Investigate cleavage of β-O-4 linkage in lignin model compounds by aerobic oxidation of Cα and Cγ hydroxyl groups

Article abstract of DOI:10.1016/j.tetlet.2016.05.105

The selective cleavage of common linkages in lignin polymers is a promising approach to generate valuable aromatic hydrocarbons. Herein, we found that on oxidation of Cα and Cγ hydroxyl groups in β-O-4 lignin model compounds with TEMPO catalyst resulted in the formation of 1,3-dicarbonyl TEMPO adduct. These oxidized products readily underwent fragmentation at Cα-Cβ bond in the presence of a catalytic amount of acid to generate corresponding carboxylic acid and phenol monomers.

Full text of DOI:10.1016/j.tetlet.2016.05.105

Accepted Manuscript
Investigate cleavage of β-O-4 linkage in lignin model compounds by aerobic
oxidation of Cα and Cγ hydroxyl groups
Nikhil D. Patil, Ning Yan
PII:
S0040-4039(16)30649-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.105
TETL 47724
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Tetrahedron Letters
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17 April 2016
25 May 2016
27 May 2016
Please cite this article as: Patil, N.D., Yan, N., Investigate cleavage of β-O-4 linkage in lignin model compounds
by aerobic oxidation of Cα and Cγ hydroxyl groups, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.05.105
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Investigate cleavage of β-O-4 linkage in Lignin model
compounds by aerobic oxidation of Cα and Cγ hydroxyl
groups
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Nikhil D. Patil and Ning Yan

2
Tetrahedron Letters
Investigate cleavage of β-O-4 linkage in lignin model compounds by aerobic
oxidation of Cα and Cγ hydroxyl groups
Nikhil D. Patil and Ning Yan
Faculty of Forestry, University of Toronto, 33 Willcocks Street, Toronto, ON, M5S 3B3, Canada
Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, M5S 3E5, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The selective cleavage of common linkages in lignin polymers is a promising approach to
generate valuable aromatic hydrocarbons. Herein, we found that on oxidation of Cα and Cγ
hydroxyl groups in β-O-4 lignin model compounds with TEMPO catalyst resulted in the
formation of 1,3-dicarbonyl TEMPO adduct. These oxidized products readily underwent
fragmentation at Cα-Cβ bond in the presence of a catalytic amount of acid to generate
corresponding carboxylic acid and phenol monomers.
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
Lignin model compounds
β-O-4 linkage
retro-Claisen
TEMPO
1
. Introduction
In recent years, many researchers have reported catalytic
aerobic oxidation of electronically active benzylic hydroxyl in
lignin model compounds. The benzylic ketone products are quite
stable and do not readily undergo fragmentation reaction.
Therefore, many researchers adopt a two-step process for
Lignin is
a
highly cross-linked aromatic polymer
biosynthesized from three common monolignol monomers: p-
coumaryl alcohol, coniferly alcohol, and sinapyl alcohol. It is an
indispensable component of the plant cell wall that protects the
plant from biodegradation, provides mechanical support, and
1
selective cleavage of β-O-4 linkage in dimer model
12-14
compounds.
Stephenson and co-workers utilized
a
2
transports liquid in plant stem. The rich aromatic structure of the
photochemical process in their study, which consisted of
chemoselective oxidation of benzylic hydroxyl group in the first
lignin has potential to produce valuable bulk chemicals and bio-
based fuel additives as well as has substantial prospect for
application in polymer resin systems, such as polyurethane and
epoxy. At present, lignin has limited high-valued commercial
applications, and hence, every year million tons of lignin
generated as a waste stream from the pulp and paper industries
are largely burned as
depolymerization processes have several practical difficulties
because of lignin’s complex rigid structure. Therefore, many
step followed by a catalytic reductive cleavage of the C-O bond
15
in the second step.
Likewise, Moody et al. reported
3-6
photochemical catalytic oxidative cleavage of lignin model
16
compounds using hydroquinone and copper nanoparticles.
Westwood et al. reported oxidative cleavage of Cβ-O linkage in
7
a
low-grade fuel. The lignin
17
β-O-4 model compounds by Zinc and NH
4
Cl treatment. Meier
and group studied selective aerobic oxidation of hydroxyl groups
using TEMPO/NaNO and DDQ/NaNO oxidation process, and
2
2
researchers took
compounds with similar linkages and functional groups to native
lignin polymer in their studies.
a simpler approach using lignin model
further cleavage of the Cα-Cβ linkages by Baeyer-Villiger
14
oxidation. Loh and co-workers studied selective oxidation of
8-11
Conducting oxidation study
benzylic alcohol and cleavage of β-O-4 linkage by amide bond
using synthetically pure lignin model compounds have several
advantages over the native lignin polymers. The selectivity of the
reaction can be properly addressed because it is possible to
separate oxidized products and characterize them using
conventional analytical techniques. And, insights gained from
studying model compounds will greatly benefit our
understanding of natural lignin depolymerization process as a
whole.
18
formation. However, most of these methods demanded an
additional step, the usage of stoichiometric amounts of reagents
(non-catalytic), transition metal catalysts, and energy intensive
reaction conditions. Other challenges involved the limited
selectivity of the oxidation process and also the fragmented
phenolic compounds further underwent in-situ polymerization.
As a result, development of a more selective depolymerization
process is still an ongoing research focus worldwide.
—
——

Corresponding author. e-mail: ning.yan@utoronto.ca

Alternatively, the selective aerobic oxidation of Cγ primary
alcohol using TEMPO/Cu system, in combination with suitable
ligand has been reported by Stahl et al. and also by Baker and
monomeric and dimeric lignin model compounds was compared
by treating 20 mol % TEMPO, CuCl, bpy each and 40 mol % of
12,19
NMI in MeCN, under an air atmosphere.
The percentage of
19,12,20
group.
Their study on lignin model compounds
recovery and yields of the products formed are listed in Table 1
and Scheme 2. In this method, bpy ligand enhanced the solubility
of copper catalyst, and NMI increased the rate of reaction. Under
these conditions, 2-phenoxyethylbenzene (Table 1, entry i) being
a non-hydroxylated simple model compound and 2-phenoxy-1-
phenylethan-1-ol (Table 1, entry ii) compound with neither γ
carbon nor hydroxyl group did not react since most of the starting
material was recovered.
demonstrated that selective oxidation of primary alcohols
facilitated cleavage of Cα-Cβ via retro-aldol reactions. However,
the yield of the oxidized product was low since catalytic
oxidation of primary alcohol groups in model compounds was
more challenging. None of the previous groups has attempted to
oxidize both primary and benzylic hydroxyl groups of the lignin
model compounds with an excess amounts oxidants in the
Scheme 1. Oxidative fragmentation pathway for β-O-4 dimeric
lignin model compounds
system.
Therefore, in this work, we aim to study the fragmentation
pattern (as shown in Scheme 1) upon oxidation of both Cα
benzylic and Cγ primary hydroxyl groups in lignin model
compounds. We believe that catalytic aerobic oxidation of Cα
and Cγ alcohol groups in model compounds will provide
important insight for depolymerizing natural lignin polymer
targeting value-added applications.
Table 1. Oxidation of lignin model compounds with
We first prepared monomeric and β-O-4 dimeric lignin model
compounds, and then opted for selective cleavage of Cα-Cβ bond
facilitated by aerobic oxidation of hydroxyl groups. In order to
address the selectivity of the oxidation process, dimer model
compounds with benzylic hydroxyl groups having different steric
surroundings were synthesized. The chemoselective oxidation of
primary alcohol in both monomer and dimer lignin model
compounds by TEMPO/CuCl/bpy/NMI system was carried out
and compared. In addition, the oxidation of benzylic and primary
alcohol in model compounds to corresponding 1,3-dicarbonyl
adducts was performed by two different pathways. In the first
pathway, step-wise selective oxidation of benzylic hydroxyl
Scheme 2. TEMPO/CuCl chemoselective oxidation of 1 – 5
[a, b]
TEMPO/CuCl
b
Entry
Substrate, (%
Products, (% yield)
a
recovery)
i.
,
(98%)
ii.
, (95%)
1
, (2%)
iii.
iv.
v.
6, (34%)
7, (35%)
8, (39%)
9, (38%)
groups and primary alcohol using TEMPO/NaNO
2
and
2
TEMPO/Cu process was studied. And then in the second
pathway, a single-step oxidation was studied using a surplus
amount of TEMPO catalyst and oxidant. Lastly, we report a
novel approach to cleave Cα-Cβ bond in lignin model
compounds to produce carboxylic acids and phenol monomers.
Although past literature has found that natural lignin could be
oxidatively degraded into methoxybenzoic acids and phenols,
their degradation pathway and mechanism were not studied and
3, (51%)
4, (43%)
5, (77%)
10, (31%)
11, (35%)
6, (13%)
6, (10%)
12, (7%)
13, (9%)
Phenol, (6%)
vi.
vii.
7, (12%)
[
a] Reaction were carried out for 20 h under air atmosphere at room temp
using 0.2eq of TEMPO, CuCl, bpy and 0.4eq of NMI. [b] Purified and
isolated products yield and recovery.
2
1,22
were unclear.
Herein, we present our findings on how the
lignin polymer undergoes oxidative fragmentation. We believe
that in depth knowledge of the fragmentation pattern can help
develop a better method for lignin depolymerization.
In monomeric model compounds, primary alcohol oxidized
product appeared to undergo retro-aldol reaction as well as in situ
dehydration of benzylic alcohol to produce corresponding
2. Results and Discussion
12
benzylic aldehydes and enal. The oxidative cleavage reaction
was not observed in 2-phenoxy-1-phenylethan-1-ol as γ carbon
and hydroxyl group were not present. We observed that primary
alcohol oxidation yield in the dimer model compound was
relatively low compared to monomeric model compounds, as less
than 13% retro-aldol products were produced. It appeared that
dimer compounds underwent Cα-Cβ cleavage to form benzyl
aldehyde and substituted 2-phenoxyacetaldehyde intermediate
which further underwent fragmentation to yield phenol and water
The most abundant β-O-4 linkage in lignin polymer has
characteristic benzylic and primary aliphatic alcohol groups.
2
3,7
Lately, various methods for selectively oxidation of
electronically active benzylic hydroxyl groups have been
reported in literature, however effective method for selective
oxidation of primary alcohols in lignin model compounds still
needs improvements. The aerobic oxidation of primary alcohols
in lignin is an important step towards depolymerization of the
lignin polymer. In 1984, Semmelhack et al. reported the catalytic
mixture of TEMPO and CuCl for aerobic oxidation of benzylic
alcohol. However, for oxidation of non-benzylic alcohol, a
15
soluble acetaldehyde. The water soluble acetaldehyde would
account for the loss of two carbons in Scheme 2. Furthermore, in
the dimer model compounds 3 – 4, less sterically hindered
secondary hydroxyl groups also underwent oxidation to produce
10 – 11 (Table 1, entry v and vi). These findings are in agreement
24
stoichiometric amount of reagent was used. Over the last two
decades, considerable progresses have been made to develop an
effective catalytic process for the oxidation of a wide range of
primary alcohols. In our study, chemoselectivity oxidation of
12
with previously published results.
We believe that catalytic
TEMPO/CuCl conditions were inadequate in oxidation of

4
Tetrahedron Letters
30,31
primary alcohol in dimer model compounds because of steric
previously report studies.
Although, we were unable to isolate
constraints around a reactive site. These oxidation conditions
were further used to accomplish oxidation reaction in Scheme 3.
fragmented products derived from 19. When model compounds
14– 15 were oxidized under conditions B, a minor amount of
unidentified dimers were isolated.
As lignin being
a
multifunctional complex polymer,
predominantly selective oxidation of primary hydroxyl groups
has several practical difficulties. We, therefore, carried out an
investigation to study the fragmentation pattern of β-O-4 model
lignin compounds by oxidation of both types of hydroxyl groups.
In stepwise oxidation study, benzylic hydroxyl groups was
initially oxidized followed by the primary alcohols groups. The
benzylic hydroxyl groups in 3 – 4 were selectively oxidized using
Table 2. Oxidation of 16 – 17, and 3 – 4.
c
Entr
Subs,
(%reco
very)
Products, (%yield)
y
i.
1
6,
18, (10%)
19, (13%)
a catalytic TEMPO and NaNO
2
system at ambient temperature
a
a
(
84%)
under air atmosphere to form 16 – 17 with ~90% yields. Later,
the primary alcohol groups in product 16 – 17 were further
oxidized by the TEMPO/CuCl system as shown in Scheme 3
ii.
iii.
iv.
17,
83%)
(
(Table 2, entry i and ii)
b
3
18,
20,
22,
12,
24,
26,
(7%)
(
37%) (10%)
(2%)
(10%) (39%)
b
4
19, (56%)
21, (23%)
23, (19%)
[
a] Conditions A: Reaction were carried out for 20 h under air
atmosphere at room temp using 0.2eq of TEMPO, CuCl, bpy and 0.4eq
of NMI. [b] Conditions B: Reaction were carried out for 14 h under air
atmosphere at room temp using 5eq of TEMPO, 5eq NaNO
HCl. [c] Purified and isolated products yield and recovery.
2
and 10eq
Scheme 3. Stepwise oxidation of benzylic and primary
alcohol in 3 – 4
We observed that under these conditions, the 1,3-diketone
oxidized products rapidly underwent the addition reaction to
produce alkoxyl amine 18 – 19 (Table 2, entry i and ii).
Similarly,5,1416
–
17 also underwent minor dehydration
2
reaction.
On the other hand, when compound 3 – 4 was
oxidized using an excess amount of TEMPO catalyst and
oxidant, the hydroxyl groups of the model compounds were
oxidized to yield 1,3-dicarbonyl-TEMPO adduct 18 – 19 as the
26,13
major products.
The detailed characterization of the
compounds were done by 2D NMR: COSY, HSQC and
CIGARAD, as shown in Scheme 4. The product 18 was
relatively labile, and thus easily underwent in-situ Cα-Cβ bond
cleavage to produce compounds 24 and 12. The phenol 12 was
only 10 % in yield, as under these conditions it might endure
2
7
oxidative polymerization. The exact mechanism is still unclear;
however, the formation of carboxylic acid suggested retro-
Claisen reaction might be one of the intermediate steps that
28,29
facilitated cleavage of Cα-Cβ linkage.
This protocol provided
a simple and effective one-pot strategy for depolymerization of
lignin model compounds. Also under these acidic reaction
conditions, products 18 – 19 reacted to form a series of products
ranging from 20 to 26, these results were in agreement with some

.
1
3
Scheme 4. 2D NMR spectrum of compounds 18. (a) COSY, (b) HSQCSE and (C) CIGARAD (In CIGARAD artifact noise between C
1
1
85-195 ppm and H 9.75-10.25 ppm)
fragmentation in the presence of a catalytic amount of acid. We
have identified an important oxidation step that promotes the
fragmentation of the linkages in the lignin polymer. Further
research will focus on depolymerization of lignin polymers to
produce valuable aromatic hydrocarbons.
[b]
2
Table 3. Oxidation of 3 and 4 with TEMPO/NaNO .
Acknowledgments
Authors gratefully acknowledge the financial support from
NSERC Discovery and NSERC Discovery Accelerator
Supplements Programs.
Scheme 5. Fragmentation of Cα-Cβ linkage by acid treatment.
Entry
i.
Substrate
Products, (% yields)
12, (78%)
a,b
References and notes
18
24, (79%)
25, (55%)
27, (64%)
28, (80%)
20, (9%)
21, (40%)
29, (14%)
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1

Highlights



Selective cleavage of β-O-4 linkages in
lignin model compounds.
Aerobic oxidation of lignin model
compounds.
Fragmentation of 1,3-dicarbonyl-TEMPO
adduct in the presence of a catalytic amount
of acid.