Heterogeneous vanadium-catalyzed oxidative cleavage of olefins for sustainable synthesis of carboxylic acids

Article abstract of DOI:10.1039/d1cc01742j

The development of green and sustainable processes to synthesize active pharmaceutical ingredients and key starting materials is a priority for the pharmaceutical industry. A green and sustainable protocol for the oxidative cleavage of olefins to produce pharmaceutically and biologically valuable carboxylic acids is achieved. The developed protocol involves 70% aq. TBHP as an oxidant over a heterogeneous vanadium catalyst system. Notably, the synthesis of industrially important azelaic acid from various renewable vegetable oils is accomplished. The catalyst could be recycled for up to 5 cycles without significant loss in yield and the protocol was successfully demonstrated at the gram-scale.

Full text of DOI:10.1039/d1cc01742j

ChemComm
View Article Online
View Journal
COMMUNICATION
Heterogeneous vanadium-catalyzed oxidative
cleavage of olefins for sustainable synthesis of
Cite this: DOI: 10.1039/d1cc01742j
carboxylic acids†
Received 1st April 2021,
Accepted 21st April 2021
Rahul Upadhyay,ab Rohit Rana,ab Aakriti Sood,a Vikash Singh,
Rahul Kumar,ab
c
c
ab
Vimal Chandra Srivastava
and Sushil K. Maurya
*
DOI: 10.1039/d1cc01742j
rsc.li/chemcomm
The development of green and sustainable processes to synthesize and are one of the most basic feedstocks in organic synthesis.
active pharmaceutical ingredients and key starting materials is a Due to the immense importance of carboxylic acids, various
priority for the pharmaceutical industry. A green and sustainable methods have been developed to synthesize these compounds.
protocol for the oxidative cleavage of olefins to produce pharmaceu- The previous methodologies for carboxylic acids utilize the
tically and biologically valuable carboxylic acids is achieved. The metal-free (H2O2,8 TBHP/I2,9 Oxone,10 and O311–13), metal-
developed protocol involves 70% aq. TBHP as an oxidant over a catalyzed (Cr,14 Mn,15 Fe,16 Co,17,18 Ni,19 Cu,20 W,21 Os,22
heterogeneous vanadium catalyst system. Notably, the synthesis of Au,23 Ag,24 Rh,25 and Ru26) and photo catalyzed reactions.27,28
industrially important azelaic acid from various renewable vegetable Azelaic acid, a dicarboxylic acid is an important building block
oils is accomplished. The catalyst could be recycled for up to 5 cycles for polymers, biodegradable lubricants, perfumery, cosmetics,
without significant loss in yield and the protocol was successfully and an active pharmaceutical ingredient used to treat acne.29–31
demonstrated at the gram-scale.
Several methods utilizing oleic acid have been reported for
azelaic acid synthesis. The current industrial process for azelaic
The development of short, efficient, and sustainable processes acid production mainly utilizes oleic acid under ozonolysis.32
for producing active pharmaceutical ingredients (APIs) and key Other developed protocols use nitric acid,33 W-complexes,34,36
starting materials (KSMs) poses a stiff challenge to the phar- Co–Mn–Br systems,35 and RuCl3/NaIO4,26 under different con-
maceutical industry.1 The exploitation of vegetable oils to ditions. However, these metal catalysts were mainly used under
synthesize value-added products has provided a sustainable homogeneous conditions, and their removal from the products
and eco-compatible route to chemists. Most of these oils is always a challenging task and adds extra steps in the
predominantly contained unsaturated fatty acids in the form synthesis. Similarly, Mo-,37 and WO3-Na2SnO3-21based hetero-
of triglycerides of oleic acid, linoleic acid, linolenic acid, etc., geneous systems, and multistep biocatalytic38 and enzymatic39
and saturated fatty acids such as palmitic acid and stearic approaches are also reported. These developed methods mostly
acid.2 These unsaturated fatty acids are converted to a range of utilize oleic acid or other unsaturated fatty acids such as
intermediates and products and can be utilized for sustained linoleic acid for the azelaic acid synthesis (Fig. 1). Most of
carboxylic acid synthesis.3
these synthetic processes used toxic oxidants such as KMnO4,15
Carboxylic acids are one of the compound’s imperative OsO4,22 and ozonolysis11–13 and required high temperature,
classes, having an enormous diversity in the chemical arena long reaction time, and a high amount of base. Moreover,
and can be obtained from oxidative cleavage of unsaturated ozonolysis is a tedious, energy intensive, and hazardous pro-
compounds. These carboxylic acids are very much populated in cess that requires sophisticated handling due to its explosive
various natural products,4 and pharmaceutical5 materials,6,7 nature and has several environmental issues. Furthermore, very
few reports utilize vegetable oils containing a predominant
a Chemical Technology Division, CSIR-Institute of Himalayan Bioresource
Technology, Palampur, Himachal Pradesh, 176 061, India.
E-mail: sushilncl@gmail.com, skmaurya@ihbt.res.in
b Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201 002, India
c Department of Chemical Engineering, Indian Institute of Technology Roorkee,
Roorkee, Uttarakhand, 247 667, India
mixture of unsaturated fatty acids. To overcome and resolve
these challenges, here we report a heterogeneous VO@TiO2
catalyzed additive-free green protocol for the synthesis of
carboxylic acids via oxidative cleavage of olefins. Moreover,
we also first report the Triadica sebifera seed oil utilization, a
non-edible renewable feedstock for azelaic acid’s sustainable
synthesis.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc01742j
This journal is © The Royal Society of Chemistry 2021
Chem. Commun.

View Article Online
Communication
ChemComm
Scheme 1 Substrate scope for styrenes. [a]Reaction conditions: styrene
(1.0 equiv., 100 mg), C-20 (10 wt%), TBHP (6.0 equiv.), 50 1C, and 12 h.
[b]Isolated yield.
Fig. 1 Previous approaches for the synthesis of azelaic acid. (A) From
oleic acid. (B) From vegetable oil/fatty acids. (C) VO@TiO2 catalyzed
synthesis of azelaic acid and benzoic acid derivatives (our approach).
With optimized conditions in hand, the substrate scope for the
For optimization studies, the 4-methoxy styrene was chosen as developed method was elaborated. The synthesis of benzoic acid
a model substrate. Firstly, reactions were performed with different was achieved by utilizing styrene and b-substituted styrenes
metal oxides; however, no significant conversion was observed containing different functionalities such as methyl, phenyl, alde-
(Table S4, ESI†, entries 1–4). Next, the reactions were attempted hyde, alcohol, nitro, and carboxylic acid groups (Scheme 1, 2a).
with a range of heterogeneous catalysts (C-05, C-10, and C-20) tert-Butyl substituted styrene was transformed into the respective
containing different percentages of V2O5 (5, 10, and 20%) carboxylic acid in a 72% yield (Scheme 1, 2b). 2,4-Ddimethyl
supported over TiO2 prepared in the lab (see the ESI†). Initially, benzoic acid was synthesized in good yield from 2,4 dimethyl
the reaction was attempted with catalyst C-5 containing 5% of styrene (Scheme 1, 2c). Methoxy substituted styrene, and b-methyl
V2O5; however, no conversion was observed (Table S4, ESI†, entry styrene provided corresponding benzoic acid derivatives in 88%
5). Furthermore, the reaction was performed with a C-10 catalyst and 82% yields, respectively (Scheme 1, 2d). The sterically
containing 10% of V2O5, and to our delight, the reaction resulted hindered substrate such as 2,4-dimethoxy cinnamic acid provided
in the formation of the desired product (Table S4, ESI†, entry 6). a 65% yield of 2,4-dimethoxy benzoic acid (Scheme 1, 2e). The
Next, a reaction with catalyst C-20 containing 20% V2O5 resulted in conversion of p-acetoxy styrene into p-acetoxy benzoic acid was
a good conversion with a 72% isolated yield (Table S4, ESI†, entry 7). achieved successfully in good yield (Schemes 1, 2f). The synthesis
C-20 was found to be the most effective catalyst and selected for of halogen-substituted benzoic acids was accomplished in good
further optimization among the tested catalysts. Different solvents yields from their corresponding styrenes (Scheme 1, 2g and 2h).
were tested for the transformation, and acetonitrile provided a 3-Nitro styrene and 3-nitro cinnamic acid gave 3-nitro benzoic
better yield than the other solvents like dichloromethane and ethyl acid in 86% and 78% yields, respectively (Scheme 1, 2i). A good
acetate leading to a poor conversion (Table S4, ESI†, entries 7–9). yield of the corresponding benzoic acid derivative was obtained by
Furthermore, the oxidant required for this transformation was utilizing the biphenyl and naphthyl-derived styrenes (Scheme 1, 2j
optimized and 6.0 equivalent of 70% aq. tert-butyl hydrogen per- and 2k). The excellent yield of acetophenone was obtained instead
oxide (TBHP) was found to be sufficient to give the desired of benzoic acid when a-methyl styrene was subjected to the
carboxylic acid (Table S4, ESI†, entries 7, 10, and 11). In continua- developed reaction conditions (Scheme 1, 2l). The amino acids
tion, when the reaction was performed in the absence of acetoni- are essential building blocks for biological macromolecules and
trile, an improved yield (88%) of the desired product was obtained play a crucial role in biological systems.40 Amino acids such as
(Table S4, ESI†, entry 12). Effect of temperature was also evaluated glycine and L-alanine coupled with styrene via an amide bond
and on increasing the temperature from 50 1C to 80 1C, no provided the corresponding carboxylic acid derivatives in good
significant improvement in the yield was observed (Table S4, ESI†, yields (Schemes 1, 2m and 2n).
entry 13) whereas, a lower conversion was observed when the
After successfully transforming aromatic alkenes, we uti-
temperature was reduced to 25 1C (Table S4, ESI†, entry 16). lized the methodology to synthesize industrially important
A reaction utilizing hydrogen peroxide as an oxidant does not result azelaic acid from various naturally occurring vegetable oils
in any improvement in the yield, and the formation of both aldehyde obtained from renewable resources. Firstly, the triglycerides
and acid was observed (Table S4, ESI†, entry 14). A decrease in were hydrolysed to furnish free fatty acids and glycerol. The free
yield was observed on lowering the catalyst loading (Table S4, ESI†, fatty acids were then oxidatively cleaved under the developed
entry 15), whereas, in the absence of catalysts and oxidants, no catalytic system to deliver the desired azelaic acid (Scheme 2).
reaction was observed (Table S4, ESI†, entries 17 and 18). Finally, The free fatty acid obtained from Triadica sebifera seed oil was
the best-optimized reaction conditions were found to be styrene chosen as a model substrate to optimize the reaction condi-
(1.0 equiv.), C-20 (10 wt%), and TBHP (6.0 equiv.) at 50 1C for 12 h. tions of the vegetable oils. A reaction under previously
Chem. Commun.
This journal is © The Royal Society of Chemistry 2021

View Article Online
ChemComm
Communication
Scheme 3 Gram-scale synthesis and recyclability experiment.
TEMPO inhibits the reaction by trapping the generated radical
1ab (detected in ESI-MS at M+Z = 350.04 value, Fig. S1, ESI†),
which indicates that the reaction involved the radical pathways
(Scheme 4, X, A). The effect of the reaction environment was also
evaluated. The reaction in the presence of a nitrogen atmosphere
shows poor conversion compared to an air or O2 environment,
which demonstrated the role of atmospheric O2 for the accelera-
tion of the reaction (Scheme 4, X, B and C). The initial GC-MS
analysis of the reaction mixture indicated the presence of styrene
oxide (1ac) and benzaldehyde (1ae) (Fig. S2 and S3, ESI†). The
presence of these intermediates was confirmed by performing
separate reactions with an aldehyde (1ae) and epoxide (1ac),
which resulted in the desired benzoic acid in good yields
(Scheme 4, X, D and E).
Scheme 2 Processing of oils and substrate scope for the azelaic acid
synthesis. [a]Reaction conditions: free fatty acid (1.0 equiv., 1.0 g), C-20
(30 wt%), TBHP (20 volume), 80 1C, and 12 h. [b]Isolated yield. [c]Oil
(1.0 equiv., 1.0 g), C-20 (10 wt%), TBHP (6.0 equiv.), 50 1C, and 12 h.
optimized conditions resulted in the low conversion and poor
selectivity for azelaic acid (Table S5, ESI†, entry 1). An increase in
the yield was observed by increasing the reaction temperature from
50 1C to 80 1C (Table S5, ESI†, entry 2). Furthermore, an increase in
the amount of oxidant resulted in the enhanced yield of the desired
product. However, the best results were obtained with 20 volumes
of TBHP (Table S5, ESI†, entries 3–6). The enhanced amount of
oxidant was required due to multiple reaction sites in polyunsatu-
rated fatty acids in hydrolysed oil. A further increase in the amount
of oxidant and reaction temperature resulted in a slight decrease in
the yield (Table S5, ESI†, entries 7 and 8).
With the modified reaction conditions in hand, different oil
types were employed, which resulted in good yields of the
desired dicarboxylic acids. For the substrate scope, free fatty
acids of various vegetable oils such as Triadica sebifera seed oil,
olive oil, and linseed oil were subjected to the developed
protocol, which resulted in desired azelaic acid in good yields
(Scheme 2, 4a). The applicability of the developed method was
also expanded to non-fatty acid-containing oil. For this pur-
pose, anise oil, which contains anethole as a principal consti-
tuent, was successfully transformed to the corresponding
benzoic acid in 80% yield (Scheme 2, 3d).
Based on controlled experiments and previously reported
literature,
a plausible mechanism for the reaction is
proposed.41–43 Initially, the reaction begins with the activation
of tert-butyl hydrogen peroxide by the catalyst, which results in
the formation of tert-butyl hydroperoxide radicals. Subse-
quently, the generated tert-butyl hydroperoxide radical reacted
with styrene to generate another radical intermediate 1ab. The
intermediate 1ab releases tert-butoxy radical to generate styrene
oxide intermediate 1ac. Next, the epoxide ring-opening of the
styrene oxide by the reaction with tert-butyl hydrogen peroxide
A gram-scale experiment was carried out to demonstrate the
translational potential of the developed protocol. Benzoic acid
and azelaic acid were smoothly obtained in 72% and 66% yields
by utilizing styrene and Triadica sebifera seed oil, respectively
(Scheme 3). These results demonstrate the potential of the
developed protocol for the industrial application to synthesize
carboxylic acids under greener and eco-compatible conditions.
Next, we investigated the catalyst’s recyclability potential for the
transformation of styrene 1a to the corresponding carboxylic
acid. The catalyst was recycled by simple filtration or centrifu-
gation, washed with acetone, dried in an oven for two hours at
100 1C, and reused to catalyze the reaction up to 5 cycles
without significant loss of catalytic activity (Scheme 3).
To elucidate the mechanism of the reaction, we performed a
series of experiments. Initially, the presence of radical scavenger
Scheme 4 Controlled experiments and the plausible catalytic cycle.
This journal is © The Royal Society of Chemistry 2021
Chem. Commun.

View Article Online
Communication
ChemComm
´
13 A. E. Kerenkan, F. Beland and T. O. Do, Catal. Sci. Technol., 2016, 6,
971–987.
resulted in intermediate 1ad. The intermediate 1ad provided
benzaldehyde intermediate 1ae, which on subsequent oxida-
tion furnished the desired benzoic acid (Scheme 4, Y).
In summary, we developed a VO@TiO2 catalyzed oxidative
cleavage of olefins to synthesize carboxylic acids, utilizing 70% aq.
TBHP as an oxidant. A range of styrene derivatives has been
transformed into their corresponding benzoic acids in good yields.
The methodology facilitates the transformation of fatty acids into
industrially important azelaic acid. Catalyst recyclability, gram-scale
synthetic applicability, and renewable biomass utilization are the
other important features of the developed protocol.
14 J. K. Thottathil, J. L. Moniot, R. H. Mueller, M. K. Y. Wong and
T. P. Kissick, J. Org. Chem., 1986, 51, 3140–3143.
15 A. P. Krapcho, J. R. Larson and J. M. Eldridge, J. Org. Chem., 1977, 42,
3749–3753.
16 T. M. Shaikha and F. E. Hong, Adv. Synth. Catal., 2011, 353,
1491–1496.
17 H. Luo, L. Wang, S. Shang, J. Niu and S. Gao, Commun. Chem., 2019,
2, 17.
18 M. T. Reetz and K. Ttillner, Tetrahedron Lett., 1995, 36, 9461–9494.
19 G. Urgoitia, R. S. Martin, M. T. Herrero and E. Dominguez, Adv.
Synth. Catal., 2016, 358, 1150–1156.
20 S. Sharma, S. Sinha and S. Chand, Ind. Eng. Chem. Res., 2012, 51,
8806–8814.
SKM gratefully acknowledges the Council of Scientific and
Industrial Research (CSIR), New Delhi, for financial support under
the Mission Project CSIR-INPROTICS-Pharma and Agro (HCP0011).
We are thankful to the Director, CSIR-IHBT, Palampur (H.P.) India,
for providing the necessary infrastructure. R. R. and R. K. thank the
CSIR-New Delhi for their fellowships. CSIR-IHBT Palampur has filed
a patent on the process reported herein. CSIR-IHBT Communica-
tion No. for this publication is 4708.
21 X. Li, J. C. P. Syong and Y. Zhang, Green Chem., 2018, 20, 3619–3624.
22 K. Lee, Y. H. Kim, S. B. Han, H. Kang, S. Park, W. S. Seo, J. T. Park,
B. Kim and S. Chang, J. Am. Chem. Soc., 2003, 125, 6844–6845.
23 S. A. C. Carabineiro, Front. Chem., 2019, 7, 702.
24 Z. Z. Zhou, M. Liu, L. Lv and C. J. Li, Angew. Chem., Int. Ed., 2018, 57,
2616–2620.
25 Y. L. Su, L. D. Angelis, L. Tram, Y. Yu and M. P. Doyle, J. Org. Chem.,
2020, 85, 3728–3741.
26 S. Rup, M. Sindt and N. Oget, Tetrahedron Lett., 2010, 51, 3123–3126.
27 A. Itoh, T. Kodama, Y. Masaki and S. Inagaki, Synlett, 2002, 522–524.
28 L. Hinda, C. Guillard, L. Hayfa, H. Marwa, R. Mariem and
H. Ammar, J. Photochem. Photobiol., A, 2017, 346, 462–469.
29 J. W. Song, E. Y. Jeon, D. H. Song, H. Y. Jang, U. T. Bornscheuer,
D. K. Oh and J. B. Park, Angew. Chem., Int. Ed., 2013, 52, 2534–2537.
30 A. E. Kerenkan, A. S. Ello and T. O. Do, Ind. Eng. Chem. Res., 2017, 56,
10639–10647.
Conflicts of interest
The authors declare no competing interests.
31 S. Chen, T. Wu and C. Zhao, ChemSusChem, 2020, 13, 5516–5522.
32 F. Zhang, C. Huang and T. Xu, Ind. Eng. Chem. Res., 2009, 48,
7482–7488.
References
1 (a) B. W. Cue and J. Zhang, Green Chem. Lett. Rev., 2009, 2, 193–211; 33 F. O. Ayorinde, G. Osman, R. L. Shepard and F. T. Powers, J. Am. Oil
(b) C. J. Li and B. M. Trost, Proc. Natl. Acad. Sci. U. S. A., 2008, 105,
13197–13202.
2 J. Orsavova, L. Misurcova, J. V. Ambrozova, R. Vicha and J. Mlcek,
Int. J. Mol. Sci., 2015, 16, 12871–12890.
Chem. Soc., 1988, 65, 1774–1777.
34 E. Antonelli, R. D. Aloisio, M. Gambaro, T. Fiorani and
C. Venturello, J. Org. Chem., 1998, 63, 7190–7206.
35 K. Fujitani, H. Manami, M. Nakazawa, T. Oida and T. Kawase, J. Oleo
Sci., 2009, 58, 629–637.
3 A. Vik and T. V. Hansen, Org. Biomol. Chem., 2018, 16, 9319–9333.
4 A. D. Olmo, J. Calzada and M. Nunez, Crit. Rev. Food Sci. Nutr., 2017, 36 A. Godard, P. D. Caro, S. T. Roux, E. Vedrenne and Z. Mouloungui,
57, 3084–3103. J. Am. Oil Chem. Soc., 2013, 90, 133–140.
5 C. Lamberth and J. Dinges, Bioactive Carboxylic Compound Classes: 37 A. S. Ello, A. E. Kerenkan, A. Trokourey and T. O. Do, J. Am. Oil Chem.
Pharmaceuticals and Agrochemicals, Wiley-VCH, 2016. Soc., 2017, 94, 1451–1461.
6 M. J. McEachran, J. F. Trant, I. Sran, J. R. D. Bruyn and E. R. Gillies, 38 S. Koppireddi, J. H. Seo, E. Y. Jeon, P. S. Chowdhury, H. Y. Jang,
Ind. Eng. Chem. Res., 2015, 54, 4763–4772. J. B. Park and Y. U. Kwona, Adv. Synth. Catal., 2016, 358, 3084–3092.
7 F. Ekiz, F. Oguz-kaya, M. Akin, S. Timur, C. Tanyeli and L. Toppare, 39 H. J. Cha, E. J. Seo, J. W. Song, H. J. Jo, A. R. Kumar and J. B. Park,
J. Mater. Chem., 2011, 21, 12337–12343. Adv. Synth. Catal., 2018, 360, 696–703.
8 M. Pickl, C. K. Winkler, S. M. Glueck, M. W. Fraaije and K. Faber, 40 F. Kudo, A. Miyanagaa and T. Eguchi, Nat. Prod. Rep., 2014, 31,
Molecules, 2017, 22, 2205. 1056–1073.
9 B. N. Patil, P. A. Sathe, B. S. Parade, K. S. Vadagaonkar and 41 C. Guo, Y. Zhang, L. Zhang, Y. Guo, N. Akram and J. Wang, ACS Appl.
A. C. Chaskar, Tetrahedron Lett., 2018, 59, 4340–4343. Nano Mater., 2018, 1, 5289–5296.
10 J. N. Moorthy and K. N. Parida, J. Org. Chem., 2014, 79, 11431–11439. 42 M. Maldonado, P. R. Guerrero and C. H. Fuentes, Catalysts, 2019,
11 J. Y. Kim, M. W. Jun, Y. J. Seong, H. Park, J. Ahn and Y. C. Park, ACS
Sustainable Chem. Eng., 2019, 7, 17958–17966.
12 B. M. Cochran, Synlett, 2016, 245–248.
9, 905.
43 M. S. Batra, R. Dwivedi and R. Prasad, ChemistrySelect, 2019, 4,
11636–11673.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2021