Sequential Cleavage of Lignin Systems by Nitrogen Monoxide and Hydrazine

Article abstract of DOI:10.1002/adsc.201901641

The cleavage of representative lignin systems has been achieved in a metal-free two-step sequence first employing nitrogen monoxide for oxidation followed by hydrazine for reductive C?O bond scission. In combining nitrogen monoxide and lignin, the newly developed valorization strategy shows the particular feature of starting from two waste materials, and it further exploits the attractive conditions of a Wolff-Kishner reduction for C?O bond cleavage for the first time. (Figure presented.).

Full text of DOI:10.1002/adsc.201901641

Title: Sequential cleavage of lignin systems by nitrogen monoxide and
hydrazine
Authors: Laura Hofmann, Dagmar Hofmann, Lea Prusko, Lisa-Marie
Altmann, and Markus Heinrich
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901641
Link to VoR: http://dx.doi.org/10.1002/adsc.201901641

Advanced Synthesis & Catalysis
10.1002/adsc.201901641
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Sequential cleavage of lignin systems by nitrogen monoxide and
hydrazine
Laura Elena Hofmann, Dagmar Hofmann, Lea Prusko, Lisa-Marie Altmann and
*[a]
Markus R. Heinrich
a
Department of Pharmaceutical Chemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, 91058 Erlangen
Phone: (+49)-(0)9131/85-65670; e-mail: markus.heinrich@fau.de
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The cleavage of representative lignin systems
has been achieved in a metal-free two-step sequence first
employing nitrogen monoxide for oxidation followed by
hydrazine for reductive C-O bond scission. In combining
nitrogen monoxide and lignin, the newly developed
valorization strategy shows the particular feature of
starting from two waste materials, and it further exploits
the attractive conditions of a Wolff-Kishner reduction for
C-O bond cleavage for the first time.
bond cleavage of model systems (Scheme 1A),
[14b]
followed by a later application to lignin.
As
[
15]
[16]
shown by Luo (Scheme 1B) and others, the two-
step strategy can also be realized by combining two
photocatalyzed reactions. Alternatively, and as
[6a]
[17]
demonstrated by Westwood (Scheme 1C), Cao
[6b]
and Zhang, the oxidative step may be coupled to a
reduction with zinc or to hydrogenation.
Keywords: Lignin • Depolymerization • Nitrogen oxides •
Hydrazine • Pyrazole
Research on the valorization of lignin and related
biomaterials has intensified dramatically of the last
decades and various methods have already been
developed that can successfully be applied to the
[1]
natural polymers. These methods can generally be
divided into one- and two-step processes. Attractive
protocols for one-step depolymerization include hot
[
2]
pressurized
water,
alkaline
oxidative
[3]
[4]
depolymerization or metal catalyzed reactions,
among others.[ The two-step strategies typically
combine an oxidative and a reductive step, whereat
the oxidation can, for example, be achieved by
5]
DDQ,[ TEMPO, peroxides or other oxidants,
6]
[7]
[8]
[9]
[6b]
Scheme 1. Two-step sequences applied for the cleavage of
lignin model systems.
and the reduction by catalytic hydrogenation
or
metal[ as well as nonmetal reductants.
10]
[11]
Even more methods are known if one includes studies
on lignin model systems. Again, the related methods
can be divided into one-step strategies, comprising
Furthermore, chemoselective aerobic[18] and anodic
oxidations have been reported, whereat the latter
both oxidative[ and reductive
12]
[13]
approaches, and
Representative two-step
[19]
approach by Stephenson (Scheme 1D) included a
photocatalyzed cleavage. Based on our recent
research on the synthetic utilization of nitrogen
two-step
protocols.
sequences, which have so far been applied to lignin
systems, are summarized in Scheme 1.
[
20]
oxides,
which frequently occur in waste gases
Particularly popular among the two-step strategies are
methods including a primary oxidation step of the
benzylic alcohol units followed by reductive C-O
bond cleavage in α-position to the newly formed
carbonyl (Scheme 1). In 2013, Stahl[14a] reported a
chemoselective metal-free aerobic alcohol oxidation
combined with a first study on the selective C-C/C-O
[21]
resulting from combustion, we aimed at a nitrogen
oxide-mediated oxidation step of lignin, since this
would lead to a novel valorization method combining
[22]
two waste materials (Scheme 1E).
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201901641
After
a
series of preliminary optimization
(2 × 0.1 equiv.). [b] Performed on 1 mmol scale using
CH CN (6 mL). [c] Isolated yield.
3
experiments with benzylic alcohol 1 and related
starting materials (see Supporting Information), we
found that the oxidation of 1 to the acetophenone 2
can be achieved with as little as 0.1 equivalents of
nitrogen monoxide and 0.05 equivalents of DDQ in a
pressure equilibrated, but closed vessel under air
The benzylic alcohols 3e and 3f already gave good to
high yields of 4e (93%) and 4f (74%) with just 0.1
equivalents of nitrogen monoxide, so that these
compounds were selected for two further experiments
on a four-fold larger 1 mmol scale providing similar
(4e: 92%) or even higher yields (4f: 90%).
Additionally, it could be shown that DDQ, which is
used as catalyst, can be recovered during work-up
with at least 50% of its original quantity. This
investigation was however complicated by the small
amounts of DDQ that are present in the reaction
mixture.
(
Scheme 2). By a control reaction, it was shown that
nitrogen monoxide is required for the desired
oxidation.
Various conditions have already been reported for the
reductive cleavage of oxidized, acetophenone-type
[
15,17]
lignin systems,
but the cheap reductant
Scheme 2. Initial experiments on the nitrogen oxide based
oxidation of benzylic alcohol 1.
[
24]
hydrazine has apparently not been investigated in
this context so far. Our interest in the use of
hydrazine arose from its use in well-known Wolff-
[25,26]
Kishner reductions
and the results obtained in
Since no more starting material 1 was detected after
the longer reaction time of 18 h, we directly applied
the optimized oxidation conditions[23] to a series of
established lignin model systems (Scheme 3).
Attempts on the oxidation of the benzylic alcohols
two preliminary experiments with the simplified
system 5 (Scheme 4).
3
a-c revealed that a larger amount of 0.2 equivalents
of nitrogen monoxide is required to achieve
reasonable yields for 4a-c in the range of 41 to 58%.
The low yield for 4d (7%), which did not much
improve on the addition of more nitrogen monoxide
(
14%), is most probably due to the free phenolic
hydroxyl group in 3d. Such group was not present in
Scheme 4. Hydrazine-mediated reductive cleavage of
model system 5. Yields determined using dimethyl
terephthalate as internal standard.
any of the other starting materials.
Besides the observation that the desired C-O bond
cleavage can indeed be achieved with hydrazine, it
turned out that the fragment resulting from the
acetophenone unit does strongly depend on the
amount of base and the gas atmosphere. While
hydrazone 6 and phenol 7 were formed in the
presence of low amounts of KOH (1 equiv.) under air,
an excess of KOH (10 equiv.) under argon provided
styrene 8 instead of 6.
The results obtained from the hydrazine-mediated
cleavage of the oxidized lignin systems 4a-c,e,f,
which were previously prepared according to Scheme
3
, are summarized in Scheme 5. For these
experiments, conditions similar to those providing
hydrazone 6 from 5 (Scheme 4) were applied.
From all experiments, the phenols 9 were obtained in
good yields ranging from 63% (for 9b from 4f) to
8
8% (for 9b from 4c). Due to the additional
Scheme 3. Oxidation of lignin systems 3a-f using nitrogen
monoxide and DDQ under air: 3 (0.25 mmol), NO (0.1
hydroxymethyl group in the oxidized systems 4a-c,e,f,
when compared to the more simple system 5 (Scheme
4), pyrazoles 10a-c were now formed instead of the
original hydrazone 6. This can be rationalized
through an intramolecular condensation step
equiv.), DDQ (0.05 equiv.), CH
3
CN (3 mL), 80 °C, closed
vessel with balloon for pressure equilibration. [a] 2 × NO
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201901641
involving the terminal nitrogen atom of hydrazone
moiety as nucleophilic position.[ The highest yield
was reached for the pyrazole 10c (76%) bearing a 4-
methoxyphenyl substituent in 3-position. However,
increased donor substitution on the phenyl unit does
not strictly correlate to lower yields, as the lowest
yield was observed for the 3,4-dimethoxy derivative
After condensation of the starting material 4b with
hydrazine to give hydrazone 11, a slow reductive C-O
bond cleavage occurs providing phenol 9a and the
secondary hydrazone 12. As shown by the time
course of the reaction and the evolution and
disappearance of the respective intermediates, the C-
O bond cleavage appears to be the rate determining
step in the overall sequence (see Supporting
Information). The oxidative cyclization of 12 to
pyrazole 10b, on the other hand, is likely to occur
much faster, as only trace amounts of 12 could be
detected. At this point, we can however not exclude a
more or less concerted, and redox-neutral direct
conversion of hydrazone 11 into 9a and 10b as
additional pathway, whereat cyclization of 11 would
proceed along with an immediate elimination of 9a.
No evidence was found for a pathway, in which C-O
bond cleavage would occur directly from 4b, then
followed by condensation and cyclization.
11b]
1
0a (from 4a) and not for the trimethoxy-substituted
3
-phenylpyrazole 10b. Among other applications, 3-
arylpyrazoles are of interest in medicinal and
agricultural chemistry.[
27]
In summary, we have shown that by using nitrogen
monoxide for the oxidation of lignin systems, two
waste materials can be successfully combined within
a novel valorization strategy. By applying conditions
typically known from Wolff-Kishner reductions, the
cleavage of the previously prepared, oxidized systems
provided phenols along with 3-arylpyrazoles in a
metal and catalyst-free reaction. Investigations by
mass spectrometry gave insights into the reaction
course. Applications of the novel two-step
depolymerisation strategy to natural lignin polymers
are currently underway in our laboratory.
Scheme 5. Hydrazine-mediated cleavage of the oxidized
systems 4a-c,e,f: 4 (0.25 mmol), H
equiv.), KOH (0.5 equiv.), ethylene glycol (4 mL), 150 °C,
6 h. Yields determined using dimethyl terephthalate as
2 2 2
NNH × H O (20
1
internal standard. [a] 4a (0.22 mmol) [b] 4b,c (0.13 mmol), Experimental Section
ethylene glycol (3 mL).
General procedure for oxidation reactions: In a 10 mL
flask, with a balloon for pressure compensation and a
reflux condenser, model systems 3a-f (1.0 mmol) and
DDQ (12.5 µmol, 2.84 mg, 0.05 eq.) were dissolved in
acetonitrile (3 mL). The solution is heated to 80 °C. At
Finally, the reaction course of the reductive C-O bond
cleavage was followed by mass spectrometry to get
insights into the mechanism and to reveal possible
intermediates. The results of this study are
summarized in Scheme 6.
8
0 °C nitrogen monoxide (25.0 µmol, 0.56 mL, 0.1 eq.)
was added with a syringe to the reaction and was stirred for
8 hours at 80 °C. After 18 hours a second amount of
1
nitrogen monoxide (25.0 µmol, 0.56 mL, 0.1 eq.) was
added and the reaction was stirred for another 6 hours.
Afterwards the solution was diluted with water (10 mL)
and extracted with dichloromethane (3 × 10 mL) first and
again with ethyl acetate (3 × 10 mL). The organic phases
were washed with saturated aqueous sodium chloride,
dried over sodium sulfate and the solvent was removed
under reduced pressure. The yields of 4a-f were
1
determined by H NMR using dimethyl terephthalate as
internal standard. Purification by column chromatography
gave the desired products 4a-f as viscous light brown oils.
General procedure for cleavage reactions: Oxidized
model systems 4a-c,e,f (1.0 mmol), hydrazine
monohydrate (20.0 mmol, 20 eq.) and potassium hydroxide
(
0.5 mmol, 0.5 eq.) were dissolved in ethylene glycol (4
mL) and stirred for 16 hours at 150 °C. Afterwards the
reaction was diluted with water (10 mL) and extracted with
ethyl acetate (3 × 10 mL). The pH-value was adjusted to a
pH 3-4 with 3 N hydrochloric acid and the reaction
mixture is extracted with ethyl acetate (3 × 10 mL) again.
The combined organic phases were washed with saturated
aqueous sodium chloride solution, dried over sodium
sulfate and the solvent was removed under reduced
Scheme 6. Proposed mechanism based on the analysis of
the reaction course by mass spectrometry.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201901641
pressure. The yields of 9a,b and 10a-c were determined by
Weber, N. Sok, T. Karbowiak, Green Chem. 2019, 21,
1
H NMR using dimethyl terephthalate as internal standard.
4
633-4641.
Purification by column chromatography gave the desired
products 9a,b and 10a-c as colorless solids.
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Acknowledgements
We are grateful for the financial support of this project by the
Deutsche Bundesstiftung Umwelt (DBU) (DBU 80014/189). We
are further grateful for experimental assistance by Sandra Topf
and for the LC-MS measurements by Jannis Beutel.
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