Photo-induced deep aerobic oxidation of alkyl aromatics

Article abstract of DOI:10.1007/s11426-021-1032-7

Oxidation is a major chemical process to produce oxygenated chemicals in both nature and the chemical industry. Presently, the industrial manufacture of benzoic acids and benzene polycarboxylic acids (BPCAs) is mainly based on the deep oxidation of polyalkyl benzene, which is somewhat suffering from environmental and economical disadvantage due to the formation of ozone-depleting MeBr and corrosion hazards of production equipment. In this report, photo-induced deep aerobic oxidation of (poly)alkyl benzene to benzene (poly)carboxylic acids was developed. CeCl₃ was proved to be an efficient HAT (hydrogen atom transfer) catalyst in the presence of alcohol as both hydrogen and electron shuttle. Dioxygen (O₂) was found as a sole terminal oxidant. In most cases, pure products were easily isolated by simple filtration, implying large-scale implementation advantages. The reaction provides an ideal protocol to produce valuable fine chemicals from naturally abundant petroleum feedstocks. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11426-021-1032-7

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https://doi.org/10.1007/s11426-021-1032-7
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Photo-induced deep aerobic oxidation of alkyl aromatics
Chang-Cheng Wang1, Guo-Xiang Zhang2, Zhi-Wei Zuo3*, Rong Zeng2, Dan-Dan Zhai1,
Feng Liu1* & Zhang-Jie Shi1,3*
1Department of Chemistry, Fudan University, Shanghai 200438, China;
2Department of Chemistry, Xi’an Jiaotong University, Xi’an 710049, China;
3State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, China
Received April 15, 2021; accepted May 25, 2021; published online June 23, 2021
Oxidation is a major chemical process to produce oxygenated chemicals in both nature and the chemical industry. Presently, the
industrial manufacture of benzoic acids and benzene polycarboxylic acids (BPCAs) is mainly based on the deep oxidation of
polyalkyl benzene, which is somewhat suffering from environmentally and economically disadvantageous due to the formation
of ozone-depleting MeBr and corrosion hazards of production equipment. In this report, photo-induced deep aerobic oxidation of
(poly)alkyl benzene to benzene (poly)carboxylic acids was developed. CeCl3 was proved to be an efficient HAT (hydrogen atom
transfer) catalyst in the presence of alcohol as both hydrogen and electron shuttle. Dioxygen (O2) was found as a sole terminal
oxidant. In most cases, pure products were easily isolated by simple filtration, implying large-scale implementation advantages.
The reaction provides an ideal protocol to produce valuable fine chemicals from naturally abundant petroleum feedstocks.
photo-induced, oxidation, alkyl aromatics
Citation:
Wang CC, Zhang GX, Zuo ZW, Zeng R, Zhai DD, Liu F, Shi ZJ. Photo-induced deep aerobic oxidation of alkyl aromatics. Sci China Chem, 2021, 64,
https://doi.org/10.1007/s11426-021-1032-7
Benzene polycarboxylic acids (BPCAs), one of the most
important compounds made by the chemical industry, are
used as key intermediates in the preparations of resins,
plasticizers, pharmaceutical acids, food preservatives, and as
the modulator in the synthesis of metal-organic frameworks
(MOF). A vast majority of chemicals are made from BPCAs.
Terephthalic acid (TPA), as an example being consumed
principally as a monomer precursor in the manufacture of
polyester (PET), has become one of the most in-demand
chemicals with an annual output of up to a hundred million
tons. Functionalized benzoic acids are extensively used in
drug discovery, material chemistry, and agrochemicals as
starting materials or critical ingredients. For instance, sal-
icylic acid is a widespread druggable molecule and princi-
pally been used in personal care and food preservatives
(Figure 1a). BPCAs are chemically synthesized via multi-
step oxidation reactions from the corresponding alkyl aro-
matics. The most notable commercial process for synthe-
sizing BPCAs is the Amoco process [1], which employs
liquid-phase aerobic oxidation with a homogeneous Co-Mn-
Br catalyst system in acetic acid medium [1–3]. The im-
portance and success of the Amoco process is beyond all
doubt. This process commonly requires a harsh reaction
condition, accompanied by high-risk safety accidents (Figure
1b) [4]. Furthermore, the use of transition metal bromides [5]
might release a possible stratospheric ozone-depletion sub-
stance, MeBr. Other approaches in direct oxidations of alkyl
aromatics including (i) stoichiometric oxidation by using
highly reactive inorganic and/or organic oxidants (KMnO4,
iodineV species, t-BuOOH, m-CPBA, H2O2, NHPI, etc.) [6–
12]; (ii) heterogeneous catalytic aerobic oxidation (e.g.,
polymer- or montmorillonite clay-supported catalysts, Pd,
*Corresponding authors (email: zjshi@fudan.edu.cn; liufeng@fudan.edu.cn;
zuozhw@shanghaitech.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021
chem.scichina.com link.springer.com

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Wang et al. Sci China Chem
Au, or Co nanoparticles) (Figure 1b) [2,13–16]. Besides,
several cerium catalyzed examples for the oxidation of al-
kylbenzenes were reported in recent years [17–19].
catalysts to develop a sophisticated chemistry pathway for
the activation of C(sp3)–H bond. After taking an in-depth
analysis of recent photocatalysis developments, we envi-
sioned that through a photo-induced, Ce-promoted benzylic
C(sp3)–H bond activation, the toluene derivatives could be
deeply oxidized to carboxylic acids in the presence of mo-
lecular oxygen, which acts as terminal oxidant through the
radical pathway (Figure 1d). This approach might unfold
green and sustainable oxidation, in both fundamental sci-
ences and chemical industry, for valuable fine chemical
productions from naturally abundant feedstocks.
We set out to investigate the desirable photo-induced
oxidation by examining 4-methyl-1,1′-biphenyl 3n as a
prototypical substrate. After careful optimization, we estab-
lished an efficient photo-oxidation protocol using CeCl3
(5 mol%) as a HAT catalyst in the presence of CCl3CH2OH
(20 mol% for mono-methyl benzenes, 1.0 equiv. for poly-
methyl benzenes), irradiated by light-emitting diode (LED)
light under O2 (1 atm) in CH3CN for 24 h (see the Supporting
Information online for details.).
Ciamician and Silber [20] reported the first photo-induced
oxidation of alkyl aromatics with molecular oxygen in 1912.
In their pioneering work, toluene, o-xylene, m-xylene, p-
xylene, and p-cymene were directly exposed to oxygen and
natural sunlight for about a year. The corresponding mono-
carboxylic acids were obtained as major products without
any photosensitizer. Besides m- and p-toluyl acids, iso and
terephthalic acids were also formed from m- and p-xylenes,
respectively (Figure 1c). In recent years, photochemistry was
re-announced, and photo-catalysts have been used to activate
specific functional groups or substrates to complete various
transformations via energy or electron transfer [21,22]. This
typical application was proved as a “green” synthetic pro-
tocol in organic synthesis [23–28]. Scientists developed
several elegant aerobic C–H bond photo-oxidation protocols
towards the synthesis of alcohol, aldehyde, ketones and
carboxylic acids in the past few decades [29–42]. Due to the
relatively high abundance and excellent photocatalytic per-
formance, cerium salts were widely used as efficient and
promising photo-catalysts. Zuo and co-workers [43–45]
utilized the synergistic effect of hydrogen atom transfer
(HAT) and ligand-to-metal charge transfer (LMCT) with Ce
The substrate scope was explored by the oxidation of to-
luene and its derivatives. Firstly, benzoic acid 2a was ob-
tained with 84% yield from toluene under standard
conditions. The three xylenes 1b–1d were then irradiated to
give the corresponding phthalic acids in good yields. The
Figure 1 The nature of benzene (poly)carboxylic acids. (a) Aromatic (poly)carboxylic acid-related products in daily life. (b) Traditional oxidation of
alkylbenzene. (c) Photochemistry on the roof: the first oxidation of alkyl aromatics with molecular oxygen explored by Ciamician and Silber 100 years ago
[20]. (d) Photo-induced deep aerobic oxidation of (poly)alkyl aromatics to aromatic (poly)carboxylic acids (color online).

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Wang et al. Sci China Chem
in-situ formed phthalic acid from oxidation of orthoxylene
1b, will be spontaneously dehydrated to o-phthalic anhydride
2b. We were happy to find out that trimethyl-, tetramethyl-,
pentamethyl-, and hexamethyl-benzenes (1e–1l) were fully
converted to benzene polycarboxylic acids (BPCAs, 2e–2l)
when introduced to the developed catalytic photo-oxidation
system. These reactions gave good yields by simple work-
up, showing industrial production and application prospect
of this oxidation protocol (Figure 2a). To demonstrate the
utility of this interesting method, the gram-scale reaction of
1a is carried out in the presence of 1 mol% of CeCl3 as
photocatalyst. After irradiated with 390 nm Kessil light for
132 h, 2a was formed with 63% isolated yield. The main
reason for this low efficiency is that the mixture turned to be
a little bit turbid, which affected the light transmittance.
We further proceeded with this reaction on various sub-
stituted toluene derivatives to extend the application scope
(Figure 2b). 2-Methoxy- and 4-methoxy toluene underwent
this oxidation smoothly and gave the corresponding benzoic
acids 4a and 4b in 65% and 78% yield. A variety of para-
substituted toluene substrates were also examined. Phenolic
ester skeletons have ocurred in many pharmaceutical mole-
cules and natural products [46–48]. The result indicates that
our method enables the structure modification of those im-
portant molecules (4c–4e). Both electron-donating groups,
like tert-butyl (4f), phenyl (4n), and electron-withdrawing
groups CF3 (4g), COOEt (4l), CN (4m), as well as halogens
(4i–4k) could tolerate this oxidation well, leaving useful
synthetic functionalities for further derivatization. The re-
action yield of 1-methyl-4-nitrobenzene (3h) is low, maybe
because of the strong electron-withdrawing effect of –NO2.
Meta-substituted toluene derivatives were oxidized to var-
ious benzoic acids (4o–4q), and slightly higher yields were
achieved than that of their corresponding ortho- or para-
isomers. In addition, oxidations of multi-substituted toluene
derivatives were investigated, showing good functional
group tolerance and synthetic diversity (4s–4x).
Aromatic heterocyclic carboxylic acids are widespread in
Figure 2 Deep areobic oxidation of (poly)methylbenzene. (a) Oxidation of polyalkyl benzene 1 to BPCAs 2. (b) Oxidation of substituted toluene 3 to
substituted benzoic acids 4. Conditions: 1 or 3 (0.1 mmol), CeCl3 (5.0 mol%), CCl3CH2OH (20 mol% for mono-methyl benzenes, 1.0 equiv. for polymethyl
benzenes) in CH3CN (2 mL) under 1 atm O2 atmosphere at 60 °C, and irradiated with a 400 nm/390 nm LED lamp for 24–72 h. See Supporting Information
online for details. (c) In a 10 mmol scale reaction, a 500 mL round bottom flask was charged with a stiring bar, and added with reagent 1a (10 mmol), CeCl3
(1 mol%), CCl3CH2OH (20 mol%), CH3CN (100 mL) under O2 atmosphere. The mixture was stirred under the irradiation of 390 nm LEDs for 132 h (color
online).

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Wang et al. Sci China Chem
bio-active natural products, pharmaceutical compounds, and
functional materials. Not only that, some could also serve as
multi-dentate ligands in coordination chemistry. We then
introduced methyl heteroarenes to this oxidation system. To
our delight, the oxidation reaction proceeds smoothly, giving
the target aromatic heterocyclic carboxylic acids with mod-
erate to good yields (Figure 3a). For example, thiophene-2-
carboxylic acid 6a, 5-acetyl thiophene-2-carboxylic acid 6b
and benzo[b]thiophene-2-carboxylic acid 6c were obtained
from the corresponding methyl-substrates 5a–5c. 4-Methyl
pyridine 5e and 3-methyl-1-phenyl-1H-pyrazole 5f were also
compatible with this system, converted to the heterocyclic
carboxylic acid 6e–6f, albeit latter with a lower efficacy.
Substances with linear and branched alkyl substituents
were then examined. We found that both benzylic C–H
oxidation and C–C bond cleavage took place subsequently,
delivering the corresponding carboxylic acid products in
moderate yields (Figure 3b, c). However, a benzylic C–H
must be presented to initiate this oxidation process. It is
important to note that when the mixture of toluene 1a,
ethylbenzene 7a, and cumene 9a was introduced to this
system, 2a was obtained as the only product with high yield
(Figure 3d). This result indicated a potent application of this
oxidation reaction in the high-value transformation of the
off-gases containing substituted benzene homolog com-
pounds. Ultimately, this method was further applied to the
late-stage modification of Celebrex, a non-steroidal anti-in-
flammatory drug, delivering the oxidized product 10 in 65%
yield in one step (Figure 3e). Considering the importance of
this kind of medicinal agent, we expect this methodology to
be useful for drug modification by introducing hydrophilic
carboxylic acid groups at a very late stage.
A series of control experiments were conducted to explore
the mechanism of this catalytic oxidation (Figure 4a). Firstly,
a radical scavenger (TEMPO) was added under standard
conditions. The targeted product 4n was not detected, in-
dicating a possible radical pathway for this oxidation reac-
tion. While we attempted to capture the intermediates with
TEMPO in the absence of O2, compound 11 was detected by
gas chromatograph-mass spectrometer (GC-MS). This result
provided reliable support for the existence of benzylic radi-
cals, which might be the initiator of this photo-induced ra-
dical oxidative procedure. 18O2 then replaced O2. Only 18O
labeled benzoic acid 4n′ was obtained with good yield,
which proved that the [O] atom in the product came from O2.
For a deep insight into the reaction mechanism, we traced the
oxidation of 3n under standard conditions and monitored it
1
by H nuclear magnetic resonance (1H NMR) spectroscopy
every 2 h (Figure 4b). Hydroperoxide 12 (red dot) was first
observed but was further oxidized after the peak at 4 h. Al-
dehyde 13 (blue spot) has been detected and reaches its
summit at around 10 h. Both the above two intermediates
were converted to the desired final product 4n (green trian-
gle) at 24 h. Based on the observations and previous studies,
a plausible mechanism was proposed in Figure 4c. First,
electrophilic alkoxy radical was generated from alcohol via
Ce (IV)-alkoxide intermediate participating in photo-in-
duced LMCT process. It then abstracted hydrogen from
Figure 3 The substrate extension of the oxidation. (a) Oxidation of the benzylic C–H bond in heterocyclic compounds. (b) Secondary benzylic C–H
oxidation to benzoic acids through sequential cleavage of C–H and C–C bonds. (c) Tertiary benzylic C–H oxidation. (d) Oxidation of toluene, ethylbenzene,
cumene mixture. (e) Late-stage diversification of medicinal reagent under standard reaction conditions (color online).

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Wang et al. Sci China Chem
Figure 4 Mechanistic investigations. (a) Control experiments. (b) Kinetic experiments. (c) Plausible mechanism for the oxidation from toluene to benzoic
acids. (d) The deep oxidation of benzyl derivatives with heteroatom group substituents (color online).
benzylic C–H bond to form benzyl radical A; subsequently,
single electron transfer occurred between molecular dioxy-
gen (O2) and Ce(III) to form superoxide radical; this in-situ
formed superoxide radical was involved in the reaction as an
oxidizer of alkyl radicals to generate hydroperoxide B. After
protonation and ROH release, D was obtained, which further
accelerated the Norrish type I oxidation process to produce
carboxylic acids 2 under illumination and heating conditions
[49]. We have proved that both benzaldehyde and acet-
ophenone could be further oxidized under these specific re-
action conditions.
By understanding the feature of herein-developed deep
oxidation of toluene derivatives, we anticipated that the
benzylic position of substituents did not affect such oxida-
tion. Therefore, we further investigated the oxidation reac-
tion of benzyl derivatives with different functionalities
(Figure 4d). To our delight, all of the tested hetero-atom-
substituted toluene derivatives, including benzylic chloride
14, benzyloxy methane 15, benzyl(methyl)-sulfane 16,
benzyl-trimethyl silane 17, and benzylic borolane 18, could
be oxidized, and with a 100% selectivity towards benzoic
acid 2a in this system. These results detailed that both C–H
oxidation and C–X bond cleavage took place under standard
conditions.
oxidation of (poly)alkylbenzene. This protocol uses in-
expensive and earth-abundant CeCl3 as catalyst and CCl3-
CH2OH as HAT reagent. Benzyl C–H, C–C bond, C–X
bonds were cleaved and finally oxidized to benzoic acid
when irradiated with LED light under O2 atmosphere. The
chemistry here showed good functional group tolerance and
could be used as an efficient strategy in the late-stage
modification in druggable molecules. Mechanistic studies
unveiled that the oxidation initiated from the hydrogen ab-
straction at the benzylic position. Thus the presence of
benzyl C–H bond was the critical requirement to proceed
with this chemistry. Not only does this development provide
a green and efficient protocol to produce the valuable sub-
stituted benzoic acids, heteroaromatic carboxylic acids and
benzene polycarboxylic acids (BPCAs), but it offers new
thinking to oxidize the aliphatic C–H bonds to oxygenated
products from feedstocks of petroleum chemistry.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (21988101, 21761132027, 22071029,
U19B6002), the Science and Technology Commission of Shanghai Muni-
cipality (19XD1400800, 18JC1411300), Shanghai Municipal Education
Commission (2017-01-07-00-07-E00058), Key-Area Research and Devel-
opment Program of Guangdong Province (2020B010188001) and Shanghai
Gaofeng & Gaoyuan Project for University Academic Program Develop-
ment. We thank Xue-Chen Luan (Fudan University) for help editing the
manuscript.
In conclusion, we have successfully developed a moderate
and practical photocatalytic protocol for the deep aerobic

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Wang et al. Sci China Chem
Conflict of interest The authors declare no conflict of interest.
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