Mechanochemical cleavage of lignin models and ligninviaoxidation and a subsequent base-catalyzed strategy

Article abstract of DOI:10.1039/d0gc00372g

Mechanochemical cleavage of lignin dimer model compounds to phenolic monomers has been developedviaa two-step strategy under milling conditions. In the first step of this process, the secondary benzylic alcohol of lignin β-O-4 linkages was selectively oxidized to the corresponding ketones over a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)/NaNO₂catalytic system under milling conditions. In the subsequent step, mechanochemical selective cleavage of the C_β-O bonds and C_α-C_βbonds of lignin β-O-4 ketones to acids and phenols was promoted by NaOH-catalyzed depolymerization. In addition, this two-step strategy was performed to depolymerize organosolv birch lignin, giving aromatic monomers with good selectivity for syringate. This approach provides an efficient method to convert the β-O-4 linkages of lignin to valuable aromatic monomers under mild reaction conditions.

Full text of DOI:10.1039/d0gc00372g

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DOI: 10.1039/D0GC00372G
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ARTICLE
Mechanochemical Cleavage of Lignin Models and lignin via
Oxidation and Subsequent Base-Catalyzed Strategy†
Received 00th January 20xx,
Accepted 00th January 20xx
Chen Sun,a Lei Zheng,a Wenhao Xu,b Alexandr V. Dushkin,b,c Weike Sua,b
*
Mechanochemical cleavage of lignin dimer model compounds to phenolic monomers has been developed via a two-step
strategy under milling conditions. In the first step of this process, the secondary benzylic alcohol of lignin β-O-4 linkages
was selectively oxidized to the corresponding ketones over a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)/NaNO2
catalyst system under milling conditions. In the subsequent step, mechanochemical selective cleavage of the Cβ-O bonds
and Cα-Cβ bonds of lignin β-O-4 ketones to acids and phenols was promoted by NaOH-catalyzed depolymerization. In
addition, this two-step strategy was performed to depolymerize organosolv birch lignin, giving aromatic monomers with
good selectivity for syringate. This approach provides an efficient method to convert β-O-4 linkages of lignin to valuable
aromatic monomers under mild reaction conditions.
DOI: 10.1039/x0xx00000x
www.rsc.org/
cleavage of the Cβ-O bond under mild conditions in the
subsequent step, which is probably due to a decrease in the
bond dissociation energy (BDE) of the Cβ-O bond from 68.2
kcal mol-1 to 55.9 kcal mol-1.34 However, selective cleavage of
the Cα-Cβ bond is still a challenge in terms of the high Cα-Cβ
bond energy35 and its intrinsic nonpolarity36. The selective
preoxidation is also considered as an effective strategy to
prevent the repolymerization caused by the possible
condensation of lignin fragments which occurs simultaneously
with depolymerization.37
Introduction
Lignin, a highly cross-linked organic biopolymer, is the major
sustainable aromatic resource in nature, accounting for
approximately 15-30% of lignocellulosic biomass.1 The use of
renewable lignin as the raw material in the production of high
value-added chemical products holds great potential.2-4
However, lignin valorization remains a huge challenge due to
its complex and recalcitrant structure.5-7 It is well known that
lignin is an amorphous biopolymer consisted of three primary
phenylpropanoid units: p-coumaryl alcohol, coniferyl alcohol,
and sinapyl alcohol, which are connected by C-O and C-C
bonds with high bond energy.8,9 Of the various types of
linkages in lignin, the β-O-4 linkages are predominant,
accounting for approximately 45-60%.10 Various strategies,
including oxidation,11-22 reduction,22-25 acidolysis,26-28 and
alkaline hydrolysis,29-31 as well as their combinations have
been employed for cleaving the β-O-4 linkages of lignin. In
addition, Transition metal catalysis, such as Rh complex
exhibited potential for the depolymerization of the β-O-4
linkages of lignin into ketones and phenols via cleaving C-O
bonds under mild conditions in water.32,33 In recent years, a
two-step strategy for lignin depolymerization has attracted
considerable interest, including selective preoxidation of the
Cα-OH groups of β-O-4 alcohols to ketones, thus allowing for
A variety of well-established catalytic systems have been
developed for the selective oxidation of secondary benzylic
alcohol in the first step, such as DDQ/t-BuONO/O2,38 DDQ/N-
hydroxyphthalimide (NHPI)/NaNO2/O2,37 4-amino-2,2,6,6-
tetramethylpiperidinyloxy (4-AcNH-TEMPO)/HCl/HNO3/O2,39
40
[4-AcNH-TEMPO]BF4
and VOSO4/TEMPO/O2.35 In the
subsequent step, tremendous efforts have been made to
cleave the Cα-Cβ bonds and Cβ-O bonds of the oxidized lignin β-
O-4 ketones to access valuable aromatic monomers, with
existing methods including NaOH/H2O2,39 Baeyer-Villiger
oxidation,41 Cu(OAc)2/1,10-phenanthroline,35 Cu(OAc)2/BF3-
OEt2,42 Zn/CO2/H2O/EtOH,43 [Ir(ppy)2(dtbbpy)]PF6/visible light40
and oxalic acid.44 Unfortunately, the vast majority of previous
studies generally involved the use of large amounts of organic
solvents, often at high temperatures, with long reaction times
and transition-metal catalysts required. Therefore, a more
efficient and sustainable catalytic system with mild reaction
conditions for the degradation of lignin is still highly desirable.
Mechanochemical approaches based on solvent-free ball
milling techniques have attracted considerable attention and
have been widely applied in biomass transformation.45-51 This
technique is considered an efficient and environmentally
friendly process in terms of the absence of organic solvents,
shorter reaction times and beneficial conditions for lignin
aKey Laboratory for Green Pharmaceutical Technologies and Related Equipment
of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University
of Technology, Hangzhou 310014, P.R. China, *E-mail: pharmlab@zjut.edu.cn
bNational Engineering Research Center for Process Development of Active
Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P.R. China,
cInstitute of Solid State Chemistry and Mechanochemistry, Novosibirsk, Russia
†Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, NMR spectra. See DOI: 10.1039/ x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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auxiliary under ball milling at 25 Hz. Additionally,VitehweArltiicglenOinnliβne-
O-4 model compounds with a hydroxymethyl substituent
Scheme 1 Two-Step Strategy for Lignin β-O-4 Cleavage
DOI: 10.1039/D0GC00372G
HO
HO
COOH
OH
Ar
Ar
showed good to excellent selectivity and reactivity, resulting in
the corresponding ketones (2f-2i) in high yields. To our delight,
the phenolic β-O-4 lignin model (1j) was also successfully
selective oxidized to the corresponding ketone (2j) with 88%
yield under our optimum conditions.
O
Ar
HO
O
O
NaOH
DDQ/NaNO2
Ar
Ar
Ball Milling
Ball Milling
Ar
Lignin -O-4 ketone
Aromatic monomers
Lignin -O-4 alcohol
Mechanochemical Depolymerization of Lignin β-O-4
Ketones Catalyzed by NaOH. We initiated our studies with 1-
(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)ethanone (2a)
as the model substrate to optimize the reaction conditions
(Table 2). First, several bases including NaOH, KOH, Na2CO3,
and NaOt-Bu were conducted (entries 1-4). A positive result
was obtained using NaOH as the base under ball milling at 25
Hz, providing the desired acid and phenol in 63% and 92%
yields, respectively (entry 1). Notably, it should be mentioned
that no conversion was observed using Na2CO3 as the base
(entry 3) suggesting that a strong base was indispensable for
this transformation.54 Reducing the rotational speed to 20 Hz
gave 3a and 4a in lower yields (entry 5). A significant increase
in the acid yield was achieved when the amount of NaOH
gradually increased from 3 equivalents to 5 and 8 equivalents
(entries 6, 7). For the comprehensive consideration, we chose
degradation reactivity.52 Combining chemical catalysis with ball
milling treatment has become a promising method for lignin
depolymerization. The use of an inorganic base as a readily
accessible catalyst has been widely applied to the conversion
of lignin.29-31,53 In 2013, Bolm and coworkers pioneered the
mechanochemical degradation of lignin β-O-4 alcohols to
phenol derivatives as the major products by cleaving the Cβ-O
bond with stoichiometric NaOH,54 which demonstrated that
mechanochemical base-catalyzed depolymerization of lignin
under milling conditions had been achieved.55 Recently, Bolm
and coworkers also successfully reported a mechanochemical
oxidation transformation of lignin β-O-4 linkages in the
presence of HO-TEMPO/KBr/Oxone under milling conditions,
affording corresponding quinones and phenol derivatives in
excellent yields.56 While efforts to cleave the Cβ-O bond have
been proven successful, mechanochemical selective cleavage
of the Cα-Cβ bond under milling conditions has rarely been
Table 1 Mechanochemical Selective Oxidation of Lignin β-
O-4 Alcohols to Ketonesa
reported. Herein, we developed
a sustainable two-step
DDQ (0.15 equiv)
NaNO2 (0.5 equiv)
Na2SO4
OH
O
mechanochemical degradation strategy for the cleavage Cβ-O
bonds and Cα-Cβ bonds of β-O-4 linkages in lignin to obtain the
corresponding aromatic acids and phenols under milling
conditions.
O
O
R3
R3
90 min, 25 Hz
R1
R1
R2
R2
1a-j
2a-j
In this context, a green and environmentally friendly
strategy for converting lignin to aromatic acids and phenols via
a two-step strategy has been reported (Scheme 1). To the best
of our knowledge, DDQ is a commonly used organocatalyst for
selective oxidation of the Cα-OH group into ketone.37,38,57,58
The combination of the DDQ/NaNO2 catalyst and ball milling
was first employed in the preoxidation step in this work, which
avoided the solvent issues caused by the poor solubility of
lignin. In the second step, the Cβ-O bonds and Cα-Cβ bonds of
lignin β-O-4 ketones were selectively cleaved to aromatic acids
and phenols in high yields by simple NaOH-promoted oxidation
under milling conditions. Furthermore, this two-step strategy
was also applied to actual lignin depolymerization, yielding
valuable aromatic monomers with good selectivity.
O
OMe
O
O
OMe
O
OMe
O
MeO
MeO
O
MeO
MeO
OMe
OMe
2b
95%
O
2a
94%
O
2c
78%
O
O
OMe
O
OMe
O
MeO
MeO
MeO
MeO
HO
OMe
OMe
OMe
2d
91%
O
2e
92%
O
2f
91%
O
OMe
O
O
OMe
O
MeO
HO
MeO
HO
OMe
MeO
HO MeO
OMe
2g
2h
82%
80%
O
2i
86%
O
OMe
HO
OMe
Results and discussion
2j
88%
Mechanochemical Oxidation of Lignin β-O-4 Model
Compounds. We applied a mechanochemical treatment for
lignin β-O-4 model compounds over a DDQ/NaNO2 catalyst
system under ball milling conditions. The results are
summarized in Table 1. To our delight, the lignin β-O-4 model
compounds with different methoxy-substituted secondary
benzylic alcohols were successfully oxidized to the ketones
(2a-2e) with 78-95% yields when Na2SO4 was the grinding
aReaction conditions: 0.2 mmol substrate 1, 15 mol % DDQ, 50
mol % NaNO2, and 250 mg Na2SO4 (grinding auxiliary), were placed
in a 50 mL stainless steel vessel with two stainless steel balls (d =
1.4 cm) for 90 min under ball milling at 25 Hz. Yields were
determined by column chromatography.
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DOI: 10.1039/D0GC00372G
Table 2 Optimization of the Reaction Conditionsa
Substrate
Products ( yield, %)
Entry
OMe
O
O
OMe
O
O
O
OMe
HO
OMe
OH
O
OH
1
HO
Base
MeO
MeO
Ballmilling
MeO
MeO
OMe
OMe
3a
OMe
OMe
2a
4a
, 80
, 95
2a
3a
4a
Entry Freq. (Hz)
Base
(equiv.)
NaOH (3)
Time
(min)
60
Yield (%)
3a 4a
63 92
O
OMe
O
O
O
OMe
O
O
O
HO
OH
OH
OH
2
1
2
3
4
5
6
7
8
9c
25
25
25
25
20
25
25
25
25
MeO
MeO
2b
3b
4b
, 92
, 99
KOH (3)
Na2CO3 (3)
NaOt-Bu (3)
NaOH (3)
NaOH (5)
NaOH (8)
NaOH (5)
NaOH (5)
60
60
59 89
O
OMe
OMe
0
0
MeO
MeO
HO
MeO
MeO
3
60
56 82
58 87
70 93
82 92
80 95
85 94
OMe
2c
OMe
4c
, 98
3c
, 88
60
O
HO
60
4
MeO
MeO
OMe
2d
OMe
60
3d
, 87
4d
, 96
120
120
O
OMe
OMe
O
O
HO
OH
5
MeO
MeO
MeO
MeO
OMe
OMe
aReaction conditions: 0.2 mmol substrate 2a, and 5 equiv. NaOH were
placed in a 50 mL stainless steel vessel with two stainless steel balls (d =
2e
4e
, 88
3e
, 84
O
OMe
OMe
O
b
1.4 cm) for 120 min under ball milling at 25 Hz. Yields was determined
O
HO
OH
6
by HPLC. c1 equiv. TEMPO was added.
MeO
HO
MeO
OMe
OMe
2f
3f
, 70
4f
, 92
5 equivalents of NaOH for the subsequent optimization.
Prolonging the reaction time from 60 min to 120 min could
also increase the yields considerably (entry 8). Next, the radical
scavenger 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) was
added, which led to no significant effect on the yield (entry 9),
demonstrating that this degradation process does not occur
via a free radical pathway.
O
OMe
OMe
O
O
HO
OH
7
MeO
HO
MeO
2g
4g
, 90
3g
, 73
O
O
O
HO
OH
8
With the optimized reaction conditions in hand, we next
evaluated the degradation method of the oxidized β-O-4
ketones with different methoxy substitutions (2b-2i).
Gratifyingly, these results demonstrated that the catalytic
system shows sufficient degradation ability and a broad range
of substrates. Notably, the yields of acids with Cγ-OH (2f-2i)
were lower than those with the lignin model compounds (2a-
2e), probably due to the presence of the Cγ-OH groups, which
made the Cα-Cβ bond more resistant to cleavage.35 The
oxidized β-O-4 ketone (2j) with hydroxyl group was also
investigated. Vanillic acid (3j) and guaiacol (4j) were obtained
with the yields of 58% and 92%, respectively, when the
reaction was conducted milling with 8 equiv NaOH at 30 Hz for
120 min.
MeO
HO
MeO
OMe
OMe
2h
3h
, 83
4h
, 96
O
OMe
OMe
O
O
HO
OH
9
MeO
HO MeO
OMe
MeO
MeO
OMe
2i
3i
, 68
4i
, 87
O
OMe
OMe
O
O
HO
OH
10c
HO
HO
OMe
OMe
2j
3j
, 58
4j
, 92
aReaction conditions: 0.2 mmol substrate 2, and 5 equiv. NaOH were
placed in a 50 mL stainless steel vessel with two stainless steel balls (d = 1.4
cm) for 120 min under ball milling at 25 Hz. bYields were determined by
HPLC. c 8 equiv NaOH at 30 Hz for 120 min.
Table
3 Mechanochemical Depolymerization of Lignin β-O-4
Ketones Catalyzed by NaOHa
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Figure 1 2D-HSQC NMR spectra of dioxasolv bircVhielwigAnrtiicnleiOnnline
Scheme 2 The Gram-scale Cleavage of Lignin Models
d6-DMSO
DOI: 10.1039/D0GC00372G
OH
OMe
O
OMe
DDQ (0.15 equiv)
NaNO2 (0.5 equiv)
180 min, 25 Hz
O
O
MeO
MeO
OMe
OMe
1a
1.216 g (4 mmol)
2a
, 75%
O
O
OMe
OMe
O
OH
NaOH (5 equiv)
180 min, 25 Hz
HO
MeO
MeO
OMe
OMe
2a
1.208 g (4 mmol)
3a
, 71%
4a
, 92%
OMe
HO MeO
HO MeO

O
HO

O
HO
2
HO
O

O



O
O

(OMe)

2
6
2
6
6

(OMe)
(OMe)


5
MeO
OMe
MeO
OMe
MeO
(MeO)

O
(MeO)
OMe
(MeO)
OMe
O
O
O
Scheme 3 Possible Reaction Mechanism
O
O
O
S
S'
G
OMe
A'
B
A
aRaction conditions: (A)Untreated birch lignin. (B) Birch lignin for
90 min at 25 Hz in the presence of DDQ/NaNO2.
O
OMe
O
OMe
O
OMe
O
O
O
O2
NaOH
O
O
H
MeO
MeO
MeO
OH
OMe
OMe
OMe
2a
5
in syringyl units and consisted of a high proportion of β-O-4
linkages. 2D-HSQC NMR spectra are widely used to
characterize the structure changes of lignin before and after
reaction.59,60 Based on integration of the signals from the
spectra shown in Figure 1, the β-O-4 linkages A signals had a
significantly reduced signal intensity following this oxidation
reaction under milling conditions. approximately 48% of the β-
O-4 linkages Aα were converted. (The conversion is calculated
by the Aα integrals relative to the methoxyl groups intergrals
on the assumption that methoxyl groups are expected to
remain unchanged during the reaction).35 Additionally, the
aromatic region of the oxidized birch lignin spectra accounting
for 31% which determined by comparison of the integrals of
oxidized S’ units and the untreated lignin samples. To our
delight, the resinol structure B was also converted completely.
These results proved that the DDQ/NaNO2 catalyst system
under ball milling conditions exhibited moderate catalytic
activity toward the oxidation conversion of the organosolv
lignin.
The degree of depolymerization for the organosolv lignin
was determined by gel permeation chromatography (GPC)
analysis (Figure S2). After the mechanochemical oxidation
followed by a mechanochemical NaOH-catalyzed process, the
molecular mass of the residual recovered lignin decreased
significantly from 9305 Da to 2342 Da (Table S1), suggesting
that the depolymerization of lignin occurred using this two-
step strategy.
Finally, the NaOH-catalyzed depolymerization of birch lignin
under milling conditions was investigated (Figure 2). the
corresponding ethyl acetate soluble products of the reactions
were analyzed by GC-MS, and the yields of monomeric
aromatics were determined by GC-FID. The direct ball milling
of birch lignin over NaOH only gave a 3.5 wt% yield of soluble
phenolic monomers (Figure S3). After the mechanochemical
preoxidation of birch lignin over the DDQ/NaNO2 system
mentioned above, the preoxidized birch lignin were
transformed to phenolic monomers with a 9.1 wt% yield
(Figure S4). Notably, this two-step mechanochemical cleavage
had proceeded with good selectivity for syringate, which
O
H
O
O
OMe
O
O
O
OMe
OMe
O
O
O
O
O
O
MeO
MeO
MeO
OMe
OMe
OMe
8
9
7
6
H
-HCOO
OH
O
OMe
OMe
OH
O
HO
H
MeO
OMe
4a
10
3a
To demonstrate the potential utility of this two-step strategy
under milling conditions, a gram-scale experiment of using 1a
(4 mmol) as the substrate was investigated. As shown in
Scheme 2, the target oxidized product 2a in the first step can
be obtained with a slightly lower yield of 75%. In the
subsequent step of NaOH-catalyzed depolymerization, the
desired acid and phenol could be isolated in 71% and 92%
yields, respectively. These results confirmed the effective of
cleaving lignin models using this two-step strategy.
Based on the results accumulated thus far and related
reports, a plausible reaction mechanism for the formation of
aromatic acids and phenols via NaOH-mediated cleavage is
proposed as shown in Scheme 2. Initially, the reaction of 1-
(3,4-dimethoxyphenyl)-2-phenoxyethanone 2a with NaOH
leads to nucleophilic enolate 5, which attacks molecular
oxygen to generate an unstable dioxetane intermediate 7 via
intramolecular nucleophilic addition of the peroxyanion to
carbonyl carbon 6. Subsequently, intermediate 7 undergoes
Cα-Cβ bond cleavage to form 8 and phenyl formate 9 via a ring
opening, with the latter undergoing facile cleavage to give 10
under basic reaction conditions. In the end, 8 and 10 can be
converted to the target products 3,4-dimethoxybenzoic acid 3a
and guaiacol 4a, respectively, via a simple acid workup.
Encouraged by the promising results achieved in the
cleavage of the lignin model compounds with our reaction
system, we tested its applicability on dioxasolv birch lignin
extracted by a previously reported procedure38, which was rich
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of lignin models to valuable aromatic chemicals under mild
View Article Online
reaction conditions.
DOI: 10.1039/D0GC00372G
Figure 2 Identified aromatic monomers obtained after
milling different lignin samples
Conflicts of interest
There are no conflicts to declare.
16
14
12
10
8
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21978270) and the Zhejiang Province Science and
Technology Plan Project (No. 2019C04023) for financial
support.
6
4
2
0
lignin(a)
lgnin(b)
lgnin(c)
Notes and references
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O
O
O
O
O
OH
O
MeO
H
MeO
HO
MeO
HO
MeO
HO
MeO
H
MeO
OMe
MeO
HO
OH
OH
HO
HO
2
OMe
OMe
OMe
aReaction conditions: 100 mg lignin, 100 mg NaOH were placed in a
50 mL stainless steel vessel with two stainless steel balls (d = 1.4 cm) for
8 h under ball milling at 20 Hz. Yields were determined by GC-FID. (a)
Untreated birch lignin. (b) Birch lignin for 90 min at 25 Hz in the
presence of DDQ/NaNO2. (c) the oxidised of birch lignin.
3
4
5
increased from 0.9 wt% to 4.8 wt%. To further verify the role
of preoxidation process in the degradation of lignin,
subsequent mechanochemical cleavage of ligninox over NaOH
catalyst was conducted. The ligninox was prepared by a
previously reported procedure12. Encouragingly, over all the
total yield of identified monomeric products was 15.5 wt%,
with high selectivity for syringate 7.5 wt% (Figure S5). A
detailed list of the products have been include in the Table S5.
As discussed above, the NaOH-catalyzed mechanochemistry
offers a promising approach for the depolymerization of real
lignin in a solvent-free process.55 However, the effectiveness of
depolymerization is limited by the generated of condensation
reactions which can be more different to depolymerize and
control the reaction selectivity.37 For the advantages of this
oxidation and subsequent base-catalyzed strategy, the NaOH
catalyst prefers to catalyze the oxidized lignin which allows for
the formation of syrigate with good selectivity.
6
7
8
9
10 S. Constant, H. L. J. Wienk, A. E. Frissen, P. de Peinder, R.
Boelens, D. S. van Es, R. J. H. Grisel, B. M. Weckhuysen, W. J.
J. Huijgen, R. J. A. Gosselink and P. C. A. Bruijnincx, Green
Chem., 2016, 18, 2651–2665.
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Conclusions
In summary, we have successfully developed a highly
effective method for the cleavage of the lignin dimer models
and birch lignin via a two-step strategy. The β-O-4 linkages of
lignin model compounds were efficiently converted to
aromatic acids and phenols via DDQ/NaNO2 catalyst oxidation,
followed by a simple NaOH-catalyzed process under milling
conditions. Furthermore, the organosolv birch lignin
succeeded in depolymerization, yielding valuable aromatic
compounds with good selectivity for syringate. This two-step
mechanochemical strategy provides a green process, and
catalytic system with high aromatic selectivity for the cleavage
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