Efficient demethylation of aromatic methyl ethers with HCl in water

Article abstract of DOI:10.1039/d0gc04268d

A green, efficient and cheap demethylation reaction of aromatic methyl ethers with mineral acid (HCl or H₂SO₄) as a catalyst in high temperature pressurized water provided the corresponding aromatic alcohols (phenols, catechols, pyrogallols) in high yield. 4-Propylguaiacol was chosen as a model, given the various applications of the 4-propylcatechol reaction product. This demethylation reaction could be easily scaled and biorenewable 4-propylguaiacol from wood and clove oil could also be applied as a feedstock. Greenness of the developed methodversusstate-of-the-art demethylation reactions was assessed by performing a quantitative and qualitative Green Metrics analysis. Versatility of the method was shown on a variety of aromatic methyl ethers containing (biorenewable) substrates, yielding up to 99% of the corresponding aromatic alcohols, in most cases just requiring simple extraction as work-up.

Full text of DOI:10.1039/d0gc04268d

Volume 23
Number 5
7 March 2021
Pages 1885-2186
Green
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PAPER
Bert U. W. Maes et al.
Efficient demethylation of aromatic methyl ethers with HCl
in water

Green Chemistry
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Efficient demethylation of aromatic methyl ethers
with HCl in water†
Cite this: Green Chem., 2021, 23,
1995
a
Jeroen Bomon, a Mathias Bal, a Tapas Kumar Achar,a Sergey Sergeyev,
Xian Wu,b Ben Wambacq,b Filip Lemière,a Bert F. Sels b and Bert U. W. Maes
*
a
A green, efficient and cheap demethylation reaction of aromatic methyl ethers with mineral acid (HCl or
H2SO4) as a catalyst in high temperature pressurized water provided the corresponding aromatic alcohols
(phenols, catechols, pyrogallols) in high yield. 4-Propylguaiacol was chosen as a model, given the various
applications of the 4-propylcatechol reaction product. This demethylation reaction could be easily scaled
and biorenewable 4-propylguaiacol from wood and clove oil could also be applied as a feedstock.
Greenness of the developed method versus state-of-the-art demethylation reactions was assessed by
performing a quantitative and qualitative Green Metrics analysis. Versatility of the method was shown on a
variety of aromatic methyl ethers containing (biorenewable) substrates, yielding up to 99% of the corres-
ponding aromatic alcohols, in most cases just requiring simple extraction as work-up.
Received 17th December 2020,
Accepted 27th January 2021
DOI: 10.1039/d0gc04268d
rsc.li/greenchem
sition and structure, many different strategies toward its depo-
lymerization have been reported, mainly producing variable
Introduction
Following the transition of a fossil toward a more sustainable mixtures of para-substituted guaiacol and syringol derivatives
bio-based economy, the biorefinery concept, requiring the which are difficult to process further.15–23 Therefore, lignin is
valorization of each component of a biorenewable feedstock, currently used in existing biorefineries as energy feedstock.
has attracted a lot of interest.1–3 The use of lignocellulose, the Though, because of its polyphenolic structure and its large
world’s most abundant organic material, has been extensively abundance in nature, lignin can be considered as renewable
studied in this context and (hemi)cellulose derived products feedstock for the production of aromatic compounds, provided
have already found some mature applications in industry.4–6 that the conversion of its intricate and reactive structure to a
However, studies toward the valorization of lignin, for other handful of chemicals can be realized effectively and
applications than energy generation, are not self-evident and economically.24–27 Recent advances in biorefinery technologies
immature.7–10 This renewable polymeric structure, comprising that focus on in planta lignin conversion, also called lignin-
15–30% of the dry weight of woody biomass, contains elec- first approaches, have demonstrated high yields of phenolic
tron-rich alkoxy-substituted arenes, and is therefore the largest monomers. For example, reductive catalytic fractionation
source of biorenewable aromatic compounds on the Earth. It (RCF) of birch wood, using Ru catalysis under a hydrogen
can be considered as a cross-linked polyphenolic, consisting of pressure, delivers a mixture mainly consisting of 4-propyl-
three main building blocks sinapyl (S), coniferyl (G) and para- guaiacol (1a) and 4-propylsyringol (1b) in a 20 : 80 ratio with a
coumaryl (H) alcohols, called monolignols, among others, total monomer yield up to 50% (carbon yield), representing
which are connected with specific C–O and C–C interlinkages. more than 50 wt% of the original lignin content.28–41
The relative occurrence of these monolignols and their inter- Treatment of pine sawdust under the same conditions gave a
linkages is mainly plant dependent.11–13 Lignin is an essential lignin oil consisting for more than 80% of 1a in an amount
component of the plant cell wall, where it endows the plant corresponding to 12 wt% of the original lignin content.
with rigidity and resistance to biotic and abiotic environ- Alternatively, compound 1a can be obtained upon reduction of
mental stress and easy rotting.14 Given its complex compo- eugenol (3), extracted from clove.42–44 The aryl methyl ether
functionalities are typically retained in these reductive depoly-
merizations of lignin and in the hydrogenation of eugenol (3).
Therefore, an efficient, cheap and green O-demethylation
method unlocking catechol and pyrogallol moieties from these
aDepartment of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020
Antwerp, Belgium. E-mail: bert.maes@uantwerpen.be
bCenter for Sustainable Catalysis and Engineering, KU Leuven, Celestijnenlaan 200F,
compounds is highly looked for in order to allow further deri-
B-3001 Leuven, Belgium
vatization toward specific target compounds (Scheme 1).45 The
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0gc04268d
obtained products can serve as a new platform toward the pro-
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Scheme 1 O-Demethylation of biorenewable 4-propylguaiacol (1a) and 4-propylsyringol (1b).
duction of aromatic chemicals, from which other useful end After all, 4-propylcatechol (2a) is known as a precursor for a
products and materials can be synthesized.7,10,16,46,47
variety of applications, as shown in Scheme 2. For example, it
In this paper, 4-propylguaiacol (1a), which can be derived has been described in the literature for the production of new
from lignin32,34–36,38,40,41 or eugenol42,43 (clove), is selected as bio-based epoxy thermoplastics (Scheme 2(a)), either via direct
a model substrate for O-demethylation reaction development. alkylation of the phenolic OH groups with epichlorohydrin,
Scheme 2 Applications of 4-propylcatechol (2a): synthesis of (a) monomers for materials, (b) agrochemicals and pharmaceuticals, (c) fragrances,
and (d) a new C1 reactant.48–53,57,58
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followed by cross-linking,48,49 or via similar functionalization double O-alkylation (Scheme 2(c)).57 Finally, 2a has also been
of a triarylmethane core 5, obtained through condensation of used to produce a new shelf stable C1 reactant with 100%
2a with renewable benzaldehydes 4.50 Recently, we have shown renewable carbon, i.e. 4-propylcatechol carbonate
9
that this compound 2a can be transformed into 3,4-dialkoxya- (Scheme 2(d)). This stable phosgene replacing C1 reactant has
nilines 7, which serve as starting point for the synthesis of been applied for carbamate synthesis, via consecutive reaction
anti-cancer medicine erlotinib and agrochemical diethofen- with alcohols and amines, allowing easy recycling of by-
carb (Scheme 2(b)).51,52 Synthesis of 3,4-dialkoxyanilines 7 product 2a.58 9 is synthesized from 2a via transesterification
from 2a involves O-alkylation followed by C-propylation with with dimethyl carbonate, derived from CO2, employing reactive
concomitant amino group introduction.53 Currently, insecti- distillation.
cide synergist piperonyl butoxide (PBO) is made via reduction
of safrole, a natural product from Sassafras plants.54,55
Despite the vast literature on the cleavage of aromatic
methyl ethers, most of them are not applicable to large scale
A
cheaper route is starting from catechol, through benzodioxole synthesis as they employ (super)stoichiometric reagents in
formation and subsequent Friedel–Crafts propanoylation, fol- undesired solvents.59,60 The most commonly used solvents for
lowed by ketone reduction.56 Though not described yet, the this type of reaction are reported in Fig. 1(b), together with
acetalization of catechol can also be applied on 4-propylcate- their classification in the CHEM21 Solvent Selection Guide,61
chol giving direct access to dihydrosafrole (8) (Scheme 2(b)), showing that none of these are classified as ‘recommended’.
which can be converted to PBO using paraformaldehyde (PFA), This ranking system is based on safety (flash point, auto
HCl and 2-(2-n-butoxyethoxy)ethan-1-ol.54 Fragrance Aldolone ignition temperature, H2xx), health (H3xx) and environmental
can be synthesized from 4-propylcatechol (2a) via double alkyl- (boiling point, REACH registration, H4xx) criteria of the sol-
ation with 1,3-dichloroacetone or other strategies involving vents. Classical reagents for the cleavage of aryl methyl ethers
Fig. 1 An overview of commonly used demethylating agents (a). Generally, they are used in one of the solvents mentioned in part (b). For these
reagents and solvents, their classification as ‘(highly) hazardous’, ‘problematic’ or ‘recommended’ is based on the CHEM21 (solvent) guide.61,83
Specifications of the new method are summarized in part (c). a Bulk chemicals: Prices for import/export based on data found on Zauba.com
retrieved in October 2020. b Research chemicals: Prices based on data from Merck (largest batch available) retrieved in October 2020.
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can be classified in different categories, according to their cular weight and thereby generate more waste, negatively influ-
function in this reaction, i.e. nucleophile, Brønsted acid, Lewis encing the most important quantitative metrics, i.e. process
acid or heterogeneous catalyst (Fig. 1(a)). As a first category (i), mass intensity (PMI) (vide infra). In addition, all reagents in
demethylation can be performed using nucleophilic reagents, Fig. 1 are used in (super)stoichiometric amount and even then
with alkanethiols as the most important representatives. These incomplete conversion of the substrate is not uncommon.
can be employed as alkanethiolates or -thiols, where in the Moreover, column chromatography is often used to isolate the
latter case a (super)stoichiometric base will be added to gene- target compound. Finally, layered Nb2O5, a heterogeneous
rate the thiolate in situ. For example, sodium ethanethiolate catalyst (iv), has been used for O-demethylation in hot pressur-
(EtSNa) is suitable to demethylate electron rich anisole deriva- ized water.81 The method has only been shown on 4-propyl-
tives.62 However, the formed ethyl methyl sulfide by-product guaiacol (1a) and no work-up and isolated yield (GC analysis)
generates an unpleasant odour, which can be circumvented by has been reported.
using a less volatile thiol reagent, such as DodSH,63 or 2-(di-
Developing a general method to demethylate aryl methyl
ethylamino)ethanethiol,64 both in combination with a base. 2- ethers to unlock phenol, catechol and pyrogallol moieties from
(Diethylamino)ethanethiol is interesting as both the methyl the corresponding methyl ethers using a catalytic amount of a
thioether by-product as well as the excess thiol reactant can be recommended reagent in a preferred solvent producing a low
easily removed by aqueous acid extraction. Unfortunately, it amount of non-harmful waste (avoiding resource intensive
was only applied on substrates bearing electron withdrawing column chromatography) is of huge interest in the context of
groups on anisole.64 Apart from thiol reagents, sodium green chemistry. HCl is a suitable candidate, since it is cheap,
cyanide was used for the demethylation of a variety of anisole recommended by the CHEM21 Metrics and features a low
derivatives substituted with different functional groups, molecular weight (Fig. 1(c)). The combination of HCl and
though not including electron donating ones.65 Given the water, the most sustainable solvent, looks very attractive. The
specific safety aspects related to this chemical requiring the expected by-product methanol is easy to remove and an impor-
use of specific equipment and handling, its use is not desired. tant bulk chemical.82 However, HCl is not strong enough to
Also LiBr and LiCl are known to behave as demethylating effectively protonate anisole derivatives, in contrast to the
agents.66,67 In a second category (ii), Brønsted acids are used more expensive and problematic HBr and HI.
for demethylation. Here, a strong acid is required to protonate
Recently, we reported on the transformation of ferulic acid
the ether functionality, after which a weak nucleophile from into catechol employing acid (HCl or H2SO4) in hot pressur-
the environment (i.e. conjugated base of acid) performs the ized water.84 This transformation comprises two consecutive
actual cleavage. The use of strong inorganic acids aq. HBr,49,68 defunctionalizations of the substrate, i.e. C–C (de-2-carboxyvi-
and aq. HI69 is common. Chemically, HI is a very suitable nylation) and C–O (demethylation) bond cleavage, occurring in
Brønsted acid as it has one of the lowest pKA of all mineral one step. The acid, its concentration and the reaction tempera-
acids. It is either used as such,69 or generated in situ from ture proved crucial to achieve high selectivity and yield, avoid-
iodocyclohexane in refluxing DMF, the latter successfully de- ing tar formation. We wondered whether these reaction con-
methylating guaiacol in 91% yield.70 Strong organic acids, ditions could be further optimized to provide a general proto-
such as HOTf and TFA, have also been applied.71,72 In col for the O-demethylation of anisole derivatives, with 4-pro-
addition, also salts based on the combination of a strong acid pylguaiacol (1a) as the model substrate.
and a weak base have been described for demethylation, as
exemplified by pyridinium chloride (Py·HCl). This has been
used for the solventless demethylation of 4-methoxyphenylbu-
Results and discussion
Reaction optimization
tyric acid at elevated temperature, even on pilot scale.73 In this
case, pyridine’s nitrogen atom acts as a nucleophile in an SN2
reaction after the substrate has been activated by the present Application of the reactions conditions developed for ferulic
HCl. Substrates unsuited for use under (strong) Brønsted acid defunctionalization [0.13 M in H2O, 50 mol% HCl,
acidic conditions can be activated with a Lewis acid (iii), after 250 °C, 50 bar N2, 3 h] on 4-propylguaiacol (1a) yielded 97%
which the actual cleavage can occur with the aid of a weak 4-propylcatechol (2a) (Table 1, entry 1).84 The low substrate
nucleophile. Often a second reagent is added for this purpose. concentration (0.13 M) and relatively high catalyst loading
BBr3 and TMSI, both in halogenated solvent, are widely used (50 mol%) are drawbacks for scaling. Gratifyingly, raising the
as sole reagents,74–76 while AlCl3 is typically employed in the substrate concentration to 0.50 M or 1.0 M did not signifi-
presence of a second reagent, e.g. NaI or Me2S.77–79 Also the cantly affect the yield (entries 2 and 3). However, at 2.0 M, a
combination of cat. Cu2O and an excess of NaOMe has been 33% decrease in yield, caused by unselective side reactions
described.80 Most of these Lewis acids react violently with giving tar, was observed (entry 4). Interestingly, this could be
water and therefore dry conditions and an inert atmosphere overcome by decreasing the reaction time to 1 h, leading to a
are required. Most of these classical reagents are classified as yield of 91% (entry 5). HCl loading could be decreased to
‘hazardous’ or ‘problematic’ based on the CHEM21 Metrics 20 mol% at 0.5 M, still achieving quantitative conversion to
(Fig. 1, top) with the exception of 2-(diethylamino)ethanethiol the desired product 2a (entry 6), which was still possible with
and Py·HCl. However, these two reagents feature a high mole- double the substrate concentration (entry 8). Even the use of
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product obtained in lignin biorefinery,34,35,38,40,41 gave 74% of
5-propylpyrogallol (2b). However, a lower substrate concen-
tration was required to suppress side product formation
(4-methyl-5-propylpyrogallol, see ESI†). Next, 4-propylveratrole
(1e), containing two methoxy groups, and its O-ethylated
counterpart (1f) delivered 4-propylcatechol (2a) in 91% yield,
proving that our methodology also enables cleavage of aryl
ethyl ethers, albeit with doubling of the reaction time. Several
modifications in the alkyl side chain were allowed without
affecting the pursued reactivity. For example, 4-ethylguaiacol
(1c), also obtained from lignin biorefinery,85–88 delivered the
expected 4-ethylcatechol (2c) in 90% yield. Similar obser-
vations could be made for 4-methylguaiacol (1d) and dihydro-
ferulic acid (1g), leading to their corresponding
O-demethylated counterparts (2d–2e) in 99% and 85% yield,
respectively. Also in the latter case, the presence of a second
methoxy functionality, i.e. O-methyl-dihydroferulic acid, did
not significantly affect the product yield (86% 2e). From piper-
onal (1i), featuring a methylene acetal of catechol, protocate-
chuic aldehyde (2f) was produced in 62% yield, even without
the addition of an acidic catalyst. Next, our attention switched
to C-unsubstituted molecules delivering dihydroxybenzenes.
Guaiacol (1l), veratrole (1m) and O-ethyl guaiacol (1n) delivered
catechol (2i) in high (89–98%) yield. Two isomers of veratrole,
p- (1o) and m- (1p) dimethoxybenzene, delivered hydroquinone
(2j) and resorcinol (2k) in a yield of 98% and 82%, respectively.
Anisole (1q), the smallest molecule used in this study, formed
phenol (2l) in 62% yield; the decrease in yield probably due to
the applied work-up because of azeotrope formation of phenol
and water and the required extraction with the organic
solvent,89,90 allowing for product loss, which was not observed
during O-demethylation of 2,4,6-trichloroanisole (1r), known
for causing cork taint in wine,91 delivering 2,4,6-trichlorophe-
nol (2m), possessing agrochemical activity,91 in 95% yield.
Other substituted anisoles, 4-methoxyphenylacetone (1s)
(found in anise oil as the oxidation product of the major oil
constituents)92 and 4-(4-methoxyphenyl)butan-2-one (1t), deli-
vered products 2n and 2o in 80% and 94% yield, respectively.
The latter product 2o is raspberry ketone and can be found in
several fruits, e.g. cranberry and blackberry, and is widely used
in the perfume industry, cosmetics or as a food additive.93
Finally, O-demethylation of APIs was tested. Nonsteroidal anti-
inflammatory drug naproxen (1u) could be O-demethylated
quantitatively.94 The temperature had to be lowered to 200 °C
to avoid benzylic decarboxylation. Interestingly, donepezil
hydrochloride (1j), a cholinesterase inhibitor used for the
treatment of Alzheimer’s disease,95 and 5,6-dimethoxy-2,3-
dihydro-1H-inden-1-one (1k), a known precursor in its syn-
thesis,96 could both be demethylated successfully in 42% and
79% yield, respectively, leaving the 2,3-dihydro-1H-inden-1-one
core and, in the case of 1j, the N-benzyl moiety unaffected.
Interestingly, 1k can also be obtained from lignin-derived dihy-
droconiferyl alcohol with dihydroferulic acid (1g) as the inter-
Table 1 Selected optimization data for the O-demethylation of 4-pro-
pylguaiacol (1a) into 4-propylcatechol (2a)
Yielda (%)
Conc.
Acid
Temp. Time
Entry 1a (M) (mol%)
pKa
(°C)
(h)
1a
2a
1
2
3
4
5
6
7
8
0.13
0.50
1.00
2.00
2.00
0.50
0.50
1.00
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
HCl (50)
HCl (50)
HCl (50)
HCl (50)
HCl (50)
HCl (20)
—
HCl (20)
HCl (10)
HCl (10)
HCl (20)
HCl (20)
HCl (20)
FeCl3 (20)
H2SO4 (20)
H2SO4 (20)
−7.0 250
−7.0 250
−7.0 250
−7.0 250
−7.0 250
−7.0 250
−7.0 250
−7.0 250
−7.0 250
−7.0 250
−7.0 225
−7.0 200
−7.0 185
3
3
3
3
1
3
3
3
3
6
3
3
3
3
3
6
3
3
3
0
0
0
0
0
0
100
0
5
<1
23
97
100
0
6
0
<1
70
100
97
97
92
64b
91 (91c)
100 (97c)
0
95 (96c)
9
90
10
11
12
13
14
15
16
17
18
19
99 (95c)
77
3
0
n/a
250
100
94
−3.0 250
−3.0 250
97 (97c)
89
H2SO4 (100) −3.0 250
H3PO4 (20)
HOAc (20)
2.2
4.8
250
250
30
0
Reaction conditions: Amount (0.4–6.0 mmol) 1a in H2O (3.0 mL) to
achieve the given concentration. a 1H NMR yield determined with
dimethyl sulfone as the internal standard. b Low mass balance due to
tar formation. c Yield of the isolated product.
10 mol% HCl led to 95% conversion and 90% yield (entry 9),
which could be pushed further to essentially full conversion by
prolonging the reaction time (entry 10). For comparison, we
showed that subcritical water, without the addition of an
acidic catalyst, is not able to O-demethylate 1a (entry 7).
Conversion of substrate 1a diminished with decreasing reac-
tion temperature, since at 225 °C, 77% 2a (entry 11) and at
200 °C, only 3% 2a were observed (entry 12), in both cases
leaving the remaining substrate unaffected, while at 185 °C,
substrate 1a could even be fully recovered (entry 13). It was
found that HCl could be successfully replaced by Lewis acid
FeCl3 leading to the quantitative conversion of 1a into 2a
(entry 14), presumably by in situ HCl generation. Also the use
of H2SO4 (entry 15) led to the desired product 2a in 94% yield.
Full conversion with this acid could be achieved by increasing
the reaction time (entry 16) or increasing acid loading to stoi-
chiometric quantity (entry 17), though in the latter case with
slightly reduced mass balance (90%). Weaker acid H3PO4
(entry 18) led to partial (30%) and HOAc to no conversion
(entry 19). A full optimization of this reaction can be found in
the ESI (section 3†).
Substrate scope
The developed O-demethylation of 4-propylguaiacol (1a) could mediate in its synthesis.97 To conclude this part, the efficiency
be applied on a variety of different substrates (Scheme 3). of our method at the larger bench scale was evaluated, as
4-Propylsyringol (1b), next to 4-propylguaiacol (1a) a major exemplified with two substrates, i.e. 4-propylguaiacol (1a) and
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Scheme 3 O-Demethylation of (substituted) anisols, guaiacols, dimethoxybenzenes, benzodioxoles, and syringols. Yield of isolated products.
Reactions were typically performed in 3 mL of H2O. General conditions: Substrate concentration = 0.50 M, 20 mol% HCl, temperature = 250 °C,
time = 3 h. a 150 mmol 1a, substrate concentration = 1.0 M, time = 6 h; b substrate concentration = 0.33 M; c purified via recrystallization from
toluene; d 50 mmol 1a, substrate concentration = 0.33 M, time = 6 h; e time = 6 h; f 0 mol% HCl; g substrate concentration = 0.13 M; h time = 1 h;
i 40 mol% HCl; j purified via column chromatography; k time = 4 h; l 100 mol% HCl; m temperature = 200 °C; n 84% ee.
4-propylsyringol (1b). These aryl methyl ethers could be Green metrics toolbox
O-demethylated with the same yield on a scale of 150 and
50 mmol, respectively. A more detailed description can be
found in the ESI (section 3.3.2†).
In order to evaluate the greenness of the developed
O-demethylation method, the optimal conditions for the con-
version of 4-propylguaiacol (1a) into 4-propylcatechol (2a) were
analyzed using the first pass CHEM21 Green Metrics Toolkit,
comprising quantitative and qualitative aspects, developed for
Lignin oil and clove oil
Finally, two natural sources of 4-propylguaiacol (1a) were discovery research.83,99,100 The same analysis has been per-
selected and used in this newly developed O-demethylation formed for classical O-demethylation methods as well. To
strategy. As a first example, softwood (Pinus) was treated under achieve this, the conditions reported on 1a have been taken
reductive conditions,45 delivering a lignin oil consisting of directly from the literature (Scheme 5) and if not reported on
64 wt% 1a, corresponding to 18 wt% of the original lignin 1a, but on similar substrates, we have applied it on 1a to
content. Subsequent HCl-catalyzed O-demethylation of this access the required data (Scheme 6). A detailed overview of
lignin oil delivered 4-propylcatechol (2a) with a yield of 77% these selected classical methods, including the scale the
for this step, corresponding to 14 wt% of the original lignin experiment was performed on and the applied work-up, can be
content (Scheme 4(a)). Secondly, eugenol (3), obtained from found in the ESI (section 4.4†). The following quantitative
Eugenia,98 was easily reduced to the desired substrate 1a with parameters were calculated for each considered method: yield,
the aid of H2 and cat. Pd/C.44 Subsequently, O-demethylation AE (atom economy), RME (reaction mass efficiency), PMI Tot
of 1a delivered 4-propylcatechol (2a) in a total yield of 89% (total process mass intensity), PMI RRC (reactants, reagents,
over 2 steps (Scheme 4(b)). Important to mention is that all catalysts), PMI Rxn (Reaction: RRC + reaction solvent), and
steps involved are extraction and filtration based and do not PMI WU (Work-up, i.e. considering the mass of all chemicals
involve column chromatography.
and solvents used in the work-up). Next to the assessment of
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Scheme 4 O-Demethylation of 4-propylguaiacol (1a) obtained from a natural resource: (a) Pinus,45 and (b) Eugenia.98 a Determined via 1H NMR
analysis with dimethyl sulfone as int. std. b The experiment was performed 2 times and samples were combined for work-up. c Eugenol (3), obtained
from Eugenia through biological extraction and purification, was bought from Merck.98
Scheme 5 O-Demethylation of 4-propylguaiacol (1a) to 4-propylcatechol
(2a) as retrieved from the literature.49,58,75,81,102,103,107 For all methods, the
applied work-up method (extraction or column chromatography) is shown
graphically. a For method C, 5% catechol (2i) was also obtained.
these mass-based metrics, qualitative aspects, i.e. solvent type,
use of critical elements, health and safety aspects of all chemi-
cals involved, energy and reagent consumption and the
applied work-up method, were also evaluated. In order to
clearly analyze these aspects, a flag system is applied. In this
regard, a green, yellow or red ‘flag’ is assigned to each of the
assessed criteria, where green denotes ‘preferred’, yellow is
‘acceptable with some issues’ and red is ‘undesirable’.
Scheme 6 O-Demethylation of 4-propylguaiacol (1a) to 4-propylcate-
chol (2a), applying methods retrieved from the literature for other guaia-
col derivatives.73,76,78,79,104 For all methods, the applied work-up
method (extraction or column chromatography) is shown graphically.
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Selection
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of
reaction
conditions
for
the
new experiment leading to a mixture of product 2a (79%), substrate
O-demethylation reaction. The newly developed method was 1a (3%) and catechol (2i, 5%) (method B) and decided not to
quantitatively evaluated under three different conditions, i.e. purify this mixture further because of its negative impact on
respectively low and high substrate concentration and HCl the Green Metrics analysis. The next two methods (C1–2) make
loading [method A1: 0.50 M 1a and 20 mol% HCl (Table 1, use of Brønsted acid HBr (aq.) in excess under reflux,49,58 with
entry 6); method A2: 1.00 M 1a and 20 mol% HCl (Table 1, the applied work-up method as the only difference.
entry 7); method A3: 2.00 M 1a and 50 mol% HCl (Table 1, Stoichiometric aluminium oxide iodide, in situ generated from
entry 5)]. As water acts both as reactant and solvent in the reac- AlI3 and DMSO, was also found to serve as a good demethyl-
tion,84 1.0 equiv. of H2O was considered as reactant and the ating agent, yielding 4-propylcatechol (2a) in nearly quantitat-
remaining amount as solvent in the calculations. When com- ive yield (method D).102 Stabilized IBX (SIBX) in excess was
paring A1 and A3 it can be seen that by increasing substrate reported for the O-demethylate substrate 1a selectively in 89%
concentration and catalyst loading, a slightly lower yield (97% yield (method E).103 Demethylation based on BBr3, followed by
vs. 91%) and RME (80% vs. 75%) were obtained (Table 2). an aqueous quenching step, was found in a patent by Ghosh
However, when looking at the PMI, this most complete mass- (method F1).75 Because of the low substrate concentration and
based metric has a beneficial impact on the greenness of the small scale applied in this last method, we reproduced this
reaction since both PMI Tot (15 g g−1 vs. 11 g g−1) and PMI example by increasing the scale and substrate concentration
Rxn (15 g g−1 vs. 4.9 g g−1) could be decreased. Logically, the without the need for chromatographic purification, yielding
higher catalyst loading slightly increased the PMI RRC value 92% of 2a (method F2).
(1.3 g g−1 vs. 1.5 g g−1). The only drawback of the more concen-
In the literature, multiple other classical demethylation
trated conditions is the need for an extractive work-up, while methods have been applied on guaiacol or anisole derivatives
in method A1 the pure reaction product could be obtained different from 4-propylguaiacol (1a), and six of these methods
with simple freeze drying. This difference reveals when were selected and applied on the standard substrate 1a. The
looking at PMI WU (0 g g−1 vs. 6.4 g g−1). For most quantitative results are summarized in Scheme 6 and a detailed description
metrics, method A2 brings an intermediate result, despite for is reported in the ESI (section 4.4.2†). For these methods, we
PMI Tot and PMI WU, which can be attributed to the extractive performed the reactions with the conditions as retrieved from
work-up with the same amount of organic solvent as method the literature on similar substrates and we only increased the
A3. The lower PMI Tot makes method A3 still the greenest and amounts of reagents and reaction temperatures if insufficient
therefore, these conditions will be used for comparison with conversion of substrate 1a was observed. Also, work-up was
classical methods (vide infra).
performed as originally described and material intensive
Selection of classical state-of-the-art methods. Six reported column chromatography was only considered if greener purifi-
methods describing the O-demethylation of 4-propylguaiacol cation methods did not deliver the desired product 2a with
(1a) are summarized in Scheme 5. One method involves a sufficient purity. Stoichiometric trimethyl silyl iodide (TMSI,
heterogeneous catalyst.101 As part of a study regarding the 1.1 equiv.) demethylated guaiacol with 67% conversion after
hydrodeoxygenation of lignin, a layered Nb2O5 (25 mol%) cata- 48 h,76 a rate that could not be improved for 4-propylguaiacol.
lyst allowed the O-demethylation of 1a in hot pressurized water Even after prolonging the reaction time to 70 h, 54% 2a and
(N2 pressure).81 Unfortunately, demethylation as a separate 26% substrate 1a recovery was achieved (method G1).
step was not the main topic of this study and the yield of 2a Increasing the amount of demethylating agent pushed the
was therefore only quantified by GC-FID. We repeated this substrate to full conversion, leading to 4-propylcatechol 2a in
Table 2 Quantitative metrics for the O-demethylation of 4-propylguaiacol (1a) to 4-propylcatechol (2a) using cat. HCl in hot pressurized water
PMI (g g−1
)
Entry
Method
Conc. 1a (M)
HCl (mol%)
Time (h)
Yield (%)
AE (%)
RME (%)
Tota
RRCa
Rxna
WUa
1
2
3
A1
A2
A3
0.50
1.00
2.00
20
20
50
3
3
1
97
96
91
83
83
83
80
79
75
15
20
11
1.3
1.3
1.5
15
8.0
4.9
0b
12b
6.4b
Results from Table 1 (entries 5 and 6); the applied work-up method (freeze drying or extraction) is shown graphically. a Tot: Total; RRC: reactants,
reagents, catalysts; Rxn: reaction; WU: work-up. b In the first example, freeze drying was sufficient to obtain pure 2a (leading to a green flag in
qualitative metrics analysis), while in the second and third example extraction was required with 10 mL of EtOAc (yellow flag).
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74–89% yield, depending on the applied work-up (methods G2 NaOtBu even did not form 4-propylcatechol (2a), enabling the
and G3). The described O-demethylation of guaiacol (1l) invol- quantitative recovery of substrate 1a.
ving Al powder, I2 and DMSO could be applied on our main
Besides chemical routes, biocatalytic routes are also poss-
substrate of interest 1a,104 even in the absence of DMSO ible for O-demethylation. In 2018, an enzymatic method,
(method H), providing 4-propylcatechol (2a) with a yield of based on corrinoid-dependent methyl transferases acting as
87%. By applying a method based on AlCl3 and NaI, delivering the methyl transferring agent, was reported.105 In the presence
quantitative double demethylation of veratrole,79 desired 2a of the respective methyl transferase (MTase I), corrinoid
was only obtained in 63% yield (with 2% remaining substrate protein (CP) and the required buffer, guaiacol (1l) were de-
1a) (method I1). Similarly, a combination of AlCl3 and methylated to catechol (2i) with a conversion of 84%, while at
dimethyl sulfide,78 led to 67% 2a and 26% remaining substrate the same time methyl acceptor protocatechuic aldehyde (2f,
(method I2), even with a large excess of the used reagents. A 5.0 equiv.) was converted into
a mixture of vanillins
pilot-scale demethylation of 4-methoxyphenylbutyric acid (Scheme 8, method L1). This experiment could not be evalu-
involving an excess of molten Py·HCl,73 was successfully ated on 4-propylguaiacol (1a) as we did not have access to
applied on 1a in 84% yield (method J). As a last method, LiBr these enzymes. Therefore, a theoretical simulation was per-
and HBr in excess, described for the demethylation of formed, assuming the reaction would occur with the same
4-methylguaiacol (1d),66 was employed on 1a, leading to 2a in efficiency (method L2, Scheme 8). This procedure was recently
82% yield (method K). Finally, three chemical methods disclosed as a reliable metrics analysis when no data are avail-
describing high-yielding demethylation of substituted anisoles able for a synthetic method on a specific substrate.106
mainly bearing electron withdrawing groups on the arene were
Quantitative aspects. From the data reported in Schemes 5
evaluated.64,74,80 As described in Scheme 7, translating these and 6 and Table 3, it can be seen that methods B (Nb2O5), I1
procedures to demethylation of electron rich 4-propylguaiacol
(1a) did not provide good results. For example, MgI2 and the
combination of Cu2O and NaOMe only partially converted 1a
to 2a, and combination of 2-diethylaminoethanethiol and
Table 3 Quantitative metrics for the O-demethylation of 4-propyl-
guaiacol (1a) to 4-propylcatechol (2a)
PMIa (g g−1
)
Yield AE
RME
Method (%) (%) (%)
Tot
RRC Rxn WU
A3
B
C1
C2
D
91
79
94
97
97
89
86
92
54c
89
74
87
63d
67e
84
82
83
83
62
62
75
92
83
83
77
77
77
75
83
83
47
62
75
65
25
26
73
81
71
76
41
68
57
65
52
55
40
9
11
92
30
21
1.5
2.1
4.1
4.0
5.0
10
4.9
30
7.0
6.8
48
6.4
63
23
14
834 (287)b
2140
786 (239)b
E
141 1999
F1
F2
G1
G2
G3
H
I1
I2
J
1394 (772)b 3.5
33
18
23
15
18
53
17
24
4.9
1362 (739)b
96
3.3
79
1254 (319)b 5.1
1231 (296)b
742 (178)b
188
757 (193)b
207
4.4
5.3
5.6
896 (225)b
842 (172)b
1272 (133)b
1208 (195)b
22
1289 (151)b 7.8
1232 (219)b 9.5
27
762
4.9
92
K
155 608
Conditions of the methods can be found in Schemes 6 and 7. a Tot:
Total; RRC: reactants, reagents, catalysts; Rxn: reaction; WU: work-up.
b The values between brackets are obtained when column chromato-
graphy is omitted from work-up. c 26% 1a was recovered. d 2% 1a was
recovered. e 20% 1a was recovered.
Scheme 7 Attempted methods for O-demethylation of 4-propylguaia-
col (1a) to 4-propylcatechol (2a), applying methods retrieved from the
literature for anisole derivatives.64,74,80 For all methods, the applied
work-up method (extraction) is shown graphically.
Scheme 8 Method L1: Biocatalytic conversion of guaiacols (1a,l) and protocatechuic aldehyde (2f) in catechols (2a,i) and vanillins 10 by MTase I
and CP.105 Method L2: Simulated data for demethylation of 4-propylguaiacol (1a), based on the data from method L1 employing guaiacol (1l).
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and I2 (AlCl3, either in combination with Me2S or NaI) were WU than methods relying on chromatography (method E vs.
the only procedures not capable of driving the reaction to full D, F1, G1, G2, H, I1 and I2).
conversion. All other demethylating agents were able to do so
Although the use of water as the solvent is a specifically
and delivered the desired product 2a with a yield of at least attractive feature in enzymatic reactions (e.g. method L),
82%. Generally, high values for AE were obtained in almost all several chemicals, e.g. buffer, need to be added for the reaction
cases, since only the methods using HBr (methods C1 and to proceed effectively. Also the reduced reaction conditions of
C2), HBr with LiBr (method K) and Py·HCl (method J) scored 10 mM (PMI RRC comprises only 8.4% of PMI Rxn) and mass-
less than 75%. In these cases, a large excess of reactants intensive work-up (PMI WU comprises 86% of PMI Tot) have
(4.0–117 equiv.) also resulted in a low RME value (9% to 40%), their impact on the mass based metrics. These factors lead to
while the other demethylating agents feature an RME ranging very high total (6890 g g−1) and partial PMI values (Table 4).
from 41% to 84%. Based on these metrics (yield, AE, RME), When considering demethylation of guaiacol (1l) via biocataly-
our newly developed approach A3, as well as classical sis, PMI Tot increases with 38% (method L1), which was also
approaches B, D, E, and F2 perform the best.
observed when applying our new approach (experimentally) on
However, also PMI, the most complete mass-based metric, this substrate 1l (Table 4, method A3). Though this biocatalytic
including all used chemicals for synthesis and work-up, needs methyl transfer is conceptually a very interesting study,
to be considered. Interestingly, for aq. HCl (method A3), the besides the high PMI Tot another problem rises. Two reactants
lowest PMI Tot as well as the subvalue for all categories was deliver one product and two isomeric co-products (2a, 2i, 10)
obtained when comparing with all literature procedures. The rather than pure 4-propylcatechol (2a). This will require separ-
method relying on Py·HCl (method J) uses the least waste gen- ation which will even further increase PMI WU, making it less
erating reaction conditions of all classical procedures. It has interesting from a preparative point of view. If we consider
the same PMI Rxn as achieved for method A3. When excluding these co-products as valorizable products and not as waste,99
the amount of solvent used (PMI RRC), differences between by adding the mass of the generated co-product in the denomi-
the methods become smaller and the method based on Nb2O5 nator of the PMI formula, a PMIFI (FI = Feedstock Intensity)
(method B) scores here second best with a slightly higher value is obtained. Similarly, AEFI and RMEFI can be defined
value than A3. It is worth mentioning that in method J molten (see ESI, section 4.5.3†), which are also reported in Table 4.
Py·HCl is used without any solvent, leading to a value for PMI PMIFI is in a sense actually moving from PMI towards the
RRC equal to that of PMI Rxn, which explains the low PMI Tot. E-factor where for the latter any input which is not waste, i.e.
In this regard, the second- and third-best demethylating useful co-product, is not included in the numerator.108 PMI
agents are HBr (methods C1 and C2) and BBr3 (methods F1 decreased with a factor 2 for all categories when the co-pro-
and F2). For method F1, the effect of working under high ducts formed are considered useful and not as waste, but
dilution becomes clear when looking at the difference between these values remain nevertheless significantly higher than the
PMI Rxn and PMI RRC, which could be halved by repeating PMIs reported for the chemical methods, revealing these co-
the method with a higher substrate concentration (method products are not the main cause of the poor performance with
F2). Obviously, the mass efficient work-up in method C2, respect to PMI of the biocatalysis. Obviously, an ideal AEFI is
based on extraction with a relatively small amount of organic obtained when co-products are not waste. Although RME
solvent, leads to low PMI WU and therefore to the lowest PMI doubles (RMEFI), the applied excess of one of the reactants is
Tot of all classical methods. However, these values are still pronounced, still leading to a low value (30%). Also for our
higher than those for method A3. Column chromatography is chemical demethylation strategy (cat. HCl, methods A), a valu-
inherently a material consuming nature, leading to (very) high able molecule is produced as by-product during the reaction,
PMI WU (methods D, F1, G1, G2, H, I1 and I2). Noteworthy, in i.e. stoichiometric methanol. Although we did not develop a
Table 3, it is shown that when extractions are not performed method for the isolation of this volatile alcohol from the water,
mass-efficiently, they can actually lead to higher values for PMI it is interesting to know its contribution to the mass based
Table 4 Quantitative metrics for the O-demethylation of 4-propylguaiacol (1a) into 4-propylcatechol (2a) and guaiacol (1l) into catechol (2i),
excluding or including formation of by-products, respectively
Excluding co-productsa
PMIb (g g−1
Including co-productsa
)
PMIFI b (g g−1
)
Method
Substrate
Yield (%)
AE (%)
RME (%)
Tot
RRC
Rxn
WU
AEFI (%)
RMEFI (%)
Tot
RRC
Rxn
WU
A3
L2
A3
L1
1a
1a
1l
91
84
93
84
83
50
77
42
75
15
72
11
11
6890
15
1.5
72
1.6
99
4.9
854
6.3
6.4
6036
8.7
100
100
100
100
91
30
93
27
9.4
3445
11
1.2
36
1.2
42
4.1
427
4.9
496
5.3
3018
6.2
1l
9523
1180
8342
3998
3503
a Co-products: Vanillins 10 for methods L, MeOH for methods A. b Tot: Total; RRC: reactants, reagents, catalysts; Rxn: reaction; WU: work-up.
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metrics. The PMIFI value decreased the earlier obtained PMI or column chromatography is used. The methods based on
further with around 15% when methanol is not considered as extraction, including the new method (A3), are the best leading
waste. Also AEFI and RMEFI increased to (almost) ideal to a yellow flag. For those classical methods relying on column
numbers.
chromatography in order to obtain pure product 2a, a red flag
Qualitative aspects. The qualitative parameters of the is scored, since this mass-intensive purification is clearly not
Toolkit were studied for each method and the results are sum- sustainable, which was already revealed in the quantitative
marized in Table 5. First we looked into solvent use. Here it metrics. Finally, in the category energy consumption, a red
can be seen that our newly developed method A3 (HCl) and flag is obtained for our HCl catalyzed demethylation due to
method B (Nb2O5) are the only methods scoring a green flag the elevated temperature, while a few examples from the classi-
for both reaction solvent and work-up solvent, in both cases cal methods could be performed at room temperature leading
H2O and EtOAc, respectively. Methods C1–2 (HBr), I1 (AlCl3 + to a green flag. However, one needs to realize that this is a very
NaI) and L2 (MTase I) also received a green flag for reaction basic first analysis of energy consumption and does not reflect
solvent, while a yellow or (dark) red flag was obtained for the final process energy consumption, which is simply not yet
work-up. Method J, relying on molten Py·HCl, is performed possible at the discovery level as reaction times are not mini-
‘neat’ and therefore a green flag is scored for the reaction mized and heat recovery, typically applied in bulk chemical
solvent. A red flag was obtained for the work-up solvent in this synthesis, is not considered yet. In development projects using
method, due to the use of MTBE, which is also applied in this new method, a more in-depth study should be performed
method K. Potentially, those work-up solvents can be altered in this respect applying second and third pass
for greener alternatives when additional research is performed, CHEM21 metrics.
making these methods potentially more acceptable from a sep-
aration point of view. In contrast, the other methods rely on
halogenated and ether solvents during reaction (e.g. CHCl3,
CH2Cl2, Et2O) and therefore bring significant issues from a
Conclusion
health and safety point of view. In these cases, solvents are In conclusion, we have developed an efficient green method
often crucial for the efficiency of the reaction and can there- for the cleavage of methyl aryl ethers catalyzed by HCl, a cheap
fore not be simply substituted by greener alternatives.
Brønsted acid, in hot pressurized water under a nitrogen atmo-
Concerning critical elements use, none of the considered sphere. Both acid and solvent are recommended with respect
methods scores a red flag, which would mean that an element to green chemistry. The versatility of our method was demon-
is used of which the remaining supply is estimated less than strated by cleaving various aryl methyl ether substrates, in
100 years. Method B, based on Nb2O5, scores a yellow flag for most cases only requiring simple extraction for the purifi-
the involvement of Nb, which has a predicted reserve of cation. Biorenewables such as 4-propylguaiacol and 4-propyl-
100–500 years. Also Li, I, Al, S and/or B lead on the same basis syringol obtained via wood biorefinery can also be used.
to a yellow flag (methods D, E, F, G, H, I, J and L). Next, health Application on multigram quantities is possible under the
and safety aspects were evaluated. The combination of H2O reaction conditions applied on a small scale. Further scaling
and HCl (method A3) or Nb2O5 (method B), followed by a will be evaluated in future research (pilot-scale testing). A full
simple work-up based on extraction with EtOAc, or the use of first pass Green Metrics Analysis of our new synthetic method
Py·HCl is clearly beneficial, since all other methods contain at revealed that in comparison with classical O-demethylation
least one chemical with an H phrase leading to a yellow or red methods our new approach scored best for most parameters
flag. Method H is clearly the worst, since three chemicals considered, both quantitatively (PMI) and qualitatively
leading to a red flag are involved (Al, I2 and heptane). It is (Solvent, Critical elements, Health and Safety, Reagent use).
important to emphasise that the substrate of our route, i.e.
4-propylguaiacol (1a), is toxic in contact with skin (H311) and
it therefore always generates a yellow flag. However, since this
is the substrate for all methods considered, it is obviously not
Author contributions
incorporated in Table 5. Concerning additional reagent use B.U.W.M. conceived the idea and designed the experiments
the new method scores very well as only a catalyst is required. together with J.B. J.B. (optimization), M.B. (optimization and
Apart from methods B (0.3 equiv. Nb2O5), C1–2 (4.9–5.0 equiv. scope) and T.K.A. (revision) carried out the experimental work
HBr) and L2 (enzyme) none of the literature methods score a regarding O-dealkylation of alkyl aryl ethers and synthesis of
green flag in this category. For methods C1–2, we should the required starting materials when not commercially avail-
mention that HBr is already considered as a reactant (since it able. X.W. synthesized the Nb2O5 catalyst and B.W. delivered
cannot be used catalytically and delivers a proton in the reac- lignin oil via reductive catalytic fractionation of pine. B.U.W.M.
tion equation) and therefore not included in this category, was guiding the scientists in Antwerp and B.S. in Leuven. J.B.
which only looks at additional reagents and catalysts. The performed the Green Metrics assessment. F.L. accomplished
effect of the excess of reactant in these methods (C1–2) has the HRMS analyses. The manuscript text was initially prepared
already been reflected in the poor AE and RME values. by J.B., which B.U.W.M. reworked. Subsequently, all authors
Comparing the applied work-up techniques, either extraction commented and gave input on the final version. B.U.W.M. and
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S.S. identified and worked out the application potential of the
synthetic methodology. S.S. assisted B.U.W.M. in the grant
applications to secure funding for this work.
14 M. Tronchet, C. Balague, T. Kroj, L. Jouanin and D. Roby,
Mol. Plant Pathol., 2010, 11, 83–92.
15 Y. Sang, M. Chen, F. Yan, K. Wu, Y. Bai, Q. Liu, H. Chen
and Y. Li, Ind. Eng. Chem. Res., 2020, 59, 7466–7474.
16 T. Renders, G. Van den Bossche, T. Vangeel, K. Van Aelst
and B. Sels, Curr. Opin. Biotechnol., 2019, 56, 193–201.
17 S. Dabral, J. Engel, J. Mottweiler, S. S. M. Spoehrle,
C. W. Lahive and C. Bolm, Green Chem., 2018, 20, 170–182.
18 F. Gao, J. D. Webb, H. Sorek, D. E. Wemmer and
J. F. Hartwig, ACS Catal., 2016, 6, 7385–7392.
Conflicts of interest
There are no conflicts to declare.
19 P. J. Deuss, C. W. Lahive, C. S. Lancefield, N. J. Westwood,
P. C. Kamer, K. Barta and J. G. de Vries, ChemSusChem,
2016, 9, 2974–2981.
20 C. Li, X. Zhao, A. Wang, G. W. Huber and T. Zhang, Chem.
Rev., 2015, 115, 11559–11624.
21 J. Zeng, C. G. Yoo, F. Wang, X. Pan, W. Vermerris and
Z. Tong, ChemSusChem, 2015, 8, 861–871.
22 A. Rahimi, A. Ulbrich, J. J. Coon and S. S. Stahl, Nature,
2014, 515, 249–252.
23 C. Xu, R. A. Arancon, J. Labidi and R. Luque, Chem. Soc.
Rev., 2014, 43, 7485–7500.
24 M. Himmel, Biomass Recalcitrance: Deconstructing the Plant
Cell Wall for Bioenergy, Wiley, 2008.
Acknowledgements
The authors acknowledge financial support from the Research
Foundation Flanders (FWO) (BioFact Excellence of Science
project Grant No. 30902231), iBOF (Next-BIOREF), UAntwerp
(BOF GOA and CASCH Excellence Center), VLAIO/Catalisti
(ARBOREF), the BIO-HarT project (established by a contri-
bution of the European Interreg V Flanders-The Netherlands
program that stimulates innovation, sustainable energy, a
healthy environment, and the labor market by means of cross-
border projects), the Hercules and Francqui Foundation. We
thank B. Loenders, G. Mollaert, and P. Franck for their
contribution.
25 A. J. Ragauskas, G. T. Beckham, M. J. Biddy, R. Chandra,
F. Chen, M. F. Davis, B. H. Davison, R. A. Dixon, P. Gilna,
M. Keller, P. Langan, A. K. Naskar, J. N. Saddler,
T. J. Tschaplinski, G. A. Tuskan and C. E. Wyman, Science,
2014, 344, 1246843.
Notes and references
1 X. Luo, Y. Li, N. K. Gupta, B. Sels, J. Ralph and L. Shuai,
Angew. Chem., Int. Ed., 2020, 59, 11704–11716.
2 P. Morone and J. H. Clark, Transition Towards
Sustainable Biobased Economy, Royal Society of Chemistry,
2020.
3 European Commission, Bio-based economy in Europe: state
of play and future potential, 2011.
4 A. Shrotri, H. Kobayashi and A. Fukuoka, Acc. Chem. Res.,
2018, 51, 761–768.
5 J. S. Luterbacher, D. M. Alonso and J. A. Dumesic, Green
Chem., 2014, 16, 4816–4838.
6 S. Van de Vyver, J. Geboers, P. A. Jacobs and B. F. Sels,
ChemCatChem, 2011, 3, 82–94.
26 Y. Liao, S. F. Koelewijn, G. Van den Bossche, J. Van Aelst,
S. Van den Bosch, T. Renders, K. Navare, T. Nicolai,
K. Van Aelst, M. Maesen, H. Matsushima, J. M. Thevelein,
K. Van Acker, B. Lagrain, D. Verboekend and B. F. Sels,
Science, 2020, 367, 1385–1390.
27 M. Tschulkow, T. Compernolle, S. Van den Bosch, J. Van
Aelst, I. Storms, M. Van Dael, G. Van den Bossche, B. Sels
and S. Van Passel, J. Cleaner Prod., 2020, 266, 1222022.
28 M. M. Abu-Omar, K. Barta, G. T. Beckham,
J. S. Luterbacher, J. Ralph, R. Rinaldi, Y. Román-Leshkov,
J. S. M. Samec, B. F. Sels and F. Wang, Energy Environ. Sci.,
2020, 262–292.
a
7 Y. M. Questell-Santiago, M. V. Galkin, K. Barta and
J. S. Luterbacher, Nat. Rev. Chem., 2020, 4, 311–330.
8 A. Kumar, Anushree, J. Kumar and T. Bhaskar, J. Energy
Inst., 2020, 93, 235–271.
9 Z. Sun, B. Fridrich, A. de Santi, S. Elangovan and K. Barta,
Chem. Rev., 2018, 118, 614–678.
29 A. De Santi, M. V. Galkin, C. W. Lahive, P. J. Deuss and
K. Barta, ChemSusChem, 2020, 13, 4468–4477.
30 X. Liu, F. P. Bouxin, J. Fan, V. L. Budarin, C. Hu and
J. H. Clark, ChemSusChem, 2020, 13, 4296–4317.
31 T. I. Koranyi, B. Fridrich, A. Pineda and K. Barta,
Molecules, 2020, 25, 2815.
10 R. Rinaldi, R. Jastrzebski, M. T. Clough, J. Ralph,
M. Kennema, P. C. Bruijnincx and B. M. Weckhuysen,
Angew. Chem., Int. Ed., 2016, 55, 8164–8215.
11 R. Vanholme, B. Demedts, K. Morreel, J. Ralph and
W. Boerjan, Plant Physiol., 2010, 153, 895–905.
12 J. D. Gargulak, S. E. Lebo and T. J. McNally, Lignin in Kirk–
Othmer Encyclopedia of Chemical Technology, John Wiley &
Sons, Inc, 2015, pp. 1–26.
32 N. Ullah, A. H. Odda, K. Liang, M. A. Kombo, S. Sahar,
L.-B. Ma, X.-X. Fang and A.-W. Xu, Green Chem., 2019, 21,
2739–2751.
33 Z. H. Sun, G. Bottari, A. Afanasenko, M. C. A. Stuart,
P. J. Deuss, B. Fridrich and K. Barta, Nat. Catal., 2018, 1,
82–92.
34 T. Renders, E. Cooreman, S. Van den Bosch, W. Schutyser,
S. F. Koelewijn, T. Vangeel, A. Deneyer, G. Van den
Bossche, C. M. Courtin and B. F. Sels, Green Chem., 2018,
20, 4607–4619.
13 L. Serrano, R. Luque and B. F. Sels, Lignin Chemistry,
Springer, 2020.
This journal is © The Royal Society of Chemistry 2021
Green Chem., 2021, 23, 1995–2009 | 2007

View Article Online
Paper
Green Chemistry
35 T. Renders, S. Van den Bosch, S. F. Koelewijn,
W. Schutyser and B. F. Sels, Energy Environ. Sci., 2017, 10,
1551–1557.
36 X. M. Huang, O. M. M. Gonzalez, J. D. Zhu, T. I. Koranyi,
M. D. Boot and E. J. M. Hensen, Green Chem., 2017, 19,
175–187.
37 J. Chen, F. Lu, X. Si, X. Nie, J. Chen, R. Lu and J. Xu,
ChemSusChem, 2016, 9, 3353–3360.
38 M. V. Galkin, A. T. Smit, E. Subbotina, K. A. Artemenko,
J. Bergquist, W. J. Huijgen and J. S. Samec, ChemSusChem,
2016, 9, 3280–3287.
55 R. Thompson and M. Carlson, J. AOAC Int., 1997, 80,
1023–1028.
56 C. Battistini, V. Borzatta and D. Brancaleoni,
EP1048664B1, 1999.
57 J.-M. Gaudin, O. Nikolaenko, J.-Y. de Saint Laumer,
B. Winter and P.-A. Blanc, Helv. Chim. Acta, 2007, 90,
1245–1265.
58 Z. Dobi, B. N. Reddy, E. Renders, L. Van Raemdonck,
C. Mensch, G. De Smet, C. Chen, C. Bheeter, S. Sergeyev,
W. A. Herrebout and B. U. W. Maes, ChemSusChem, 2019,
12, 3103–3114.
39 T. Renders, S. Van den Bosch, T. Vangeel, T. Ennaert,
S.-F. Koelewijn, G. Van den Bossche, C. M. Courtin,
W. Schutyser and B. F. Sels, ACS Sustainable Chem. Eng.,
2016, 4, 6894–6904.
59 P. G. M. Wuts, Greene’s Protective Groups in Organic
Synthesis, John Wiley & Sons, Inc., 5th edn, 2014.
60 P. J. Kociensky, Protecting Groups, Georg Thieme Verlag,
3rd edn, 2005.
40 S. Van den Bosch, W. Schutyser, R. Vanholme,
T. Driessen, S. F. Koelewijn, T. Renders, B. De Meester,
W. J. J. Huijgen, W. Dehaen, C. M. Courtin, B. Lagrain,
W. Boerjan and B. F. Sels, Energy Environ. Sci., 2015, 8,
1748–1763.
61 D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy,
S. Abou-Shehada and P. J. Dunn, Green Chem., 2016, 18,
288–296.
62 G. I. Feutrill and R. N. Mirrington, Tetrahedron Lett., 1970,
11, 1327–1328.
41 Q. Song, F. Wang, J. Y. Cai, Y. H. Wang, J. J. Zhang,
W. Q. Yu and J. Xu, Energy Environ. Sci., 2013, 6, 994–
1007.
63 J. Chae, Arch. Pharmacal Res., 2008, 31, 305–309.
64 J. Magano, M. H. Chen, J. D. Clark and T. Nussbaumer,
J. Org. Chem., 2006, 71, 7103–7105.
42 A. A. Khalil, U. u. Rahman, M. R. Khan, A. Sahar,
T. Mehmood and M. Khan, RSC Adv., 2017, 7, 32669–
32681.
43 L. Petitjean, R. Gagne, E. S. Beach, D. Q. Xiao and
P. T. Anastas, Green Chem., 2016, 18, 150–156.
44 S. K. Chittimalla, C. Bandi, S. Putturu, R. Kuppusamy,
K. C. Boellaard, D. C. A. Tan and D. M. J. Lum, Eur. J. Org.
Chem., 2014, 2565–2575.
65 J. R. McCarthy, J. L. Moore and R. J. Cregge, Tetrahedron
Lett., 1978, 19, 5183–5186.
66 Z. Li, E. Sutandar, T. Goihl, X. Zhang and X. Pan, Green
Chem., 2020, 22, 7989–8001.
67 Z. Fang, G. C. Zhou, S. L. Zheng, G. L. He, J. L. Li, L. He
and D. Bei, J. Mol. Catal. A: Chem., 2007, 274, 16–23.
68 K. Hwang and S. Park, Synth. Commun., 1993, 23, 2845–
2849.
45 W. Schutyser, S. Van den Bosch, J. Dijkmans, S. Turner,
M. Meledina, G. Van Tendeloo, D. P. Debecker and
B. F. Sels, ChemSusChem, 2015, 8, 1805–1818.
46 W. H. Faveere, S. Van Praet, B. Vermeeren,
K. N. R. Dumoleijn, K. Moonen, E. Taarning and
B. F. Sels, Angew. Chem., Int. Ed., 2020, DOI: 10.1002/
anie.202009811.
69 L. Canonica, B. Rindone, E. Santaniello and C. Scolastico,
Tetrahedron, 1972, 28, 4395–4404.
70 L. Zuo, S. Yao, W. Wang and W. Duan, Tetrahedron Lett.,
2008, 49, 4054–4056.
71 G. G. Li, D. Patel and V. J. Hruby, Tetrahedron Lett., 1993,
34, 5393–5396.
72 Y. Kiso, S. Nakamura, K. Ito, K. Ukawa, K. Kitagawa,
T. Akita and H. Moritoki, J. Chem. Soc., Chem. Commun.,
1979, 971–972.
47 J. Huang, S. Fu and L. Gan, Lignin Chemistry and
Applications, Elsevier, 2019.
48 S. Zhao and M. M. Abu-Omar, ACS Sustainable Chem. Eng.,
2016, 4, 6082–6089.
73 C. R. Schmid, C. A. Beck, J. S. Cronin and M. A. Staszak,
Org. Process Res. Dev., 2004, 8, 670–673.
49 S. Zhao and M. M. Abu-Omar, Biomacromolecules, 2015,
16, 2025–2031.
50 S. Zhao and M. M. Abu-Omar, Macromolecules, 2017, 50,
3573–3581.
74 K. Bao, A. Fan, Y. Dai, L. Zhang, W. Zhang, M. Cheng and
X. Yao, Org. Biomol. Chem., 2009, 7, 5084–5090.
75 S. S. Ghosh, S. W. Miller, R. E. Davis and W. H. Moos,
WO9937294A2, 1999.
51 G. Marzaro, A. Guiotto, G. Pastorini and A. Chilin,
Tetrahedron, 2010, 66, 962–968.
76 E. H. Vickery, L. F. Pahler and E. J. Eisenbraun, J. Org.
Chem., 1979, 44, 4444–4446.
52 S. Xu, L. Sun, X. Fei, M. Sun, H. Wang, S. Wang, Y. Li,
W. Wang, Q. Yang and Y. Li, Yingyong Huagong, 2010, 39,
30–32.
53 E. Blondiaux, J. Bomon, M. Smoleń, N. Kaval, F. Lemière,
S. Sergeyev, L. Diels, B. Sels and B. U. W. Maes, ACS
Sustainable Chem. Eng., 2019, 7, 6906–6916.
54 S. Wang, J. Liu, C. Qian and X. Chen, Res. Chem.
Intermed., 2011, 38, 147–160.
77 D. Sang, X. Tu, J. Tian, Z. He and M. Yao, ChemistrySelect,
2018, 3, 10103–10107.
78 B. Arifin, D. F. Tang and S. S. Achmadi, Indones. J. Chem.,
2015, 15, 77–85.
79 M. Ghiaci and J. Asghari, Synth. Commun., 1999, 29, 973–
979.
80 L. Liu, Z. Li, C. Chen, H. Li, L. Xu and Z. Yu, Tetrahedron,
2018, 74, 2447–2453.
2008 | Green Chem., 2021, 23, 1995–2009
This journal is © The Royal Society of Chemistry 2021

View Article Online
Green Chemistry
Paper
81 L. Dong, Y. Xin, X. Liu, Y. Guo, C.-W. Pao, J.-L. Chen and
Y. Wang, Green Chem., 2019, 21, 3081–3090.
95 J. S. Birks, Cochrane Database of Systematic Reviews, 2006,
DOI: 10.1002/14651858.CD005593.
82 J. Ott, V. Gronemann, F. Pontzen, E. Fiedler,
G. Grossmann, D. Burkhard Kersebohm, G. Weiss and
C. Witte, Methanol in Ullmann’s Encyclopedia of Industrial
Chemistry, Wiley–VCH Verlag GmbH & Co., 2012.
83 C. R. McElroy, A. Constantinou, L. C. Jones,
L. Summerton and J. H. Clark, Green Chem., 2015, 17,
3111–3121.
84 J. Bomon, E. Van Den Broeck, M. Bal, Y. Liao, S. Sergeyev,
V. Van Speybroeck, B. F. Sels and B. U. W. Maes, Angew.
Chem., Int. Ed., 2020, 59, 3063–3068.
96 A. Kleemann, J. Engel, B. Kutscher and D. Reichert, in
Pharmaceutical Substances, Georg Thieme Verlag,
Stuttgart/New York, 4th edn, 2001.
97 Z. Sun, G. Bottari, A. Afanasenko, M. C. A. Stuart, P. J. Deuss,
B. Fridrich and K. Barta, Nat. Catal., 2018, 1, 82–92.
98 Merck, Eugenol, natural, ≥98%, https://www.sigmaal-
drich.com/catalog/product/aldrich/w246719?lang=en&re-
gion=BE, (accessed October 2020).
99 K. Lokesh, A. S. Matharu, I. K. Kookos, D. Ladakis,
A. Koutinas, P. Morone and J. Clark, Green Chem., 2020,
22, 803–813.
85 J. Behaghel de Bueren, F. Héroguel, C. Wegmann,
G. R. Dick, R. Buser and J. S. Luterbacher, ACS Sustainable 100 CHEM21 Metrics Toolkit, https://www.chem21.eu/project/
Chem. Eng., 2020, 8, 16737–16745. metrics-toolkit/, (accessed April 2020).
86 M. Talebi Amiri, G. R. Dick, Y. M. Questell-Santiago and 101 Zeolyst, Zeolite Beta, https://www.zeolyst.com/our-pro-
J. S. Luterbacher, Nat. Protoc., 2019, 14, 921–954.
87 W. Lan, M. T. Amiri, C. M. Hunston and J. S. Luterbacher,
Angew. Chem., Int. Ed., 2018, 57, 1356–1360.
ducts/standard-zeolite-powders/zeolite-beta.html,
(accessed October 2020).
102 J. Tian, D. Sang, X. Tu, Z. He and M. Yao, Synthesis, 2019,
51, 704–712.
88 L. Shuai, M. T. Amiri, Y. M. Questell-Santiago,
F. Heroguel, Y. Li, H. Kim, R. Meilan, C. Chapple, J. Ralph 103 A. Ozanne, L. Pouysegu, D. Depernet, B. Francois and
and J. S. Luterbacher, Science, 2016, 354, 329–333. S. Quideau, Org. Lett., 2003, 5, 2903–2906.
89 N. L. Egutkin and A. M. Syrkin, Oil Gas Bus., 2014, 206– 104 J. Tian, H. Yue, P. Yang and D. Sang, ChemistrySelect,
219, DOI: 10.17122/ogbus-2014-1-206-219. 2019, 4, 38–41.
90 M. Weber, M. Weber and M. Kleine-Boymann, Phenol, in 105 J. E. Farnberger, N. Richter, K. Hiebler, S. Bierbaumer,
Ullmann’s Encyclopedia of Industrial Chemistry, Wiley–VCH
Verlag GmbH & Co. KGaA., 2004.
M. Pickl, W. Skibar, F. Zepeck and W. Kroutil, Commun.
Chem., 2018, 1, 82.
91 H. Pereira, Chapter 14 - Wine and cork, in Cork, ed. H. 106 E. R. Monteith, P. Mampuys, L. Summerton, J. H. Clark,
Pereira, Elsevier Science B.V., Amsterdam, 2007, pp.
305–327.
B. U. W. Maes and C. R. McElroy, Green Chem., 2020, 22,
123–135.
92 A. Orav, A. Raal and E. Arak, Nat. Prod. Res., 2008, 22, 227– 107 M. L. Stone, E. M. Anderson, K. M. Meek, M. Reed,
232.
R. Katahira, F. Chen, R. A. Dixon, G. T. Beckham and
Y. Román-Leshkov, ACS Sustainable Chem. Eng., 2018, 6,
11211–11218.
93 J. Beekwilder, I. M. van der Meer, O. Sibbesen,
M. Broekgaarden, I. Qvist, J. D. Mikkelsen and R. D. Hall,
Biotechnol. J., 2007, 2, 1270–1279.
94 H. Sevelius, E. Segre and K. Bursick, J. Clin. Pharmacol.,
1980, 20, 480–485.
108 R. A. Sheldon, Towards Environmentally Friendly
Chemical Processes, in Current Topics in Flavours and
Fragrances, ed. K. A. D. Swift, Springer, Dordrecht, 1999.
This journal is © The Royal Society of Chemistry 2021
Green Chem., 2021, 23, 1995–2009 | 2009