Sustainable Production of Benzylamines from Lignin

Article abstract of DOI:10.1002/anie.202105973

Catalytic conversion of lignin into heteroatom functionalized chemicals is of great importance to bring the biorefinery concept into reality. Herein, a new strategy was designed for direct transformation of lignin β-O-4 model compounds into benzylamines and phenols in moderate to excellent yields in the presence of organic amines. The transformation involves dehydrogenation of C_α?OH, hydrogenolysis of the C_β?O bond and reductive amination in the presence of Pd/C catalyst. Experimental data suggest that the dehydrogenation reaction proceeds over the other two reactions and secondary amines serve as both reducing agents and amine sources in the transformation. Moreover, the concept of “lignin to benzylamines” was demonstrated by a two-step process. This work represents a first example of synthesis of benzylamines from lignin, thus providing a new opportunity for the sustainable synthesis of benzylamines from renewable biomass, and expanding the products pool of biomass conversion to meet future biorefinery demands.

Full text of DOI:10.1002/anie.202105973

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Accepted Article
Title: Sustainable production of benzylamines from lignin
Authors: Changzhi Li, Bo Zhang, Yuxuan Liu, Tenglong Guo, Fritz E.
Kühn, Chao Wang, Zongbao K. Zhao, Jianliang Xiao, and Tao
Zhang
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10.1002/anie.202105973
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COMMUNICATION
Sustainable production of benzylamines from lignin
Bo Zhang[a], Tenglong Guo[a], Yuxuan Liu[a], Fritz E. Kühn[b], Chao Wang[c], Zongbao K. Zhao[d],
Jianliang Xiao[e], Changzhi Li*[a], Tao Zhang[a]
[a]
Dr. B. Zhang, Dr. T. Guo, Dr. Y. Liu, Prof. C. Li, Prof. T. Zhang
CAS Key Laboratory of Science and Technology on Applied Catalysis,
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
E-mail: licz@dicp.ac.cn
[b]
[c]
Prof. F. E. Kühn
Molecular Catalysis, Catalysis Research Center and Department of Chemistry
Technical University of Munich, Lichtenbergstr. 4, D-85747, Garching bei München, Germany.
Prof. C. Wang
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education
Ministry of Education, School of Chemistry and Chemical Engineering
Shaanxi Normal University, Xi’an, 710062, China.
Prof. Z. K. Zhao
Division of Biotechnology,
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
Prof. J. Xiao
[d]
[e]
Department of Chemistry,
University of Liverpool, Liverpool, L69 7ZD, UK.
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
Abstract: Catalytic conversion of lignin into heteroatom
functionalized chemicals is of great importance to bring the biorefinery
concept into reality. Herein, a new strategy was designed for direct
transformation of lignin β-O-4 model compounds into benzylamines
and phenols in moderate to excellent yields in the presence of organic
amines. The transformation involves dehydrogenation of Cα-OH,
hydrogenolysis of the Cβ-O bond and reductive amination in the
presence of Pd/C catalyst. Experimental data suggest that the
dehydrogenation reaction proceeds over the other two reactions and
secondary amines serve as both reducing agents and amine sources
in the transformation. Moreover, the concept of “lignin to
benzylamines” was demonstrated by a two-step process. This work
represents a first example of synthesis of benzylamines from lignin,
thus providing a new opportunity for the sustainable synthesis of
benzylamines from renewable biomass, and expanding the products
pool of biomass conversion to meet future biorefinery demands.
for functionalization of lignin products and the sake of energy,
environmental and sustainable economics.
Nitrogen-containing aryl chemicals are widely used in the
production of polyurethane precursors, synthetic dyes, and
pharmaceuticals.[11] Currently, aliphatic amines, aromatic amines
and amino-alcohols are prevailing generated from fossil refinery
by chemical reactions with ammonia or ammonia derived
feedstock,[12] which suffers from several issues such as heavily
reliance on non-renewable resource, the multi-step synthetic
routes with low overall efficiency, excessive carbon emission with
environmental concerns, and harsh reaction conditions. The
development of sustainable routes for the synthesis of nitrogen-
containing aryl chemicals is highly desirable. Taking the aromatic
feature of lignin into account, introducing nitrogen (N) during lignin
depolymerization might allow a new C-N bond formation in the
products, thus providing an alternative strategy for the production
of aromatic amines from renewable resource. To achieve this
hypothesis, tandem cleavage of the C-O/C-C bonds and
formation of the C-N bonds should be efficiently coupled in the
transformation. However, it remains a huge challenge due to the
complicated structure and intractable property of lignin,
incompatible catalytic systems and reaction conditions.
With accelerating consumption of fossil resources and the
increasing environmental concerns, lignocellulosic biomass as a
renewable and abundant source of chemicals and fuels has
recently attracted substantial attention.[1] Lignin,
component of lignocellulose and complex plant-derived
a major
a
State-of-the-art of N-participated routes concentrates on the
lignin-derived monomers or modification of model compounds
before transformation. For example, lignin monomers (phenol,
guaiacol and other monophenols) were converted to N-
substituted anilines using ammonia, organic amine, hydrazine
hydrate, and methyl glycinate as amine resource (Scheme 1,
routes 1-2).[13] Amination of the lignin dimers was also explored,
affording corresponding α-ketone amide[14] and isoxazole
derivatives[15] (Scheme 1, routes 3-4) as the major products.
However, the hydroxyl group is more difficult to be transformed
than the carbonyl group, in this process, the oxidation of the β-O-
heteropolymer, is an unique precursor for aromatic compounds.[2]
However, most lignin in the paper and pulp industry has been
discarded or burnt as a low value fuel,[3] which not only wastes
renewable resources, but also poses different environmental
concerns. Lignin transformation has therefore become a major
topic in biomass conversion area and would play an important role
in improving the economics of the overall biorefinery associated
with addressing the problem of environmental impacts. So far,
great efforts have been devoted to selective cleavage of C-O or
4]
C-C linkages with the aim to obtain phenols,[1a,
arenes,
[5]cycloalkanes,[6] aldehydes,[7] ketones,[3a,
acids,[9] and
8]
4
model compounds to their α-ketone derivatives is an
benzoquinones.[10] The products are limited to C, H, O containing
compounds, while value-added heteroatom-containing products
are rarely reported. Hence efficient strategy for the selective
conversion of lignin into such kind of products is highly demanded
indispensable step in order to guarantee the amination
reaction.[14-15] Besides the above investigations, another important
progress has been made in the conversion of diphenyl ether (4-
O-5 linkage in lignin) over Pd(OH)2/C catalysts.[16] Formal cross-
1
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10.1002/anie.202105973
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COMMUNICATION
Scheme 1. The strategies for reacting lignin model compounds with amines.
coupling of diaryl ethers with organic amines was achieved via
dual C(Ar)−O bond cleavage, leading to amine derivatives as the
targeted products. Notwithstanding, there is still a big barrier for
the direct transformation of typical β-O-4 model compound into
amines, let alone the direct conversion of realistic lignin. Noting
that β-O-4 linkage accounts for the highest portion in all the
linkages of lignin (approximately 50% depending on the types of
lignin),[1a] overcoming direct transformation of β-O-4 moieties
would give us a guideline for the production of amines from
Table 1. Conversion of β-O-4 model compound 1a with pyrrolidine 2a at
different conditions. [a]
Entry
Catalyst
Temp.
Conv.
[%]
Yield 3a
Yield
4a
[%]
--
Yield
5
[%]
[%]
--
1
2
3
4
5
6
7
8
9
PdCl2
120
120
120
120
120
100
110
130
120
--
--
realistic lignin. Herein, we describe
a new strategy by
Pd(NH3)4Cl2
Pd(OAc)2
--
--
--
--
heterogeneous catalysis for the direct converting of lignin β-O-4
model compounds to nitrogen-containing aryl chemicals (Scheme
1), which offers a potential one-pot route for the sustainable
production of benzylamines. Moreover, such a strategy could be
applied in the conversion of realistic lignin, hence demonstrates
the feasibility of amine production from native lignin.
65
51
100
65
70
100
--
40
62
47
98
57
64
92
--
8
[b]
Pd(acac)2
22
80(81)[c]
19
6
Pd/C
Pd/C
Pd/C
Pd/C
--
26
36
75
--
29
26
2
To examine the possibility of this proposal, the β-O-4 model
compound 1a in Table 1 was chosen as a probe molecular and
pyrrolidine (2a) was used as an amine source for the
transformation. Noting that Pd-based catalysts exhibited good
catalytic activity for the cleavage of C-O bond in lignin[17] and
different coupling reactions,[13b, 13d, 16a] the screening of various
Pd-based catalysts was first investigated. As shown in Table 1,
PdCl2 and Pd(NH3)4Cl2 were inactive for the reaction, while
Pd(OAc)2, Pd(acac)2 and Pd/C could catalyze the reaction of 1a
with pyrrolidine (2a), providing 1-(1-phenylethyl)pyrrolidine (3a)
and guaiacol (4a) as the major products (Table 1, entries 1-5, and
Figures S1-S2). In contrast to Pd(OAc)2 and Pd(acac)2, Pd/C has
exceptionally higher activity for the transformation, yielding 80%
of 3a and 98% of 4a (entry 5). The results also suggest that the
reaction was strongly dependent on the reaction temperature.
Increasing the reaction temperature, the yield of 3a and 4a
increased first then decreased as indicated in Table 1, entries 5-
8. The best result for the conversion of β-O-4 with pyrrolidine was
obtained at 120 oC (entry 5). In comparison, no reaction occurred
in the blank experiment without catalyst (entry 9).
--
[a]Substrate 1a (0.2 mmol), pyrrolidine 2a (1.0 mmol), toluene (2 mL), t = 8 h,
catalyst (5 mol% Pd) under an argon atmosphere, and the results were
[b]
determined by GC-FID analysis with mesitylene as an internal standard;
Pd(acac)2 = Bis(acetylacetonato)palladium (II), [c]Isolated yield.
Encouraged by the above results, we then investigated the
scopes of the substrates and amine sources for this
transformation. The results showed that the catalytic system was
effective not only for various β-O-4 model compounds, but also
for a broad range of amine sources. As shown in Table 2, all the
β-O-4 model compounds bearing methoxy groups with different
numbers and positions could be converted to targeted
benzylamines 3a-3c, along with corresponding phenol derivatives
4a-4c (entries1-6), indicating that C-O bond cleavage associated
with C-N bond formation occurred in a one-pot fashion. Moreover,
methoxyl substitute on the left aryl ring (C-terminus aryl ring)
resulted in diminished yields (<44%) compared with aryl ring
without functional group (>66%) (entry 1 vs 4, and 2 vs 5) even
o
by increasing reaction temperature to 140 C, probably owing to
the electronic effects of methoxy group that increases the bond
2
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Table 2. Reacting various lignin β-O-4 model compounds with amines catalysed
by Pd/C.[a]
Figure 1. Time course profile of compound 1a conversion over Pd/C.
(3d-3e). It is worth noting that no additional reducing reagent was
required in the reactions with secondary amines 2a, 2b and 2c,
suggesting that secondary amines per se may serve as reducing
agents (vide infra), which is the main reason that excess amount
of amine was used. It should be noted that the boiling points of
the employed amine reactants are much lower than that of β-O-4
model compounds and the coresponding benzylamine products
(Figure S4), therefore, the unreacted amines can be easily
distillated from the reaction mixture for recycling. When using
HCO2Na as a hydrogen source, the amount of the secondary
amine 2a could be reduced. For instance, in the presence of
HCO2Na, 1a reacted with a reduced amount of 2a (2 equiv.) under
the standard conditions as given in Table 1 entry 5 and gave
higher yields of 3a and 4a (Table S1, entry 1) than those shown
in Table 1, entry 5. Results with other lignin model compounds 1b,
1d and the second amine 2b also showed improved yields in the
presence of 2 equiv. of HCO2Na (Table S1, entries 2-4). Thus,
HCO2Na could be used as a reducing agent in the reaction to
reduce the amount of secondary amine. Moreover, the reaction
worked well at higher substrate concentration. For example, when
the loading of 1a was increased by 5-fold to 1.0 mmol (14 wt%
concentration), 3a and 4a were obtained in yields of 57% and 75%,
respectively, in the presence of 2 mmol of 2a and HCO2Na (Table
S1, entry 5). To further demonstrate the versatility of this strategy,
different primary amines were tested. Unexpected, the
experiment without hydrogen source only led to 26% yield of imine
intermediate N-butyl-1-phenylethan-1-imine as the major product
along with 7% yield of benzylamine 3f (entry 9). These results
probably attributed to the relatively weak dehydrogenation ability
of the primary amine, which could not generate enough hydrogen
for the subsequent cleavage of C-O bonds (hydrogenolysis), and
reduction of imine intermediates. Delightfully, an experiment
using HCO2Na as additional hydrogen source greatly improved
the yield of 3f to 95% (entry 9). Moreover, long chain aliphatic
primary amines such as n-heptylamine provided amination
product 3g with the yield up to 98% under this condition (entry 10).
Aliphatic amine with donating methoxyl group led to 59% yield of
3h (entry 11). Two comparative experiments (entries 12-13)
suggest that aliphatic amine (cyclohexanamine 2g) exhibited
much higher activity than aryl amine (aniline 2h) in the
transformation, mainly attributing to the relative lower
[a]Unless otherwise specified, the reaction condition is: β-O-4 model compounds
(0.2 mmol), Pd/C (5 wt% Pd, 21 mg), amine source (1 mmol) in toluene (2 mL)
under an argon atmosphere, 120 oC, 8h; and the results were determined by
GC-FID with an internal standard method; [b]140 oC, 24 h; [c]TFA (10 uL) was
used, 140 oC, 24 h; [d]TFA (10 uL) was used; [e]TFA (10 uL) and HCO2Na (5
equiv.) were used, 140 oC, 24 h.
dissociation energy of β-O-4 linkage. In addition, the highly
substituted β-O-4 model compound with γ-OH led to
comparatively lower yield of target products 3c and 4a, as well as
several by-products (entry 6, and Figure S3); while the presence
of trifluoroacetic acid (TFA) could facilitate the imine
intermediates formation so as to enhance the yields of
benzyleamines (entries 7-8). The scope of the amine source in
the conversion of lignin β-O-4 model compounds was also
explored. As shown in Table 2 (entries 1, 7-8 ), other secondary
amines were effective to form their corresponding benzylamines
3
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condition, obtaining amine product 3a with the yield of 37% rather
than the imine product (Reaction 3 in Scheme 2), implying that
compond 5 is an important intermediate and pyrrolidine itself
could serve as both an amine source and a reducing reagent. The
following experiments give direct evidences on the dual role of
pyrrolidine 2a: the reaction using 2a as sole substrate under the
same condition was conducted, 5-(pyrrolidine-1-yl)-3,4-dihydro-
2H-pyrrole (8) was produced in conjunction with hydrogen gas,
which was determined by GC-MS, NMR and FT-ICR MS
(Reaction 4 in Scheme 2, and Figures S1, S5-S6). This compound
8 was also detected in the catalytic reactions when using
pyrrolidine 2a as an amine source for the conversion of different
β-O-4 model compounds (such as Figures S1 and S3). Moreover,
additional reductant is not required when 2b and 2c were
employed as amine sources (Table 2, entries 7-8), hence, an
assumption can be made that secondary amine serves as both
amine source and a reducing reagent in the reductive amination
of β-O-4 model compounds. The isotopically-labeling experiment
further confirmed the dual role of 2a: if β-O-4 model compound
reacted with deuterated pyrrolidine under identified reaction
conditions of Table 1, entry 5, deuterated amination products with
m/z 180 and 181 were detected, indicating that the released D2
from pyrrolidine has transferred to amination products (Reaction
5 in Scheme 2, and Figure S7). Specifically, the product of m/z
179 suggests that H2, in-situ generated from dehydrogenation of
substrate 1a (verified by reaction 1 in Scheme 2, and Figure 1),
took part in the following C-O bond cleavage process via
hydrogenolysis reaction. On the basis of the above results, one
can conclude that both the β-O-4 substrate and the secondary
amine may have acted as the hydrogen source in this consecutive
transformation. Taking the above results and the time profile
experiment into account, a tentative reaction pathway using 1a
and 2a as the substrates is proposed: the whole transformation
follows a consecutive route initiates by the dehydrogenation of Cα-
OH in 1a to form intermediate 6, then cleavage of the C-O bond
of intermediate 6 occurs to release 5, followed by organic amines
participated amination of 5 to form active imine intermediate (A or
B), which is liable to be hydrogenated to the desired amine
product E (path a in Scheme 3).
nucleophilicity of the latter one. Moreover, 3-phenylpropylamine
2i provided the corresponding benzylamine 3k in 93% yield.
Hence, both primary amines and secondary amines were
effective to form their corresponding benzylamines (3a-3k).
Based on all above results, one can conclude that Pd/C has great
ability not only to cleave the C-O bonds, but also to promote C-N
bonds formation, affording the corresponding amine products,
highlighting the practical advantage in direct conversion of lignin
β-O-4 model compounds to new type of benzylamines without
modification (Scheme 1).
To explore the reaction pathway, the time course of 1a and 2a
was monitored (Figure 1). Results showed that 1a was almost
quantitatively converted to 3a, 4a, and 5 at the initial stage (within
5 h). Noting that only a trace amount of compound 6 was
observed and 5 burst initially but decreased over time. These
results suggested that compounds 5 and 6 were probably the
intermediates for the transformation.
To verify the above hypothesis and gain further insight into the
mechanism, several control experiments were performed. The
conversion of 1a catalyzed by Pd/C in the absence of amine
resource led to 5, 4a and 6 in yields of 20%, 22% and 13%,
respectively, suggesting that Pd/C can promote dehydrogenation
and C-O bond cleavage reactions (Reaction 1 Scheme 2), which
hence is a redox-neutral process through self-hydrogen-transfer
without additional hydrogen source.[8a] In combination with the
remarkably improved performance in the presence of amine
source pyrrolidine 2a (entry 5 in Table 1), one may conclude that
the amination reaction did help promoting the cleavage of C-O
bonds. It is interesting to note that when the hydroxyl group on Cα
position of compound 1a was replaced by methoxy group, the
substrate 7 could not undergo dehydrogenation and failed to be
converted (Reaction 2 in Scheme 2), indicating that the
dehydrogenation process was a key step in the conversion of 1a,
which was also supported by the formation of the intermediate 6
in Figure 1. On the other hand, acetophenone 5 (produced in
Reaction 1) could react with pyrrolidine 2a under the same
To investigate the crucial role of the intermediate 6, its direct
transformation with pyrrolidine 2a was performed (Reaction 6 in
Scheme 2). The reaction afforded 6% yield of 3a, 58% yield of 5,
79% yield of 4a, and 23% yield of a new compound 9 (confirmed
by GC-MS and FT-ICR MS, Figures S8-S9) within 8 h, implying
that formation of enol-form compound 9 via the intermediate and
amines occurred (Figures S8-S9). Extending the reaction time to
24 h could greatly increase the yield of the target amine 3a to 53%
(Figure S10). Moreover, the time-online profile showed that the
Scheme 3. Proposed reaction pathways for transformation of lignin β-O-4
model compound.
Scheme 2. Control experiments.
4
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10.1002/anie.202105973
Angewandte Chemie International Edition
COMMUNICATION
formation of 9 was very fast, and the yield reached up to 71%
within 0.5 h, and then decreased with prolonging the reaction time
(Figure S10). These above results revealed another pathway to
amine products (path b in Scheme 3): intermediate 6 directly
reacting with amine to produce imine C and its tautomer enamine
D, which undergoes the C-O bond cleavage to form A or B, and
subsequent hydrogenation to form final product E. Therefore, the
whole transformation of β-O-4 model compound with amine
through two pathways is proposed in Scheme 3. Obviously, the
present pathways bring advantages over reported β-O-4
conversion routes that need additional Cα-OH oxidation step in
the presence of oxidants and obtained different amination
products.[14]
has also been demonstrated. The production of lignin-derived
heteroatom products needs to overcome the structural complexity
of lignin in order to obtain the high yield of a pure product, while
avoiding the competing reaction to ensure sole amination reaction.
Our ongoing work focuses on improving the yield of benzylamines
from realistic lignin. We believe this methodology could provide
some new ideas to produce value-added chemicals from
heteroatom-participated biomass conversion.
Acknowledgements ((optional))
Support from National Key R&D Program of China
(2019YFC1905300), the National Natural Science Foundation of
China (22078317, 21878288, 21721004, 21690083), the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB17020100), and the 2017 Royal Society
International Collaboration Award (IC170044) is gratefully
acknowledged.
Scheme 4. The catalytic strategy for native lignin conversion.
Inspired by the above results, the production of benzylamines
from the conversion of realistic lignin was investigated (Scheme
4). Direct amination of lignin feedstock using current condition is
hard to realize, mainly because dehydrogenation of native lignin
to form keto-functional lignin obeying the mechanism of lignin
model compound in Scheme 3 over Pd/C did not occur, instead
the competitive hydrogenolysis reaction provided small amount of
phenol derivatives. Although current condition did not satisfy the
one-pot conversion of lignin, an alternative two-step process for
amination of lignin was developed. First, the lignin-oil was
obtained through mild depolymerization of lignin catalyzed by a
binuclear rhodium complex,[8a] leading to 8.3 wt% yield of
aromatic keto-monomers along with oligomers in the oily products
as determined by MALDI-TOF spectroscopy (Table S2 and Figure
S11-S14). Subsequently, direct conversion of lignin-oil with
pyrrolidine 2a over Pd/C was conducted, successful affording 0.4
wt% yield of corresponding benzylamines I-IV in Scheme 4 (see
Figures S15-S16 and Table S3 for identification of these
compounds). The relatively low yield of amine products might due
that the complexed oily components including large number of
oligomers are vast barriers for the amination reaction. Another
possible reason is the competitive hydrogenation reaction of the
keto-monomers. We are still working on the improvement of the
overall efficiency including the amination reaction. So far,
screening of the reaction conditions and efforts with other
reducing agent, nitrogen source, and oxidative modification of
lignin did not allow us to fully meet the target. Nevertheless, new
multifunctional catalytic system will be designed to couple all
elementary reactions, and particular attention will be paid to the
depolymerization of lignin to ketone intermediates and the
amination of aromatic ketones. Furthermore, amination of lignin[18]
prior to depolymerization might be another approach to obtain
benzylamines. Nevertheless, the above case offers a potential
protocol for the conversion of native lignin to bio-based
benzylamines. It is important to note that compounds I-IV in
Scheme 4 have broad applications in pharmaceuticals as a base
Keywords: Biomass • Lignin • Benzylamines• β-O-4 model
compounds
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6
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Entry for the Table of Contents
An efficient strategy for the conversion of lignin β-O-4 model compound into benzylamines through a one-pot C-O bond cleavage and
C-N bond formation with secondary amines serving as both amine sources and reducing agents was developed. The feasibility for
the production of bio-based benzylamines from lignin in a two-step process was introduced in these processes.
7
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