4-N,N-dimethylaminopyridine promoted selective oxidation of methyl aromatics with molecular oxygen

Article abstract of DOI:10.3390/molecules17043957

4-N,N-Dimethylaminopyridine (DMAP) as catalyst in combination with benzyl bromide was developed for the selective oxidation of methyl aromatics. DMAP exhibited higher catalytic activity than other pyridine analogues, such as 4-carboxypyridine, 4-cyanopyridine and pyridine. The sp³ hybrid carbon-hydrogen (C-H) bonds of different methyl aromatics were successfully oxygenated with molecular oxygen. The real catalyst is due to the formation of a pyridine onium salt from the bromide and DMAP. The onium salt was well characterized by NMR and the reaction mechanism was discussed.

Full text of DOI:10.3390/molecules17043957

Molecules 2012, 17, 3957-3968; doi:10.3390/molecules17043957
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
4-N,N-Dimethylaminopyridine Promoted Selective Oxidation of
Methyl Aromatics with Molecular Oxygen
Zhan Zhang 1,2, Jin Gao 1, Feng Wang 1 and Jie Xu 1,*
1
State Key Laboratory of Catalysis, Dalian National Laboratory for Clean Energy,
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;
E-Mails: zhangzhan@dicp.ac.cn (Z.Z.); gaojin@dicp.ac.cn (J.G.); wangfeng@dicp.ac.cn (F.W.)
2
Graduate university of Chinese Academy of Sciences, Beijing 100049, China
* Author to whom correspondence should be addressed; E-Mail: xujie@dicp.ac.cn;
Tel./Fax: +86-0411-8437-9245.
Received: 2 March 2012; in revised form: 23 March 2012 / Accepted: 27 March 2012 /
Published: 30 March 2012
Abstract: 4-N,N-Dimethylaminopyridine (DMAP) as catalyst in combination with benzyl
bromide was developed for the selective oxidation of methyl aromatics. DMAP exhibited
higher catalytic activity than other pyridine analogues, such as 4-carboxypyridine,
4-cyanopyridine and pyridine. The sp3 hybrid carbon-hydrogen (C–H) bonds of different
methyl aromatics were successfully oxygenated with molecular oxygen. The real catalyst is
due to the formation of a pyridine onium salt from the bromide and DMAP. The onium salt
was well characterized by NMR and the reaction mechanism was discussed.
Keywords: organocatalysis; selective oxidation; methyl aromatics; molecular oxygen;
4-N,N-dimethylaminopyridine
1. Introduction
Selective oxidation of methyl aromatics to oxygenated aromatic chemicals is a fundamental process
in the chemical industry. The corresponding carbonyl products are versatile building blocks in plastics,
synthetic fibers, the pharmaceutical and perfume industries [1–3]. Traditionally, stoichiometric
oxidants, such as KMnO4 and HNO3, were used for the oxidation, which leads to large amounts of
chemical waste [3]. In contrast, the catalytic oxidation using molecular oxygen as terminal oxidant is
attractive from both the economical and environmental viewpoints [4].

Molecules 2012, 17
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Many catalytic systems have been developed for the catalytic oxidation of methyl aromatics with
molecular oxygen, most of which involve metal species [2,5,6]. However, traces of toxic metal ions
could contaminate the products, and metal catalysts subject to deactivation [7–9]. Organocatalysts
which exhibit good performance have attracted much attention, and is an area that has rapidly
developed recently [10]. Encouraging advances have been reported in the field of metal-free oxidation
with organocatalysts. For example, 10-methyl-9-phenylacridinium ion derivatives were developed for
the highly selective oxygenation of p-xylene [11,12]. 2-Chloroanthroquinones were also reported
as efficient organocatalysts for the oxidation of methyl aromatics under mild conditions [13]. These
processes were performed under light irradiation. Our group has focused on the catalytic system
consisting of the N-hydroxyphthalimide (NHPI) analogues and different organic mediators for catalytic
oxidation of hydrocarbons with molecular oxygen [1,14–19]. All these works demonstrated the great
potential of organocatalytic systems for metal-free oxidation with molecular oxygen.
Bromo species were efficient for activating C–H bonds in the oxidation of methyl aromatics. The
most widely used commercial catalytic package for industrial oxidation of methyl aromatics usually
combines cobalt acetate, manganese acetate and a bromide source (e.g., HBr, NaBr) [20]. However,
transition metals are generally indispensable to catalysis. It was reported that bromo sources such
as allylbromide and CBr4 could catalyze metal-free oxygenation with molecular oxygen under
photo-irradiation [21,22]. We recently utilized a catalytic amount of bromine for the metal-free
oxidation of various aromatic hydrocarbons promoted by nitrogen-containing compounds (e.g.,
1, 10-phenanthraline, acridine yellow, methyl violet) in acetonitrile [23–25]. Now catalysis by
4-N,N-dimethylaminopyridine (DMAP) in combination with benzyl bromide has been developed for
the same purpose. DMAP exhibited higher catalytic activity than other pyridine analogues, such as
4-carboxypyridine, 4-cyanopyridine and pyridine.
2. Results and Discussion
2.1. Catalytic Oxidation of p-xylene with Molecular Oxygen Using DMAP/Benzyl Bromide
Initially solvent-free oxidation of p-xylene was selected as the model reaction (Scheme 1). The
results are listed in Table 1. Few oxygenated products were detected without any catalyst or in the
presence of DMAP (Table 1, entries 1–2). When benzyl bromide was used, only 6% conversion of
p-xylene was obtained (Table 1, entry 3), which indicated benzyl bromide was a catalytically inert
bromo source [26,27]. When DMAP was employed in combination with benzyl bromide (Table 1,
entry 4), the p-xylene conversion increased substantially to 49% under the same reaction conditions.
It is proposed that DMAP and benzyl bromide have a synergistic effect in the catalysis. They exhibited
different characteristics from metal catalysts. For the reaction in the presence of DMAP and benzyl
bromide, the major product was p-toluic acid (4) with a selectivity of 58%; the selectivities for
p-tolyl alcohol (2) and p-tolualdehyde (3) were 7% and 13%, respectively; and the selectivity for
4-methylbenzyl 4-toluate (5) was 19%. In metal catalyzed oxidations of p-xylene, p-toluic acid or
terephthalic acid were usually obtained as the major products [8,20]. The primary oxidation products
such as 2 and 3 were easily further oxidized, and product 5 was usually formed with low selectivity.

Molecules 2012, 17
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Scheme 1. Catalytic oxidation of p-xylene.
CH3
CH2OH
CHO
COOH
O
O2
O
+
+
+
CH3
H3C
CH3
CH3
CH3
CH3
1
2
3
4
5
Table 1. Oxidation of p-xylene under solvent-free conditions [a].
Product selectivity (%)
Conversion
(%)
Entry
Catalyst
2
-
-
50
7
3
-
-
50
13
4
-
-
5
-
Others
1
2
3
4
None
DMAP
benzyl bromide
DMAP/benzyl bromide [c]
<2
<2
6
-
-
-
n.d. [b]
58
n.d.
19
n.d.
3
49
[a] Reaction conditions: p-xylene (100 mmol), catalyst (2.5 mmol), 1.0 MPa O2, 160 °C, 3 h;
[b] n.d., not detected; [c] 2.5 mmol of DMAP and 2.5 mmol of benzyl bromide were used.
2.2. Influence of DMAP/Benzyl Bromide Molar Ratio
The molar ratio of DMAP/benzyl bromide has great effect on the oxidation (Figure 1). Decreasing
n(DMAP):n(benzyl bromide) from 1.0 to 0.5 slightly reduced the p-xylene conversion from 49% to 41%.
Figure 1. Influence of DMAP/benzyl bromide molar ratio; reaction conditions: 100 mmol
of p-xylene, 2.5 mmol of benzyl bromide, 160 °C, 1.0 MPa O2, 3 h.
60
Conversion
p-Tolyl alcohol
p-Tolualdehyde
p-Toluic acid
4-Methylbenzyl 4-toluate
50
40
30
20
10
0
0.0
0.5
1.0
1.5
2.0
n(DMAP):n(Benzyl bromide)
However, when the n(DMAP):n(benzyl bromide) ratio was increased to 1.5, the p-xylene
conversion was sharply reduced to 5%, and an even higher ratio of n(DMAP):n(benzyl bromide) = 2

Molecules 2012, 17
3960
resulted in no activity. Previous studies have reported amine bases could work as anti-oxidants [8,26].
Therefore, excess amount of DMAP probably inhibited the oxidation process.
2.2. Influence of Different Pyridine Analogues
Encouraged by the results, we further tested several different pyridine analogues for catalytic
oxidation of p-xylene (Figure 2). DMAP showed better catalytic activity than 4-carboxypyridine,
4-cyanopyridine and pyridine. The conversion of p-xylene increased in the order of 4-carboxy-pyridine
< 4-cyanopyridine < pyridine < DMAP. Electron-donating group substituted pyridine exhibited higher
activity than electron-withdrawing group substituted pyridine.
Figure 2. p-Xylene oxidation with different pyridine analogues; reaction conditions:
p-Xylene (100 mmol), benzyl bromide (2.5 mmol), pyridine analogues (2.5 mmol),
1.0 MPa O2, 160 °C, 3 h.
DMAP
Pyridine
4-Cyanopyridine
p-Toluic acid
p-Tolualdehyde
p-Tolyl alcohol
4-Methylbenzyl 4-toluate
4-Carboxypyridine
0
10
20
30
40
50
p-Xylene Conversion (%)
2.3. Optimization of Reaction Conditions
More detailed optimization of the reaction conditions including temperature and time was also
carried out. The influence of temperature on the oxidation of p-xylene is shown in Figure 3. When the
temperature was increased from 160 °C to 170 °C, the p-xylene conversion increased a little from
49% to 53%, accompanied by an increase in the by-products including 2-benzyl-p-xylene and
2,5,4'-trimethyldiphenylmethane. The formation of the by-products could be caused by alkylation of
p-xylene [28,29]. The decreased reaction temperature led to much lower conversion. Therefore, the
reaction temperature was optimized as 160 °C.
The time-on-course of p-xylene oxidation is shown in Figure 4. The p-xylene conversion increased
steadily along the reaction in first 3 h. After 3 h there was no remarkable increase in
p-xylene conversion by prolonging the reaction time. In the solvent-free oxidation, it was noticed that
the solubility of the oxidation product of p-toluic acid 4 is low. The increasing amount of the solid
product 4 may hinder the mass transfer for the oxidation process.

Molecules 2012, 17
Figure 3. The influence of temperature; reaction conditions: p-Xylene (100 mmol), DMAP
3961
(2.5 mmol), benzyl bromide (2.5 mmol), 1.0 MPa O2, 3 h.
80
Conversion
p-Tolyl alcohol
p-Tolualdehyde
60
40
20
0
p-Toluic acid
4-Methylbenzyl 4-toluate
140
150
160
170
Temperature (oC)
Figure 4. The influence of time; reaction conditions: p-Xylene (100 mmol), DMAP
(2.5 mmol), benzyl bromide (2.5 mmol), 1.0 MPa O2, 160 °C.
Conversion
p-Tolyl alcohol
p-Tolualdehyde
p-Toluic acid
60
4-Methylbenzyl 4-toluate
40
20
0
0
1
2
3
4
5
Time (h)
In order to improve the catalytic results, we investigated the effect of the different solvents listed in
Table 2. Using water as the solvent, the oxidation of p-xylene was inhibited (Table 2, entry 1). Acetic
acid is a good solvent for many oxidation reactions [8,30], but a reaction between acetic acid and the
oxidation intermediate occurred in this case, which led to the formation of 4-methylbenzyl acetate
(Table 2, entry 2). In acetonitrile, a p-xylene conversion of 87% was obtained with a selectivity of 82%
for p-toluic acid 4 (Table 2, entry 3). This improvement could be due to the improved mass transfer.

Molecules 2012, 17
3962
We attempted to perform the reaction under lower temperatures, but the reaction was still sluggish
(Table 2, entries 4 and 5). Despite the fact the conversion of p-xylene was improved in solvents,
several points should be considered. On the one hand, the loss of solvent cannot be neglected under the
reaction conditions. On the other hand, the neat reaction may give a clear reaction result with less
interference for understanding the oxidation process. Therefore, the subsequent experiments were still
conducted in the absence of solvent.
Table 2. Oxidation of p-xylene in different solvents [a].
Product selectivity (%)
Temperature
(°C)
Conversion
(%)
Entry
Solvent
3
-
4
-
5
-
Others [b]
1
2
3
4
H2O
160
160
160
140
120
<2
66
87
28
<2
-
Acetic acid
Acetonitrile
Acetonitrile
Acetonitrile
17
7
31
-
60
82
67
-
1
2
-
22 [c]
9
2
-
5
[a]
-
Reaction conditions: p-xylene (10 mmol), benzyl bromide (0.25 mmol), DMAP
[b]
(0.25 mmol), solvent (5 mL), 1.0 MPa O2, 160 °C, 3 h; Mainly 4-carboxylic benzaldehyde and
terephthalic acid; [c] Mainly 4-methylbenzyl acetate.
2.4. Oxidation of Different Methyl Aromatics
To investigate the scope and limitation of our catalytic system, the oxidation of several different
methyl aromatics were carried out (Table 3). As can be seen, the use of this catalytic system could be
extended to different methyl aromatics. Relative high conversions were obtained for xylenes,
1,3,5-trimethylbenzene and p-tert-butyltoluene (Table 3, entries 1–4). This should be attributed to the
activation of the methyl group by those electron donating substitutent groups. Without this substitution
effect, toluene, p-chlorotoluene, p-bromotoluene and 1-methylnaphthalene were less easily oxidized,
even at elevated temperature (Table 3, entries 5–8).
Table 3. Oxidation of different methyl aromatics [a].
Product selectivity (%) [b]
Alcohol Aldehyde Acid Ester Others
Conversion
Entry
Substrate
(%)
CH3
1
56
5
8
75
10
2
CH3
CH3
2
41
3
4
82
10
1
CH3

Molecules 2012, 17
3963
Table 3. Cont.
Product selectivity (%) [b]
Alcohol Aldehyde Acid Ester Others
Conversion
Entry
Substrate
CH3
(%)
3
49
3
6
7
89
86
1
4
1
t-Bu
CH3
4
39
2
1
H3C
CH3
CH3
5 [c]
17
14
10
6
16
18
58
56
14
17
2
3
CH3
CH3
6 [c]
Cl
Br
7 [c]
12
<2
7
-
17
-
63
-
11
-
2
-
CH3
8 [c]
[a]
Reaction conditions: substrate (100 mmol), DMAP (2.5 mmol), benzyl bromide (2.5 mmol),
[b]
160 °C, 1.0 MPa O2, 3 h;
were detected as the main products; [c] Reaction was carried out at 180 °C.
For multimethyl aromatics, only monomethyl oxygenated products
2.5. Interaction of DMAP and Benzyl Bromide
In order to better understand the reaction, control experiments were carried out (Table 4). When
benzyl chloride was used instead of benzyl bromide, the conversion of p-xylene was only 2%, which
was much lower than that seen with the usage of benzyl bromide (Table 4, entry 1 and Table 1, entry 4).
This result indicated that bromo species was crucial for the catalysis. Different combinations of
bromo-containing chemicals with DMAP were compared for the oxidation (Table 4, entries 2–5). With
molecular bromine, only 6% of p-xylene was converted and bromination of the aromatic ring was
observed. Ammonium bromide was also less efficient, with a conversion of only 20%. In contrast,
when alkyl bromides such as n-butylbromide and n-dodecylbromide were employed, the p-xylene
conversion reached 45% and 44%, respectively, which was slightly lower than that seen when benzyl
bromide was used. The alkyl bromides were preferred in combination with DMAP for solvent-free
oxidation of p-xylene.

Molecules 2012, 17
Table 4. Comparison of different bromide sources for p-xylene oxidation [a].
3964
Product selectivity (%)
Others
Conversion
Entry Catalysts
(%)
2
6
20
45
44
2
16
27
20
5
3
4
5
1
2
3
4
5
benzyl chloride + DMAP
bromine + DMAP
84 n.d. [b] n.d.
n.d.
30[c]
3
43
19
8
n.d.
39
65
n.d.
19
20
ammonium bromide + DMAP
n-butyl bromide + DMAP
n-dodecyl bromide + DMAP
1-benzyl-4-N,N-dimethyl
pyridinium bromide [d]
2
9
11
58
21
1
6
51
6
15
59
17
3
[a]
Reaction conditions: p-Xylene (100 mmol), DMAP (2.5 mmol), bromo-containing chemical
[b]
[c]
(2.5 mmol), 160 °C, 1.0 MPa O2, 3 h;
n.d., not detected;
Bromination products were
determined as the main byproducts; [d] 2.5 mmol of pyridinium onium salt was used as catalyst.
For oxidations of methyl aromatics involving bromo species, benzyl bromide (or its analogues) are
easily formed, and are usually thought to be inert for catalytic oxidation [26,27]. When DMAP was
introduced, benzyl bromide readily reacted with this nucleophlic base and formed the corresponding
onium salt. Previous reports have noticed that the onium salts were effective in promoting hydrocarbon
oxidations [31,32]. Therefore, the in situ formation of a pyridine onium salt may account for the
enhanced activity of DMAP/benzyl bromide. Indeed, when DMAP and benzyl bromide were stirred
under 160 °C in p-xylene, the pyridine onium salt can be separated as a pure product. The structure
was confirmed by 1H-NMR as 1-benzyl-4-N,N-dimethylpyridinium bromide [δ = 8.48 (d, 2H), 7.55–7.29
(m, 5H), 7.12–7.04 (m, 2H), 5.51–5.42 (m, 2H), 3.24–3.14 (m, 6H); Figure 5]. Using this onium salt as
catalyst, the p-xylene oxidation proceeded with a conversion of 51% (Table 3, entry 6), which is
comparable to the result employing DMAP and benzyl bromide as shown in Table 1, indicating that the
real catalyst could be the corresponding pyridine onium salt.
1
Figure 5. H-NMR of the separated pyridine onium salt; the signal at 2.51 ppm is
attributed to DMSO solvent residue, and that at 3.35 ppm is attributed to water existed in
DMSO-d6.

Molecules 2012, 17
3965
2.6. Tentative Reaction Mechanism
The liquid-phase oxidation of hydrocarbon generally follows the radical chain oxidation mechanism.
The present reaction may be also based on the same mechanism, which is supported by the observed
inhibition of oxidation in the presence of trace amount of p-cresol. In light of all information above, we
propose the reaction mechanism to be as shown in Scheme 2. Alkyl bromide readily reacts with
DMAP and forms the corresponding onium salt. The organic bromide is converted into ionic bromide,
which is easily oxidized into a bromo radical under elevated temperature [8,33]. The bromo radical
then abstracts hydrogen atom from the benzylic positions. Similar activation of hydrocarbons by a
bromo source is observed in photooxidations [21,22]. This may explain why the bromo source is
crucial for the catalysis. The benzyl radical traps molecular oxygen and forms a peroxy radical and
hydroperoxide. According to previous reports, the decomposition of hydrperoxide can be promoted by
onium salts, which is favorable for further propagation of the radical chain oxidation and affords
oxygenated products [31,32].
Scheme 2. Tentative reaction route.
N
N
N
N
+
+
RBr
Br
(1)
(2)
Br
N
R
N
R
a
[O]
Br
Br
Ar-CH2
Ar-CH3
Br
Br
O2
(3)
(4)
Ar-CH3
Ar-CH2
Ar-CH2OO
Ar-CH2OOH
a
Oxygentated products
Ar-CH2OOH
3. Experimental
3.1. General
All reagents and materials were commercially available products purchased from J&K Chemical Co.
Ltd. and Tianjin Kermel Chemical Reagent Co. Ltd., China. Different methyl aromatics were used
after removing water by adding 5 wt% of 4Å molecular sieves and treating for 24 h. Other reagents
were directly used without further purification. The conversion of methyl aromatics and selectivity
of products were determined using an Agilent-7890 GC equipped with a FID and using
1,2-dichlorobenzene as the internal standard. The products were identified on an Agilent 6890N
1
GC/5973 mass spectrometer (MS). The H-NMR spectra were recorded in DMSO-d6 on a Bruker
400 MHz NMR spectrometer with TMS as internal standard.

Molecules 2012, 17
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The reactions were carried out in a closed Teflon-lined 100 mL autoclave equipped with a magnetic
stirrer and an automatic temperature controller. In a typical experiment, p-xylene (100 mmol) were
added into the autoclave followed by DMAP (2.5 mmol) and benzyl bromide (2.5 mmol). After the
autoclave was sealed, the air inside was purged and replaced with O2 three times, then the autoclave
was heated to 160 °C. The pressure was kept at 1.0 MPa during the reaction by continuously
recharging oxygen as needed. After 3 h the autoclave was cooled to room temperature and carefully
depressurized. Dimethyl formamide (DMF, 10 mL) was used to dissolve the products before analysis.
4. Conclusions
In summary, a metal-free catalytic system consisting of DMAP and benzyl bromide was developed.
The primary carbon-hydrogen bonds in different methyl aromatics could be oxidized with molecular
oxygen using this catalyst. The major products are single-substituted organic acids. The in situ
formation of a pyridine onium salt via reaction of DMAP and benzyl bromide may function as the real
catalyst in the reaction. Our study contributes to the basic understanding of organocatalytic systems for
metal-free oxidation.
Acknowledgments
This study was financially supported by the National Natural Science Foundation of China
(21103206).
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Sample Availability: Samples of the all reagents used in the study and the 1-benzyl-4-N,N-
dimethylpyridinium bromide are available from the authors.
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