Nuclear versus side-chain bromination of 4-methoxy toluene by an electrochemical method

Article abstract of DOI:10.1080/00397911.2014.905599

GRAPHICAL ABSTRACT The electrochemical bromination of 4-methoxy toluene by two-phase electrolysis yields 3-bromo 4-methoxy toluene at first, which subsequently undergoes side-chain bromination to give 3-bromo 4-methoxy benzyl bromide as a final product in 86% yield. The two-phase electrolysis consists of 25-50% NaBr as aqueous electrolyte and CHCl₃ containing aromatic compound as organic phase. The reaction temperature is maintained at 10-25 °C. The probable orientation of bromine atom in an alkyl aromatic compound (nuclear versus side chain) is explained from the experimental result.

Full text of DOI:10.1080/00397911.2014.905599

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Nuclear Versus Side-Chain Bromination
of 4-Methoxy Toluene by an
Electrochemical Method
K. Kulangiappar a , M. Anbukulandainathan a & T. Raju a
a Electroorganic Division, Council of Scientific and Industrial
Research , Central Electrochemical Research Institute , Karaikudi ,
India
Accepted author version posted online: 30 Apr 2014.Published
online: 01 Jul 2014.
To cite this article: K. Kulangiappar , M. Anbukulandainathan & T. Raju (2014) Nuclear Versus Side-
Chain Bromination of 4-Methoxy Toluene by an Electrochemical Method, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:17, 2494-2502,
DOI: 10.1080/00397911.2014.905599
To link to this article: http://dx.doi.org/10.1080/00397911.2014.905599
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Synthetic Communications1, 44: 2494–2502, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.905599
NUCLEAR VERSUS SIDE-CHAIN BROMINATION OF
4-METHOXY TOLUENE BY AN ELECTROCHEMICAL
METHOD
K. Kulangiappar, M. Anbukulandainathan, and T. Raju
Electroorganic Division, Council of Scientific and Industrial Research,
Central Electrochemical Research Institute, Karaikudi, India
GRAPHICAL ABSTRACT
Abstract The electrochemical bromination of 4-methoxy toluene by two-phase electrolysis
yields 3-bromo 4-methoxy toluene at first, which subsequently undergoes side-chain bromin-
ation to give 3-bromo 4-methoxy benzyl bromide as a final product in 86% yield. The
two-phase electrolysis consists of 25–50% NaBr as aqueous electrolyte and CHCl3 contain-
ing aromatic compound as organic phase. The reaction temperature is maintained at
10–25 ꢀC. The probable orientation of bromine atom in an alkyl aromatic compound
(nuclear versus side chain) is explained from the experimental result.
Keywords Aromatic compound; bromination; 3-bromo 4-methoxy benzyl bromide;
electrochemical; organic phase; two-phase electrolysis
INTRODUCTION
Halogenated aromatic compounds have been used as intermediates for the
synthesis of natural products and bioactive materials[1] and proved as important
and useful reagents in organic syntheses by functionalization through carbon–
carbon bond formation of diarenes and ethylenic condensations using transition
metals.[2] In aromatic halogenations it is well known that bromine is more reactive
than iodine and bromination gives more selective products than chlorination. When
using elemental bromine it is difficult to control single bromination which depends
Received September 13, 2013.
Address correspondence to T. Raju, Electroorganic Division, Council of Scientific and Industrial
Research, Central Electrochemical Research Institute, Karaikudi 630 006, India. E-mail: traju@cecri.
res.in; rajuorganic@yahoo.co.in
2494

ELECTROCHEMICAL BROMINATION OF 4-METHOXY TOLUENE
2495
Scheme 1. Electrochemical bromination of 4-methoxy toluene.
on the reaction conditions,[3] especially for the electron-rich aromatic compounds.
Thus there have been numerous reported bromination reagents such as NBS (N-
bromosuccinimide),[4] HBr=TBHB (t-butylhydroperoxide),[5] quaternary ammonium
tribromide,[6] PHP (pyridinium hydrobromide perbromide),[7] KBr=NaBO3,[8]
NaBr=NaClO2=Mn(acac)3=moist montmorillonite,[9] LiBr=CAN (ceric ammoniunm
nitrate),[10] BuOBr=zeolite,[11] benzyltriphenyl phosphonium tribromide,[12] NaBr=
dimethyl dioxirane,[13] and HBr=NaBO3.[14] However, many of them suffer from
regioselectivity of bromination of activated aromatic compounds, so the control over
the degree of bromination and the regioselectivity is still needed.
In our earlier publication we reported that two-phase electrolysis of aqueous
NaBr yielded benzyl bromide (91% yield) form toluene and 4-bromoanisole (92%
yield) from anisole.[15,16] Hence we studied the orientation of bromine in 4-metoxy
toluene, which has both the methyl (prefers side-chain bromination) and methoxy
(prefers nuclear bromination) groups. After passing a charge of 6 F=mol, 3-bromo-4-
methoxy-benzyl bromide is obtained in 86% yield as shown in Scheme 1. The
reaction was monitored through high-performance liquid chromatography (HPLC)
to study the stepwise orientation of bromine. The experimental results of similar
molecules are summarized in Table 1. The reaction was conducted galvanostatically
at a current density of 30 mA=cm2 at 10–25 ꢀC using 50 ml of 25–50% NaBr solution
containing 5 ml of 47% HBr. Platinum electrodes each of 10 cm2 area were used as
electrodes.
DISCUSSION
Generally a hydroxyl or methoxy group substituted benzene ring has greater
reactivity in electrophilic substitution reactions than the unsubstituted one. In con-
trast a nitro group decreases the ring’s reactivity. Thus the activation or deactivation
of benzene ring toward electrophilic substitution may be correlated with the
electron-donating or electron-withdrawing influence of the substituent by molecular
dipole moments. The electron-donating substituents (blue dipoles) activate the ben-
zene ring toward electrophilic attack, and electron-withdrawing substituents (red
dipoles) deactivate the ring.
The substituent can influence the reactivity of the benzene in two ways. The
first one is the inductive effect of the substituent. The second effect exhibited is
because of conjugation of a substituent function with the aromatic ring. This conju-
gative interaction facilitates electron pair donation or withdrawal to or from the
benzene ring, in a manner different from the inductive effect.

2496

2497

2498

ELECTROCHEMICAL BROMINATION OF 4-METHOXY TOLUENE
2499
Under the reported electrochemical bromination conditions toluene (entry 1)
gives benzyl bromide as a sole product in 91% yield. The reaction follows a free rad-
ical mechanism. When electron-donating groups such as -OH, –OMe (entries 3–6)
are present at the benzene ring, the ring brominated products are formed after pass-
ing a charge of 2 F=mol. The reactive species involved in this reaction is bromonium
ion, and the product formed is ring brominated compound due to electrophilic sub-
stitution. Two differently oriented bromine substituted compounds are obtained
when the aromatic ring is substituted by either a mild activating group (ꢁCH3,) or
a strong activating group (ꢁOCH3, ꢁOH).
In the case of 4-methoxy toluene (entry 2) on passing a charge of 2 F=mol a
mixture of 3-bromo-4-methoxy toluene (37%) and 3-bromo-4-methoxy benzyl bro-
mide (13%) is obtained along with starting material (50%). In this electrochemical
reaction, the bromonium ion is formed first and attacks electron-rich benzene ring
at the ortho position to the ꢁOCH3 group. Once the monobromination at the aro-
matic ring is over, subsequently the ring brominated compound undergoes side-chain
bromination at the methyl group, even though some amount of starting material
(4-methoxy toluene) is present as such. After passing a charge of 4 F=mol, 3-
bromo-4-methoxy benzyl bromide is formed in 56% along with 34% 3-bromo-4-
methoxy toluene. On further electrolysis 3-bromo-4-methoxy benzyl bromide is
formed in 86% yield along with 14% 3-bromo-4-methoxy toluene after passing a
charge of 6 F=mol. This is confirmed by NMR and HPLC analysis.
From these experimental results, it is observed that in the electrochemical
bromination of 4-methoxy toluene, ring bromination is preferred over side-chain
bromination at the initial stage and the final product 3-bromo-4-methoxy benzyl
bromide is obtained after passing a total charge of 6 F=mol.
In the case of 3,5-dimethyl phenol (entry 3) the highly activating substituent
(ꢁOH) predominates in directing the orientation of bromine atom even though there
are two mild activating –CH3 groups present in the molecule. Consequently
2,4,6-tribromo-3,5-dimethyl phenol was obtained as a single product, after passing
a charge of 6 F=mol (theoretical current required for three bromine substitution)
and the molecule is confirmed by the absence of aromatic proton signal in 1H
NMR spectra.
The bromination of 3,5-dimethyl phenol after protecting its phenolic group
[to its methyl ether (entry 4)] afforded 2,6-dibromo-3,5-dimethyl anisole as
product after passing a charge of 4 F=mol. In this case the bromination took
place in a controlled manner; that is, only the ortho-position to the methoxy group
is substituted even though the para-position is vacant. The reason may be that the
presence of two methyl groups in the phenyl ring makes the molecule more electron
rich.
2,6-Dibromo-4-methyl phenol is formed as a product in 95% yield when
p-cresol (entry 5) is brominated. 4-Methyl acetanilide (entry 6) gives regioselective
ring brominated products; that is, bromine is substituted at the ortho-position to
the acetamide group. Side-chain bromination is preferred when the benzene ring
is substituted with a nonactivating [–H, (entry 1)] or mild deactivating group
(ꢁOCOPh, ꢁCOOH, and ꢁBr, entries 7–9) with an average yield of 60–89%. When
a strong deactivating group ꢁNO2 is substituted (entry 10), side-chain brominated
product is formed in lower yields (27%) with less current efficiency.

2500
K. KULANGIAPPAR ET AL.
Mechanism
The electrochemically generated bromine molecule combines with water and
gives one molecule of hypobromous acid and one molecule of HBr. As the hypobro-
mous acid is unstable because of its high ionic nature and in the presence of hydro-
bromic acid, one molecule of water is removed from the hypobromous acid giving
Brþ, which attacks the electron-rich aromatic ring (Scheme 2). The product obtained
under these conditions is exclusively ring brominated (ortho to the ꢁOCH3 group).
Subsequently on passing a further 2 F of charge benzylic bromination takes place by
free radical mechanism (Scheme 3).
In conclusion when there are strong electron-denoting groups present at the
aromatic ring, bromination occurs selectively on the aromatic ring with good yield.
When slightly electron-donating, electron-neutral, or electron-withdrawing groups
are attached, bromination occurs selectively on the benzylic position with lower
yield.
Scheme 2. Mechanism for electrophilic substitution reaction.
Scheme 3. Side-chain bromination of 3-bromo 4-methoxy toluene by free radical mechanism.

ELECTROCHEMICAL BROMINATION OF 4-METHOXY TOLUENE
2501
EXPERIMENTAL
General Procedure for Electrochemical Bromination
A solution of 4-methoxy toluene (0.625 g, 5 mmol) in 25 ml chloroform was
taken in a beaker-type undivided cell. A 25% aqueous sodium bromide solution
(50 ml) containing 5 ml of 47% HBr was added to it. Platinum electrodes (each of
10 cm2 area) were placed in the upper layer of the aqueous phase. The organic phase
alone was stirred with a magnetic stirrer at a rate of 40 rpm in such a way that the
organic layer did not touch the electrodes. The electrolysis was conducted galvanos-
tatically at a current density of 30 mA=cm2 until the quantity of charge indicated in
Table 1 was passed at 15 ꢀC.
After completion of electrolysis, the lower organic phase was separated,
washed with 10% sodium thiosulfate solution followed by water (2 ꢂ 25 ml), and
dried with anhydrous Na2SO4. The solvent was removed under reduced pressure
to afford 1.46 g (86% yield) of 3-bromo 4-methoxy benzylbromide as product.
The electrolysis was monitored by high-performance liquid chromatography
(Shimadzu) using a Shimpack ODS column (120 ꢂ 4.5 mm) as the stationary phase.
The eluent consisted of methanol–water (70:30) at a flow rate of 1 ml=min. Samples
were analyzed using an ultraviolet (UV) detector at a wavelength of 254 nm. The
proton NMR spectra were recorded with a Bruker NMR spectrometer (400 MHz).
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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