Haifang Mao, Lizhi Wang, Feifei Zhao, Jianxin Wu, Haohua Huo and Jun Yu*
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, P.R. China
(Received: Sept. 1, 2015; Accepted: Dec. 10, 2015; Published Online: Jan. 26, 2016; DOI: 10.1002/jccs.201500357)
A novel, simple, one-step method of synthesizing vanillin and vanillic acid from eugenol has been devel-
oped. The method uses ligand- and additive-free Co(OAc)2×4H2O as catalyst and molecular oxygen as oxi-
dant to achieve catalytic process without isomerizing eugenol. Extensive screening efforts were used to
optimize eugenol to obtain vanillin and vanillic acid. Under optimal conditions, the reaction provided
vanillin and vanillic acid with 68.5% and 15.2% yields, respectively. Apart from the desired products,
coniferyl alcohol 9-methyl ether and 4-hydroxy-3-methoxycinnamaldehyde as two intermediates were
also detected in the reaction process. Level changes of all compounds over time were presented in the re-
action. The reaction pathway from eugenol to vanillic acid was validated by conducting several control
experiments. Furthermore, a possible reaction mechanism dominated by a circular redox reaction from
Co(III) and Co(II) species was proposed. This method offers a potentially practical alternative for manu-
facturing vanillin and vanillic acid efficiently.
J. Chin. Chem. Soc. 2016, 63, 261-266 © 2016 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 261
Article Mao et al.
4-methyl guaiacol to vanillin by using ethylene glycol as perature improves oxidation efficiency. Obviously, the oxi-
the solvent. A circular redox reaction from Co(III) and dation reaction could not proceed with the absence of
Co(II) species is the key for oxidation.6 However, this cata- NaOH (entry 4). However, a 5.0 equiv. of NaOH turned out
lyst is rather complex and hard to synthesize. In addition, to be sufficient to produce the highest yields for 2 and 3 at
despite ethylene glycol being an ideal solvent, its high boil- 66.7% and 16.2%, respectively (entry 5). However, mini-
ing point makes it difficult to recycle. Hence, industrial mal change was observed in these yields when NaOH con-
production of these products is constrained by the use of tent was increased to 6.0 equiv. (entry 6). It is indicated that
impractical metal-ligand-coordinated catalysts and high- NaOH is important in triggering the oxidation. The large
boiling ethylene glycol. excess of NaOH, offering strong alkaline conditions, was
In this study, Co(OAc)2 without ligand and additive necessary to maintain high selectivity for the desired prod-
was used as the reaction catalyst, and its catalytic perfor- ucts. 21 The same yields were achieved using 1.5 or 1.0
mance for aerobic oxidation of eugenol to vanillin and mol% Co(OAc)2×4H2O (entries 5 and 7; entry 7 with opti-
vanillic acid was investigated for the first time (Scheme 3). mal reaction condition). When using a lower catalyst load-
The reaction was performed under the mediation of NaOH ing of 0.5 mol%, the yields of 2 and 3 dropped sharply to
and methanol without isomerizing eugenol. The effects of 61.4% and 11.9%, respectively, and most impurities were
main reaction parameters, NaOH amount, temperature, and formed (entry 8). One possible reason for this observation
catalyst loading were also analyzed. The desired products was that a small amount of catalyst limited the generation
and two intermediates were separated in the reaction pro- of products. In addition, only trace amounts of 2 and 3 were
cess. Level changes of all compounds as a function of time observed under nitrogen atmosphere without oxygen (en-
were clearly presented. Then, the reaction pathway from try 9).
eugenol to vanillic acid was determined by several control Level changes of all compounds over time are labeled
experiments. In addition, a possible reaction mechanism in Figure 1. It shows that, apart from the desired products 2
was proposed through further studies. and 3, coniferyl alcohol 9-methyl ether (4) and 4-hydroxy-
3-methoxycinnamaldehyde (5) were also isolated in the re-
action process (the structures of all compounds are shown
Scheme 3 One-step synthesis of vanillin and vanillic
acid from eugenol
262 www.jccs.wiley-vch.de © 2016 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2016, 63, 261-266
JOURNAL OF THE CHINESE
Level Changes of All Compounds over Time CHEMICAL SOCIETY
J. Chin. Chem. Soc. 2016, 63, 261-266 © 2016 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.jccs.wiley-vch.de 263
Article Mao et al.
264 www.jccs.wiley-vch.de © 2016 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2016, 63, 261-266
JOURNAL OF THE CHINESE
Level Changes of All Compounds over Time CHEMICAL SOCIETY
Scheme 8 A possible mechanism for the formation of After neutralization of the reaction system, methanol was
intermediates removed in vacuo. The resulting solution was extracted with tolu-
ene (3 ´ 200 mL), and the organic layers were combined and con-
centrated in vacuo to give a yellow solid. vanillin (2) was ob-
tained by recrystallization from ethanol–water mixtures (150
mL). The mother liquor was concentrated in vacuo to give a yel-
low solid. After flash chromatography on silica gel (200–300
mesh), vanillic acid (3) and the remaining vanillin (2) were sepa-
rated.
Procedure related to the mechanism: Another reaction
was conducted under similar conditions as the above to determine
the reaction mechanism. The reaction mixture was removed as a
function of time.
After neutralization of the reaction mixture, methanol was
removed in vacuo. The resulting solution was extracted with tolu-
ene (3 ´ 200 mL), and the organic layers were combined and con-
centrated in vacuo to give a yellow solid. After flash chromato-
graphy on silica gel (200–300 mesh), vanillin (2), vanillic acid
(3), coniferyl alcohol 9-methyl ether (4), and 4-hydroxy-3-me-
thoxycinnamaldehyde (5) were isolated.
CONCLUSIONS
A novel, simple, one-step method to synthesize vanil-
lin and vanillic acid from eugenol has been developed. The
EXPERIMENTAL process uses ligand- and additive-free Co(OAc)2×4H2O as
Materials and Instruments: All reagents and solvents catalyst and molecular oxygen as oxidant to achieve the cat-
were purchased from Sinopharm Chemical Reagent Co., Ltd and alytic process without isomerizing eugenol. The effects of
used without additional purification. 1H NMR spectra were re- the main reaction parameters, such as NaOH amount, tem-
corded on a Bruker DPX 500 MHz spectrometer in CDCl3 and perature, and catalyst loading, were investigated to optimize
DMSO-d6 with Me4Si (TMS) as internal standard at room tem- the oxidation of eugenol to vanillin and vanillic acid. Under
perature. Chemical shifts are given in ppm. Mass spectra were re- the optimal reaction condition of 80 °C, Co(OAc)2× 4H2O
corded on a Waters Micromass GCT Premier mass spectrometer. (1.0 mol%) and NaOH (5.0 equiv.), the reaction produced
Melting points (m.p.) were determined by employing a Hanon vanillin and vanillic acid with 68.5% and 15.2% yields, re-
MP470 automated melting point instrument without further cor- spectively. Apart from these products, coniferyl alcohol
rection. 9-methyl ether and 4-hydroxy-3-methoxycinnamaldehyde
General reaction procedure: The oxidation reactions as two intermediates were also isolated in the reaction pro-
were carried out in a 500 mL autoclave equipped with a thermo- cess. Level changes of all compounds as a function of time
meter and a mechanical stirrer. were then presented. Several control experiments were con-
In a typical reaction, NaOH (40.0 g; 5.0 equiv.) and metha- ducted to investigate the reaction pathway. This pathway in-
nol (150 mL) were added into the reactor and vigorously stirred at volves generating coniferyl alcohol 9-methyl ether from
room temperature. When the alkali had dissolved completely, eugenol. The ether then produces 4-hydroxy-3-methoxycin-
eugenol (32.8 g; 0.2 mol) was added to the system and stirred for namaldehyde, which subsequently transforms to vanillin
10 min to ensure the conversion of eugenol to sodium salt. and vanillic acid. More efforts were employed to further ex-
Co(OAc)2×4H2O (1.0 mol%) was then introduced quickly. Reac- plore the mechanism of the oxidation reaction. Finally, a
tions were performed at 80 °C (Psystem, 1.0 atm without O2) with mechanism that involves a powerful generation of the high
the reaction system (1.5 atm) filled with pure O2 (0.5 atm) and redox active Co(III) species derived from Co(II) species via
concluded at 20 h. oxygenation, two phenoxy radical processes, mediation of
J. Chin. Chem. Soc. 2016, 63, 261-266 © 2016 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.jccs.wiley-vch.de 265
Article Mao et al.
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ACKNOWLEDGEMENTS
G.; Valdés, R. H.; Antunes, O. A. C. Org. Process Res. Dev.
The authors gratefully acknowledge financial support 2006, 10, 941-943.
from the started project of scientific research for the intro- 15. Gusevskaya, E. V.; Menini, L.; Parreira, L. A.; Mesquita, R.
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