechanistic pathway electrogenerated bromine
molecule, can subsequently react with substrate in a homogeneous
chemical reaction.
2Br -
Br2 + 2 e-
Br2 + AH
………..
ABr + HBr ……………
(1.4)
(1.5)
3. A more probable mechanism would involve generation of bromine
radical at the electrode surface.
This would then attack the
substrate forming product by radical substitution route.
Br -
AH + Bro
Ho
Bro
+ e-
…………
ABr + Ho …………..
H+ + e-
................
25
(1.6)
(1.7)
(1.8)
4.
Electrogenerated bromine can also attack the substrate along
with the solvent or any other solvent related nucleophile. This process
is generally prevalent in the halogenation reactions of olefins.
- 2eC = C + 2Br
-
C - C
Nu
Br
Br
Except for a few specific examples the exact mechanistic pathway has
not been clearly established for many of the commercially important
electrohalogenation reactions.
1.5 Further work
The literature survey described above show a wide scope for
further search. A variety of reactions like chlorination, bromination and
iodination of a number of aromatic compounds have already been
reported in the literature.
A number of patents and reviews have also been covered for
these studies.
However most of these processes did not give very
good yield and regioselectivity. In some of the reactions either equal
amount of starting material or side product is present along with the
26
product [12,13].
Even in the area of laboratory scale optimization
studies of the electrochemical reactions, only a few detailed reports
are available. So we revisited the electrohalogenation reactions to
optimize the yield and conversion with high selectivity.
Electrochemical bromination was investigated in different
solvents [78 - 85] and most of the work dealt with ring brominated
products. Side-chain bromination has not been much explored. Hence
the electrochemical bromination of alkyl aromatic compounds in twophase systems has been selected as our present study and the results
are reported in detail.
Two phase electrolysis has distinct advantages over conventional
homogeneous electrolysis [86]. In the homogenous systems less
selectivity is observed due to oxidation of the substrate on the surface
of the electrode giving a mixture of nuclear (ortho / para isomers) and
side chain brominated products. In a two-phase electrolysis system
the reactive species formed by the electrolytic oxidation of a halide ion
in the aqueous phase can be taken continuously into the organic phase
and
then
reacted
with
the
substrate
regioselectively in very high yield.
27
to
give
the
products
1.5.1 Side chain bromination
we propose to present a simple electrochemical method for the
α-bromination
of
toluene
and
substituted
toluenes
to
get
the
corresponding benzyl bromides in very good yield by two phase
electrolysis at different temperature of 0 - 25o C.
Using this system
the regioselectivity of bromination can be achieved very high level in
the side chain bromination of toluenes with high product yield
(Chapter 3). The proposed two phase system consisted of an aqueous
sodium bromide solution (25-50%) containing catalytic amount of
hydrobromic acid as an aqueous phase and chloroform containing
aromatic compound as an organic phase.
1.5.2 Nuclear bromination
The
nuclear
bromination
of
aromatic
compounds
and
its
derivatives were reported by a number of authors as the ring
brominated aromatic compounds are useful intermediates in the
synthesis of organometallic species and pharmaceutically important
compounds [87-89]. Solvent free conditions also attempted to achieve
this goal.
Even under these optimized conditions, the yield and
efficiency were found to be rather low and the reagents involved for
this reaction was hazardous molecular bromine that is toxic, corrosive
and pollutes the environment. The metal ions used as catalyst are
generally expensive.
28
Using electrochemical technique a number of activated aromatic
compounds were treated for nuclear bromination and the experimental
details are given in this chapter (Chapter 4). Aqueous sodium bromide
was used as bromine source. On passing current the brominating
species formed in the aqueous phase was taken into the organic phase
to proceed the reaction smoothly without leaving any spent reagent.
This reaction is a best example of environment friendly process.
1.5.3 α-Bromination of Ketones
The α-bromination of carbonyl compounds is an important
transformation in synthetic organic chemistry and the resulting
products are used as biologically active compounds.
A number of
methods have been described for the halogenation of ketones. All the
above method required costly reagents and suitable catalyst. Here we
report the
α-bromination of carbonyl compounds without any catalyst
in a mixture of CH3CN - HBr by an electrochemical method at a
temperature of 10 oC. (Chapter 5)
1.5.4 α, α–Dibromination of alkyl aromatic compounds
Poly-p-phenylene vinylene (PPV) and related derivatives formed
essentially by functionalization of the phenylene or vinylene units
constitute a very attractive family of conjugated polymers for
electroluminescent devices. To prepare these type of polymers, bis
29
bromomethyl arene [90], α,α,α’,α’-tetrabromo-p-xylene [91], as well
as poly bis (bromomethyl) arenes [92] are used as starting materials.
Even though only very few reports are available in literature for the
preparation of the above mentioned multibromo molecules there is no
electrochemical method reported. Hence we made an attempt in the
preparation of dibromo substitution at the benzylic position by a simple
electrochemical
method.
Electrochemical
dibromination
of
alkyl
aromatic compound may yield dibromomethyl, bis (bromomethyl),
bis(dibromomethyl) arenes by two-phase electrolysis.
The reaction can be carried out in single compartment cell using
sodium bromide solution (25-50%) containing catalytic amount of HBr
as an aqueous phase (electrolyte) and chloroform containing alkyl
aromatic compound as an organic phase.(Chapter 6)
Hydrolysis of Benzylic bromides
Benzyl alcohol is one of the important organic chemical which
can be synthesized from toluene by oxidation using various oxidizing
agents. The side chain of toluene and substituted toluenes can be the
source of alcohol, aldehydes, and acids which are of commercial
interest due to much usefulness as key intermediates for the
production of a variety of fine or speciality chemicals such as drugs,
30
dye stuffs, pesticides and perfume compositions. Although various
chemical methods using a variety of oxidizing agents such as chromyl
chloride ceric ammonium nitrate, benzene seleninic anhydride or
peroxydisulfate / copper ion was reported for the transformation of
substituted toluenes to the corresponding substituted benzaldehydes,
their synthetic utility have been considerably limited owing to low
yield,
poor
selectivity,
serious
pollution
of
environment,
and
troublesome procedure.
Hence an attempt has been made to prepare the benzylic
alcohols from the substituted toluenes by a simple two step process
consists of (i) Electrochemical side chain bromination of toluene
followed by (ii) Hydrolysis of benzyl bromide to the corresponding
benzyl alcohols using microwave energy in short duration. Benzylic
alcohols can be simply oxidized electrochemically to the corresponding
aldehydes in excellent yield and environment friendly method in 94%
yield [93]. The hydrolysis of benzyl bromide is to be carried out at
different temperature using microwave synthesizer in very short time
(within 10 minutes). The experimental part and the advantages of the
process are discussed in detail (Chapter 7).
31
1.5.6
The
Conversion of benzylic bromides to the corresponding
benzaldehydes using sodium nitrate as mild oxidant.
functionalization
of
benzyl
bromide
to
other
useful
intermediate benzaldehyde is an important transformation in synthetic
organic chemistry. Even though a number of reagents involved for the
above mentioned transformation, in the present study we propose a
simple and effective approach for the synthesis of benzaldehyde from
benzyl bromide using different concentration of sodium nitrate solution
as a mild oxidant without forming over oxidized product benzoic acid
at different temperature (Chapter 8).
32
1.6 References
1. Sasson, Y. Formation of Carbon–Halogen Bonds (Cl, Br, I). : Patai
S.; Rappoport, Z. Editors, The Chemistry of Functional Groups,
Supplement D2: The Chemistry of Halides, Pseudo Halides and
Azides, Part 2, Wiley, Chichester, UK ,1995, 535.
2. March, J.; Smith, M. B. Advanced Organic Chemistry (5th ed.),
Wiley, New York, NY, 2001.
3. De la Mare, P. B. D.
Electrophilic Halogenation, Cambridge
University Press, Cambridge, 1976.
4. Banks, R.E.; Smart, B.E.; Tatlow, J. C. Editors, Organofluorine
Chemistry: Principles and Commercial Applications, Plenum, New
York, NY, 1994.
5. Hiyama, T. Organofluorine Compounds: Chemistry and Applications,
Springer, Berlin, 2000.
6.
Laali,
K.K,
Editor,
Advances
in
Organic
Synthesis,
Modern
Organofluorine Chemistry-Synthetic Aspects, Bentham Science,
Hilversum, The Netherlands, 2006.
7. Jolles, Y.E. Bromine and its Compounds, Ernest Menn, London,
1966.
8. Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 1487.
9. Smart. B. E. J. Fluor. Chem. 2001,109, 3.
33
10. Shaikh, T.M.; Sudalai, A. Tetrahedron Lett. 2005, 46, 5587.
11. Eissen, M.; Lenoir, D. Chem. E. J. 2008, 14, 9830.
12. Chakradhar, A.; Roopa, R.; Rajanna, K.C.; Saiprakash, P.K. Synth.
Commun. 2009, 39, 1817.
13. Mestres, R.; Palenzuela, J. Green Chem. 2002, 4, 314.
14. Lund, H.; Hammerich, O. Organic Electrochemistry, 4th ed.;
Marcel Dekker: New York, 2001.
15. Shono, T. Electroorganic Chemistry as a New Tool in Organic
Synthesis; Springer: Berlin, 1984.
16. Fry, A. J. Electroorganic Chemistry, 2nd ed.; Wiley: New York,
2001.
17. Shono, T. Electroorganic Synthesis; Academic Press: London,
1990.
18. Little, R. D., Weinberg, N. L., Eds.; Electroorganic
Synthesis; Marcel Dekker: New York, 1991.
19.
Shono,
T.
The
New
Chemistry;
Hall,
N.,
Ed;
Cambridge
University Press: Cambridge, 2000, 55.
20. Grim Shaw, J. Electrochemical Reactions and Mechanisms
in Organic Chemistry; Elsevier: Amsterdam, 2000.
34
21. Sainsbury,M., Ed.; Rodd’s Chemistry of Carbon Compounds;
Elsevier: Amsterdam, 2002.
22. Torii, S. Electroorganic Reduction Synthesis; Kodansha: Tokyo,
2006, Vols. 1 and 2.
23. Schafer, H. J. Angew. Chem. Int. Ed. Engl. 1981, 20, 911.
24. Shono, T. Tetrahedron 1984, 40, 811.
25. Utley, J. Chem. Soc. Rev. 1997, 26, 157.
26. Moeller, K. D. Tetrahedron 2000, 56, 9527.
27. Lund, H. J. Electrochem. Soc. 2002, 149, 521.
28. Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605.
29. Yoshida, J.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev.
2008, 108, 2265.
30. Hoormann, D.; Kubon, C.; Jorissen, J.; Kroner, L.; Putter, H. J.
Electroanal. Chem. 2001, 517, 215.
31. Pletcher, D.; Walsh, F. C. Industrial Electrochemistry, 2nd ed.;
Chapman and Hall: London, 1990.
32. Beck, F. J. Appl. Electrochem. 1972, 2, 59.
33. Baizer, M. M. J. Appl. Electrochem. 1980, 10, 285.
34. Mathews, M. A. Pure Appl. Chem. 2001, 73, 1305.
35. Yoshida, J.;Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.;
Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546.
35
36. Suga, S., Suzuki, S.; Yamamoto, A.; Yoshida. J.
J. Am. Chem.
Soc. 2000, 122, 10244.
37. Yoshida, J.; Suga, S. Chem. Eur. J. 2002, 8, 2650.
38. Suga, S.; Watanabe, M.; Yoshida, J. J.Am.Chem. Soc., 2002,
124, 14824.
39. Suga, S.; Nishida, T.; Yamada, D.; Nagaki, A.; Yoshida, J.
J.
Am. Chem. Soc. 2004, 126, 14338.
40. Okajima, M.; Suga, S.; Itami, K.; Yoshida, J. J. Am.Chem. Soc.
2005, 127, 6930.
41. Maruyama, T.; Suga, S.; Yoshida, J. J. Am. Chem. Soc. 2005,
127, 7324.
42. Suga, S.;
Matsumoto, K.; Ueoka, K.; Yoshida J. J. Am. Chem.
Soc. 2006, 128, 7710.
43. Selected recent examples:
(a) Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605.
(b) Raju, T.; Manivasagan, S.;
Revathy,B.; Kulangiappar, K.;
Muthukumaran, A. Tetrahedron Lett. 2007, 48, 3681.
(c) Olivero, S.; Perriot, R.; Dunach, E.; Baru, A. R.; Bell, E. D.;
Mohan,. R. S. Synlett. 2006, 13, 2021.
(d) Elinson, M. N.; Feducovich, S. K. Vereshchagin, A. N.;
Gorbunov, S. V.; Belyakov, P. A.; Nikishin, G. I. Tetrahedron Lett.
2006, 47, 9129.
36
(e) Okimoto, M.; Yoshida, T.; Hoshi, M.; Hattori, K.; Komata, M.;
Numata, K.; Tomozawa, K. Synlett 2006, 11, 1753.
(f) Zha, Z. G.; Hui, A. L.; Zhou, Y. Q.; Miao, Q.; Wang, Z. Y.;
Zhang, H. C. Org. Lett. 2005, 7, 1903.
(g) Palma, A.; Frontana-Uribe, B. A.; Ca´rdenas, J.; Saloma, M.
Electrochem. Commun. 2003, 5, 455.
44. N. L. Weinberg in techniques of chemistry - Technique of
Electroorganic synthesis.Vol. V, Part II, (N.L.Weinberg Ed.),Wiley
Interscience, New york (1975).
45. T. Shono,”Electro Organic Chemistry as a new tool in organic
synthesis”. Springer-Verlag, Berlin.1984, 48, 98.
46. Rifi, R.; Covitz, F, H. Introduction to organic electrochemistry.
Marcel Deckker Inc. New York.(1974), 296.
47. Torii, S. “Electro Organic synthesis, Methods and Applications” Part
1.Oxidations. kodansha Ltd, Tokyo; Japan,VCH, 1985.
48. Lamchen, M. J. Chem. Soc., 1950, 747.
49. Sasaki, K.; Urata, H.; Uneyama, K.; Nagaura, S. Electrochim.
Acta., 1967, 12,137.
50. Landenberg, R.; Lohse, H. J. Prakt. Chem., 1961, 12, 253.
51. Bejarango, T.; Ciliyadi, E. Electrochim. Acta., 1976, 21, 231.
37
52. Torii, S. Uneyama, K.; Tanaka, H.; Yamanaka, T.; Yasuda, T.;
Ono, M.; Khomoto, Y. J. Org. Chem. 1981, 46, 3312.
53. Millington, J.P. J. Chem. Soc. (B) 1969, 982.
54. Casalbore, C.; Mastragostino, M.; Velcher, S. J.Electroanal. Chem.,
1976, 68, 123.
55. Casalbore, C.; Mastragostino, M.; Velcher, S. J. Electroanal.
Chem. 1975, 61, 33.
56.
SU
311886-A,1971,
Perm
Applied
Chemistry
IN
(Per-Non
Standard).
57. Taniguchi, T.; Yano, M.; Yamaguchi, H.; Yasukouchi, K.
J.
Electroanal. Chem. 1982, 132, 233.
58. Visy, C.S.; Novak, M.N. Electrochimica acta, 1987, 32, 1757.
59. Ilyushin, V.A.; Russian Chemical Bulletin. 1988, 37, 391.
60. Mitani, M.; Kobayashi, Koyama, K. J. Chem. Soc. Chem. Comm.
1991, 1418.
61. Vasudevan, D.; Anantharaman, P.N. Journal of Applied
Electro
chemistry, 1993, 23, 808 .
62. Malyszko, J.; Malyszko, E.; Rutkowska-Ferchichi, E.; Kaczor, M.
Analitica chimica Acta, 1998, 376, 357.
63. Billon-Souquet, F.; Martens, T.; Royer, J. Tetrahedron Lett. 1999,
40, 3731.
38
64. Torii, S.; Inokuchi, T.; Misima, S.; Kabayasi, T. J. Org. Chem.,
1980, 45, 2731.
65. Chan, R, H.; Vedo, C.; Kuwana, T. J. Am. Chem. Soc.1983, 105,
3713.
66. Miller, A.D.; Langer, S.H. J. Electrochem. Soc. 1973, 120, 1995.
67. Rossen, K.; Volante, R.P.; Reider, P. J.; Tetrahedron Lett. 1997,
38, 777.
68. Nematollahi, D.; akabery, N. Bulletin of Electrochemistry, 2001,
17, 61.
69. Tanaka, H. Kawakami, Y. Kurobushi, M, Torii, S. Heterocycles,
2001, 54, 825.
70. Nematollahi, D.; Akaberi, N. Molecules, 2001, 6, 639.
71. Kashparova, V.P.; Kagan, E. Sh.; Zhukova, I. Yu.; Russian Journal
of Applied Chemistry, 2004, 77, 1790.
72.Ogamino,
T.;
Mori,
K.;
Yamamura,
S.;
Nishiyama,
S.;
Electrochomica Acta, 2004, 49, 4865.
73. Soloveichik, Grigorii Lev., US Patent- December 2004
74. Smiljka S. Milisavljevic, Klaus Wurst, Gerhard Laus, Mirjana D.
Vukicevic and Rastko D. Vukićević, Steroids, 2005, 75, 867.
39
75. Damljanovic, I.; Vukicevic, M.; Vukicevic, R.D. Bulletin of the
chemical society of Japan. 2007, 80, 407.
76. Colovic, M.; Vukicevic, M.; Dejan Segan, D.; Manojlovic, O.; Sojic,
N.; Laszlo somsak, L,; and Vukicevic, R. D. Adv.Synth.catal.,
2008, 350, 29.
77. Rudakov, D. A.; Potkin, V. I.; Lantsova, I, V. Russian journal of
electrochemistry. 2009, 45, 813.
78. Casalbore, G., Mastragostino, M.; Valcher, S. J . Electroanal.Chem.
1975, 61, 33.
79. Casalbore,G., Mastragostino,M.; Valcher,S. J. Electroanal.Chem.
1976, 68, 123.
80. Casalbore, G.; Mastragostino, M.; Valcher, S. J.Electroanal.Chem.
977, 77, 373.
81. Mastragostino, M.; Valcher, S.; Lazzari, P. J. Electroanal.Chem.
1981, 126, 189.
82. Mastragostino,M.; Valcher,S.; Biserni,M. J. Electroanal.Chem.
1983, 158, 369.
83. Nematollahi,D.; Akaberi,N.; Molecules, 2001, 6 ,639.
84. Nematollahi,D.; Akaberi,N. J.; Electroanal.Chem. 2000, 481, 208.
85. Ogamino, T.; Yamamura, S.; Nishiyama, S. Electrochim.Acta,
2004, 49, 4865.
40
86. Forsyth S.R.; Pletcher, D.: Extended abstracts of Ist International
symposium on
Electro organic synthesis, Kurashiki; 1986; p.35
87. Carreno, M.C.; Garcia Ruano, J.L.; Sanz, G.; Toledo, M.A.; Urbano,
A.N. J. Org. Chem.1995, 60, 5328.
88. Vyas, P.V.; Bhatt, A.K.; Ramachandraiah, G.; Bedekar, A.V.
Tetrahedron Lett. 2003, 44, 4085.
89. Mathew, L.M.; Yogesh, R.M.; Steven, M. Tetrahedron Lett. 2005,
46, 4749.
90. Bernado, A.; Uribe, F.; Heinze, J. Tetrahedron.Lett. 2006, 4635.
91. Silva, A. M. L.; Li, R. W. C.; Matos, J. R.; Gruber, J. J. O. Thermal
Anal and calorimetry, 2000, 675.
92. Burrough, D. D. C.; Bradley, A. R.; Marks, R. N.; Mackay, R. H.;
Friend, P. L.; Holmes, A. B. Nature, 1990, 347, 539.
93. Raju, T.; Manivasagan, S.; Revathy, B.; Kulangiappar, K.;
Muthukumaran, A. Tetrahedron.Lett. 2007, 48, 3681.
41