Transformation of lignin model compounds to: N -substituted aromatics via Beckmann rearrangement

Article abstract of DOI:10.1039/c8gc00920a

Here we present the highly effective cleavage of C-C bonds in lignin model compounds for the production of N-substituted aromatics in up to 96% total yield, including benzonitriles and amides, via oxime formation followed by Beckmann rearrangement (BR). The amides could be further hydrolyzed to anilines (>92% yield) and carboxylic acids (>90% yield), respectively. In addition, the employment of a substrate with a γ-OH group will lead to the formation of C-2 monosubstituted oxazole. A one-pot process involving the BR reaction and hydrolysis has also been developed to directly afford an up to 96% total yield of benzonitriles, benzamides, and anilines. This strategy enabled us to successfully apply the BR reaction to the degradation of lignin model compounds to N-functionalized aromatic products under mild conditions.

Full text of DOI:10.1039/c8gc00920a

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Transformation of Lignin Model Compounds to N-substituted
Aromatics via Beckmann Rearrangement
Yinling Wang, Yiman Du, Jianghua He,* and Yuetao Zhang*
Received 00th January 20xx,
Accepted 00th January 20xx
Here we represented the highly effective cleavage of C-C bonds in lignin model compounds for the production of N-
substituted aromatics in up to 96% total yield, including benzonitriles and amides, via the oxime formation followed by
Beckmann rearrangement (BR). The amides could be further hydrolyzed to anilines (> 92% yield) and carboxylic acids (> 90%
yield), respectively. In addition, the employment of a substrate with a γ-OH group will lead to the formation of C-2
monosubstituted oxazole. A one-pot process involving BR reaction and hydrolysis has been also developed to directly
afford an up to 96% total yield of benzonitriles, benzamides, and anilines. This strategy enabled us to successfully apply
the BR reaction to the degradation of lignin model compounds to N-functionalized aromatic products under mild
conditions.
DOI: 10.1039/x0xx00000x
www.rsc.org/
bond, Stahl and co-workers successfully cleaved the C-C bonds
via the H2O2 oxidized Dakin reaction.16a Most recently, we also
successfully applied the Baeyer-Villiger (BV) oxidation in the
Introduction
As the second abundant biomass only next to cellulose and
an alternative renewable energy source to fossil fuel, lignin
(20-35% in wood) is the most abundant natural source of
aromatic molecules.1 However, so far lignin is highly
degradation of oxidized lignin model compounds followed by
hydrolysis under mild condition, affording esters and phenols
in excellent yields by the transformation of the inert C-C bonds
in the oxidized lignin models to active ester bonds.14a
However, more examples of metal-free strategies for the
selective C-C bond cleavage under mild conditions are needed
to provide a significant foundation for the degradation and
valorization of lignin.
,2
underutilized and only less than 5% of lignin is used to deliver
low value commercials, such as low grade-fuel and concrete
additive,3 due to its complicated polymeric structure and
inherent inert chemical activities.4 Various methods have been
developed for the effective cleavage of the C-O and/or C-C
bonds in lignin model compounds.5-15 Compared to the
comprehensive studies in the cleavage of the C-O bonds,5
the selective cleavage of C-C bonds in lignin still remains
N-substituted aromatics are very important synthetic
-10 intermediates for production of plastic,17 pharmaceutical
industries,18,19,20 and electronic materials.21 Such as nitriles
could be used as the precursors for the organic synthesis of
acids, esters, amines, amides, aldehydes, benzamidines, and
challenging to the chemists and generally catalyzed by
11,12
transition metal catalysts
or required harsh reaction
nitrogen-containing heterocycles,23 but with the requirement
of metal catalyst or equivalent azide in general.24 Whereas
metal-mediated organic transformation is commonly used for
the synthesis of amides, which play an important role in
preparation of plastic, lubricant, and intermediates.20d The
production of aromatic amines generally involves nitrification of
aromatic hydrocarbons with a concentrated mixture of nitric acid
and sulfuric acid as well as hydrogenation reduction,22 which are
16 dangerous and environmentally unfriendly. Therefore, it is desirable
to develop an efficient method for the production of aromatic
amines from renewable resources under mild conditions.
conditions. Recently, advancements have been made in the
development of metal-free methods for the cleavage of C-C
bonds13 or transformation of C-C bonds to reactive bonds.14a
Since Beckham and co-workers discovered that the oxidation
of α-hydroxyl of β-O-4 linkages to ketone would facilitate the
cleavage of Cβ-O bond due to the reduction of the dissociation
energy of the Cβ-O bond from 69.2 kcal mol-1 to 55.9 kcal mol-
1 15
,
various effective strategies have been developed for the
-O-4 lignin model compounds
and degradation of oxidized lignin.10b,14 By using the oxidized
-O-4 lignin model with a lower dissociation energy of the C-O
oxidation of α-hydroxyl of
β
β
Recently, Fu and co-workers produced aromatic amines and
N-doped carbon from the pyrolysis of lignin with ammonia
over zeolite catalysts.17a We envisioned that if lignin could be
degraded to N-containing aromatics, it will greatly expand the
utility of lignin. As we know, ketones could react with
hydroxylamine hydrochloride to prepare oximes, a useful and
important N-containing key intermediates in the generation of
nitriles via dehydration and amides via Beckmann rearrangement
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methoxyphenoxy)acetate, sodium borohydride, inorganic salts
and solvents were purchased from Titan. All chemicals were
used as received unless otherwise specified as follows. THF
was dried over sodium/potassium alloy distilled under
nitrogen atmosphere prior to use for the synthesis of lignin
model compound Fox. CH3CN was dried over calcium hydride
distilled under nitrogen atmosphere prior to use for Beckmann
The oxidized lignin model compounds Aox
27a
rearrangement
Cox
.
,
Box
,
,
Dox
,
Eox
,
and Fox were prepared according
27a
27a
27a
27b
16a
to literature procedures.
General procedure for the synthesis of ligninoxime
To a solution of mixture of lignin model compound (10
mmol) in EtOH:H2O (1:3, 80 ml) was added NH2OH·HCl (15
mmol, 1.5 eq.), NaOAc·3H2O (25 mmol, 2.5 eq.) at room
temperature. The mixture was heated to reflux for respective
time. After the reaction, the mixture was extracted with ethyl
acetate for three times and washed with saturated brine. The
organic phase was dried by anhydrous magnesium sulfate. The
solvent was removed under reduced pressure. The product
was purified on silica gel with EtOAc:petroleum ether to
provide a mixture of Z and E isomers.
(BR).25,26 Inspired by our previous successful example
, we
General procedure for the Beckmann rearrangement reaction
Oxime (Aoxime Foxime) (0.1 mmol) was added to a 5 ml round
-
envisioned that the application of the BR reaction to the
ketone form, oxidized lignin model compounds, should lead to
the production of N-substituted aromatics. Here we
represented the preparation of N-containing aromatics from
the highly effective transformation of the C-C bonds in the
oxidized lignin model compounds to reactive C-N bonds via the
oxime formation followed by BR reaction and hydrolysis (Scheme
1). It is noted that the employment of a substrate with a γ-OH
group will lead to the formation of C-2 monosubstituted oxazole.
Moreover, a simplified, one-pot process of BR reaction and
hydrolysis would produce an up to 96% total yield of
bottom flask equipped with a magnetic stirring bar. A solution
of SOCl2 (0.5 eq.) in dry CH3CN 0.5ml was subsequently added
dropwise at 80 °C. The mixture was stirred at 80 °C. After the
reaction, it was quenched by saturated sodium bicarbonate
solution. Using methanol, the mixture was dissolved to
constant volume in a 25 ml volumetric flask and then filtered.
The filtrate was measured by HPLC.
General procedure for hydrolysis of amides
Amide dimer (ABR FBR) (0.1 mmol) was added to a 5 ml
-
benzonitriles, benzamides, and anilines. The reaction mechanism
of BR reaction was also included into this study.
round bottom flask equipped with a magnetic stirring bar. And
then 2M NaOH aq. (0.5 ml) and EtOH (0.5 ml) were
subsequently added with a syringe. The mixture was stirred at
80°C. After the reaction, using methanol, the mixture was
dissolved to constant volume in a 25 ml volumetric flask and
then filtered. The filtrate was measured by HPLC.
Experimental
Materials and methods
All syntheses and manipulations of air- and moisture-
sensitive materials were carried out in flamed Schlenk-type
glassware on a dual-manifold Schlenk line, a high-vacuum line,
or an argon-filled glove box. NMR spectra were recorded on a
General procedure for one-pot process of BR and hydrolysis
Oxime (Aoxime Foxime) (0.1 mmol) was added to a 5 ml round
-
Bruker Avance II 500 (500 MHz, H; 126 MHz, 13C) instrument
1
at room temperature (RT). Chemical shifts for 1H and 13C
spectra were referenced to internal solvent resonances and
were reported as parts per million relative to SiMe4.
bottom flask equipped with a magnetic stirring bar. A solution
of SOCl2 (0.5 eq.) in dry CH3CN 0.5ml was subsequently added
dropwise with a syringe at 80 °C. The mixture was stirred for 2
min at 80 °C. And then 2M NaOH aq. (0.5 ml) and EtOH 0.5 ml
were subsequently added with a syringe. The mixture was
continued to stir for 2 h at 80 °C. After the reaction, using
methanol, the mixture was dissolved to constant volume in a
25 ml volumetric flask and then filtered. The filtrate was
measured by HPLC.
2-Bromoacetophenone, guaiacol, diisopropylamine, n-BuLi
(1.6 M solution in hexane), 3,4-dimethoxybenzaldehyde, 2-
bromo-4’-methoxyacetophenone,
and
the
standard
substances benzonitrile (aa1), 4-methoxybenzonitrile (aa2),
3,4-dimethoxybenzonitrile (aa3), benzamide (ab1), and 4-
methoxybenzamide
(
ab2), aniline
ac2), 3,4-dimethoxyaniline ac3), phenol
ba2), 2-phenoxyacetic acid, and 2-(2-
(
ac1), 4-methoxyaniline
(
(
(ba1), 2-
Product analysis
methoxyphenol
(
Reactions were monitored by thin layer chromatography
(TLC) visualizing with ultraviolet light (UV); column
methoxyphenoxy)acetic acid were purchased from J&K.
NH2OH·HCl, NaOAc·3H2O, 4-acetamido-TEMPO, ethyl (2-
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the X-ray single crystal structure analysis (Figure 1a) and 1H NMR
chromatography purifications were carried out using silica gel.
The reaction mixture was analyzed referred to the standard
spectrum (Figure 1b). The selectivity of E- and Z-ligninoxime was
curves of standards using Waters make High Performance determined by their corresponding integral of β-H group in 1H NMR
Liquid Chromatograph (HPLC) system equipped with
autosampler, C18 column (Length: 150mm, Internal diameter:
4.6mm, 35 °C) and UV/Vis detector (λ = 220 nm). CH3OH: H2O
(45:55 or 25:75) was used as a mobile phase with a flow rate of
1.0 ml/min. Mass spectra were recorded on the Bruker
MicroTOF Q II.
spectra (Figure 1c). For most simple, oxidized
β-O-4 lignin
model compound Aox, 98% isolated yield of Aoxime was
obtained in the mixture of 23% E-Aoxime and 77% Z-Aoxime
within 1 h (entry 1, Table 1). For Box with o-methoxyl
substituent on ether benzene, 96% of Boxime is produced with
25% E-Boxime and 75% of Z-Boxime (entry 2, Table 1). 98% and 95%
isolated yields of Coxime and Doxime were achieved for Cox and
Dox, respectively (entries 3 and 4, Table 1). Moreover, 93%
yield of Eoxime was also easily prepared with 12% E-Aoxime and
88% Z-Aoxime from lignin model Eox (entry 5, Table 1). It worth
Results and discussion
The synthesis of ligninoxime
. In general, an oxime can be easily
prepared from the nucleophilic addition of an aldehyde or a
ketone with hydroxylamine, such as hydroxylamine
hydrochloride (NH2OH·HCl), along with the acid-binding
agents.28 If the aryloxide group (blue) is on the same side with the
hydroxyl group of the oxime, it is defined as Z-oxime, and vice
noting that for Fox with a
γ-OH group, an excellent 97% isolated
yield of Foxime was obtained but with the much enhanced 46%
yield of E-Foxime and reduced 54% yield of Z-Foxime (entry 6,
Table 1). The varying of the acid-binding agents, solvents and
temperature only exhibited slight impact on the selectivity of
E- and Z-ligninoxime (Table S1). Moreover, many attempts to
separate E- and Z-type ligninoxime by column chromatography
were also unsuccessful. Therefore, after purification with flash
column chromatography, the mixture of both E- and Z-type
ligninoxime was directly used for next step.
versa it is defined as E-oxime. The substituents on the carbonyl
group will affect the yield of E-oxime and Z-oxime.
We initiated our study for the preparation of ligninoxime by
using oxidized lignin models (Aox
-
Fox) as substrates. The
overall performance is excellent and over 93% isolated yield of
ligninoxime is obtained in the mixture of E- and Z-ligninoxime
(Table 1). The molecular structure of Z-type Foxime is confirmed by
The BR reaction of ligninoxime The high-yield of ligninoxime
.
enabled us to further investigate the application of the BR
reaction in the degradation of lignin model compounds. During
BR reaction, the rearrangement of the hydroxyl group with the
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substituent residing on its anti-position converted oximes to product), and polyphosphoric acid, is generally required for
amide derivatives in presence of various acids,26,29 which could conventional BR reaction.26 However, these strong protonic
be further transformed to corresponding carboxylic acids and acids can easily hydrolyze oxime back to ketone. From economy
amines by means of hydrolysis. The BR reaction of Z-ligninoxime and safety prospective, thionyl chloride (SOCl2) and phosphorus
will lead to the formation of corresponding ligninBR (Scheme pentachloride (PCl5) are more commonly used. We examined
2a); while for E-ligninoxime, abnormal BR reaction pathway is the efficacy of both SOCl2 and PCl5 for the BR reaction of
adopted and produces benzonitrile (aa) and phenol (ba
)
ligninoxime (Table S2). It turned out that SOCl2 exhibited better
product (Scheme 2b) due to the existence of strong electron- performance and thus was chosen for the following
donating trans- OH group, which enabled the stabilization of investigation (Table 2). It should be noted that benzonitriles
the carbenium ions and thus adopting an abnormal BR
(aa) and phenols (ba) are produced from the BR reaction of E-
reaction pathway to generate the corresponding nitrile (see ligninoxime, while amides ligninBR are obtained from the BR
26
.
mechanism, vide infra)
reaction of Z-ligninoxime. When Aoxime is used as substrate, a
High temperature and large amounts of strongly acid, such 96% total yield of N-substituted products was obtained with 33%
as concentrated H2SO4 (leading to ammonium sulfate by- yield of benzonitrile (aa1) and 63% yield of amide ABR along
with 27% yield of phenol (ba1) at 80 °C for only 2 min,
respectively (entry 1, Table 2). While high total yield of N-
substituted product was also obtained for the mono-methoxy-
substituted Boxime (94%: 36% of aa1 and 58% of BBR) and Coxime
(89%: 20% of aa2 and 69% of CBR) (entries 2 and 3, Table 2). In
presence of more methoxy substituents on benzene rings, a
slightly reduced total yield of N-substituted product was
obtained for Doxime (86%: 26% of aa2 and 60% of DBR) and Eoxime
(81%: 12% of aa3 and 69% of EBR) (entries 4 and 5, Table 2).
Interestingly, for Foxime with a
γ-OH group, the BR reaction
afforded an N-heterocyclic compound in addition to above
mentioned cleavage products due to the presence of
nucleophilic γ-OH group (see mechanism, vide infra). On one
hand, Z-Foxime was converted to amide FBR in 28% yield via BR
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reaction; on the other hand, E-Foxime was transformed to 3,4- and sodium carboxylate bb1 in 94% yield (entry 1, Table 3). Likewise,
dimethoxybenzonitrile (aa3) in 18% yield, 2-methoxyphenol this condition was also applied to the other amides (BBR - EBR), and
(
ba2) in 52% yield along with 29% yield of N-heterocyclic over 92% yield of anilines were achieved for all ligninBR (entries 2-5,
compound 2-(3,4-dimethoxyphenyl)oxazole (aa3’) after BR Table 3). It should be noted that γ-OH group did not affect the
reaction (entry 6, Table 2). As an important class of hydrolysis of FBR, but prolonged reaction time of 2 h is required to
heterocycle exhibiting diverse biological activities 30
C-2 achieve 92% yield of 3,4-dimethoxyaniline (ac3) and 90% yield of
,
monosubstituted oxazoles is very important synthetic carboxylate bb3
.
intermediates for the synthesis of natural products and
pharmaceuticals. However, the application of C2-substituted
One-pot process of BR and hydrolysis. As seen from the above
oxazoles in the synthetic chemistry was limited due to the lack discussion, we succeeded in the production of N-substituted
of practical preparation methods.30 Moreover, we noticed that aromatics and phenol products from the multiple-step degradation
the total yields of benzonitriles and phenols were actually of oxidized lignin model compounds. For economic reason, we
higher than the amount of E-ligninoxime obtained from the simplified this procedure and carried out both BR reaction and
oxidized lignin model compounds, which might be ascribed to hydrolysis in a one-pot process (Table 4). Taking Aoxime as example,
the partial inversion between E- and Z-ligninoxime during the once the BR reaction was completed, sodium hydroxide solution
destruction of intramolecular hydrogen bond under acidic and ethanol were directly added to the above mixture and then
condition.31
stirred at 80 °C for 2h, affording aniline ac1 in 64% yield and sodium
carboxylate bb1 in 59% yield along with 4% amides product ABR
,
The hydrolysis of ligninBR. After achieving successful BR reaction while the abnomal BR reaction produced benzamide (ab1) in 25%
of ligninoxime, we turned our focus on the cleavage of C-N bond in yield and phenol (ba1) in 28% yield along with 7% yield of
the amide ABR to FBR. It is well known that the amide bonds in the benzonitrile aa1 (Table 4, entry 1). Therefore, a 96% total yield of
polyamides are degradable and could be easily hydrolized to N-substituted aromatics was obtained for Aoxime (ligninBR was not
corresponding anilines and carboxylic acids in high yield in the counted). Compared to the multiple-step process, the drastically
presence of strong base. Our study also indicated that the amide reduced amount of aa1 might be attributed to the hydrolysis of aa1
bonds in the ligninBR can be hydrolyzed in the presence of sodium to ab1 under alkaline condition, which could be verified by control
hydroxide solution at 80 °C. As shown in Table 3, it took amide ABR experiment (Scheme S1). It should be noted that neither aa1 nor
30 min to complete hydrolysis to afford aniline (ac1) in 95% yield ABR could reach complete hydrolysis in such one-pot process, no
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Scheme 3. Possible mechanism of BR reaction.
26
c
matter how we changed the reaction time, temperature, or the Route
c
,
which could be further converted to an
e
amount of alkali (Table S3). Similar results was also achieved for the oxycarbenium ion VIII, a precursor for the 2-oxazole (aa’). 19
one-pot process involving BR and hydrolysis of Boxime to Eoxime
,
producing benzamides, phenols, anilines, and carboxylic acids in up
to 95% total yield of the N-substituted product) (entries 2-5, Table
4). For Foxime with a γ-OH group, a 61% total yield of the N-
substituted product was obtained (entry 6, Table 4).
Conclusions
In this study, we developed a highly effective method for
preparation of N-substituted aromatics from the degradation
of oxidized lignin model compounds via oxime formation,
followed by Beckmann rearrangement. In this strategy,
NH2OH·HCl reacts with carbonyl group of the oxidized lignin
model compound to form the mixture of Z/E ligninoxime. In the
Possible mechanism for BR reaction. We proposed a plausible
mechanism for the BR reaction of ligninoxime as shown in
Scheme 3. For Z-ligninoxime, the sulfate ester intermediate
I is
presence of acid catalyst, the Z-ligninoxime with or without
γ-OH
rearranged to generate amide product via BR reaction, which
rapidly generated from the reaction of SOCl2 with the hydroxyl
group of oxime by eliminating hydrogen chloride molecule,32
which is subsequently protonated to generate intermediate
could be hydrolyzed to anilines (> 92%) and carboxylic acids (>
90%). For E-ligninoxime without
γ
-OH, nitriles and phenols were
obtained via abnormal BR reaction (Route , Scheme 3B) and
BR reaction (Route
, Scheme 3B); while for E-ligninoxime with
OH, C-2 substituted oxazole was also available, except for
nitriles and phenols (Route , Scheme 3B). In a one-pot process
II 32
position of hydroxyl group, a nitrilium ion III is formed, which is
the contribution structure of the carbenium intermediate IV 17
The attack of the carbenium intermediate IV with water led to
the formation of intermediate . After the elimination of
.
After the migration of substituent located at the anti
a
b
γ-
.
c
V
of BR and hydrolysis, we could achieve up to 96% total yield of
N-substituted aromatics, including benzonitriles, benzamides
(from hydrolysis of benzonitriles) and anilines. This strategy
enabled us not only to achieve the highly effective cleavage of
C-C bond in oxidized lignin model compounds, but also
synthesize various N-substituted aromatic compounds, which
should expand the application of lignin chemistry. To realize
the true “green chemistry” process, it is our next goal to
hydrogen chloride molecule and followed by isomerization,
amide ligninBR is obtained (Scheme 3A).26 On the other hand, E-
ligninoxime proceeds with three different reaction paths
(Scheme 3B). Just like Z-ligninoxime, the reaction of SOCl2 with
the hydroxyl group of E-ligninoxime rapidly generated sulfate
ester intermediate I’, with the release of hydrogen chloride,32
which was protonated to afford an intermediate II’ afterwards.
If there existed strong electron-donating group on the trans- develop
a recyclable catalyst system containing sulfonyl
chloride for the BR reaction. Applied this method in the
degradation of real lignin currently is under way.
OH group of oxime, abnormal BR reaction would occur along
the Route since it could stabilize the carbeniums, and thus
yielding stable nitrile26,33 and oxonium ion VI 34
which could be
a
,
further converted to intermediate VI’, and then to phenol
product. While for BR reaction, nitrilium ion III’ and its
resonance structure IV’ were formed after the migration of the
substituent located at the opposite position of hydroxyl group.
For nitrilium ion III’, the nitrile was also liberated by the
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
cleavage of Cβ-N bond by β-O lone pair as shown in Route
whereas for intermediate IV’, the attack of carbenium by the
nucleophilic -OH group resulted in a small tension and thus
b;
This work was supported by the National Natural Science
Foundation of China (Grant no. 21422401, 21374040,
21774042), 1000 Young Talent Plan of China funds, the startup
funds from Jilin University, Talents Fund of Jilin Province.
γ
generated a stable five-membered heterocycle VII as shown in
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