Experimental and Theoretical Study of the Reaction Kinetics of 2,5-Dimethylterephthalonitrile Bromination Compared to 1,4-Dimethylbenzene Bromination

Article abstract of DOI:10.1055/s-0036-1591750

Experimental and theoretical studies showed the differences observed in the benzylic tetrabromination reactions in 2,5-dimethylterephthalonitrile compared to 1,4-dimethylbenzene. It was observed that the compound containing the nitrile substituent underwent a slower bromination reaction, with the formation of four intermediate compounds, while for the compound without substituents, the reaction was faster and only two intermediate compounds were observed.

Full text of DOI:10.1055/s-0036-1591750

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–E
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C. M. A. Villalba et al.
Paper
Synthesis
Experimental and Theoretical Study of the Reaction Kinetics
of 2,5-Dimethylterephthalonitrile Bromination Compared to
1,4-Dimethylbenzene Bromination
Cibeli M. A. Villalba*
Thiago de C. Rozada
Fábio S. dos Santos
Leandro Scorsin
Jarem R. Garcia
Barbara C. Fiorin
Chemistry Departament: State Universit of Ponta Grossa,
Campus Uvaranas - Av. General Carlos Cavalcanti, 4748,
84030-900, Ponta Grossa-PR, Brazil
cmavillalba@uepg.br
Received: 30.11.2017
Accepted after revision: 01.12.2017
Published online: 29.01.2018
brominated is added to a flask along with benzoyl peroxide
as radical initiator, and N-bromosuccinimide (NBS) in
carbon tetrachloride solvent as source of bromine.9
DOI: 10.1055/s-0036-1591750; Art ID: ss-2017-z0564-op
The p-xylene compound was converted into the
α,α,α′,α′-tetrabromide-p-xylene compound, which has
been studied so that its pharmaceutical applications can be
explored; studies have shown interesting properties in tri-
als for the treatment of Alzheimer’s, and for medications
against AIDS and cancer.10 Moreover, it is used to obtain PPV
polymers (polyphenylenevinylene) through electrosynthe-
sis; such polymers have been drawing the attention of re-
searchers since the 1990s because their properties allow
them to be used in organic light-emitting diodes (OLEDs),
organic photovoltaic films (OPVs), and in photovoltaic
cells.11 The 2,5-dicyano-p-xylene compound was converted
into α,α,α′,α′-tetrabromide-2,5-dicyano-p-xylene, which
has been studied as part of the search for conducting poly-
mers with well-defined properties to be used in photo-
voltaic devices12 and photoluminescent materials, among
others.13
In this study we aimed to compare the bromination re-
actions that occur in 1,4-dimethylbenzene and in 2,5-di-
methylterephthalonitrile. To do so, the experimental syn-
thesis of both compounds was completed using the Wohl–
Ziegler reaction.9 The synthesis was monitored for
10 hours, and the formation of mono-, di-, tri- and tetra-
brominated compounds over time was assessed by 1H NMR
spectroscopic analysis. Furthermore, a theoretical study
was carried out wherein density functional calculations
were performed to understand the electronic changes in
the methylene groups during the addition of bromine
atoms to the reactants and, thus, explain the experimental
data obtained.
Abstract Experimental and theoretical studies showed the differences
observed in the benzylic tetrabromination reactions in 2,5-dimethyl-
terephthalonitrile compared to 1,4-dimethylbenzene. It was observed
that the compound containing the nitrile substituent underwent a
slower bromination reaction, with the formation of four intermediate
compounds, while for the compound without substituents, the reac-
tion was faster and only two intermediate compounds were observed.
Key words bromination reactions, 1,4-dimethylbenzene, 2,5-dimeth-
ylterephthalonitrile, α,α,α′,α′-tetrabromide-p-xylene, α,α,α′,α′-tetra-
bromide-2,5-dicyano-p-xylene
Aromatic compounds that are brominated either in the
side chain or ring, have been synthesized and studied for a
long time. These compounds are interesting because of
their applications, primarily as intermediates in syntheses
to later reach functions and complex organic structures.1,2
They are also used in the synthesis of materials, agrochemi-
cals, antioxidants and pharmaceuticals.3–5
Different methods of syntheses have been studied to
obtain such compounds. Electrochemical bromination
methods6 as well as other brominations with solvents such
as 1,2-dichlorobenzene,1 ionic liquid,7 and water,8 among
others, have been performed.
In this study, benzylic tetrabrominations were per-
formed in p-xylene (1,4-dimethylbenzene) and in 2,5-di-
cyano-p-xylene (2,5-dimethylterephthalonitrile) by using
the Wohl–Ziegler Reaction,9 which has been the most com-
monly used method. The reaction is performed under heat-
ing with light provided by a light bulb. The compound to be
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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C. M. A. Villalba et al.
Paper
Synthesis
A kinetic study of the bromination reaction of 1,4-di-
methylbenzene and 2,5-dimethylterephthalonitrile was un-
dertaken to explain the differences in the rate of incorpora-
tion of bromine atoms in the methyl groups when the com-
pound has CN substituents on the ring and when it does
not.
also increases to approximately 20%. Meanwhile, the rela-
tive percentages of the structures with two bromine atoms
start to decrease. The reaction continues for 10 hours and
an increase in the percentage of tetrabrominated com-
pound CN_6, occurs.
The Wohl–Ziegler reaction is radical. In its mechanism,
NBS generates molecular bromine (Br2), which reacts with
the initiating agent (benzoyl peroxide, which is broken
homolytically in the presence of light/heat). Thus, the bro-
mine radical is produced. This radical removes a hydrogen
atom from the allylic or benzylic position of the compound
to be brominated, generating a benzylic radical (stabilized
by resonance) and HBr. HBr reacts with NBS and forms
more Br2 and succinimide. The benzylic radical removes a
bromine atom from the Br2 compound, yielding the bromi-
nated compound.9
The presence of six compounds, the structures of which
are shown in Figure 1, was found during the reaction of 2,5-
dimethylterephthalonitrile.
Br
Br
7
2
Figure 2 Graph of the kinetics of the bromination reaction of 2,5-di-
methylterephthalonitrile
NC
NC
NC
1
3
4
6
CN
CN
CN
5
8
For the 1,4-dimethylbenzene, the formation of only two
intermediate compounds, H_3 and H_5, was observed (Fig-
ure 3).
Br
Br
CN_1
Br
CN_2
Br
CN_3
Br
Br
Br
Br
NC
NC
NC
Br
Br
7
1
6
2
CN
CN
CN
5
3
Br
Br
4
CN_4
CN_5
CN_6
8
Br
Br
Figure 1 Bromination of 2,5-dimethylterephthalonitrile
H_1
H_2
H_3
Br
Br
Br
Br
Br
Br
Br
The percentage of each compound present in the reac-
tion mixture during 10 hours was calculated (Figure 2).
Such calculations were performed based on the integral re-
lated to the signals of each compound in the 1H NMR spectra.
It was observed that, in the beginning of the reaction,
first, the formation of approximately 40% CN_2 was neces-
sary for two bromine atoms to enter the methyl groups
(CN_3 and CN_4). It is seen that the entrance of bromine at-
oms into opposite methyl groups or into the same methyl
group occurs in almost the same proportion, but with a
slight preference for the opposite methyl group due to the
greater number of effective collisions provided by its geom-
etry. For the formation of structures with three bromine
groups to increase significantly, it is necessary that there be
approximately 20% of structures with two bromine atoms
(CN_3 and CN_4). The formation of structures with four
bromine atoms (CN_6) only starts to occur after the relative
percentage of the structures with three bromine groups
Br
H_4
H_5
H_6
Figure 3 Bromination of 1,4-dimethylbenzene
The formation of the compound with only one bromine
atom (H_2) was not observed, with the first sample (with-
drawn after 15 minutes of reaction) indicating the forma-
tion of 100% of compound H_3, with two bromine atoms
one at each methyl group (Figure 4). Increased relative per-
centage of the compound with three bromine atoms (H_5)
was then observed with a decrease in the relative percent-
age of the H_3 compound. When the relative percentage of
H_5 was approximately 30%, an increased relative percent-
age of α,α,α′,α′-tetrabromide-p-xylene (H_6), with four
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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C. M. A. Villalba et al.
Paper
Synthesis
bromine atoms, was observed. The relative amount of H_6
increases throughout the reaction time until all the NBS is
consumed.
Figure 5 Structures of 1,4-dimethylbenzene (H_1) and 2,5-dimethyl-
terephthalonitrile (CN_1)
Table 1 ATP and NBO Atomic Charges for the Derivatives of 2,5-Di-
methylterephthalonitrile Calculated at M06-2X/6-311++G(2d,2p)
C7 (ATP)
C8 (ATP)
0.01543
C7 (NBO)
C8 (NBO)
CN_1
CN_2
CN_3
CN_4
CN_5
CN_6
0.01543
0.33954
0.33186
0.65489
0.64519
0.63763
–0.63483
–0.43337
–0.43696
–0.38264
–0.38349
–0.41465
–0.63483
–0.60722
–0.43696
–0.60578
–0.43936
–0.38510
0.00405
0.33186
-0.00094
0.32272
0.64231
Figure 4 Graph of the bromination reaction of 1,4-dimethylbenzene
The reactions observed for the 1,4-dimethylbenzene,
with and without substituents on the ring, differed with re-
spect to velocity. After 1 hour of reaction, the 1,4-dimethyl-
benzene already had a relative percentage of 20% of the
tetrabrominated compounds. Meanwhile, the compound
containing substituents (CN_1) presented a slow reaction;
after 10 hours of reaction, it had only ca. 15% tetrabromi-
nated compounds. It is believed that the reaction of 2,5-di-
methylterephthalonitrile requires a higher energy of activa-
tion and, thus, is slower.
Calculations on the electronic structure were per-
formed to better explain what happens in each structure.
Potential energy surface calculations were performed and
all minima were optimized, but some conformations ob-
tained in this preliminary analysis converged to more stable
conformations. The electrostatic potential maps of the most
stable conformations of the derivatives of the two com-
pounds were studied. It was observed through the map of
electrostatic potential that the higher the number of bro-
mine atoms bonded to the methyl group, the greater the
positive character of the carbon to which they were at-
tached.
Table 2 ATP and NBO Atomic Charges for the Derivatives of 1,4-Di-
methylbenzene Calculated at M06-2X/6-311++G(2d,2p)
C7 (ATP)
C8 (ATP)
C7 (NBO)
C8 (NBO)
H_1
H_2
H_3
H_4
H_5
H_6
0.05079
0.45798
0.44700
0.79655
0.77433
0.77066
0.05079
0.03560
0.44699
0.02910
0.42480
0.77069
–0.59260
–0.40475
–0.41002
–0.34447
–0.35150
–0.35369
–0.59260
–0.59465
–0.41001
–0.59587
–0.41391
–0.35367
Based on the positive character of carbons C7 and C8, a
comparison between these theoretical values and experi-
mental data can be made. Thereby, an explanation for the
distinct behavior of both reactions can be suggested. The
reactions occur with the formation of radicals; the carbon
with greater charge deficiency (higher charge) causes a
weakening of the carbon–hydrogen bond, making removal
of the hydrogen easier, thus, facilitating the formation of
the benzylic radical. It is suggested that because of the ob-
served charge differences, the formation of the H_3 com-
pound, containing a bromine atom in C7 and C8, is very fast,
and the H_2 compound cannot be detected in the first sam-
ple withdrawn at 15 minutes of reaction. What is observed
at this time is the formation of 100% of H_3 and, afterwards,
other compounds appear.
The atomic charge was determined with three different
methods to verify this observation: charge analysis through
the natural bond orbital method (NBO),14 Mulliken charges,
and ATP charges. Since the atomic charge is not a quantum
observable, all methods to compute it are necessarily arbi-
trary.15 In this discussion, the results of Mulliken charges
will not be presented due to the restrictions on the distri-
bution of atomic charges in the molecules.
Table 1 and Table 2 show the values of the ATP and NBO
charges obtained for the C7 and C8 carbon atoms for both
compounds (Figure 5).
When observing the ATP charge for CN_2, it can be seen
that the values for C7 and C8 are quite different because the
charge of C8 has a very low value due to the entrance of a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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C. M. A. Villalba et al.
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Synthesis
bromine atom on the opposite side. For H_2, the charge val-
ues observed are not so different. In this case, the charge of
C8 is only a little less positive than the charge of C8 in H_1.
Such behavior of the charges is significant, because, when
compared with the other experimental data, it can be noted
that 1,4-dimethylbenzene (H_1) is completely dibrominat-
ed right at the beginning of the reaction and, later, other
compounds appear, whereas the 2,5-dimethylterephthalo-
nitrile (CN_1) first has 40% of its structure monobrominat-
ed and, only then, other dibrominated structures appear.
For CN_2, entrance of the second bromine atom does
not occur so fast because of the effect of the ATP charges of
carbons C7 and C8, and also for steric reasons. Therefore,
the relative percentage of the dibrominated compounds
formed (CN_3 and CN_4) is only 20–30%, after a reaction
time of approximately 250 minutes, with CN_3 being
formed in greater quantity.
quired for the reaction to occur. The reaction occurs with
the formation of essentially only two intermediates. Theo-
retical calculations of charges are consistent with the ex-
perimental observations.
It took longer for four bromine atoms to enter the struc-
ture containing the nitrile substituents, and four intermedi-
ates were observed.
The reactions were carried out by using the Wohl–Ziegler9 method
(Scheme 1) to perform the kinetic study. CCl4 (30 mL), 2,5-dicyano-p-
xylene (1.65 g), NBS (8.25 g) and benzoyl peroxide (1.5 mg) were add-
ed to a flask. A reflux condenser was connected to the flask. After re-
flux started, the reaction was run for 10 h under strong stirring and
lighting with a 500 W incandescent bulb. Samples (0.6 mL) were col-
lected for the kinetic study. The same procedure was carried out for
the reaction with p-xylene, substituting 2,5-dicyano-p-xylene for p-
xylene (1.92 mL). In the first 2 h, samples were collected every
15 min; in the next 2 h, every 30 min; in the next 3 h, every 1 h, and,
subsequently, every 2 h, with a total of 16 samples. The samples were
filtered and redissolved in chloroform so that the 1H NMR spectrum
could be acquired to determine the percentage of each compound
formed during the reaction. The theoretical studies were conducted
with workstations running in a Linux environment using the Gauss-
ian 09 software package16 for the electronic structure calculations
and the NBO 5.9 module17 for analyses involving natural bond orbital
theory.
The third bromine atom can add to either the C7 or the
C8 atom in the structure without substituents. Therefore,
the structures containing two bromine atoms (H_3) are
quickly converted into H_5 and stabilize after 60 minutes
from the beginning of the synthesis.
The energy between the dibrominated structures CN_3
and H_3 (two bromine atoms on different methyl groups)
and CN_4 and H_4 (two bromine atoms on the same methyl
group) can be compared. The CN_3 and H_3 compounds are
more stable than the CN_4 and H_4 compounds. The differ-
ence between CN_3 and CN_4 is 2.22 kcal mol–1 and the dif-
ference between H_3 and H_4 is 3.63 kcal mol–1. The oppo-
site is found for radicals that lead to the formation of the
second bromination. The radical on the methyl group that
has already undergone monobromination is more stable
than the radical on the methyl group without bromine at-
oms. However, the difference in energy was greater for the
radicals of the derivative of 2,5-dimethylterephthalonitrile
(2.51 kcal mol−1) than for radicals of the derivative of 1,4-
dimethylbenzene (1.44 kcal mol−1).
Br
Br
CCl4
+ 3 NBS
110 °C + hν
Br
Br
Br
Br
CN
CN
CCl4
+ 4 NBS
110 °C + hν
NC
NC
Br
Br
Scheme 1 Bromination reaction of 1,4-dimethylbenzene and 2,5-di-
The entrance of a third bromine atom can occur after 75
minutes of reaction for the structure with substituents
(CN_3 or CN_4). It can be promoted by the insertion of a
bromine atom in the C7-Br, forming the C7-Br2, or in the
C8-H, leading to C8-Br.
The entrance of the fourth bromine atom into both
structures is determined by the amount of steric hindrance
as well as by the character of the radical reaction. The per-
centage of formation of the H_6 structure becomes con-
stant when it reaches approximately 18% after 75 minutes
of reaction. The CN_6 structure is only detected at 150 min-
utes, with a percentage of 0.44%, has a gradual percentage
increase, and, even with no stabilization after 600 minutes,
it reaches a value of only 14.93%.
methylterephthalonitrile
Potential energy surface calculations related to the C-C-C-Br dihedral
angles were performed at the M06-2X/6-31G level of theory for each
compound, with 24 steps of 15°. The minima were minimum points
then optimized with the DFT (Density Functional Theory) method
M06-2X18 and basis set 6-311++G(2d,2p)19 in a vacuum. The M06-2X
hybrid functional method is suitable for obtaining thermochemical
and kinetic data, and for cases in which noncovalent interactions are
important in systems involving atoms of the main group.20 Calcula-
tions of frequency with the same level of theory were performed to
characterize the obtained structures as stationary points or transition
states, and to obtain thermodynamic properties and the zero-point
energy (ZPE).21
In conclusion, we observed that the bromination reac-
tions in the compound without substituents are faster. It is
believed that this is due to the lower activation energy re-
Funding Information
We thank the Capes and CNPq for financial support.
)(
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C. M. A. Villalba et al.
Paper
Synthesis
Supporting Information
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M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E