Synthesis of potential bisphenol A substitutes by isomerising metathesis of renewable raw materials

Article abstract of DOI:10.1039/c7gc00553a

Isomerising metathesis is introduced as a sustainable method to produce dihydroxystilbene derivatives from eugenol, a clove oil ingredient, and cardanol from cashew nut shell liquid. Hydrogenation of the dihydroxystilbenes provided their di(hydroxyphenyl)ethane analogues. Initial studies to convert these monomers into polycarbonates and thiol-ene polymers support their potential to replace the petrol-derived bisphenol A (BPA). The estrogenic activity of the monomers derived from cardanol was found to be in the same range as that of BPA, a known endocrine disruptor. In contrast, eugenol-derived materials were found to be non-estrogenic, opening up new perspectives for bio-based food packaging materials.

Full text of DOI:10.1039/c7gc00553a

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Synthesis of potential bisphenol A substitutes by isomerising
metathesis of renewable raw materials
A. S. Trita,a L. C. Over,b J. Pollini,a S. Baader,a S. Riegsinger,b M. A. R. Meierb* and L. J. Gooßena*
Received 00th January 20xx,
Accepted 00th January 20xx
Isomerising metathesis is introduced as a sustainable method to produce dihydroxystilbene derivatives from eugenol, a
clove oil ingredient, and of cardanol from cashew nut shell liquid. Hydrogenation of the dihydroxystilbenes provided their
di(hydroxyphenyl)ethane analogues. In initial studies to convert these monomers into polycarbonates and thiol-ene
polymers support their potential to replace the petrol-derived bisphenol A (BPA). The estrogenic activity of the monomers
derived from cardanol was found to be in the same range as BPA, a known endocrine disruptor. In contrast, the eugenol-
derived materials were found to be non-estrogenic, opening up perspectives for bio-based food packaging materials.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Polymers are prevalent in everyday life, and their manufacture
represents a major sector of the chemical industry.1 With
rising public concern over the rapid depletion of petrochemical
resources, efforts to incorporate biomass into the chemical
value chain are booming,2-4 for instance in the field of bio-
based polymers.5-7
construction materials, toys,
bottles, f ood containers
n
poly carbonates
f lame retardant
thermal paper
Bisphenol A (BPA) is one of the highest-volume monomers
currently produced on about 4.5 million t/a scale (Figure 1).8 It
is the main precursor of polycarbonates and epoxy resins.
These polymers present excellent thermal, mechanical, optical
and electrical properties.9-11 They find broad application in end
products ranging from construction materials to coatings,
thermal paper and electronic equipment all the way to food
packaging and containers.12-14 However, especially for uses in
infant feeding bottles, health concerns have been raised on
the grounds of the ability of BPA to mimic the hormone
estradiol.15,16 Its ability to coordinate to estrogen receptors
arises from the presence of para-hydroxy groups with a
defined distance.17,18 BPA exposure has been shown to affect
the cardiovascular,19 reproductive,20 and immune system21 as
well the neurobehavioral development of children.22
bisphenol A (BPA)
electronic equipment,
paints, coatings, adhesives
n
epoxy resins
Figure 1 Applications of bisphenol A.
products are highly desirable. For such small-scale
applications, health and safety aspects dominate, and sourcing
from biomass would constitute a welcome add-on. However,
large-volume manufacturing of construction materials would
benefit to the greatest degree from the exploitation of
renewable raw material sources.
In view of recent US and European legislation banning the use
of BPA in the production of polycarbonate infant feeding
bottles,23,24 potential substitutes for BPA for food-related
In continuation of our work on the valorisation of bio-based
resources by catalytic methods,25-27 we searched for
renewable monomers that would give polymers structurally
similar to the BPA-derived materials. Ideally, the target
structures would compare favourably with established
bisphenol building blocks such as bisphenols A, B, F or S, with
regard to estrogenicity.28,29
Our plan was to convert naturally occurring alkenyl phenols to
the corresponding dihydroxystilbenes via isomerising olefin
metathesis (Scheme 1).30-32 We were optimistic that the
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Journal Name
Pd-1
isomerising
HO
R
HO
R
metathesis
R
OH
eugenol
n
[Ru]
Br
tBu3P Pd Pd PtBu3
CNSL
Br
Pd-1
anacardic acid
cardanol
cardol
Scheme 1 Synthesis of dihydroxystilbenes from alkenyl phenols.
=
stilbenes or their hydrogenated di(hydroxyphenyl)ethane
analogues would be suitable monomers for the intended
application, considering that the utility of the
dihydroxystilbene substance class in polymer synthesis has
previously been shown.33-35 The stilbenes can be expected to
have greater rigidity36 and to permit cross-linking,37 whereas
the di(hydroxyphenyl)ethanes would be more flexible, inert
building blocks. For this reason, both substance classes
appeared to be desirable test materials.
1) 0.2 mol% HG1, C H (10 bar)
2
4
toluene, r.t., 12 h
2) distillation/decarboxylation
1
Figure 2 Eugenol and CNSL ingredients.
Isomerising metathesis is an orthogonal tandem catalysis
process, in which an isomerisation catalyst continuously moves
a double bond along a carbon chain, while a metathesis
catalyst simultaneously shuffles the substituents at the double
bond. A special application is the ethenolysis of alkenyl arenes,
which leads to the continuous shortening of the alkenyl side
chains with concomitant conversion of ethylene to the
valuable propylene. This concept has successfully been applied
to the synthesis of styrenes from allylarenes, and of the tsetse-
attractant kairomones from cashew nut shell liquid (CNSL).27
CNSL (Figure 2) would be an ideal starting material also for the
present application, because it is a waste product of the
cashew nut industry, for which no competition occurs between
land use for food or raw material production.38 Its annual
production amounts to about 450,000 tonnes.39 Crude CNSL
consists of a mixture of phenols, terpenes, resorcinols, and
salicylic acids bearing C-15 aliphatic side chains with different
degrees of unsaturation.40 Common commercial CNSL is
obtained by dry distillation of the nut shells, resulting in
decarboxylation of the acids and condensation of a liquid
fraction containing mostly cardanols.41 We have previously
demonstrated that this CNSL fraction can be converted into 3-
Another potential raw material is eugenol, an allylarene
contained in the essential oils of several plants, such as clove,
basil, bay, and tarragon.50 It has found applications in the
pharmaceutical, flavour and fragrance industries.51,52 Although
it may also be synthesised from guaiacol and allyl chloride,53
eugenol is preferentially isolated from natural sources. About
2000 t/a are produced from clove oil.54 Starting from eugenol,
an isomerising metathesis should directly lead to 3,3’-
dimethoxy-4,4’-dihydroxystilbene
(2). This approach is
challenging, because it combines a difficult alkenylarene
metathesis with an in situ double-bond isomerisation. Bruneau
et al. have shown that under standard metathesis conditions,
the stilbene is formed only as a minor side product.55 Hitce et
al.
successfully
prepared
4,4’-dihydroxy-3,3’-
dimethoxystilbene (
2
) from isoeugenol (Scheme 2),56 of which
the preparation requires additional reaction steps.57,58 It was,
however, unclear whether their metathesis catalyst would be
compatible with an isomerisation catalyst.
We herein report the preparation of di(hydroxyphenyl)
monomers from bio-based starting materials, their conversion
into polycarbonates and thiol-ene polymers, and their
evaluation with regard to monomer estrogenicity and some
basic polymer properties.
(non-8-enyl)phenol (
followed by distillation.27 When subjected first to isomerising
ethenolysis and then to self-metathesis, we reasoned that
1) in up to 89% yield by ethenolysis
1
would be converted to 3,3’-dihydroxystilbene. The main
uncertainty associated with this synthetic approach was the
feasibility of the final self-metathesis step, since in previous
ethenolysis experiments, no more than traces of the stilbene
had been detected as a side product. The self-metathesis of
vinyl arenes is also far from trivial, with few known examples
of functionalised stilbenes accessed this way.42-49
self -metathesis
isoeugenol
2
Scheme 2 Hitce’s synthesis of 4,4’-dihydroxy-3,3’-dimethoxystilbene 2.
2 | J. Name., 2012, 00, 1-3
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under reduced pressure to yield
95%).
3
as a white solid (1.30 g,
Experimental
General Methods
One-pot synthesis of 4,4'-dihydroxy-3,3'-dimethoxy-
diphenylethane (3) starting from eugenol
All reactions were performed in oven-dried glassware
containing a teflon-coated stirring bar. Solvents were purified
and dried by standard procedures, and degassed by three
freeze-pump-thaw cycles or in case of cyclohexane by argon
sparge prior to use prior to use. GC analyses were carried out
using a HP6890 with HP-5 capillary column (Phenyl Methyl
Siloxane 30 m x 320 x 0.25, 100/2.3-30-300/3) and a time
program beginning with 2 min at 60 °C, followed by a
30 °C/min ramp to 300 °C, then 3 min at this temperature.
Commercial substrates were used as received unless otherwise
stated. Cardanol was received from Cardolite and used after
purification via acidic and basic aqueous work-up. The
metathesis catalysts used herein are commercially available,
for example from Umicore or Sigma Aldrich. Ethylene was
purchased from Air Liquide GmbH (purity 99,95%).
In a glove box, a 250 mL autoclave equipped with a teflon
beaker and a teflon-coated stirring bar was successively
charged with Pd-1 (23.3 mg, 0.03 mmol), M51 (9.83 mg,
15.0 µmol) and eugenol (4.69 mL 30.0 mmol). The autoclave
was stirred at 70 °C for 4 h outside the glovebox. After cooling
down to r.t., Pd/C (160 mg, 0.15 mmol) and EtOH (120 mL)
were added. The reaction mixture was stirred at 70 °C for 4 h
outside the glovebox. After cooling down to r.t., Pd/C (160 mg,
0.15 mmol) and EtOH (120 mL) were added. The autoclave was
pressurised with 10 bar H2 and the reaction mixture was
stirred at 50 °C for 5 h. After depressurising, the suspension
was filtered through a plug of celite and eluted with EtOH (100
mL). The volatiles were removed under reduced pressure and
the resulting solid was washed with a minimum of toluene
(3x2 mL) and pentane (3x2 mL) to yield a white solid (3.28 g,
80%). The analytical data obtained matched those reported in
the literature.67
Optimisation of the reaction conditions for the isomerising
metathesis of eugenol
Under a nitrogen atmosphere an oven-dried 20 mL vial with a
teflon-coated stirring bar was charged with eugenol (156 µL,
1.00 mmol). A stock solution containing Pd-1 (3.89 mg, 50.0
µmol) and the metathesis catalyst (10.0 µmol) in the given
solvent (1 mL) was added via syringe. The resulting mixture
was stirred at the given temperature for the given time. After
cooling down to r.t., the precipitated product was filtered off,
washed with toluene (5 mL) and pentane (2 mL), and dried
under reduced pressure. To the combined organic phases n-
decane (50.0 µL, 258 µmol) was added and a representative
sample was filtered through a plug of celite and MgSO4 and
analysed by GC / GC-MS.
Optimisation of the reaction conditions for the isomerising
metathesis of 3-(non-8-enyl)phenol (1)
In a glove box, a 35 mL oven-dried Ace pressure vessel with a
teflon-coated stirring bar was charged with Pd-1 (5.83 mg,
7.50 µmol) and the metathesis catalyst (10.0 µmol).
Subsequently, 3-(non-8-enyl)phenol (109 mg, 0.50 mmol) and
the solvent (2 mL) were added. The vessel was pressurised
with ethylene outside the glovebox and the mixture was
allowed to stir at the given temperature for the given time.
After cooling down to r.t., the precipitated product was
filtered off, washed with toluene (5 mL) and pentane (2 mL),
and dried under reduced pressure. To the combined organic
phases n-decane (50.0 µL, 258 µmol) was added and a
representative sample was filtered throught a plug of celite
and MgSO4 and analysed by GC / GC-MS.
Preparative scale synthesis of (E)-4,4'-dihydroxy-3,3'-
dimethoxystilbene (2) by isomerising metathesis of eugenol
In a glove box, an oven-dried 50 mL vial with a teflon-coated
stirring bar was charged with Pd-1 (23.3 mg, 30.0 µmol) and
M51 (9.83 mg, 15.0 µmol). Eugenol (4.69 mL 30.0 mmol) was
added via syringe under nitrogen atmosphere outside the
glovebox. The resulting mixture was stirred at 70 °C for 4 h.
After cooling to r.t., the precipitated product was filtered off,
washed with toluene (3x10 mL) and pentane (3x2 mL) and
dried under reduced pressure to yield the desired product as a
pale pink solid (3.31 g, 81%). The analytical data obtained
matched those reported in the literature.56 Quantitative GC /
GC-MS analysis of the combined organic phases revealed 10%
unreacted isoeugenol, 3% of the cross-metathesis by-product
between eugenol and isoeugenol (2a) and 4% of the eugenol
self-metathesis by-product (2b).
Preparative scale synthesis of (E)-3,3'-hydroxystilbene (4) by
isomerising metathesis of 3-(non-8-enyl)phenol (1)
In a glove box, a 185 mL oven-dried Ace pressure vessel with a
teflon-coated stirring bar was charged with Pd-1 (117 mg,
0.15 mmol) and M73iPr (165 mg, 0.20 mmol). Subsequently, 3-
(non-8-enyl)phenol (2.18 g, 10.0 mmol) and cyclohexane
(40 mL) were added. The vessel was pressurised with 4 bar
ethylene (ca. 3 equiv.) outside the glove box and the resulting
mixture was stirred at 50 °C for 6 h. The excess ethylene was
then removed by flushing the reaction vessel with argon and
the reaction was allowed to stir at 50 °C for another 12 h. After
cooling down to r.t., the precipitated product was filtered off,
washed with toluene (3x5 mL) and pentane (3x2 mL) and dried
under reduced pressure to yield the desired product as a gray
solid (782 mg, 74%). The analytical data obtained matched
those reported in the literature.59 Quantitative GC / GC-MS
analysis of the combined organic phases revealed 21% of the
Synthesis of 4,4'-dihydroxy-3,3'-dimethoxy-diphenylethane (3)
starting from (E)-4,4'-dihydroxy-3,3'-dimethoxystilbene (2)
A 50 mL glass reactor was charged with
2 (1.37 g, 5.00 mmol),
Pd/C (0.05 mmol) and EtOH (20 mL). The reactor was
pressurised with 7 bar H2 and heated at 50 °C for 5 h. After
depressurising, the suspension was filtered through a plug of
celite and eluted with EtOH (30 mL). The solvent was removed
C-2 phenol derivative 5, 4% of the C-3 phenol derivative 6.
Synthesis of 3,3'-dihydroxy-diphenylethane (7) starting from (E)-
3,3'-hydroxystilbene (4)
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A 50 mL glass reactor was charged with
4
(1.06 g, 5.00 mmol), 1, see also Table S1 in the SI).27 Since no metathesis product
Pd/C (0.05 mmol) and EtOH (20 mL). The reactor was was formed (entry 1), we systematically screened various
pressurised with 7 bar H2 and heated at 50 °C for 5 h. After solvents and found toluene to be uniquely effective. This was
depressurising, the suspension was filtered through a pad of unexpected, because dichloromethane and THF generally
celite and eluted with EtOH (30 mL). The solvent was removed perform better in olefin metatheses (entries 2, 3 and 4).65,66
under reduced pressure to yield
99%).
7 as a white solid (1.01 g,
Table 1 Isomerising metathesis of eugenola
One-pot synthesis of 3,3'-dihydroxy-diphenylethane (7) starting
from 3-(non-8-enyl)phenol (1)
In a glove box, a 185 mL oven-dried Ace pressure vessel with a
teflon-coated stirring bar was charged with Pd-1 (117 mg,
0.15 mmol) and M73iPr (165 mg, 0.20 mmol). Subsequently, 3-
(non-8-enyl)phenol (2.18 g, 10.0 mmol) and cyclohexane
(40 mL) were added. The vessel was pressurised with 4 bar
ethylene (ca. 3 equiv.) outside the glove box and the resulting
mixture was stirred at 50 °C for 6 h. The excess ethylene was
then removed by flushing the reaction vessel with argon and
the reaction was allowed to stir at 50 °C for another 12 h. After
cooling down to r.t., a solution of activated charcoal (1.20 mg,
0.10 mmol) in EtOH (40 mL) was added. The vessel was
pressurised with 7 bar hydrogen and stirred at 50 °C for 5 h.
After depressurising, the suspension was filtered through a
plug of celite and eluted with EtOH (50 mL). The volatiles were
removed under reduced pressure and the resulting solid was
washed with a minimum of toluene (3x2 mL) and pentane
(3x2 mL) to yield the desired product as a white solid (770 mg,
72%). The analytical data obtained matched those reported in
the literature.60
Pd-1 / Ru-cat.
solvent, T
eugenol
2
Entry
Ru-cat. / (mol%)
T (°C)
Solvent
2 (%)
1
2
M51 (0.1)
50
"
THF
n.d.
n.d.
62
82
67
31
n.d.
79
80
63
85
91
88
84
93
81
"
DCM
3
"
"
cyclohexane
4
"
"
toluene
5
G2 (0.1)
"
"
6
M31 (0.1)
"
"
7
M42 (0.1)
"
"
8
M73 (0.1)
"
"
9
M93 (0.1)
"
"
10
11
12
13
14b
15b, c
16b, c, d
M51 (0.1)
r.t.
60
70
80
70
"
"
"
"
"
"
General procedure for the synthesis of polycarbonates
"
"
M51 (0.05)
"
"
A 30 mL radley carousel tube was charged with bisphenol (1
equiv.), diphenyl carbonate (193 mg, 900 µmol, 1 equiv.) and
lithium hydroxide (1.10 mg, 46.0 µmol, 5 mol%) under argon
atmosphere. The resulting mixture was heated at 180 °C for
24 h. The reaction was quenched by cooling to r.t. and addition
of THF (3 mL). The polymer was precipitated in cold methanol
(30 mL), filtered and dried over phosphorous pentoxide at
10-3 mbar for 24 h.
"
"
"
none
a Reaction conditions: eugenol (1 mmol), Ru-cat. (0.1 mol%), Pd-1 (0.5 mol%),
solvent (1 mL), 1 h, isolated yields; b Pd-1 (0.1 mol%); c 4 h; d 30 mmol scale.
The screening of various ruthenium-based metathesis catalysts
(Figure 3) revealed that the modified Hoveyda-Grubbs catalyst
M51 performed best (entries 5-9). The yields could be
improved further by raising the temperature, with optimum
catalyst performance at 70 °C (entries 10-13). Even at catalyst
loadings as low as 0.05 mol% M51 and 0.1 mol% Pd-1, near-
quantitative yields were obtained if the reaction time was
increased from 1 h to 4 h (entries 14 and 15). Under these
optimal conditions, the reaction proceeded highly selectively.
General procedure for the synthesis of thiol-ene polymers
A 10 mL Ace pressure vessel was charged with diallyl (1 equiv.)
and decane dithiol (146 mg, 707 µmol, 1 equiv.) under argon
atmosphere. After stirring at 50 °C for 10 min, AIBN (2.8 mg,
17.0 µmol, 2.5 mol%) was added and the resulting mixture was
heated at 75 °C for 5 h. The mixture was then dissolved in THF
(2 mL) and the polymer was precipitated in cold methanol
(30 mL), filtered and dried over phosphorous pentoxide at
10-3 mbar for 24 h.
The pure product
2 precipitated in 93% yield and was isolated
by filtration. Analysis of the filtrate by GC / GC-MS showed 3%
yield of isoeugenol, but no eugenol self- or cross-metathesis
side products. By performing the reaction under more
sustainable bulk conditions, we were able to scale up the
reaction and provide sufficient material for polymerisation
Results and discussion
Synthesis of di(hydroxyphenyl) derivatives from eugenol
tests (entry 16). In the absence of solvent,
2 was isolated in
81% yield, but the amount of undesired side products
increased to 4 % of eugenol self-metathesis products and 3%
of cross-metathesis products between eugenol and
isoeugenol. A substantial decrease in the E-factor (total kg
waste per kg product) from 7.1 to 0.5 was achieved.
As a starting point, the isomerising metathesis of eugenol was
investigated using a combination of 0.5 mol% isomerisation
catalyst [Pd(µ-Br)(tBu3P)]2 (Pd-1
61-64
)
and 0.1 mol% metathesis
catalyst M51 in THF at 50 °C while applying the conditions
previously described in a related isomerising ethenolysis (Table
4 | J. Name., 2012, 00, 1-3
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The stilbene double bond was then hydrogenated using 1 manufacture, the lower is the content of anacardic acids (see
mol% Pd/C either starting from isolated , or by adding the Figure 2). Ideally, any of these mixtures should directly be
palladium catalyst to the crude reaction mixture and stirring it converted into 3,3’-dihydroxystilbene ( ) when first subjected
2
4
for another 5 h at 50 °C with 10 bar hydrogen pressure. The to isomerising metathesis in the presence of ethylene with
one-step procedure afforded 80% overall yield of the constant removal of volatile olefins, and then to high-
di(hydroxyphenyl)ethane 3 (Scheme 3). When using the metals temperature distillation with concomitant decarboxylation.
already present in the solution as hydrogenation catalysts, the However, present isomerisation catalysts are incompatible
conversion of the one-pot procedure was high but not with the polyene components present in crude cardanol. For
quantitative.
this reason, an additional ethenolysis step is required upfront.
We thus first treated a commercial CNSL containing mostly
phenols with saturated, mono- and polyunsaturated side
chains with 10 bar ethylene in toluene in the presence of 0.2
mol% HG1 (Figure 2). Fractional distillation caused any
anacardic acids to decarboxylate, so that 3-(non-8-enyl)phenol
N
N
N
N
N
N
Br
Mes
O
Mes
Mes
Mes
Mes
Mes
Cl
Cl
Cl
Cl
Ru
O
Ru
Cl Ru
PCy3
Cl
NMe2
(1) was isolated in 84% yield as the distillate, whereas
resorcinols and saturated C-15 phenols formed the distillation
residue and volatile olefins evaporated.
M51
G2
M93
The next step towards dihydroxystilbene
4 was the
N
N
N
N
development of a tandem isomerising ethenolysis / homo-
metathesis process. First, isomerising ethenolysis would
Mes
O
Mes
PCy3
Mes
Mes
Ph
Ph
Cl
Cl
Cl
Cl
Cl
Ru
O
Ru
N
Ru
N
continually shorten the nonenyl chains of
1 with release of
volatile short-chain olefins. The resulting 3-vinylphenol
intermediate would then undergo self-metathesis with release
of ethylene to form the desired product. Because most
catalysts would preferentially mediate the metathesis
between two substrates with longer alkenyl chains, the key
challenge was to maximise ethylene intake. At the same time,
the catalyst would have to be capable of a self-metathesis of
vinylarenes, which have a particularly low reactivity.
M42
M31
HG1
iPr
Mes
iPr
N
N
N
N
Mes
Cl
Cl
Cl
Cl
O
O
Ru
Ru
O
OiBu
OiBu
N
H
N
H
O
We started our search for a suitable catalyst system with
conditions developed for the synthesis of vinylarenes from
cardanol,27 involving 1.5 mol% of isomerisation catalyst Pd-1
and 2 mol% of metathesis catalyst M51 (Table 2, see also Table
M73
M73iPr
Figure 3 Metathesis catalysts.
S2 in the SI). In THF, C-2 and C-3 phenol derivatives
were formed as major products, indicating
5
and
6
a
too-high
preference for ethenolysis (entry 1). In other common
metathesis solvents, mixtures of longer-chain alkenyl phenols
were obtained (R>CH3), indicating that the reaction rate is
rather slow (entries 2-4). Systematic evaluation of ruthenium-
based metathesis catalysts in cyclohexane revealed the unique
selectivity profile of M73iPr (entry 5), which was the only one
0.1 mol% Pd-1
0.05 mol% M51
70 °C, 4 h, neat
eugenol
2
3.31 g
81%
4.98 g (30 mmol)
to give the desired product in reasonable yield. The yield of
4
H
(10 bar)
was further improved by fine-tuning the reaction conditions,
i.e. adjusting the ethylene pressure to 1 bar (ca. 3 equiv.),
investigating the optimal reaction temperature, and removing
excess ethylene by argon exchange after 6 h and continuing to
stir overnight (entries 8, 9, 10). Under the optimal conditions
2
EtOH, 50 °C, 5 h
1 mol% Pd/C
(entry 10),
4 precipitates and was isolated in pure form in 79%
yield simply by washing the precipitate with toluene and
pentane. The combined filtrates contained a further 5% yield
3
3.28 g
80%
of product
4, along with 12% yield of side products 5 and 6,
Scheme 3 Synthesis of di(hydroxyphenyl) derivatives from eugenol via isomerising
along with traces of longer-chain alkenyl arenes (R>CH3).
metathesis and optional hydrogenation.
When ethylene was left out altogether, the product was still
obtained in 30% yield, which may be explained with a
preference of the catalyst for vinylarene homo-metathesis or
the exceptionally low energy of formation of the stilbene
product (entry 11), since the equilibrium content of the
Synthesis of di(hydroxyphenyl) derivatives from CNSL
Cashew nut shell liquid is commercially available in various
qualities. The higher the thermal stress applied in its
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Scheme 4 Synthesis of di(hydroxyphenyl) derivatives from 3-(non-8-enyl)phenol via
conjugated alkenylphenol is 35% rather than the 60% required
for this reaction outcome purely by statistics.
isomerising metathesis and optional hydrogenation. A.C. = activated charcoal.
Table 2 Isomerising metathesis of 3-(non-8-enyl)phenol (1)a
Polymerisation studies
Polycarbonates. The first chosen application for the stilbene-
based monomers was as polycarbonates (PCs), a typical end
product of BPA. Thus, polycarbonates PC2
were prepared in a sustainable fashion from the diphenols
and with diphenyl carbonate and catalytic LiOH at 180
, PC3, PC4, and PC7
Pd-1
Ru-cat.
2,
solv ent
n
3,
4
7
°C, rather than using the conventional phosgene process
(Scheme 5). As a reference material, a polycarbonate PCBPA
was prepared from BPA by the same process.
5 (R = H
6 (R = Me)
1
4
5 + 6
R > CH3
(%)b
traces
76
Entry
Solvent
Ru-cat.
4 (%)
(%)b
1
2
THF
M51
n.d.
n.d.
n.d.
n.d.
68
93
(PhO) CO
2
n
DCM
"
23
5 mol% LiOH
3
toluene
"
8
90
180 °C, 24 h
4
cyclohexane
"
M73iPr
M73
M93
M73iPr
"
n.d.
18
99
5
"
"
"
"
"
"
"
traces
64
6
n.d.
n.d.
72
36
7
8c
9c, d
10c, e
11f
n.d.
14
99
traces
traces
traces
60
69
15
monomer poly carbonate
monomer
poly carbonate
"
79
12
Y = CH=CH:
CH -CH :
4
7
PC4
PC7
2 (R = OMe)
3 (R = OMe)
BPA (R = H)
PC2 (R = OMe)
"
30
traces
PC3 (R = OMe)
PCBPA(R = H)
2
2
a Reaction conditions: 1 (0.5 mmol), Pd-1 (1.5 mol%), Ru-cat. (2 mol%), C2H4
C(CH ) :
3
2
(6 bar), solvent (2 mL), 50 °C, 18 h, isolated yields; b yields were determined
Scheme 5 Polycarbonate synthesis.
c
d
by GC using n-decane as internal standard;
C2H4 (1 bar);
70 °C;
e C2H4-argon exchange after 6 h; f without C2H4.
Table 3 summarises the properties of the polycarbonates
obtained from stilbenes
from BPA.
2 and 4, dihydrostilbenes 3 and 7, and
We were pleased to see that the results were comparable on
preparative scale (Scheme 4). The low solubility of the stilbene
in non-polar solvents allows isolating the product simply by
filtration of the reaction mixture and washing the precipitate
with toluene.
The eugenol-derived monomers
2 and 3 and the CNSL-derived
monomer 7 gave polycarbonates with comparable but rather
low average molecular weight (Mn) after 24 hours reaction
time. Under the same conditions, BPA led to THF-insoluble
polymer PCBPA1. In order to allow a comparison with the bio-
based polycarbonates, the reaction time for BPA was reduced
to 3 hours, affording PCBPA2 with a Mn in the desired range.
The one-pot procedure can be extended further to include
hydrogenation of
4 to the di(hydroxyphenyl) ethane 7. A
ruthenium-on-charcoal hydrogenation catalyst was generated
in situ from M73iPr by adding ethanol, 1 mol% activated
charcoal, and pressurising with 7 bar hydrogen. After 5 hours
The CNSL-derived monomer
already after 40 min, so that no Mn could be measured. The
dispersity (Ɖ) values for the soluble polymers PC2 PC3 PC7
and PCBPA2 vary between 1.5 and 2.0, as can be expected for
step-growth polymerisation. Thus, the Mn as well as
4 led to THF-insoluble polymer
at 50 °C,
4
was quantitatively converted to 7.
,
,
,
OH
a
OH
C H (3 equiv .)
2
4
dispersities of the PCs from renewables, both comparable to
PCBPA2, demonstrate that these monomers are reactive in
polycarbonate synthesis.
1.5 mol% Pd-1
2 mol% M73iPr
50 °C, 18 h
cyclohexane
n
Thermal properties, such as melting points and glass transition
temperature, depend on the chemical structure of the polymer
as well as on Mn. Thus, only polymers with similar Mn can be
compared, especially for rather low-molecular-weight
materials as obtained here. The melting points of
1
4
OH
2.18 g (10.0 mmol)
0.78 g
74%
H
(7 bar)
2
EtOH, 50 °C, 5 h
OH
1 mol% A.C.
polycarbonates PC2, PC3, and PC7 were below 150 °C,
whereas the BPA-based polymer PCBPA2 with similar Mn
melted at 224-228 °C, a difference attributable to structural
factors.
The glass transition temperature (Tg) ranges from 25 °C for PC7
to 127 °C for PC2 for the polymers with Mn of 2000-3500.
7
0.77 g
72%
OH
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Polymer PC3 showed a Tg of 81 °C, in agreement with
literature reports.67 This temperature is comparable to that of
PCBPA2 at similar molecular weights, indicating a similar
rigidity of the two polymers. Hydrogenation of the stilbene
increases the flexibility of the chain reflected by a decrease in
Tg of polymers PC3 and PC7 compared to their unsaturated
equivalents PC2 and PC4. Steric hindrance in the proximity of
the hydroxyl group could be a reason why eugenol-derived
HO
R
O
R
OH
R
O
4 equiv. DAC
1 equiv. TBAB
120 °C, 20 h
Y
Y
R
2.5 mol% AIBN
75 °C, 5 h
HS
S
SH
10
(C3H6)
O
R
S
O
(C3H6)
polymer PC3 presents higher Tg than its CNSE equivalent PC7
.
H
S
S
H
n
A decrease in the melting points from the unsaturated
polymer PC2 to more flexible polymer PC3 was also observed.
For PC4 and PC7, the melting points are hard to interpret due
to differences in the Mn. All polymers showed semicrystalline
behaviour, which is typical for PCs precipitated from
methanol.68
10
10
Y
R
R
R
O
O
O
O
Y
Y
monomer
Table 3 Summary of the analytical results of polycarbonatesa
thiol-ene
polymer
thiol-ene
poly mer
monomer
Polymer
PC2
Mn (g/mol)
Ɖ
mp (°C)
Tg (°C)
127
160
81
Td 5% (°C)
305
Y = CH=CH: A4
CH -CH : A7
TE4
TE7
A2 (R = OMe) TE2 (R = OMe)
A3 (R = OMe) TE3 (R = OMe)
ABPA(R = H) TEBPA (R = H)
2800
b
2.0
b
146 – 148
258 – 262
106 – 108
143 – 146
280 – 290
224 – 228
PC4
-
-
313
2
2
C(CH ) :
PC3
3500
2200
1.5
1.6
319
3
2
PC7
25
292
Scheme 6 Thiol-ene polymerisation. DAC = diallyl carbonate.
b
b
PCBPA1
PCBPA2c
-
-
115
79
332
2700
1.3
314
Table 4 Summary of the analytical results of thiol-ene polymersa
a
Reaction conditions: bisphenol monomer (1 equiv.), diphenyl carbonate (1
equiv.), LiOH (5 mol%), 180 °C, 24 h; b insoluble in THF; 3 h reaction time;
c
Polymer
TE2b
mp (°C)
25 – 50
25 – 50
25 – 50
25 – 50
r.t.
Mn [g/mol]
2700
Ɖ
Td 5% [°C]
301
1.7
7.1
3.0
5.3
3.6
properties of materials precipitated from methanol, see SI for details.
TE4
3100
316
TE3
4300
336
All polymers present excellent degradation temperatures
(Td 5%). For materials with a similar molecular weight range,
Td 5% for PC3 (319 °C) is closest to that of the BPA-based
polymer PCBPA2 (314 °C). PC2 and PC7 have slightly lower
degradation temperatures, but the values for all
polycarbonates are within a narrow range between 292 and
332 °C.
TE7
16600
5200
311
TEBPA
270
a
Reaction conditions: diallyl monomer (1 equiv.), decane dithiol (1 equiv.),
AIBN (2.5 mol%), 75 °C, 5 h. b in THF; properties of material precipitated from
methanol, see SI for details.
Polymer TE3 showed similar Mn and Ɖ values to TEBPA, but
the best reactivity (highest Mn) was observed for CNSE-derived
Overall, polymers with a wide range of thermal properties
were obtained. The reactivity of the monomers and
characteristics of the polymers are promising in terms of a
possible substitution of bisphenol A, but intensive future
research will be required to ultimately prove this.
monomer
7 to form polymer TE7 with a molecular weight of
16000 g/mol. The liquid mixture became viscous already after
30 min. reaction time. The broad dispersity value (Ɖ = 5.3) of
polymer TE4, as well as a broadening of the 1H NMR peaks (see
SI), indicate that cross-linking took place. The same
phenomenon was observed for polymer TE2, but with a lower
reactivity, which may be explained by the increased steric
Thiol-ene polymerisation. To complement our studies, we
investigated the reactivity of our di(hydroxyphenyl) derivatives
in a different polymer class. We chose thiol-ene addition,
which is an efficient, sustainable polymerisation technique
performed under mild conditions.69,70
hindrance of the ortho-methoxy group in 2. The allylated CNSE
derivative A4 is liquid at room temperature, whereas the
eugenol counterpart A2 has a melting point of 141 °C, making
The first step was the allylation of the phenols to afford diallyl
derivatives. The procedure can be carried out either via
conventional Williamson reaction or via a more sustainable
route using diallyl carbonate instead of the toxic allyl bromide
(Scheme 6).71 Both pathways afforded the allylated monomers
the reaction in bulk impossible. For the polymerisation of A2
,
additional solvent was required and consequently, the lower
concentration could have also decreased the molecular weight
obtained. The thermal properties were similar for all thiol-ene
polymers, with degradation temperatures ranging from 270 °C
A2, A4, A3, A7 and ABPA in good-to-excellent yields (see SI).
The thiol-ene polymerisation was carried out using the
allylated monomer and one equivalent of decane dithiol, using
AIBN as radical initiator, as shown in Scheme 6. The properties
of the thiol-ene polymers and the analogous BPA-based
reference polymer TEBPA are summarised in Table 4.
in the case of TEBPA to 336 °C for TE3
.
The results obtained in the thiol-ene polymerisation point to
another potential application of these monomers derived from
renewable resources. The saturated monomers are suitable for
linear polymers, whereas cross-linking in the stilbene-based
monomers allows their use in resin synthesis.72 Comparing
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these results to those for PCs described above, a wide range of we were pleased to find that the eugenol-derived monomers
2
properties may be achieved. Unsurprisingly, the thiol-ene and
3
showed considerably lower estrogenicity.74 The lower
polymers were obtained in higher molecular weights due to estrogen receptor affinity caused by the ortho-methoxy groups
better solubility during polymerisation as well as less steric may be attributed to steric hindrance. This is in line with
hindrance of the monomers employed. These preliminary observations made for the ortho-methoxy-substituted BPA
investigations suggest that the polymers prepared starting analogue 2,2-bis(4-hydroxy-3-methoxyphenyl)propane, which
from renewable resources have promising properties, but was found not to displace estradiol in a competitive binding
further investigations are clearly required to assess the assay.75
mechanical properties of the bulk materials.
Conclusions
Estrogenicity assay
Overall, it was demonstrated that isomerising metathesis is a
viable concept for the sustainable synthesis of
di(hydroxyphenyl) derivatives starting from renewable
resources including eugenol and cardanol. The estrogenic
activity of the monomers derived from cardanol was found to
be in the same range as BPA, whereas the eugenol-derived
materials were found to be non-estrogenic. Polycarbonate and
thiol-ene polymers were prepared from the dihydroxystilbene
and dihydroxy-dihydrostilbene monomers, demonstrating
their general usefulness. Future studies need to address
mechanical as well as other material properties of these novel
polymers in order to ascertain the viability of the present
strategy to replace bisphenol A with sustainable alternatives.
The lack of estrogenic activity in the eugenol-derived
monomers makes them suitable candidates for the
development of novel bio-based food packaging materials,
while the polymers derived from cashew nut shell liquid may
become a welcome alternative to petrol-derived BPA materials
in non-food applications.
For potential applications in food packaging, degradation of
the polymers with release of estrogenic monomers is a major
concern. To assess the estrogenicity of the di(hydroxyphenyl)
building blocks 2, 4, 3, and 7, we subjected them to a yeast
estrogen screen (YES).73 YES is a reporter gene assay that
measures human estrogen receptor alpha (hERα) activation.
The yeast cell nucleus is genetically modified to contain the
gene for the human estrogen receptor along with a vector
composed of a promoter region and lacZ gene. The estrogen
receptor is expressed by the yeast cell and attaches to the
estrogen receptor elements (ERE) within the promoter.
Binding of an estrogenic substrate to the receptor switches on
the promoter, leading to expression of the lacZ gene and
production of β-galactosidase. This enzyme is released into the
medium, where it converts added chlorophenol red-β-D-
galactopyranoside (CPRG) to chlorophenol red (CPR). The
colour change from yellow to red is quantified
photometrically.
Figure 4 shows the concentration-response curves for hERα
activation by our test compounds along with a BPA calibration
curve. The measurements were run at concentrations ranging
from 11 to 750 µg/L. At 750 µg/L BPA, the receptor activation
equals that of estradiol at a concentration of 0.05 µg/L.
Acknowledgements
The authors thank Carl-Zeiss-Stiftung (Zentrum für
ressourceneffiziente Chemie und Rohstoffwandel, RCR), the
Deutsche Forschungsgemeinschaft (Collaborative Research
Centre SFB/TRR 88 ‘3MET’ and Cluster of Excellence RESOLV,
EXC 1069), and the Deutsche Bundesstiftung Umwelt
(fellowships to S.B., J.P. and L.C.O.) for financial support,
Cardolite and Umicore AG for donation of chemicals,
Bundesanstalt für Gewässerkunde (BfG) for YES measurements
and Q. Liu and M. Poß from the group of Prof. Feldmann for
TGA measurements.
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Plant-derived alkenyl arenes were converted to polymer building blocks with low estrogenic activity via
isomerising metathesis.
low estrogenic activity
HO
R
[Pd]
[Ru]
HO
R
OH
R
n
poly carbonates thiol-ene poly mers