Ultrasonically assisted halogenation of aromatic compounds using isoquinolinium bound hypervalent chromium and tetrabutylammonium halides in PEG-600 solutions under acid free and solvent-free conditions

Article abstract of DOI:10.14233/ajchem.2018.21413

Isoquinolinium bound Cr(VI) reagents like isoquinolinium dichromate (IQDC) and isoquinolinium chlorochromate (IQCC) have been successfully accomplished as efficient reagents for oxidative halogenation of aromatic compounds using tetrabutylammonium halide (TBAX) as halogenating agents in aqueous polyethylene glycol (PEG-600) under acid free conditions. Tetrabutylammonium bromide (TBAB) has been used for bromination and tetrabutylammonium iodide (TBAI) for iodination. The halogenation reactions that occurred smoothly in 2 to 7 h under conventional conditions are accelerated magnificently under sonication with few minutes (25 to 70 min) of reaction time and fairly good yields. The reactions occurred at moderate temperature under mild and environmentally safe conditions with simple work up.

Full text of DOI:10.14233/ajchem.2018.21413

Asian Journal of Chemistry; Vol. 30, No. 8 (2018), 1892-1896
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21413
Ultrasonically Assisted Halogenation of Aromatic Compounds using
Isoquinolinium Bound Hypervalent Chromium and Tetrabutylammonium
Halides in PEG-600 Solutions under Acid Free and Solvent-Free Conditions†
1
2
1
A. SAMBASHIVA RAO , KOLA RAMESH , K.C. RAJANNA3,* and I. CHAKRVARTHI
1Department of Chemistry, Rayalaseema University, Kurnool-518002, India
2Department of Chemistry, Maturi Venkata Subba Rao Engineering College, Hyderabad-501 510, India
3Department of Chemistry, Osmania University, Hyderabad-500 007, India
*Corresponding author: E-mail: kcrajannaou@yahoo.com
Received: 28 April 2018;
Accepted: 1 June 2018;
Published online: 30 June 2018;
AJC-18992
Isoquinolinium bound Cr(VI) reagents like isoquinolinium dichromate (IQDC) and isoquinolinium chlorochromate (IQCC) have been
successfully accomplished as efficient reagents for oxidative halogenation of aromatic compounds using tetrabutylammonium halide
(TBAX) as halogenating agents in aqueous polyethylene glycol (PEG-600) under acid free conditions. Tetrabutylammonium bromide
(TBAB) has been used for bromination and tetrabutylammonium iodide (TBAI) for iodination. The halogenation reactions that occurred
smoothly in 2 to 7 h under conventional conditions are accelerated magnificently under sonication with few minutes (25 to 70 min) of
reaction time and fairly good yields. The reactions occurred at moderate temperature under mild and environmentally safe conditions with
simple work up.
Keywords: Isoquinolinium dichromate, Isoquinolinium chlorochromate, Bromination, Tetrabutylammonium iodide, PEG-600.
KBrO3) is also being used in presence of mineral acid for the
generation of bromonium ion and there by effective bromina-
tion of aromatic compounds. In these protocols, large amount
of acid waste is sent through the laboratory outlets after compl-
etion of the reaction, which may trigger environmental pollution.
Several methods [4-15] have been tried in the past several years,
which to address the environmental issues as well as to avoid
the use of hazardous, toxic and corrosive Cl2 and Br2. Recently,
we have reported isoquinolinium chlorochromate (IQCC) and
isoquinolinium dichromate (IQDC) as cost-effective oxidation
catalysts to trigger halogenation of aromatic compounds [14,15]
in presence of alkali metal halides (KCl, KBr and KI) and
small amount of KHSO4. The use of mineral acid is completely
avoided in these protocols. On the other hand, polyethylene
glycol (PEG) is considered as safe and eco-friendly reaction
medium because of its low vapor pressure, non-flammability,
non-hazardous, inexpensive and the ease of work up. In several
cases, it is also used as an efficient phase transfer catalyst. In
view of the foregoing striking features, PEG has been used in
a large number of reactions in organic synthesis [16-24]. In a
recent study, we have successfully explored aqueous polyethylene
INTRODUCTION
Halogenation of aromatic compounds is one the most
important key areas of organic synthesis because organic halides
can be easily transformed into other functional groups under
mild conditions. In addition, organic halides are also used
as important building blocks for the synthesis of life saving
drugs and bioactive molecules [1-9]. A perusal of literature
revealed that the two main preparatory routes viz., direct
halogenation and diazonium salt methods to obtain aryl halides
[1-10]. Direct halogenation methods of aromatic compounds
include the use of molecular halogen (X2) either through thermal
or photochemical routes. Friedel-Crafts method is also one of
oldest and efficient methods of halogenation, in which Lewis
acids are used as catalysts. Metal chlorides such as FeCl3,AlCl3
are the most popular metal chlorides in these reactions [1,2].
However, phenols, anilines and aromatic compounds with electron
donating groups are known to undergo halogenation in the
presence of halogens (molecular chlorine or bromine) even in
the absence of Lewis acids to give halogenated products [3].
On the other hand, brominating mixture (a mixture of KBr and
†This work is a part of A. Sambashiva Rao’s Ph.D. Thesis (PPCHE.030) submitted to Rayalaseema University, Kurnool, India.

Vol. 30, No. 8 (2018)
Oxidative Halogenation of Aromatic Compounds Using Tetrabutylammonium Halide in PEG-600 Solutions 1893
glycols (PEG) as efficient reaction media for nitration of aromatic
compounds using a variety of metal nitrates under acid free
conditions [18]. Encouraged by these aspects coupled with
the green chemistry guidelines [25], we have tried to develop
a synthetic protocol, under acid-free and metal-free conditions,
for halogenation of aromatic compounds using aqueous PEG-
600 and tetrabutylammonium halide (TBAX).
properties in aqueous solutions. PEG produces non-ionic surfac-
tants when coupled to hydrophobic molecules [22].
In order to have much more insight into the PEG interactions
with isoquinolinium bound Cr(VI), the morphologies of phenol
and PEG-600 are presented in Fig. 1 showed that sheet like
structure embedded with flakes, which are slightly bigger in
the case of PEG-600.
EXPERIMENTAL
The chemicals used in this study were purchased either from
Aldrich, Merck, Avra, Loba or Fluka. Melting points of the
reaction products were recorded on BUCHI B-545 by placing
capillary tube loaded with the solid product. Perkin Elmer FT-
IR spectrometer is used to record infrared (IR) spectra, while
Varian VNMRS-400 MHz spectrometer is for NMR spectra,
with TMS internal standard.All the chemical shifts are reported
as ppm values relative to CHCl3 (7.26). ZAB-HS mass spectro-
meter is used to record the mass spectra of products with ESI
ionization.
General procedure for halogenation of aromatic comp-
ounds in aqueous PEG-600 solution: Phenol (1 mmol, 10
mL) dissolved in 1M PEG-600, isoquinolinium dichromate
(IQDC) or isoquinolinium chlorochromate (IQCC) reagent, and
tetrabutylammonium halide (TBAX) (1.1 mmol each) were
taken in a reaction flask and refluxed with constant stirring at
about 25 to 30 ºC, till the completion of reaction, as ascertained
by thin layer chromatography. Then the contents of reaction
were diluted with ethylacetate (10 mL) and separated from aqu-
eous layer. Organic layer was then washed two to three times
with 5 mL water and separated. Finally, the resultant mass is
dried over sodium sulphate. The anhydrous ethylacetate layer
was separated under reduced pressure to give crude product,
which was further purified by column chromatography (silica
gel, 100-200 mesh) using EtOAc-hexane (3:7).
Fig. 1. Scanning electron microscope (SEM) images of reactants and PEG600
However, SEM images of IQCC and IQDC in presence of
PEG-600 (Fig. 2) exhibited altogether different textures with
bundles micro-belts, while SEM images of (IQCC + phenol) exhi-
bited bundles of micro-size grains, spread over on the sheet.
However, the morphology of IQDC and phenol mixture depicted
bundles of flakes (belts) arranged one over the other. Interes-
tingly, SEM images of (phenol + IQCC + PEG) and (phenol +
IQDC + PEG) also shows nano-like structures, even though the
morphology of (phenol + IQCC + PEG) is entirely different
from that of (phenol + IQDC + PEG) with relatively smaller
For the separation and recyclization of PEG, aqueous mother
liquor (reaction mixture of PEG-600 and water) was treated
with ether because PEG is insoluble in ether. The aqueous layer
obtained after the removal of ether, was then distilled directly
at 100 ºC to remove water and recover PEG-600. The recovered
PEG-600 could be reused for consecutive runs.
General procedure for ultrasonically assisted halogen-
ation of aromatic compounds in aqueous PEG-600 solution:
Ultrasonically assisted halogenation of aromatic compounds
is almost similar to the conventional reaction. The reaction vessel
containing ingredients (TBAX, IQCC or IQDC, aromatic substrate,
PEG-600 and solvent) was introduced into ultrasonic bath till
the reaction is completed. TLC technique is used to monitor the
progress of reaction.After confirming completion of the reaction,
product was isolated following similar work-up procedure as
mentioned above.
RESULTS AND DISCUSSION
In the present study, halogenation of phenols has been accom-
plished using TBAX in aqueous PEG-600 solution in the
temperature range of 25 to 30 ºC. Literature survyed showed
that PEG is soluble in water (due to hydrogen bonding) and
also in aqueous alkaline media like NaOH, KOH or Na2CO3.
This aspect supports the contention that PEG exhibits mild acidic
Fig. 2. Scanning electron microscope (SEM) images for PEG-600 inter-
actions with reactants

1894 Rao et al.
Asian J. Chem.
size nanostructures. Further, it is important to recall that
initially IQDC hydrolyzes to afford active [(IQH+HCrO4−]"
(IQ bound chromic acid species), according to the following
equilibrium:
[(IQH+CrO(OH)2XCl−] yields halogenated aromatic substrate
through a cyclic intermediate as shown in Scheme-I.
On the basis of the foregoing observations and discussions,
it can be reasonably substantiated that PEG-600 bound structures
also act like micro to nanoreactors as in the case of micelle catal-
yzed reactions and accelerate the halogenation of aromatic
compounds in the presence of tetrabutylammonium bromide
(TBAB) and iodination in presence of tetrabutylammonium
iodide (TBAI). Interestingly, under sonication the reaction times
are drastically reduced to few minutes followed by marginal
yield enhancements all the protocols. Rate enhancements in
H2O
(IQH)2Cr2O7
2[IQH)+(HCrO4)–]
Almost, a similar type of mechanism is more likely in iso-
quinolinium chlorochromate (IQCC) initiated reactions through
the formation of [IQH+CrO3Cl−]. The species thus formed
may further react with TBAX to give [(IQH+CrO(OH)2XCl−].
Finally, the reaction between aromatic substrate and
Electron cloud on PEG
Polyethylene glycol(PEG)
O
H
H
O
H-(O-CH2-CH2)n-O-H
n
IQCC
TBAX
[N(Bu)4]+
X
[(IQH)+(CrO3Cl)
(PEG bound IQCC)
]
H
H-(O-CH2-CH2)n-O
(PEG bound TBAX)
[(IQH)(CrOX(OH)2Cl)]
(HQI)
(PEG bound TBAX)
+
H2O
TBAOH
Y
Y
R
[(IQH)(CrOX(OH)2Cl)]
R
[(IQH)(OCr(OH)2Cl] + H2O
Y
Y
X
OH
R
X
Cr
O
H
..
....
OH
Cl
R
Scheme-I: Mechanism of IQCC triggered halogenation in PEG-600 medium

Vol. 30, No. 8 (2018)
Oxidative Halogenation of Aromatic Compounds Using Tetrabutylammonium Halide in PEG-600 Solutions 1895
TABLE-1
ULTRASONIC EFFECTS OF BROMINATION IN PEG-600 UNDER ACID FREE CONDITIONS
TBAB/IQCC assisted bromination
Conventional Sonication
TBAB/IQDC assisted bromination
Conventional Sonication
Entry
Substrate
Product
4-Bromo phenol
4-Bromo-2-methylphenol
2-Bromo-4-methylphenol
4-Bromo-3-methylphenol
4-Bromo-2-bromo phenol
2-Bromo-1-naphthol
RT
(h)
3.0
4.0
5.3
4.0
6.0
5.0
9.0
7.0
7.0
7.0
Yield
(%)
72
70
70
66
60
70
45
RT
Yield
(%)
70
65
65
60
66
70
45
RT
(h)
Yield
(%)
72
RT
Yield
(%)
70
(h)
40
50
50
50
60
60
80
70
60
50
(h)
30
40
40
40
50
50
70
60
50
40
1
2
3
4
5
6
7
8
9
Phenol
o-Cresol
p-Cresol
m-Cresol
3.0
4.0
5.0
4.5
6.0
5.5
10.0
8.0
8.0
7.0
70
70
66
60
70
45
60
60
65
65
60
66
70
40
60
60
4-Bromo phenol
1-Naphthol
4-NO2 phenol
2-OH benzaldehyde 5-Bromo-2-OH-benzaldehyde
4-OH benzaldehyde 3-Bromo-2-OH-benzaldehyde
4-NO2-2-bromo phenol
60
60
60
60
60
70
10
Toluene
2-Bromo toluene
60
70
TABLE-2
ULTRASONIC EFFECTS OF IODINATION IN PEG-600 UNDER ACID FREE CONDITIONS
TBAB/IQCC assisted iodination TBAB/IQDC assisted iodination
Conventional Sonication Conventional Sonication
Entry
Substrate
Product
4-Iodo phenol
4-Iodo-2-methylphenol
2 Iodo-4-methylphenol
4-Iodo-3-methylphenol
4-Iodo-2-bromo phenol
2 Iodo-1-naphthol
RT
(h)
2.0
3.0
4.0
4.0
6.0
3.5
8.0
4.0
4.0
6.0
Yield
(%)
80
80
78
75
72
81
60
RT
Yield
(%)
70
70
65
66
65
65
60
RT
(h)
2.5
3.0
4.0
4.5
6.0
3.5
9.0
4.5
4.0
4.0
Yield
(%)
80
70
77
75
70
75
55
RT
Yield
(%)
70
70
65
66
65
65
60
(h)
30
25
30
30
30
40
60
45
40
50
(h)
30
30
40
30
30
40
50
35
40
50
1
2
3
4
5
6
7
8
9
Phenol
o-Cresol
p-Cresol
m-Cresol
4-Bromo phenol
1-Naphthol
4-NO2 phenol
2-OH benzaldehyde 5-Iodo-2-OH-benzaldehyde
4-OH benzaldehyde 3-Iodo-2-OH-benzaldehyde
4-NO2-2-iodo phenol
70
70
65
55
60
60
70
70
66
55
60
60
10
Toluene
2-Iodo toluene
sonicated reactions could be attributed to cavitation effects as
mentioned literature reports [26-30]. At the same time faster
rate accelerations are observed in CTAB/USAR protocols than
inTX-100/USAR protocols. These trends could probably indicate
that electrostatic interactions overweighed non-electrostatic
(hydrophobic) interactions on one hand, and cavitation effect
arising from ultrasonic transmission through the reaction mixture
[23-25]. During sonication, compression of the liquid is followed
by rarefaction (expansion), in which a sudden pressure drop
forms small, oscillating bubbles of gaseous substances. These
bubbles expand with each cycle of the applied ultrasonic energy
until they reach an unstable size and they can then collide and/
or violently collapse. Cavitation induces very high temperatures
in the liquid and enhances mass transfer.All the products were
characterized by IR, 1H NMR, mass spectra and physical data
with authentic sample and found to be satisfactory. Reaction
times and yield (%) of the products obtained in these protocols
are presented in Tables 1&2 are characterized by 1H NMR and
mass spectra. The use of IQCC or IQDC /tetrabutylammonium
halide (TBAX) as halogenating agents afforded high yields of
iodo compounds with complete regioselectivity under neutral
and mild reaction conditions. Direct iodination of wide range
of aromatic compounds substituted with electron donating groups
such as methoxy, hydroxy or amino groups have been achieved
with high regioselectivity under mild conditions in excellent
yields. Data presented in Tables 1 & 2 further substantiate
that reaction times for TBAB are less than TBAI, showing the
selectivity of the reactions.
Conclusion
In summary, the oxidative halogenation of aromatic comp-
ounds using tetrabutylammonium halide (TBAX) as halogena-
ting agents [tetrabutylammonium bromide (TBAB)] for bromi-
nation and tetrabutylammonium iodide (TBAI) for iodination
in aqueous PEG-600 solution under acid free conditions have
been successfully accomplished. Highly sluggish conventional
halogenation reactions are accelerated highly significantly.
Under sonication the reactions are enhanced with much more
ease. The reactions occurred under mild and under environm-
entally safe conditions with simple work up at room temperature.
It is therefore, believed that the present protocols are important
contributions in the area of halogenation reactions that occurred
under very mild conditions with a simple and clean workup.
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