Effect of the Catalyst Nature on the Structure of Products of the Reaction of 4-(Dibromomethyl)Benzaldehyde with Trialkyl Orthoformates

Article abstract of DOI:10.1134/S1070363217120052

Reactions of 4-(dibromomethyl)benzaldehyde with trialkyl orthoformates in the presence of both Br?nsted (H₂SO₄) and Lewis (ZnCl₂) acids involved acetalization of the aldehyde group. In the first case, the corresponding acetal is formed as the only product, whereas in the second case the reaction is accompanied by transformation of the dibromomethyl group to give terephthalaldehyde and its mono- and bis-acetals.

Full text of DOI:10.1134/S1070363217120052

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ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 12, pp. 2783–2788. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.B. Gazizov, S.Yu. Ivanova, N.Yu. Bashkirtseva, Sh.N. Ibragimov, R.A. Khairullin, N.N. Gazizova, A.D. Kostenko, 2017, published
in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 12, pp. 1965–1970.
Effect of the Catalyst Nature on the Structure of Products
of the Reaction of 4-(Dibromomethyl)benzaldehyde
with Trialkyl Orthoformates
M. B. Gazizov*, S. Yu. Ivanova, N. Yu. Bashkirtseva, Sh. N. Ibragimov, R. A. Khairullin,
N. N. Gazizova, and A. D. Kostenko
Kazan National Research Technological University, ul. K. Marksa 68, Kazan, 420015 Tatarstan, Russia
*e-mail: mukattisg@mail.ru
Received June 15, 2017
Abstract—Reactions of 4-(dibromomethyl)benzaldehyde with trialkyl orthoformates in the presence of both
Brønsted (H2SO4) and Lewis (ZnCl2) acids involved acetalization of the aldehyde group. In the first case, the
corresponding acetal is formed as the only product, whereas in the second case the reaction is accompanied by
transformation of the dibromomethyl group to give terephthalaldehyde and its mono- and bis-acetals.
Keywords: 4-(Dibromomethyl)benzaldehyde, zinc chloride, terephthalaldehyde, α-bromo ether
DOI: 10.1134/S1070363217120052
Functionally substituted aromatic aldehydes and
acetals are heterofunctional compounds that are widely
used in organic synthesis [1–4]. From the practical
viewpoint, it is important to find conditions affecting
the structure of reaction products and order of reaction
of different groups with the same reagent. The goal of
the present work was to elucidate how the catalyst
nature affects the structure of final products and
transformation sequence of functional groups in the
reaction of 4-(dibromomethyl)benzaldehyde (1) [5–7]
with trialkyl orthoformates 2.
The reaction in the presence of a Lewis acid (an-
hydrous zinc chloride) followed a considerably more
complicated path (Scheme 2). Depending on the re-
actant ratio, terephthalaldehyde (5) (1:2 = 1:1), its
mixture with monoacetal 6 (1:2 = 1:2), or bis-acetal 7
(1:2 = 1:4) was formed.
Obviously, in the reaction with equimolar amounts
of compounds 1 and 2, the dibromomethyl group in 1
is converted to aldehyde. Taking into account that
Lewis acids activated organic halides [8], initial
reaction of ortho ester 2 at the dibromomethyl group of
1 in the presence of ZnCl2 can be expected. On the
other hand, acetalization of aldehydes with ortho esters
in the presence of such Lewis acids as zirconium(IV)
chloride [9], indium(III) chloride [10], bismuth tri-
fluoromethanesulfonate [11], lithium tetrafluoroborate
[12], and copper(II) tetrafluoroborate [13] has been
We have found that sulfuric acid catalyzes the
reaction of aldehyde 1 with ortho ester 2 only at the
aldehyde group. Presumably, the reactive intermediate
is protonated aldehyde 3 which is converted to the
corresponding acetal, 1-(dialkoxymethyl)-4-(dibromo-
methyl)benzene 4 (Scheme 1).
Scheme 1.
H+
4-Br2CHC6H4CHO + CH(OR)3
[4-Br2CHC6H4CHOH] + CH(OR)3
1
2
3
4-Br2CHC6H4CH(OR)2 + HCOOR
_H+
4
R = Me (a); Et (b).
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2784
GAZIZOV et al.
Scheme 2.
4-Br2CHC6H4CHO + CH(OR)3
1
2
1 : 1
1 : 2
4-OCHC6H4CHO + RBr
5 (98%)
10 mol % ZnCl2
O
4-(MeO)2CHC6H4CHO +
+ HCOOMe + MeBr
O
6 (55%)
5 (33%)
+2a ZnCl2
1 : 4
4-(RO)2CHC6H4CH(OR)2 + 3HCOOR + 2RBr + HC(OR)3
7 (99%)
R = Me (а), Et (b).
reported. It should be particularly noted that Anupam
et al. [14] performed acetalization of aromatic, hetero-
aromatic, and alicyclic aldehydes with a trialkyl
orthoformate at a ratio of 1:2 in the presence of cheap
and safe ZnCl2 (10 mol %) on heating in cyclohexane–
methanol (3:1). Using the reaction of benzaldehyde 8
with trimethyl orthoformate as model, we succeeded in
considerably improving this procedure: the reactant
ratio was reduced from 1:2 to 1:1, and the amount of
the catalyst was reduced from 10 to 1 mol %. The
reaction was carried out under solvent-free conditions
at room temperature, and the reaction time was 24 h
NMR when the reaction of 1 with triethyl orthoformate
2b was carried out in benzene at 80°C. After heating
for 0.5 h, ortho ester 2b was consumed completely, and
the reaction mixture contained initial dibromide 1
(52%), acetal 4b (16%), terephthalaldehyde (4%), and
monoacetal 6 (28%). Further heating for 2 h led to the
formation of terephthalaldehyde as the only product.
Thus, we have proved experimentally that heterofunc-
tional compound 1 initially reacts with ortho ester in
the presence of ZnCl2 through the aldehyde group to
give acetal 4. The reaction of the latter with another
equivalent of 2 under mild conditions (room
temperature, 10 mol % of ZnCl2, 22 h) yields a mixture
of monoacetal 6 (71%) and bis-acetal 7 (23%), as well
as terephthalaldehyde (6%), while trialkyl ortho-
1
(Scheme 3). According to the H NMR data, the
conversion of aldehyde 8 to acetal 9 was 100%. It was
also found that monoacetal 6 can readily be acetalized
with ortho ester in the presence of ZnCl2 to produce
terephthalaldehyde bis-acetal 7 in almost quantitative
yield.
1
formate is consumed completely, and the H NMR
spectrum contains no signal at δ 6.75 ppm typical of
dibromomethyl group. When the reaction of 1 with
2 equiv of 2 was carried out under analogous condi-
tions, compounds 6, 7, and terephthalaldehyde were
formed at a ratio of 77:9:13.
In order to find out which of the dibromomethyl
and aldehyde groups in 1 will react first, we used the
1
competitive reaction method. According to the H
1
NMR data, in the reaction of trimethyl orthoformate
with a mixture of benzylidene bromide and benzal-
dehyde, the former reacted exclusively with benzal-
dehyde, whereas dibromomethyl group in benzylidene
bromide remained unchanged. Taking into account
these results, the reactions of 1 with ortho esters were
carried out in carbon tetrachloride at room tem-
No bis-acetal 7 was detected by H NMR in the
reaction of 1 with 2 at a ratio of 1:2 at 50°C (2 h), and
the products were aldehyde 6 and terephthalaldehyde
(67 and 37%, respectively). This indicates that raising
the temperature from 20 to 50–80°C favors the trans-
formation of the dibromomethyl group to aldehyde
rather than to acetal, which may be due to partial
elimination of alkyl bromide from intermediate
α-bromo ether 11 resulting from the direct reaction of
dibromide 1 with ortho ester 2.
1
perature. In fact, the H NMR data showed that
aldehyde 1 was completely converted to acetal 4.
Intermediate formation of acetal 4b was detected by 1H
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EFFECT OF THE CATALYST NATURE ON THE STRUCTURE OF PRODUCTS
Scheme 3.
2785
10 mol % ZnCl2
4-Br2CHC6H4CHO + 4-(MeO)2CHC6H4CHO
2 4-OCHC6H4CHO + 2 MeBr
1
6
5
10 mol % ZnCl2
50°C, 1 h
4-Br2CHC6H4CH(OMe)2
4-OCHC6H4CHO + 2 MeBr
5 (96%)
4а
Scheme 4.
a
ArCHBr2 + CH(OR)3
[ArCH(OR)Br]
−BrCH(OR)2
10a
11
d
c
ArCHBr2
b, CH(OR)3
BrCH(OR)2 + ArCH(OR)2
ArCHO + RBr
9
8
The fact that the dibromomethyl group under mild
conditions (20−25°C) is converted to aldehyde through
intermediate acetal was confirmed by model reactions
of benzylidene halides 10 with trimethyl orthoformate
at a ratio of 1:1 in the presence of 5–10 mol % of
methyl group to aldehyde [15]. The dibromomethyl
and acetal groups in 1, 4a, and 6 react with each other,
giving rise to terephthalaldehyde (5) (Scheme 3).
Thus, we have obtained important experimental
data that are of fundamental significance for organic
chemistry. In the transformation of dibromomethyl-
arene to aromatic aldehyde by the action of trialkyl
orthoformate (1:1, 20−25°C), intermediate α-bromo
ether is formed according to two consecutive paths:
1
ZnCl2. According to the H NMR data, in 1 h after
mixing the reactants, the major components of the
reaction mixture were benzaldehyde acetal 9 (δ
5.55 ppm), initial benzylidene chloride PhCHCl2 10b
(6.83 ppm), and methyl formate (δ 3.90, 8.19 ppm);
traces of the ortho ester (δ 5.11 ppm) were also
detected, but there was no benzaldehyde. The latter
was detected only after 1.7 h (a weak signal at δ 10.1
ppm). Next followed gradual decrease in the intensity
of the signals at δ 5.78 and 6.23 ppm, and a signal at δ
10.1 ppm appeared. After 24 h, the signal at δ 10.1
ppm became the major one. Thus, we have proved
experimentally the transformation of benzylidene
halides 10 to benzaldehyde 8 by the action of trialkyl
orthoformate at room temperature through inter-
mediate formation of acetal. Furthermore, the observed
transformations were simulated by the competitive
reaction of benzylidene bromide with acetal 9a and
ortho ester 2a at a ratio of 1:1:1. In this case, ortho
ester 2a was consumed completely, whereas no
benzaldehyde was present in the reaction mixture
which contained (1H NMR) acetal 9a and initial
dibromide 1 at a ratio of 2.2:1.0. Here, it should be
noted that we have recently reported a catalytic
reaction of dibromomethylarenes with benzaldehyde
dimethyl acetal (ZnCl2, 10 mol %; 50−80°C), which
results in complete transformation of the dibromo-
(1) Direct reaction of 0.5 equiv of ortho ester with
0.5 equiv of the dibromide (path a); the remaining
ortho ester reacts with intermediate α-bromo ether to
give the corresponding acetal and bromo(dialkoxy)
methane (path b); analogous transformation of α-halo
ethers to acetals by the action of ortho ester under mild
conditions was described by us previously [16];
(2) The reaction of benzylidene bromide with the
resulting acetal at a ratio of 1:1 yields the same α-
bromo ether (path c), and elimination of alkyl bromide
from the latter (path c) completes the transformation of
benzylidene bromide to aldehyde (path d). Under mild
conditions (20°C), the reaction follows the sequence
a–d , and the contribution of the sequence a, d is likely
to become appreciable at 50−60°C (Scheme 4).
A probable mechanism of catalytic debromoalkoxy-
lation of dibromomethylarenes involves initial forma-
tion of a donor–acceptor complex which is converted
to contact (13a) and loose ion pairs (13b). Attack of
O-nucleophile ([trialkyl orthoformate (2) or
benzaldehyde dialkyl acetal (9)]) of the CH carbon
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

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2786
GAZIZOV et al.
Scheme 5.
ArCHBr2 + ZnCl2
ArCH Br ZnCl2
DAA
Br
ArCHBr [ZnCl2BrH]
ArCHBr // ZnCl2Br
13a
13b
XHC(OR)2,
X = OR (2), Ph (9)
Br X(RO)CH
O
R
CHBrAr
ArCH(OR)Br + X(RO)CHBr
_ZnCl2
14
11
X = Ph (11), RO (12).
atom in 13a or 13b leads to the formation of new ion
pair 14 with liberation of zinc chloride, and ion pair 14
decomposes to α-bromo ether 11 and bromo acetal 12.
The latter is readily converted to alkyl formate and
alkyl bromide (Scheme 5).
mixture of 2.00 g (0.0072 mol) of compound 1 and
3.06 g (0.0288 mol) of trimethyl orthoformate (2a).
The reaction was accompanied by heat evolution. The
mixture was left to stand for 24 h at room temperature,
and volatile components were removed under reduced
pressure to obtain 2.22 g (98%) of 1-(dibromomethyl)-
In summary, 4-(dibromomethyl)benzaldehyde reacts
with trialkyl orthoformates in the presence of sulfuric
acid (Brønsted acid) to give the corresponding acetal
as the only product. Analogous reaction in the presence
of a soft Lewis acid (anhydrous zinc chloride) also
involves initial acetalization of the aldehyde group,
and the subsequent reaction at the dibromomethyl
group leads to the formation of terephthalaldehyde and
its mono- and bis-acetals, depending on the reactant
ratio and conditions. The obtained results are of
fundamental significance for organic chemistry.
1
4-(dimethoxymethyl)benzene (4a) as colorless oil. H
NMR spectrum, δ, ppm: 3.28 s (6H, Me), 5.40 s (1H,
3
CHO2), 6.62 s (1H, CHBr2), 7.42 d (2H, C6H4, JHH
=
8.4 Hz), 7.55 d (2H, C6H4, JHH = 8.4 Hz). 13C NMR
spectrum, δC, ppm: 40.77 (CHBr2), 52.81 (OMe),
102.37 (CHO2), 126.48 (CHarom), 127.11 (CHarom),
139.94 (Carom), 142.02 (Carom). Mass spectrum, m/z (Irel,
%): 247 (0.26) [M – CH(OMe)2]+, 199 (96.5) [M –
OMe – Me – Br]+, 168 (8.6) [M – CH(OMe)2Br]+, 89
(100.0) [C7H5]+, 63 (80.9) [C5H3]+, 50 (21.7) [C4H2]+.
Found, %: C 36.84; H 3.65; Br 49.21. C10H12Br2O2.
Calculated, %: C 37.06; H 3.74; Br 49.32.
3
The key intermediate in the transformation of
dibromomethylarene to the corresponding aldehyde by
the action of 1 equiv of trialkyl orthoformate is α-
bromo ether which is formed via direct reaction of the
dibromide with ortho ester or intermediate acetal.
b. Following an analogous procedure, from 1.00 g
(0.0036 mol) of aldehyde 1 and 3.20 g (0.0216 mol) of
triethyl orthoformate (2b) we obtained 1.23 g (97%) of
1-(dibromomethyl)-4-(diethoxymethyl)benzene (4b) as
1
EXPERIMENTAL
colorless oil. H NMR spectrum, δ, ppm: 1.23 t (6H,
3
3
CH2Me, JHH = 7.1 Hz), 3.54 q (4H, CH2Me, JHH
=
1
The H and 13C NMR spectra were recorded on
7.1 Hz), 5.50 s (1H, CHO2), 6.63 s (1H, CHBr2), 7.60
1
Tesla BS-567A (100 MHz for H) and Bruker Avance
3
d and 7.69 d (2H each, C6H4, JHH = 8.7 Hz). Found,
400WB spectrometers (400.13 MHz for 1H and 100.61
MHz for 13C) using CDCl3 as solvent and reference.
The mass spectra were obtained on a Thermo Electron
DFS GC/MS instrument (Germany); electron impact,
70 eV; ion source temperature 250°C; BPX5 SGE
capillary column, 50 m×0.32 mm; carrier gas helium.
Ion peaks for most abundant isotopes are given (79Br).
%: C 40.71; H 4.43; Br 45.31. C12H16Br2O2. Cal-
culated, %: C 40.91; H 4.55; Br 45.45.
Reaction of 4-(dibromomethyl)benzaldehyde (1)
with trimethyl orthoformate (2a) in the presence of
ZnCl2. a. Reactant ratio 1:1. A mixture of 1.00 g
(0.0036 mol) of compound 1, 0.38 g (0.0036 mol) of
ortho ester 2a, and 0.05 g (0.36 mmol) of zinc chloride
was heated for 5 min at 80°C. The mixture was
extracted with hot isooctane to isolate 0.47 g (98%) of
Reaction of 4-(dibromomethyl)benzaldehyde (1)
with trialkyl orthoformates in the presence of
sulfuric acid. a. A drop of sulfuric acid was added to a
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017