Oxidation of Iodo- and Bromo-Substituted Polymethylbenzenes in the System PbO2–CF3COOH–CH2Cl2

Article abstract of DOI:10.1134/S1070428018030053

The oxidation of mono- and diiodo- and -bromo-substituted polymethylbenzenes (mesitylene and durene) in the system PbO₂–CF₃COOH–CH₂Cl₂ at room temperature (2–70 h) leads mainly to the formation of iodo- and brom

Full text of DOI:10.1134/S1070428018030053

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 3, pp. 397–402. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © M.A. Sandzhieva, E.S. Aryamova, S.M. Sukharzhevskii, E.V. Grinenko, A.V. Vasilyev, 2018, published in Zhurnal Organicheskoi
Khimii, 2018, Vol. 54, No. 3, pp. 393–398.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on her jubilee
Oxidation of Iodo- and Bromo-Substituted Polymethylbenzenes
in the System PbO2–CF3COOH–CH2Cl2
M. A. Sandzhievaa, E. S. Aryamovaa, S. M. Sukharzhevskiib,
E. V. Grinenkoa, and A. V. Vasilyeva, c*
a St. Petersburg State Forest Technical University, Institutskii per. 5, St. Petersburg, 194021 Russia
*e-mail: aleksvasil@mail.ru
b Magnetic Resonance Research Center, St. Petersburg State University,
Universitetskii pr. 26, St. Petersburg, 198504 Russia
c Institute of Chemistry, St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
Received December 16, 2017
Abstract—The oxidation of mono- and diiodo- and -bromo-substituted polymethylbenzenes (mesitylene and
durene) in the system PbO2–CF3COOH–CH2Cl2 at room temperature (2–70 h) leads mainly to the formation of
iodo- and bromobenzyl alcohols as result of oxidation of methyl group. The reaction involves intermediate
formation of haloarene radical cations. ESR study of these radical cations made it possible to determine the
structure of their singly occupied molecular orbitals a2 or b1 and interpret their reactivity.
DOI: 10.1134/S1070428018030053
Iodo- and bromo-substituted arenes are important
substrates in cross-coupling reactions such as Heck,
Sonogashira, and Suzuki couplings [1–10]. Iodo- and
bromoarenes are commonly synthesized by direct
electrophilic halogenation of aromatic compounds.
Another synthetic route to new haloarenes implies
modification of side-chain substituents in arenes
already containing halogen in the aromatic ring. The
most efficient methods of modification of the benzylic
position in alkyl substituents of arenes are halogena-
tion [11–18], hydroxylation [19], and oxidation to
carbonyl or carboxy group [20–30].
The goal of the present work was structural modi-
fication of methyl groups in mono- and diiodo- and
bromopolymethylbenzenes (mesitylene and durene)
via oxidation in the system PbO2–CF3COOH–CH2Cl2.
Lead(IV) oxide (PbO2) in strong acids (CF3COOH,
FSO3H, HF, etc.) is known as a single-electron oxidant
used to generate radical cations from arenes, alkenes
[31, 32], and alkynes [33]. Lead(IV) oxide–strong acid
systems are capable of oxidizing methyl groups in
arenes and forming new carbon–carbon bonds via
oxidative dimerization involving radical cations of
organic compounds [31–33].
The oxidation of 1,4-diiodo- and 1,4-dibromotetra-
methylbenzenes 1a and 1b in PbO2–CF3COOH–
CH2Cl2 at room temperature (70 h) afforded the
corresponding benzyl alcohols 2a and 2b (Scheme 1).
The oxidation of monohaloarenes 3a and 3b required
a considerably shorter time (2 and 4 h, respectively).
From iododurene 3a we obtained two isomeric
alcohols 4a and 5a as the major products, whereas
the oxidation of bromodurene 3b was more selective,
and only one isomer 4b was formed. The structure of
4a and 5a was confirmed by the NOESY spectra which
showed correlations between the CH2 protons and
protons of the neighboring methyl group and aromatic
proton (Fig. 1). In addition, a small amount of
Scheme 1.
X
X
PbO2, CF3COOH
CH2Cl2, 20°C, 70 h
Me
Me
Me
Me
Me
Me
OH
Me
X
X
1a, 1b
2a, 2b
X = I (a), Br (b).
397

SANDZHIEVA et al.
398
Scheme 2.
Me
X
X
I
I
Me
PbO2, CF3COOH, CH2Cl2
20°C, 2 h (3a) or 3 h (3b)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OH
+
+
I
OH
Me
Me
Me
Me
Me
3a, 3b
4a, 4b
5a
6a
X = I (a), Br (b).
Scheme 3.
X
X
X
PbO2, CF3COOH
CH2Cl2, 20°C, 40 h
Me
Me
Me
Me
Me
Me
+
Me
CHO
9a, 9b
OH
8a, 8b
7a, 7b
X = I (a), Br (b).
diarylmethane 6a was isolated in the oxidation of 3a
(Scheme 2).
durenes 1b, 3a, and 3b (cf. the data on SOMO types
reviewed in [31–33]). The observed positive spin
density distribution in radical cations generated from
haloarenes 1a, 1b, 3a, and 3b makes the methyl groups
therein reactive sites, so that the oxidation involves the
methyl group (Schemes 1, 2). We failed to record ESR
spectra of primary radical cations generated from
haloarenes 1b, 3a, 3b, 7a, and 7b under analogous
conditions (PbO2–FSO3H, –80°C) because of their
high reactivity. Instead, only complex unresolved
spectra of secondary radical cation intermediates were
obtained.
The oxidation of 2-iodo- and 2-bromo-1,3,5-tri-
methylbenzenes 7a and 7b afforded benzyl alcohols 8a
and 8b and benzaldehydes 9a and 9b, respectively
(Scheme 3). The reaction selectively involved only one
methyl group in the para position with respect to the
halogen atom.
We then proceeded with a study aimed at generat-
ing and detecting by ESR spectroscopy radical cation
intermediates in the above oxidative transformations.
Radical cation [2b]+· was generated by oxidation of
dibromodurene 2b in PbO2–FSO3H at low temperature
(–80°C). Its ESR spectrum (Fig. 2) consists of thirteen
equidistant lines (tridecet) due to interaction of
unpaired electron with twelve protons of the four
methyl groups with a hyperfine coupling constant
aHMe of 11.1 G (12H). This spectrum indicates that the
singly occupied molecular orbital (SOMO) of radical
cation [2b]+· is of a2 type with localization of positive
spin density on the aromatic carbon atoms bearing
methyl groups (Fig. 2). The same character of SOMO
a2 should be typical of radical cations derived from
The fact that only the para-methyl group was
oxidized in halomesitylenes 7a and 7b (Scheme 3)
suggested a different type of SOMO of radical cations
[7a]+· and [7b]+·, namely b1 (Fig. 3). In this case, the
positive spin density in [7a]+· and [7b]+· is largely
localized on the aromatic carbon atom in the para
position with respect to the halogen atom, and the
oxidation involves mainly the para-methyl group.
The main transformation paths and mechanisms of
reactions with participation of radical cation inter-
mediates have been considered in [31–34]. Taking
I
OH
Br
OH
I
Me
Me
Me
Me
Me
Me
Me
OH
Me
Me
H
H
H
4a
4b
5a
Fig. 1. Correlations in the 1H–1H NOESY spectra of compounds 4a, 4b, and 5a.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 3 2018

OXIDATION OF IODO- AND BROMO-SUBSTITUTED POLYMETHYLBENZENES
399
Br
Br
Me
Me
Me
Me
Me
Me
Me
Me
aHMe = 11.1 G
g = 2.0026
PbO2, FSO3H, –80°C
+·
–e–
SOMO a2
Br
Br
2b
[2b]+·
11 G
3300
3350
3400
3450
B, G
Fig. 2. ESR spectrum of radical cation [2b]+· generated from dibromodurene 2b in the system PbO2–FSO3H at –80°C.
these data into account, the following scheme can be
proposed for one-electron oxidation of haloarenes 1a,
1b, 3a, 3b, 7a, and 7b (Scheme 4). Deprotonation of
initially formed radical cation A gives benzyl radical B
which is oxidized to benzyl cation C. The latter can
react along different paths. The reaction of C with
nucleophile (trifluoroacetic acid or its anion) leads to
benzyl trifluoroacetate D whose hydrolysis on treat-
ment of the reaction mixture with aqueous alkali (see
Experimental) yields benzyl alcohol 2, 4, 5, or 8 as
final product (Scheme 4). Another reaction direction is
electrophilic substitution in the initial arene with
formation of diarylmethane 6 (see also Scheme 2).
Ester D can also be oxidized to bis-trifluoroacetate E
which undergoes hydrolysis to aldehyde 9 (Scheme 3).
Deeper oxidation of the methyl groups in 1a, 1b, 3a,
3b, 7a, and 7b results in the formation of benzoic acids
10. When the reaction mixture is treated with aqueous
alkali, alkali metal salts of acids 10 remain in solution,
which reduces the overall yield of the isolated
products. Therefore, the yields of 2, 4, 5, 6, 8, and 9
are moderate. All reactions were carried out using
1 equiv of PbO2 (see Experimental). If smaller or
larger amount of the oxidant was added, the yields of
benzyl alcohols were lower.
In summary, we were the first to study oxidation of
(di)iodo- and (di)bromopolymethylbenzenes (halo-
genated mesitylenes and durenes) in the system PbO2–
CF3COOH–CH2Cl2. These reactions led to the forma-
tion of the corresponding halogenated benzyl alcohols
which are promising substrates for various cross-cou-
pling reactions. The oxidation involves intermediate
formation of haloarene radical cations whose reactivity
X
Me
Me
+·
SOMO b1
Me
[7a]+·, [7b]+·
X = I (a), Br (b).
Fig. 3. Structure of the singly occupied molecular orbital
(SOMO) of radical cations [7a]+· and [7b]+· generated by
one-electron oxidation of iodo- and bromomesitylenes 7a
and 7b, respectively.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 3 2018

SANDZHIEVA et al.
400
Scheme 4.
·
+·
Ar Me
Ar Me
Ar CH2
Ar CH2
–e–
–H+
–e–
1, 3, 7
A
B
C
ArH (3a)
–H+
Ar CH2 Ar
H2O
6
Ar
CH2OH
2, 4, 5, 8
CF3COOH
–H+
Ar CH2 OC(O)CF3
H2O
Ar CHO
OC(O)CF3
D
CF3COOH
–e–, –H+
9
Ar
OC(O)CF3
Ar COOH
10
–e–, –H+
E
gel column chromatography using petroleum ether–
ethyl acetate as eluent. Given below are the yields of
the isolated compounds.
was rationalized by the character of their singly
occupied molecular orbitals (a2 or b1), determined by
ESR spectroscopy.
(2,5-Diiodo-3,4,6-trimethylphenyl)methanol (2a).
Yield 35%, colorless crystals, mp 152–154°C.
1H NMR spectrum, δ, ppm: 1.94 s (1H, OH), 2.62 s
(3H, CH3), 2.64 s (3H, CH3), 2.73 s (3H, CH3), 5.01 s
(2H, CH2). 13C NMR spectrum, δC, ppm: 28.6 (CH3),
29.4 (CH3), 29.9 (CH3), 70.3 (CH2), 111.4, 113.1,
138.3, 139.2, 139.8, 140.8. Mass spectrum: m/z 402
[M]+. HRMS: found: 402.9059; calculated for
C10H13I2O: [M + H]+ 402.9050.
EXPERIMENTAL
The H and 13C NMR spectra were recorded at
1
room temperature on a Bruker AM-500 spectrometer at
500 and 125 MHz, respectively, using CDCl3 as
solvent and reference (CHCl3, δ 7.26 ppm; CDCl3,
δC 77.0 ppm). GC/MS analysis was performed on
an Agilent Technologies G2570A 6850 GC/MSD in-
strument (HP-5MS capillary column, 3 m × 0.25 mm,
film thickness 0.25 μm). The high-resolution mass
spectra were obtained on a Varian 902-MS MALDI
mass spectrometer. The ESR spectra of radical cations
in the system PbO2–FSO3H were recorded at –80°C on
a Bruker ELEXSYS E580 spectrometer. The purity of
the isolated compounds was checked by TLC on
Silufol UV-254 plates. The product mixtures were
separated by column chromatography on silica gel
(Chemapol, 40–100 μm) using petroleum ether–ethyl
acetate as eluent.
General procedure for the oxidation of halo-
arenes 1a, 1b, 3a, 3b, 7a, and 7b in the system
PbO2–CF3CO2H–CH2Cl2. Compound 1a, 1b, 3a, 3b,
7a, or 7b, 0.57 mmol, was added with vigorous stirring
at 20°C to a solution of 0.2 mL (2.6 mmol) of tri-
fluoroacetic acid in 3 mL of methylene chloride,
136 mg (0.57 mmol) of lead(IV) oxide was then added,
and the mixture was stirred for 2–70 h. When the
reaction was complete, the mixture was treated with
water (50 mL) and extracted with chloroform (3×
50 mL). The combined extracts were washed with
water, a saturated aqueous solution of NaHCO3, and
water again and dried over Na2SO4, and the solvent
was distilled off. The residue was subjected to silica
(2,5-Dibromo-3,4,6-trimethylphenyl)methanol
(2b). Yield 30%, colorless crystals, mp 179–181°C.
1H NMR spectrum, δ, ppm: 1.89 s (1H, OH), 2.49 s
(3H, CH3), 2.50 s (3H, CH3), 2.60 s (3H, CH3), 4.94 s
(2H, CH2). 13C NMR spectrum, δC, ppm: 21.3 (CH3),
22.0 (CH3), 22.4 (CH3), 64.2 (CH2), 127.9, 129.0,
135.5, 136.5, 136.7, 138.1. Mass spectrum: m/z 306
[M]+. HRMS: found: 306.9321; calculated for
C10H13Br2O: [M + H]+ 306.9328.
(2-Iodo-3,4,6-trimethylphenyl)methanol (4a).
1
Yield 15%, colorless crystals, mp 86–88°C. H NMR
spectrum, δ, ppm: 1.66 s (1H, OH), 2.33 s (3H, CH3),
2.44 s (3H, CH3), 2.45 s (3H, CH3), 4.88 s (2H, CH2),
6.94 s (1H, Harom). Mass spectrum: m/z 276 [M]+.
HRMS: found: 277.0076; calculated for C10H14IO:
[M + H]+ 277.0084.
(2-Bromo-3,4,6-trimethylphenyl)methanol (4b).
1
Yield 35%, colorless crystals, mp 75–77°C. H NMR
spectrum, δ, ppm: 1.69 s (1H, OH), 2.29 s (3H, CH3),
2.36 s (3H, CH3), 2.42 s (3H, CH3), 4.84 s (2H, CH2),
13
6.95 s (1H, Harom). C NMR spectrum, δC, ppm: 19.7
(CH3), 19.9 (CH3), 21.2 (CH3), 69.9 (CH2), 128.9,
131.2, 134.4, 135.5, 135.9, 137.9 (Carom). Mass spec-
trum: m/z 228 [M]+. Calculated: M 228.0.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 3 2018

OXIDATION OF IODO- AND BROMO-SUBSTITUTED POLYMETHYLBENZENES
401
2. Nichihara, Y., Applied Cross-Coupling Reactions,
(3-Iodo-3,4,5-trimethylphenyl)methanol (5a).
Yield 23%, colorless crystals, mp 80–82°C. H NMR
1
Berlin: Springer, 2013.
3. Metal-Catalyzed Cross-Coupling Reactions, De
Meijere, A. and Diederich, F., Eds., Weinheim: Wiley-
VCH, 2004, 2nd ed.
spectrum, δ, ppm: 1.55 s (1H, OH), 2.35 s (3H, CH3),
2.48 s (3H, CH3), 2.51 s (3H, CH3), 4.69 s (2H, CH2),
7.09 s (1H, Harom). Mass spectrum: m/z 276 [M]+.
HRMS: found: 277.0081; calculated for C10H14IO:
[M + H]+ 277.0084.
4. Diederich, F. and Stang, P.J., Metal-Catalyzed Cross-
Coupling Reactions, Weinheim: Wiley-VCH, 1998.
5. Chinchilla, R. and Nájera, C., Modern Alkyne Chem-
istry: Catalytic and Atom-Economic Transformations,
Trost, B.M. and Li, C.-J., Eds., Weinheim: Wiley-VCH,
2014.
1-Iodo-4-[(2-iodo-3,4,6-trimethylphenyl)methyl]-
2,3,5,6-tetramethylbenzene (6a). Yield 5%, colorless
1
crystals, mp 110–112°C. H NMR spectrum, δ, ppm:
2.15 s (6H, CH3), 2.17 s (3H, CH3), 2.44 s (3H, CH3),
2.57 s (6H, CH3), 2.62 s (3H, CH3), 3.93 s (2H, CH2),
6.23 s (1H, Harom). Mass spectrum: m/z 518 [M]+.
HRMS: found: 519.0048; calculated for C20H25I2:
[M + H]+ 519.004.
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(4-Iodo-3,5-dimethylphenyl)methanol (8a). Yield
1
8. Nicolaou, K.C., Bulger, P.G., and Sarlah, D., Angew.
Chem., Int. Ed., 2005, vol. 44, p. 4442.
15%, yellow crystals, mp 71–72°C [35]. H NMR
spectrum, δ, ppm: 1.70 s (1H, OH), 2.48 s (6H, CH3),
9. Chinchilla, R. and Nájera, C., Chem. Rev., 2007,
13
4.60 s (2H, CH2), 7.06 s (1H, Harom). C NMR spec-
vol. 107, p. 874.
trum, δC, ppm: 29.6 (CH3), 64.6 (CH2), 107.0, 125.5,
140.3, 142.3. Mass spectrum: m/z 262 [M]+. Cal-
culated: M 262.1.
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(4-Bromo-3,5-dimethylphenyl)methanol (8b).
Yield 10%, colorless crystals, mp 80–82°C [36, 37].
1H NMR spectrum, δ, ppm: 1.76 s (1H, OH), 2.41 s
(6H, CH3), 4.59 s (2H, CH2), 7.07 s (1H, Harom).
13C NMR spectrum, δC, ppm: 23.8 (CH3), 64.7 (CH2),
126.5, 126.8, 138.5, 139.2. Mass spectrum: m/z 214
[M]+. Calculated: M 214.0.
12. Lücke, B., Narayana, K.V., Martin, A., and Jähnisch, K.,
Adv. Synth. Catal., 2004, vol. 346, p. 1407.
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4-Iodo-3,5-dimethylbenzaldehyde (9a). Yield
17%, yellow crystals, mp 65–67°C [38]. H NMR
spectrum, δ, ppm: 2.55 s (6H, CH3), 7.51 s (2H, Harom),
9.93 s (1H, CHO). Mass spectrum: m/z 260 [M]+.
Calculated: M 260.0.
1
16. De Almeida, L.S., Esteves, P.M., and de Mattos, M.C.S.,
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4-Bromo-3,5-dimethylbenzaldehyde (9b). Yield
1
12%, colorless crystals, mp 67–69°C [39]. H NMR
spectrum, δ, ppm: 2.49 s (6H, CH3), 7.56 s (2H, Harom),
9.93 s (1H, CHO). Mass spectrum: m/z 212 [M]+.
Calculated: M 212.0.
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This study was performed under financial support
by the Foundation for Innovations (project no. 11304
GU/2016, Apr 14, 2017). ESR studies were performed
at the Magnetic Resonance Research Center,
St. Petersburg State University.
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