Review Article

LigninLignin 4, 10-17 (2023)

DOI: https://doi.org/10.62840/lignin.4.0_10

The Lignin Society

Insights into Production of Hydroxybenzaldehydes
via Lignin Oxidation
Takashi Hosoya,a,* Yuki Hirano,a Takuya Hayashi,aAyami Ishikawa,a Yuto Otsuka,a and Hisashi MiyafujiaaGraduate School of Life and Environmental Sciences, Kyoto Prefectural University, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-8522, Japan.
*Corresponding author: hosoya_t@kpu.ac.jp
Received: 7 April 2023; revised in form: 19 June 2023; accepted: 23 June 2023

Abstract
Hydroxybenzaldehydes (HBAs) are ubiquitous in reaction mixtures obtained from various types of lignin
degradation, particularly oxidative degradation. This article reviews the formation behaviors, pathways, andmechanisms of HBAs during alkaline nitrobenzene and alkaline aerobic oxidations of lignin. The former isa well-known analytical method for lignin, while the latter is of industrial importance from the viewpoint of
the production of bio-based aromatics.
Keywords: Nitrobenzene; Mechanism; Molecular oxygen; Oxidation; Vanillin

INTRODUCTION
Hydroxybenzaldehydes (HBAs) are a group of ubiquitous compounds found in reaction
mixtures obtained from many types of lignin degradation. These compounds reflect the substitution
patterns of the aromatic nuclei in lignin and mainly include vanillin, syringaldehyde, and phydroxybenzaldehyde. The formation of HBAs is particularly prominent in oxidative degradation
reactions of lignin, as expected from their structures 1-8). For instance, in the alkaline nitrobenzene (AN)oxidation method for lignin analysis, the yield of HBAs can reach 30−50% depending on the lignin
sample used 7,8). Apart from AN oxidation, HBAs are also produced as major products in oxidation
reactions using other oxidants, such as molecular oxygen, sometimes accompanied by the formation ofrelatively minor amounts of carboxylic acids and p-hydroxyacetophenone derivatives 1-6). These facts
suggest that HBAs are present at major energy minima in the potential energy maps of various oxidative
degradation reactions of lignin. It therefore becomes obvious that gaining an accurate understanding of
the principles underlying this phenomenon holds immense significance in lignin chemistry.
The oxidative degradation of lignin to produce HBAs, such as vanillin (4-hydroxy-3methoxybenzaldehyde), has significant industrial importance. Vanillin is not only well-known as aflavoring agent but also serves as a raw material for pharmaceuticals and polymers, and has establisheditself as one of the platform chemicals in the chemical industry 6,9,10). Moreover, syringaldehyde
obtained from hardwood lignin has high potential as a chemical product and is expected to be utilized
as a raw material for pharmaceuticals 9). One of the methods for producing vanillin involves converting
lignosulfonate, which is a byproduct of sulfite pulping, into vanillin through aerobic oxidation. This was
the major vanillin production method in the world until the 1990s 6,10).
Despite the academic and industrial significance of generating HBAs through the oxidation oflignin, the mechanism underlying HBA production from lignin remains incompletely understood. For
example, although AN oxidation has long been a vital method for lignin analysis, few studies haveinvestigated the detailed reaction pathways and mechanisms of AN oxidation. Also, mechanistic
insights into the aerobic oxidation for vanillin production would be useful for the development andimprovement of chemical processes. However, studies in related fields are more on the application side,
focusing mostly on the development of catalysts and elucidating the relationship between various

10Review Article

LigninLignin 4, 10-17 (2023)

DOI: https://doi.org/10.62840/lignin.4.0_10

The Lignin Society

reaction conditions and vanillin yield 11-15). There are only a few instances of extensive investigations
into the reaction mechanism of aerobic oxidation from the viewpoint of vanillin production.
Our research group is primarily focused on generating vanillin from softwood lignin, and weare currently conducting studies to elucidate the molecular mechanisms of the oxidation process. As
previously mentioned, the crucial oxidants for vanillin production are nitrobenzene and molecularoxygen, which have different academic and industrial perspectives. In this review, we survey thereported mechanisms of vanillin production using these oxidants and introduce our research results on
elucidating the vanillin production reaction using molecular oxygen, in particular.
Alkaline nitrobenzene (AN) oxidation
AN oxidation is typically carried out by reacting lignin-containing samples (such as wood flouror isolated lignin) with an excess of nitrobenzene in 2 M NaOH aqueous solution (aq.) at 170-180℃ for2.0-2.5 h. The AN oxidation method is advantageous in that it can be relatively easily performed byadapting the reaction system to the high pressure required, and can be applied to solid samples such as
wood flour. Additionally, the produced HBAs can be accurately analyzed by various chromatography
techniques. Despite the recent development of direct analysis methods for lignin samples such as twodimensional (2D) nuclear magnetic resonance (NMR), AN oxidation retains its position as a major
lignin analysis method due to those advantages. As we will discuss below, ether linkages in lignin are amajor source of HBAs generated in AN oxidation with the other types of linkages in lignin, mainly CC linkages, having relatively minor contribution.
The reaction mechanism of AN oxidation has been studied using model compounds since themethod was first reported. In 1971, Chan and Allan conducted a review of previous reports up to thattime 16). The presence of a phenolic OH group at the p-position to the alkyl side-chain and/or a-OH or
Ca=Cb moieties in the side-chain play important roles in the efficient generation of Ca-aldehyde
structures by AN oxidation. Based on these phenomena, they proposed that nitrobenzene ionically (2electronically) oxidizes the reactant and intermediates to produce vanillin, as shown in Figure 1A using
isoeugenol (2-methoxy-4-(2-propenyl)phenol) as an example. Isoeugenol is known to give vanillin in ayield of more than 90 mol% by AN oxidation 16). Although not discussed in detail, it is considered that
nitrobenzene attacks the negatively charged site (phenolic OH groups, b-position in the side-chain, etc.)of the deprotonated isoeugenol molecule.

A
−2e−
+OH−

−2e−
+OH−

+OH−

−H+

B
Alkalinehydrolysis

−e−
−H+
R

Fig. 1. The ionic oxidation of isoeugenol by nitrobenzene proposed by Chan and Allan (A) 16) and theoxidation of a middle non-phenolic unit by nitrobenzene through the radical mechanism proposed by
Schultz and Templeton (B) 17).

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DOI: https://doi.org/10.62840/lignin.4.0_10

The Lignin Society

On the other hand, Schulz and co-workers have proposed an AN oxidation mechanism based on aradical mechanism (1-electron mechanism), as shown in Figure 1B 17-20). A plausible initial step of thismechanism is the formation of a complex between the a-OH of the side-chain and nitrobenzene. The N-Obond in this complex is then homolytically cleaved, resulting in the formation of an a-oxyl radical. An aaldehyde structure is generated by the further progress of b-elimination reaction from this radical 17,20). The
experimental results supporting this mechanism include: 1) a significant decrease in reactivity in AN
oxidation for model compounds without the a-OH group in the side-chain, and 2) electron spin resonance(ESR) analysis of the reaction solution suggesting the generation of radical species.
While there are various chemical phenomena that support both the ionic and the radical
mechanisms, definitive evidence to confirm their existence has not yet been reported. Additionally,
many of the model compounds used in the mechanistic studies, such as those observed in isoeugenol,
contain structures that are not present in native lignin. Chan and Allan have deduced the pathway forvanillin production from the phenolic b-O-4 structure shown in Figure 2, based on the reaction
mechanisms reported in studies on the above ionic AN oxidation mechanism and alkaline degradation
under soda cooking 16). In this pathway, the non-oxidative alkaline decomposition of the b-ether in lignin
generates an enol ether intermediate, which is gradually oxidized by nitrobenzene in a manner similar
to that in Figure 1A, resulting in the formation of a HBA. However, the existence of this pathway has
not been experimentally confirmed, for example by subjecting the isolated enol ether to AN oxidation.

Alkalinehydrolysis

PhNO2
HCHO

Fig. 2. Production of HBA (vanillin in this case) through the oxidation of an enol ether intermediate 16).

Despite the limited knowledge regarding the reaction mechanism, there are several systematic
reports on the relationship between the partial structures in lignin and HBAs yield 21,22). In these cases,
models that relatively well reflect the structures in lignin are often used. For example, the yield ofvanillin produced from guaiacylglycerol-β-guaiacyl ether GG, a model compound that represents thelignin structure, under typical AN oxidation conditions was 60-90 mol% 21,22). On the other hand, theyield of vanillin from a model compound of a phenolic b-5 structure is lower, around 55 mol% 21).
Somewhat lower HBA yield of 31 mol% is reported for a phenolic b-b type model 16). The high stabilityof the 5-5' linkage under the AN oxidation conditions has been demonstrated 16,23). Furthermore,
protecting the phenolic OH group significantly reduces the reactivity of these model compounds
towards AN oxidation 21,22). The reactivity of condensed structures, such as a-5, which are generated
during the denaturation process of lignin under high-temperature alkaline conditions, such as those insoda cooking, is known to be significantly low 22,24). These experimental facts make it plausible that
HBAs production under AN oxidation mainly proceeds from the phenolic b-O-4 structure, while HBAs
production from condensed structures and non-phenolic ether units is less efficient.
Alkaline aerobic oxidation oriented to chemical production
The AN oxidation method is the most efficient among many lignin oxidation methods for
producing HBAs. However, if this method is to be utilized industrially, the coexistence of unreacted
nitrobenzene and its reduced products with HBAs in the reaction mixture can cause separation andremoval problems 6,10). The toxicity of nitrobenzene is another factor that impedes its industrial
application. Against this background, the production of vanillin from softwood lignin (specifically,
softwood-derived lignosulfonate), which has long been industrialized, adopts similar high-temperature

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LigninLignin 4, 10-17 (2023)

DOI: https://doi.org/10.62840/lignin.4.0_10

The Lignin Society

alkaline conditions to those of AN oxidation. Nevertheless, inexpensive and non-toxic molecularoxygen is utilized as the oxidizing agent. In other words, the production of vanillin involves the reactionof lignosulfonate with a copper (II) oxide catalyst in a sodium hydroxide solution at a temperature of
approximately 170℃ under pressurized air 6,10, 25-27).
The production of vanillin from lignin has been mostly replaced by the formylation of guaiacol(2-methoxyphenol), a fossil fuel-based method, due to difficulties in treating waste liquids containing
sulfur compounds from the raw materials, the need for complex purification processes resulting fromlow product yields, and harsh reaction conditions 6,10). However, in today's society, where the transition
to non-fossil resources is being encouraged, the production of vanillin from lignin is once again gaining
attention as an industrialized method of lignin conversion. Among the aforementioned issues, theproblem of waste liquids containing sulfur compounds has become a bottleneck in this method, andprocess improvements are required to solve this problem. One of the various solutions is to use lignin
raw materials that do not contain sulfur. Utilizing native lignin in sawdust generated during thelumbering process, for instance, would be an effective solution.
Few studies have investigated the reaction mechanism of vanillin production from native lignin,
which should be useful for the development and improvement of vanillin production processes, except
for several examples proposing vanillin production through retro-aldol reactions using simple modelcompounds 28,29). On the other hand, although the reaction conditions are quite different (lower
temperatures and thinner alkaline concentrations are employed), several detailed reports using modelcompounds exist in studies related to pulp bleaching using molecular oxygen 30-32). A mechanism has
been proposed in which vanillin is produced by homolysis of a dioxirane intermediate generated by theattack of O2 on the Ca=Cb structure of the enol ether generated from GG as shown in Figure 3 30). Thismechanism is interesting in that vanillin is generated via the enol ether formed by the alkaline
decomposition of GG, similar to the reaction pathway in AN oxidation shown in Figure 2. It is known
that fragmentation reactions to produce various carboxylic acids, aldehydes, etc. other than vanillin
production occur under pulp bleaching conditions 30,31,33). It has been also shown that powerful oxidants
such as OH radical are generated from superoxide ions produced by one-electron transfer between
molecular oxygen and phenolate ions, and these active oxygen species play important roles 34-37).
However, further investigation is necessary to determine whether these complex reactions in pulp
bleaching are also functioning similarly under vanillin production conditions.

O2

Fig. 3. Vanillin formation via the dioxirane intermediate generated by the oxidation of the enol ether,reported as one of the reaction pathways involved in the degradation of GG under the condition for O2 pulp
bleaching 30).

The vanillin-forming reaction shown in Figure 3 proceeds in the phenolic b-O-4 structure.
When this reaction is applied to actual lignin molecules, vanillin production occurs from phenolic
structures that already exist in the lignin molecule or those generated by alkaline hydrolysis of middle
b-ether units. Meanwhile, in our laboratory, a vanillin production pathway based on non-phenolic
structures has been proposed under catalyst-free conditions with [OH−] = 1.25−4.0 mol/L, 120℃, andunder O2 or air atmosphere, as shown in Figure 4 38,39). In this pathway, the C3 side-chain of thearylglycerol structure formed by alkaline hydrolysis of the b-ether undergoes oxidation to form a13

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LigninLignin 4, 10-17 (2023)

DOI: https://doi.org/10.62840/lignin.4.0_10

The Lignin Society

vanillin precursor with a Ca-aldehyde structure. The final vanillin is produced by further alkalinehydrolysis of this precursor structure.
The vanillin production pathway depicted in Figure 4 is supported by experimental results thatsystematically examine the effects of organic cations on vanillin yields during the alkaline aerobic
oxidation of various lignin samples and model compounds 38,39). The yield of vanillin from native lignin
in Japanese cedar (Cryptomeria japonica) wood during its alkaline aerobic oxidation significantly
increased in the presence of organic cations, such as complex cations between Na+ and polycyclic ethersand quaternary ammonium ions 38-42). In particular, when the wood flour was reacted with Bu4NOH aq.
as a reaction medium under O2 at 120℃, vanillin was generated in a yield (23.2 weight percent (wt%)
on a Klason lignin basis) similar to that obtained by AN oxidation (27.2 wt%) 39). To investigate thereason for the increased vanillin yield in the presence of the organic cations, the effects of Bu4N+ werecompared for the generation of Ca-aldehydes from the phenolic model GG and the non-phenolic model(erythro-veratrylglycerol β-guaiacyl ether, VG) shown in Figure 5 39). The presence of Bu4N+ in thereaction solution increased the yield of vanillin and veratraldehyde from VG, whereas it had an
inhibitory effect on vanillin production from GG. These results clarify that the positive effects of theorganic cation on the vanillin production cannot be explained without considering the vanillin
production pathway from the non-phenolic structure shown in Figure 4.

Alkalinehydrolysis

Oxidation

Alkalinehydrolysis

Fig. 4. Vanillin production from a b-O-4 middle unit of lignin 39).

One of the proposed mechanisms for the effect of organic cations on the generation of the Caaldehydes from VG involves a cage effect caused by the organic cations that suppresses thedisproportionation reaction of veratraldehyde to the corresponding alcohol and acid in Figure 5 38,39).
However, since the chemical structure of veratraldehyde differs considerably from that of the Caaldehyde end unit formed in actual lignin (Figure 4), further investigation using model compounds thatare more representative of actual lignin is necessary. In the alkaline degradation of a β-O-4 modelcompound with a vanillin residue introduced at the β-position of the side-chain (2-(4-formyl-2methoxyphenoxy)-1-(3,4-dimethoxyphenyl)ethanol), migration reactions of the vanillin residues toother positions of the side-chain have been reported 43,44). The effects of the organic cations are ofinterest in relation to these migration reactions.
The oxidative process depicted in Figure 4 involves the conversion of the C3 side-chain of thearylglycerol structure to the Ca-aldehyde. It is therefore acknowledged that alkaline aerobic oxidation
is a complex process that comprises both oxidative and non-oxidative processes. The oxidative
degradation mechanism of the glycerol side-chain to the Ca-aldehyde has been studied by analyzing thedetailed reaction behaviors of several model compounds, including VG and veratrylglycerol. Threeoxidative pathways have been proposed, as shown in Figure 5: 1) oxidation of the a-OH group to acarbonyl group; 2) generation of the Cg-aldehyde intermediate from the Ca=O via keto-enol
tautomerization; 3) generation of the Ca-aldehyde via a retro-aldol reaction 45). However, the detailed
elementary reaction mechanisms involved in this oxidative process, including the identity of theoxidants responsible for the oxidation of the a-OH group, remain unclear. Furthermore, the role of this14

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LigninLignin 4, 10-17 (2023)

DOI: https://doi.org/10.62840/lignin.4.0_10

The Lignin Society

mechanism under conditions other than those employed in the model experiment, which employs arelatively low-temperature, catalyst-free reaction condition (4.0 mol/L NaOH aq./120°C/air), requires
further extensive investigation.

Ox

VG

+

Fig. 5. Pathways involved in the aerobic oxidation of a non-phenolic mode compound, veratrylglycerol βguaiacyl ether VG 38,39,45).

CONCLUSIONS
1. The production of HBAs in AN oxidation seems to occur mainly from phenolic b-O-4 units via theenol ether intermediate, according to studies with lignin model compounds.
2. Detailed molecular mechanisms involved in AN oxidation currently remains unclear.
3. The formation of HBAs, especially vanillin from guaiacyl lignin, by alkaline aerobic oxidation
involves reactions occurring in both phenolic and non-phenolic structures.
4. It is possible to modify the reactions involved in the vanillin production from the non-phenolic unit
to achieve higher yields of vanillin.

ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research (C) (No. 21K05715 and23K05343) from the Japan Society for the Promotion of Science.
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