Chemo-enzymatic functionalization of gallic and vanillic acids: Synthesis of bio-based epoxy resins prepolymers

Article abstract of DOI:10.1039/c2gc35558b

The chemo-enzymatic epoxidation of allylated gallic and vanillic acids with lipase B from Candida antarctica and aqueous hydrogen peroxide in the presence of caprylic acid was investigated. The use of 1 molar eq of caprylic acid and 1.8-2 molar eq of H₂O₂ per allylic double bond led to a high degree of conversion to epoxides (89% yield for allylated gallic acid and 87% yield for allylated vanillic acid) comparatively to the hazardous peracid mCPBA (1.5-3.2 molar eq per double bond allowed 75-85% yield). The epoxidized products obtained could be used in the formulation of novel bio-based epoxy resins.

Full text of DOI:10.1039/c2gc35558b

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PAPER
Chemo-enzymatic functionalization of gallic and vanillic acids: synthesis of
bio-based epoxy resins prepolymers†
Chahinez Aouf,*a,b,c Jérôme Lecomte,d Pierre Villeneuve,d Eric Dubreucqe and Hélène Fulcranda,b,c
Received 13th April 2012, Accepted 7th June 2012
DOI: 10.1039/c2gc35558b
The chemo-enzymatic epoxidation of allylated gallic and vanillic acids with lipase B from Candida
antarctica and aqueous hydrogen peroxide in the presence of caprylic acid was investigated. The use
of 1 molar eq of caprylic acid and 1.8–2 molar eq of H2O2 per allylic double bond led to a high degree
of conversion to epoxides (89% yield for allylated gallic acid and 87% yield for allylated vanillic acid)
comparatively to the hazardous peracid mCPBA (1.5–3.2 molar eq per double bond allowed 75–85%
yield). The epoxidized products obtained could be used in the formulation of novel bio-based epoxy
resins.
precocious puberty,6 decreased sperm count and infertility,7,8
Introduction
increased risks of breast and prostate cancers,9 behavioural
effects,10,11 and altered immune functions.12 The negative
Epoxy resin is a prepolymer of two or more reactive terminal
oxirane groups. It finds useful applications in bulk structural
composites, thin speciality protective coating, encapsulation and
electrical–electronic insulation.1–3
With wide formulation possibilities in the presence of a curing
agent and processing versatilities, epoxy resin produces cross-
linked or thermoset plastics, which have excellent strength,
toughness, chemical resistance, adhesive, and electrical
properties.1–3
Epoxy resins are usually prepared from materials having two
or more reactive hydrogen atoms and epichlorohydrin. More
than 75% of epoxy resins derived from diglycidyl ether of
bisphenol-A (DGEBPA),1 prepared by the coupling of epichloro-
hydrin (EP) and bisphenol-A (BPA). BPA is one of the highest
volume chemicals produced worldwide. Current estimates indi-
cate that more than 4 million tons of BPA are produced annually
and approximately 100 tons may be released into the atmosphere
each year.4 However, this petroleum-based compound, which is
very pervasive in our environment and in our daily lives, may
lead to several negative health effects. Indeed, many studies on
the possible hazardous effects of BPA have been published. This
endocrine disruptor has been reported to have significant effects
on living beings. These effects involve increased growth rate,5
impact of BPA on human health and the environment makes
necessary the development of research aiming at the substitution
of BPA by non-harmful compounds in the manufacture of epoxy
resins.
Recent years have witnessed an increasing demand on poly-
mers derived from renewable resources in industrial applications
due to environmental issues, waste disposal, and depletion of
non-renewable resources.13–16 Renewable resources can provide
an interesting sustainable platform to substitute petroleum-based
polymers through the design of bio-based polymers that can
compete or even surpass the existing petroleum-based materials
on
a cost-performance basis with high eco-friendliness
values.17,18 In epoxy resin manufacturing, attention has been
paid to the development of biopolymers from vegetable oil
derivatives. Indeed, several researchers have investigated the
curing and conversion of epoxidized oils into flexible, semiflex-
ible, and rigid crosslinked resins with various approaches.19–22
However, the properties and performance of epoxy resins are
highly dependent on their molecular architecture. If the chemical
structures of epoxy resins constitute of flexible or aliphatic
chains, their thermal resistance is inferior to those containing
aromatic and/or heterocyclic rings.23 Hence, in order to obtain
epoxy resins with high toughness and good thermal resistance,
we have turned our attention to natural phenolic compounds.
Natural polyphenols (lignin, condensed tannins and gallotannins)
are among the most abundant renewable natural resources,
available in large quantities from forest/agricultural biomass
or residues, and are now being used in many industrial
applications.24–26 More particularly, non-functionalized gallic
acid, produced from hydrolysis of gallotannins has been
involved in some epoxy resins formulations.27–29
aINRA, UMR1083 Sciences Pour l’Oenologie, F-34060 Montpellier,
France. E-mail: Chahinez.Aouf@supagro.inra.fr;
Fax: (+33) 4 9961-2857; Tel: (+33) 4 9961-2454
bMontpellier SupAgro, UMR1083 Sciences Pour l’Oenologie, F-34060
Montpellier, France
cUniversité Montpellier I, UMR1083 Sciences Pour l’Oenologie,
F-34060 Montpellier, France
dCIRAD, UMR IATE, F-34060 Montpellier, France
eMontpellier SupAgro, UMR IATE, F-34060 Montpellier, France
†Electronic supplementary information (ESI) available: Analytical data
of compounds 4b, 4b′, 4c, 5b, 5b′, 5c and 5d and the copies of
1H NMR, 13C NMR and HMBC spectra. See DOI: 10.1039/c2gc35558b
Nevertheless, the industrial approach consisting in functiona-
lizing natural phenolic compounds with epichlorohydrin is not
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Scheme 1 Alkaline assisted allylation of gallic acid and vanillic acid.
satisfactory in terms of green chemistry concepts. The other
route to incorporate oxirane rings into the backbone of phenolic
compounds is the alkaline assisted alkylation of phenolic
hydroxyls followed by the epoxidation of the resulting double
bonds. Epoxides can be readily prepared from alkenes through a
number of methods, including transition metal catalyzed oxi-
dation with hydrogen peroxide or molecular oxygen and treat-
ment with sulfonic peracids, m-chloroperoxybenzoic acid
(mCPBA) or dimethyldioxirane.30–34 However, the hazardous
nature of these techniques and the potential to hydrolyse the
epoxide35 preclude their use on a large scale. An alternative
method to epoxidize alkenes, mediated by a lipase in the pres-
ence of a small amount of free fatty acids was described by
Björkling in the early 1990s.36,37 The reaction proceeds in two
steps. Firstly, fatty acids are converted into peroxy acids by
lipase-catalysed perhydrolysis. Then, peroxy acids are recon-
verted into fatty acids by transferring oxygen to double bonds to
form oxirane rings. The process takes place under mild con-
ditions and gives high epoxide yields. Later, progress was made
towards reducing the limitations of industrial scale syntheses by
making the procedure a more environmentally acceptable
alternative especially for vegetable oil transformations.38–41
The aim of the present work is to adapt this technology to the
functionalization of alkylated gallic acid (derived from the
hydrolysis of gallotannins) and vanillic acid (subunit of lignin)
allowing the synthesis of bio-based epoxy prepolymers under
eco-friendly conditions. The capacity of the biocatalytic method
to epoxidize the alkylated phenolic compounds was compared
with that of mCPBA.
commercially available 70% m-chloroperbenzoic acid (mCPBA)
and a chemo-enzymatic approach involving a peroxy acid gener-
ated from the reaction of a fatty acid with hydrogen peroxide in
the presence of an immobilised lipase.
Allylation of phenolic compounds
The treatment of gallic acid and vanillic acid by allyl bromide
(molar ratio hydroxyl group/allyl bromide, 1 : 1) in the presence
of potassium carbonate (molar ratio hydroxyl group/potassium
carbonate, 1 : 1) in DMF allowed the total O-allylation of these
phenolic compounds to give the tetraallylated derivative of gallic
acid 1 and the diallylated derivative of vanillic acid 2 in 84%
and 94% yield respectively (Scheme 1). The substitution of phe-
nolic and carboxylic protons by the allylic groups was confirmed
1
by the appearance of specific H NMR signals. Signals in the
range of 5.16–6.03 ppm are assigned to the allylic double bond
and those located at 4.50–4.80 ppm belong to the oxygen
bonded methylenes (see Experimental).
In order to design a phenolic structure close to bisphenol
A (containing two aromatic rings), the allylated derivative 3 was
prepared in two steps from vanillic acid. The first step synthesis
involved the reaction of an excess of vanillic acid (3.5 eq) with
1,5-dibromopentane (1 eq) in the presence of 2.2 eq of potass-
ium carbonate at room temperature. This allowed the coupling of
two vanillic acid molecules by esterification. Then, the phenolic
hydroxyl groups underwent an alkaline assisted allylation in the
presence of allyl bromide to give compound 3 as the main
product and compound 2 as secondary product (Scheme 2).
Interestingly, in spite of the alkaline medium, only the car-
boxylic hydroxyl groups were alkylated by 1,5-dibromopentane.
This difference of reactivity may be explained by the higher
acidity of the carboxylic hydroxyl group (pKa = 4.51) compared
to that of the phenolic hydroxyl group (pKa = 9.39),42 which can
induce a higher reactivity of the carboxylic OH towards
electrophiles.
Results and discussion
In the present study, three phenolic compounds were chosen as
raw materials for glycidylation: commercial gallic acid and vanil-
lic acid as well as a phenolic derivative synthesized by the coup-
ling of two vanillic acid molecules.
The epoxy prepolymers have been synthesized by a two-step
functionalization method: the alkaline assisted allylation of
phenolic and carboxylic hydroxyls followed by the epoxidation
of the resulting double bonds. Two epoxidation approaches were
Epoxidation of allylated phenolic compounds 1, 2 and 3
Two methods were compared for the epoxidation of the allylic
implemented and compared:
a
chemical approach using
double bonds of compounds 1, 2 and 3: a classical epoxidation
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Scheme 2 Synthesis of compound 3.
Table 1 Experimental conditions of the epoxidation of 1 by the chemical and the chemo-enzymatic approaches
Time
(h)
Temperature
(°C)
Remaining 1
(%)
4 Yield
(%)
5 Yield
(%)
6 Yield
(%)
7 Yield
(%)
Total epoxidation
yield, %b
Entry
OX (eq/double bond)
1
2
3
4
5
6
C8/H2O2 (0.8 : 1.3)
C8/H2O2 (1 : 1.8)
mCPBA (1.0)
mCPBA (1.5)
mCPBA (2.0)
48
48
24a
24
24
24
40
40
25
25
25
25
—
—
14
—
—
—
12
3
52
23
11
—
38
8
16
36
26
8
25
60
—
26
32
17
13
18
—
—
16
60
88
89
68
85
85
85
mCPBA (3.2)
a The same results were observed when the reaction time was extended to 48 h. b Isolated yield.
using m-chloroperbenzoic acid (mCPBA) at different molar
ratios (Table 1) and a chemo-enzymatic process based on the
enzyme catalysed formation of peracid from fatty acid and an
oxidant such as hydrogen peroxide (H2O2).
Based on these data, the chemo-enzymatic epoxidation of ally-
lated compound 1 was initially studied under different reaction
conditions. Compound 1 in toluene (0.1 M) treated with caprylic
acid (molar ratio C8/CvC, 1 : 1) and hydrogen peroxide (molar
ratio H2O2/CvC, 1 : 1.8) during 48 h at 40 °C in the presence of
Novozym 435 (20 wt% relative to the weight of substrate) were
found to be the optimum conditions for this epoxidation reaction
(Table 1, entry 2). However, the gradual addition of hydrogen
peroxide (addition over 8 h) was necessary to achieve the satis-
factory overall yield of 89%. At the same time, we have verified
that no detectable epoxidation is observed after 48 h in the
absence of lipase.
The epoxidation results for the same compound with different
molar equivalents of the peracid mCPBA are listed in Table 1.
Products 4, 5, 6 and 7 correspond respectively to the mono-,
di-, tri- and tetra-epoxidized derivatives of allylated gallic acid 1.
As shown in Table 1, the total yield of double bonds epoxida-
tion was almost similar for both chemical and chemo-enzymatic
methods except when 1 eq per double bond of mCPBA was
used. However, yields of the epoxidized products 4–7 seem to
be highly influenced by the oxidant concentration. Indeed, in the
case of the chemo-enzymatic epoxidation, the yield of tri-epoxi-
dized derivative 6 (60%) was improved by the increase of the
C8/H2O2 ratio. Similarly, an increase in the mCPBA concen-
tration was accompanied by an increase in the highest epoxidized
products 6 and 7.
Chemo-enzymatic epoxidation of compounds 1, 2 and 3 was
investigated in the presence of immobilized lipase B from
Candida antarctica (Novozym 435) using toluene as the reaction
medium, based on an earlier report with other substrates that
showed the reaction was more efficient in aromatic solvents.43
Caprylic acid (C8) was chosen as the active oxygen carrier
because of its high solubility in toluene, allowing it to be used at
a wider range of concentrations and temperatures. Hydrogen per-
oxide was selected as the oxygen donor. The double bonds of
the allylated phenolic compounds were epoxidized by per-
caprylic acid generated by the reaction of caprylic acid and
H2O2. In the evaluation of the potential of this chemo-enzymatic
approach to epoxidise compounds 1–3, two major aspects were
taken into account. First, the low electron density of the allylic
double bonds induced by their terminal position and by the
vicinity of the allylic oxygen electron-withdrawing group, which
limits their reactivity for electrophilic oxygen transfer. Secondly,
the possible lipase denaturation in the presence of organic
solvents, hydrogen peroxide or the formed peracid.
Indeed, even if the applicability of chemo-enzymatic epoxida-
tion using lipase B from Candida antarctica (CALB) has been
demonstrated with different substrates such as several fatty acids,
fatty acid esters including vegetable oils, and other olefins,44–46
this reaction is influenced by various experimental parameters
and hydrogen peroxide concentration is the most critical para-
meter influencing the reaction rate and the degree of epoxidation.
Törnvall et al.41 and Orellana-Coca et al.44 have conducted
detailed investigations on the source of enzyme deactivation,
concluding that elevated temperatures (above 60 °C) together
with hydrogen peroxide at high concentrations (6 M–12 M)
resulted in a rapid loss of enzyme activity, again illustrating that
careful dosage of H2O2 increased the operational lifetime of the
biocatalyst.
Interestingly, to reach the proportions of tri- and tetra-epoxi-
dized derivatives obtained with the chemo-enzymatic oxidation
(Table 1, entry 2), it was necessary to use 2 to 3.2 molar eq of
mCPBA per double bond which represents a large excess of this
hazardous chemical compound (entries 5 and 6).
The double bonds of diallylated vanillic acid 2 have been
epoxidized in the same manner to give mono- and di-epoxidized
products 8 and 9 respectively. The experimental conditions of
oxidation along with related yields are listed in Table 2.
The highest yield of epoxidation was obtained by the chemo-
enzymatic method (Table 2, entry 2) using caprylic acid (molar
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Table 2 Experimental conditions of the epoxidation of 2 by the chemical and the chemo-enzymatic approaches
Entry
OX (eq/double bond)
Time (h)
Temperature (°C)
Remaining 2 (%)
8 Yield (%)
9 Yield (%)
Total epoxidation yield, %b
1
2
3
4
5
C8/H2O2 (1 : 1.8)
C8/H2O2 (1 : 2.0)
mCPBA (1.0)
mCPBA (2.0)
mCPBA (3.0)
48
48
24a
24
24
40
40
25
25
25
8
52
17
62
45
22
23
70
—
24
53
75
87
62
69
75
—
20
14
5
a The same results were observed when the reaction time was extended to 48 h. b Isolated yield.
Fig. 1 UV and ESI-MS spectra of recovered tetraallylated gallic acid 1.
Scheme 3 Regioisomers of epoxidized products of compound 1 and their experimental ratio.
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ratio C8/CvC, 1 : 1) and hydrogen peroxide (molar ratio H2O2/
CvC, 2 : 1) in the presence of 20 wt% (relative to the weight of
substrate) of Novozym 435. These reaction conditions led to the
total disappearance of the allylated compound 2 and the for-
mation of the di-epoxidized product 9 in fair yield (70%), while
by using up to 3 molar eq of mCPBA per double bond, allylated
compound 2 did not totally react and only 53% of compound 9
were produced (entry 5).
Hence, we can conclude that the enzymatic-assisted generation
of percaprylic acid from caprylic acid and hydrogen peroxide is
more efficient for the epoxidation of the allylic double bonds of
1 and 2 than the widely used mCPBA. Moreover, hydrolysis of
allylic esters by the action of Novozym 435 in the aqueous
medium was not observed. To confirm this unexpected obser-
vation, tetraallylated gallic acid 1 was dissolved in toluene in the
presence of CALB and C8 as described in Table 1, entry 2
except that hydrogen peroxide was replaced by water. After 48 h
at 40 °C, no hydrolysis of allylated ester was observed (Fig. 1).
Thus, allylated gallic and vanillic esters are not good sub-
strates for CALB. The low activity of this lipase on some other
esters has already been reported (see example Juhl et al.47). This
feature is particularly suitable for our application, where water is
necessarily supplied with H2O2 in the reaction medium and
where hydrolysis side activity is unwanted.
and equivalent isomers 6b and 6b′ are allylated in C3 and C5.
The allylic group of the isomer 6c is bonded to the carboxyl
group. Relative proportions were calculated by proton
integrations.
Is the addition of oxygen atom on each allylic double bond
based on statistical laws or is it controlled by some reactivity
rules?
To answer this question, we have calculated the epoxidation
ratio on each reactive site i.e. on the allylic double bonds linked
to C4, to C3/C5 and to the carboxylic group at the end of the
epoxidation reaction.
The different regioisomers obtained at the end of the reaction
belong to four groups: mono-, di-, tri- and tetra-epoxidized pro-
ducts. Statistically, with respect to the monoepoxidized products
group, one regioisomer over fourth is epoxidized at C4 position.
On the other hand, in both cases, the formation of fully epoxi-
dized products (7 and 9) seems to be difficult even if a large
amount of oxidant was used. The total epoxidation could not be
prevented by steric hindrance alone. The reactivity of each
double bond may also be influenced by the number and the rela-
tive positions of the other oxirane rings initially formed. These
reactivity aspects will be studied in the future.
A finer purification of the epoxidation products of 1 (Table 1,
entry 2), allowed the separation of the regioisomers of each
epoxidized product. Their 2D NMR analysis (HMBC) revealed
the relative positions of the different oxirane rings. The set of all
possible regioisomers of the products 4, 5, 6 and 7 are shown in
Scheme 3.
Relative proportions of regioisomers were calculated either
from the yield after purification or by NMR analysis in the case
of regioisomer mixtures. As an example, the HMBC NMR was a
helpful technique in the determination of the relative proportions
of regioisomers of compound 6. Indeed, the proton signals
related to CH2 in α of CvC (6a, 6b, 6b′ and 6c, Fig. 2) of the
1
three isomers were located at 4.57–4.80 ppm by H NMR. Then
the HMBC allowed the discrimination of different isomers by
the localization of their positions on the aromatic ring. As shown
in Fig. 2 for isomer 6a, the allylic group is linked to carbon 4
Fig. 2 HMBC NMR of compound 6.
Table 3 Theoretical and experimental epoxidation ratio of the different epoxidation sites
Ratio of C4
epoxidation site
Ratio of COO
epoxidation site
Ratio of C3/C5
epoxidation site
Degree of
epoxidation
Yield
(%)
Total number
of isomers
Total exp. ratio of
isomers (Scheme 3)
Theor
Exp
Theor
Exp
Theor
Exp
Mono
Di
Tri
3
8
60
18
4
6
4
1
4
6
4
1
1/4
3/6
3/4
1/1
1.7/4
2.0/6
3.7/4
1.0/1
0.773
1/4
3/6
3/4
1/1
0.6/4
3.7/6
2.7/4
1.0/1
0.638
2/4
5/6
4/4
1/1
1.7/4
5.3/6
4.0/4
1.0/1
0.863
Tetra
Epoxidation ratio (Er)
0.677
0.677
0.861
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In the same way, there are 3/6 regioisomers epoxidized at C4
position in the di-epoxidized products group, 3/4 isomers in the
tri-epoxidized products group and 4/4 regioisomers in the last
(Table 2, entry 2). The di-epoxidized product 11 was obtained in
fair yield (66%) along with the mono-epoxidized compound 10
(Scheme 5). Interestingly, the absence of an allylic ester linked
to the aromatic ring does not influence the reactivity of the phe-
nolic allylic double bond. Product 11 containing two glycidyl
ether groups linked to two aromatic rings could be a homologue
of diglycidyl ether of bisphenol A (DGEBPA) .
group (Table 3). Taking into account the yield obtained in each
th
C4
group, we can calculate the theoretical epoxidation ratio (Er
on the C4 position according to the eqn (1):
)
th
1
3
3
ErC4 ¼ ð4 ꢀ 0:03Þ þ ð6 ꢀ 0:08Þ þ ð4 ꢀ 0:60Þ þ ð1 ꢀ 0:18Þ ð1Þ
Using the same equation, the experimental epoxidation ratio
(EreCx4p) for the C4-linked isomers can be calculated (eqn (2)):
Conclusion
In this work, we were interested in two important aspects. The
first one was to use natural phenolic compounds in the synthesis
of epoxy resins prepolymers. The second aspect was to carry out
the functionalization of these phenolic compounds under mild
reaction conditions. Thus, the bio-based prepolymers synthesis
involved a first step of O-allylation followed by the epoxidation
of the resulting double bonds. The conversion to the epoxides
was achieved using caprylic acid as an oxygen carrier and
immobilized lipase B from Candida antarctica (Novozym 435)
as a biocatalyst. This recyclable and catalytic method demon-
strated a good performance in the epoxidation of the allylic
double bonds comparatively to the hazardous peracid mCPBA.
The epoxidation products were characterized by NMR and
different regioisomers were discriminated. In order to clarify the
influence of the oxirane rings initially formed on the reactivity of
residual double bonds, it seems necessary to isolate the mono-
epoxidized product regioisomers and to study kinetics of their
transformation into the highest epoxidized products. This work
will be realized in the future.
exp
1:7
2:0
3:7
ErC4 ¼ ð ꢀ 0:03Þ þ ð 6 ꢀ 0:08Þ þ ð 4 ꢀ 0:60Þ
þ4ð1 ꢀ 0:18Þ
ð2Þ
Based on the same reasoning, the epoxidation ratio of the
other epoxidation sites (COO and C3/C5) can be calculated. The
results are listed in Table 3.
The experimental epoxidation ratios compared to the theoreti-
cal ones revealed that the choice of the epoxidation position is
generally dictated by the statistical laws except for the C4-linked
allylic double bond, which is more epoxidized than expected in
mono- and tri-epoxidized products while the COO position is
less reacted than expected in the tri-epoxidized products.
However, a random distribution of the epoxidation sites was
observed, with equal proportions of the regioisomers of the
monoepoxidized product 8, where only C4 and COO positions
were available for epoxidation (Scheme 4), which indicates that
the phenomena involved in the regional reactivity of allyl bonds
is complex. The understanding of this apparent difference in
reactivity would require a careful experimental and mathematical
study of the kinetics of the reaction, taking into account the
various reacting species.
In summary, we have developed an alternative method for the
synthesis of epoxy resins prepolymers free of bisphenol A and
epichlorohydrin under mild conditions.
Finally, the synthesized product 3 was epoxidized in the
experimental conditions applied to the allylated vanillic acid 2
Experimental
Material and methods
Gallic acid (97.5%), vanillic acid (≥98%), allyl bromide
(99.0%), caprylic acid (≥98%), immobilized lipase B from
Candida antarctica (Novozym 435), meta-chloroperbenzoic acid
(mCPBA, ≤77%), 1,5-dibromopentane (97%), DMF (99.8%),
toluene (99.8%) and CH2Cl2 (99.8%) were purchased from
Sigma-Aldrich (France). Hydrogen peroxide (35 wt% in H2O)
was purchased from Acros Organics (France) and was buffered
to pH = 5 with sodium phosphate.
Scheme 4 Regioisomers of compound 8.
Scheme 5 The epoxidation of compound 3.
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All the reactions were monitored by TLC. TLC was performed
on silica gel 60 F254. 1H and 13C NMR spectra were recorded in
DMSO-d6, CDCl3 and methanol-d4 solutions at 500 MHz using
a VARIAN Unity-Inova spectrometer. Chemical shifts are
reported in ppm relative to DMSO [signals for residual DMSO-
123.03 (6), 123.88 (C–CO), 133.09 (d), 133.49 (d′), 149.63
(C–OMe), 153.00 (C–Oallyl), 166.65 (CvO) ppm. [C14H16O4 +
H+]: 249.0.
Synthesis of compound 3
1
h6 in the DMSO-d6: 2.50 for H NMR and 39.4 for 13C NMR],
CDCl3 [signals for residual CHCl3 in the CDCl3: 7.26 for
1H NMR and 77.0 for 13C NMR] and methanol-d4 [signals for
residual methanol-h4 in the methanol-d4: 3.31 for 1H NMR
and 49.15 for 13C NMR]. ESI-MS analyse in positive mode
were performed using a Brucker Daltonics Ion trap mass spectro-
photometer (Bremen, Germany) coupled to Reversed-Phase
Ultra Performance Liquid Chromatography (UPLC). Samples
(5 μL) were directly injected to the UPLC system coupled to
ESI-MS. The liquid chromatography system was an Acquity
UPLC (Waters, Milford, MA) equipped with a Photodiode
Array Detector. The column was a BEH C8 1.0 × 50 mm,
1.7 μm. The flow rate was 0.30 mL min−1 and the gradient con-
ditions were solvent A (H2O); solvent B (CH3CN); initial 0.1%
B; 0–3 min, 30% B linear; 3–6 min, 60% B linear; 6–8 min,
99.9% B linear.
Potassium carbonate (2.2 mmol, 0.3 g) was added at 0 °C to a
solution of vanillic acid (3.5 mmol, 0.6 g) in DMF (10 mL).
After five minutes, 1,5-bromopentane (1 mmol, 0.13 mL) was
added slowly to the mixture. The solution was stirred for 30 min
at 0 °C and 48 h at 25 °C. 30 mL of water was added and the
aqueous solution was extracted with 3 × 30 mL of ethyl acetate.
The organic phase was washed with 50 mL of brine then dried
over MgSO4 and vacuum concentrated. The crude product
obtained was dissolved in 10 mL of DMF. Potassium carbonate
(4.3 mmol, 0.6 g) and allyl bromide (5.2 mmol, 0.45 mL) were
then added at 0 °C and the solution was stirred 48 h at 25 °C.
The work up mentioned above was repeated and the residue was
purified by flash chromatography on silica gel with petroleum
ether/ethyl acetate, 60 : 40 to give:
Pentane-1,5-diyl bis(4-(allyloxy)-3-methoxybenzoate) 3. Col-
1
ourless oil. (1.11 mmol, 65%). H NMR (500 MHz, DMSO-d6)
General procedure for the allylation of phenolic compounds
δ = 1.53 (m, 2H, c), 1.77 (m, 4H, b), 3.80, (s, 6H, Me), 4.26 (t,
J = 6.4 Hz, 4H, a), 4.62 (d, J = 5.3 Hz, 4H, d), 5.27 (d,
J = 10.5 Hz, 2H, f) 5.40 (d, J = 17.3 Hz, 2H, g), 6.04 (m,
2H, e), 7.01 (d, J = 8.5 Hz, 2H, H-5), 7.43 (s, 1H, H-2), 7.53
(d, J = 8.5 Hz, 2H, H-6) ppm. [C27H32O8 + H+]: 485.0.
A 250 mL two-necked flask equipped with a septum cap and
magnetic stirring bar was charged with 100 mL of DMF and
17 mmol of gallic acid or vanillic acid. The solution was cooled
with an ice bath and potassium carbonate (68 mmol for gallic
acid and 34 mmol for vanillic acid) was added. After five
minutes, allyl bromide (68 mmol for gallic acid and 34 mmol
for vanillic acid) was added dropwise by a dropping funnel.
The solution was stirred for 30 min at 0 °C and then at 25 °C
during 48 h. 100 mL of water was added and the aqueous phase
was extracted with 3 × 100 mL of ethyl acetate. The organic
phase was washed with 100 mL of brine then dried over MgSO4
and vacuum concentrated.
Procedures for the epoxidation of allylated phenolic compounds
(1) With mCPBA
A 50 mL two-necked flask equipped with a dropping funnel
and magnetic stirring bar was charged with a solution of 1 mmol
of allylated phenolic compound in 5 mL of CH2Cl2. The
specified amount of meta-chloroperoxybenzoic acid ≥70%
(wt/wt) was dissolved in 10 mL of CH2Cl2 and added slowly at
0 °C over 5 min. The solution was then stirred 24 h at 25 °C.
After this time, 30 mL of 10% (wt/v) of Na2SO3 aqueous
solution was added followed by 30 mL of saturated aqueous
solution of NaHCO3 and 30 mL of brine. The aqueous phase
was extracted with 2 × 30 mL of CH2Cl2. The organic phase was
dried over MgSO4 and vacuum concentrated.
The residue was purified by silica gel chromatography (pet-
roleum ether/ethyl acetate, 90 : 10) to give:
Allyl-3,4,5-tris(allyloxy)benzoate 1. Pale yellow oil. (14.2 mmol,
1
84%). H NMR (500 MHz, DMSO-d6) δ = 4.54 (d, J = 5.7 Hz,
2H, a′), 4.63 (d, J = 5.0 Hz, 4H, a′′), 4.78 (d, J = 5.3 Hz, 2H, a),
5.16 (d, J = 10.6 Hz, 1H, c′), 5.26 (d, J = 10.5 Hz, 2H, c′′),
5.29 (d, J = 15.2 Hz, 1H, d′), 5.32 (d, J = 17.2 Hz, 1H, d′′),
5.35 (d, J = 10.6 Hz, 1H, c), 5.41 (d, J = 17.0 Hz, 2H, d), 6.03
(m, 4H, bb′b′′), 7.25 (s, 2H, H2) ppm. 13C NMR (125 MHz,
DMSO-d6) δ = 65.27 (a), 69.30 (2C, a′′), 73.30 (a′), 108.13 (2C,
2), 117.34 (2C, c′′), 117.65 (c), 118.00 (c′), 124.70 (C–CO),
132.80 (b), 133.60 (2C, b′′), 134.50 (b′), 141.26 (C–O), 152.05
(C–O), 165.00 (CvO) ppm. [C19H22O5 + H+]: 331.1.
The crude product obtained was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 90 : 10–30 : 70).
(2) With Novozym 435/caprylic acid/H2O2
The chemo-enzymatic epoxidation reactions were performed
in 50 mL two necked flask equipped with a magnetic stirrer. In
the first step, allylated phenolic compound (1 mmol), and capri-
lyc acid were dissolved in 10 mL of toluene as non-polar
solvent. Then, immobilized lipase B from C. antarctica (20 wt%
relative to the weight of substrate) was added and the mixture
was heated to 40 °C. In the second step, the specified amount of
35% hydrogen peroxide was added over 8 to 10 h. All syntheses
were carried out for 48 h. Conversion of double bonds to epoxy
groups was followed by TLC. When epoxidation was completed,
catalyst beads were removed from the reaction mixture by fil-
tration, the filtered reaction mixture was washed with 2 × 30 mL
of water and the aqueous phase was extracted with 3 × 30 mL of
Allyl-4(allyloxy)-3-methoxybenzoate 2. Colorless oil. (16 mmol,
1
94%). H NMR (500 MHz, methanol-d4) δ = 3.81 (s, 3H, Me),
4.56 (d, J = 5.2 Hz, 2H, a), 4.72 (d, J = 5.5 Hz, 2H, a′), 5.23
(dd, J = 10.63, 5.3 Hz, 2H, bb′), 5.36 (t, J = 15.3 Hz, 2H, cc′)
6.01 (ddd, J = 16.9, 10.2, 5.0 Hz, 2H, dd′), 6.90 (d, J = 8.5 Hz,
1H, H-5), 7.48 (s, 1H, H-2), 7.56 (d, J = 8.5 Hz, 1H, H-6) ppm.
13C NMR (125 MHz, methanol-d4) δ = 55.71 (CMe), 65.70 (a′),
69.83 (a), 112.67 (2), 112.81 (5), 117.43 (b′), 117.57 (b),
2334 | Green Chem., 2012, 14, 2328–2336
This journal is © The Royal Society of Chemistry 2012

View Article Online
ethyl acetate. The organic phase was dried over MgSO4 and
vacuum concentrated.
H-2), 7.59 (d, J = 8.4 Hz, 2H, H-6) ppm. [C14H16O5 + H+]:
265.0.
The crude product obtained was purified by silica gel chrom-
atography (petroleum ether/ethyl acetate, 90 : 10–30 : 70).
Oxiran-2-ylmethyl3-methoxy-4(oxiran-2-ylmethoxy)benzoate 9.
Colourless oil. 1H NMR (500 MHz, DMSO-d6) δ = 2.72 (td, J =
4.3, 2.0 Hz, 2H, a,a′), 2.85 (td, J = 9.7, 4.6 Hz, 2H, b,b′), 3.33
(m, 2H, c,c′), 3.84 (s, 3H, Me), 3.90 (dd, J = 11.3, 6.7 Hz, 1H,
d′), 4.06 (dd, J = 12.3, 6.4 Hz, 1H, d), 4.41 (dd, J = 11.4, 2.3
Hz, 1H, e′) 4.61 (dd, J = 12.3, 2.3 Hz, 1H, e), 7.10 (d, J = 8.4
Hz, 1H, H-5), 7.48 (s, 1H, H-2), 7.60 (d, J = 8.4 Hz, 1H, H-6)
ppm. [C14H16O6 + H+]: 281.0.
Products of epoxidation of allylated gallic acid
Allyl-3,5-bis(allyloxy)-4-(oxiran-2-ylmethoxy)benzoate 4a.
1
Colourless oil. H NMR (500 MHz, DMSO-d6) δ = 2.60 (dd,
J = 5.0, 2.65 Hz, 1H, d), 2.75 (t, J = 4.4 Hz, 1H, e), 3.26, (ddd,
J = 9.5, 4.2, 2.8 Hz, 1H, c), 3.88 (dd, J = 11.6, 6.5 Hz, 1H, a),
4.25 (dd, J = 11.6, 2.9 Hz, 1H, b), 4.65 (d, J = 5.0 Hz, 4H, a′),
4.80 (d, J = 5.3 Hz, 2H, a′′), 5.30 (d, J = 10.7 Hz, 3H, d′,d′′)
5.40 (m, 3H, c′,c′′), 6.04 (m, 3H, b′,b′′), 7.26 (s, 2H, H-2) ppm.
[C19H22O6 + H+]: 347.0.
Products of epoxidation of 3
5-(3-Methoxy-4-(oxiran-2-ylmethoxy)benzoyloxy)pentyl 4-
(allyloxy)-3-methoxybenzoate 10. Colourless oil. 1H NMR
(500 MHz, DMSO-d6) δ = 1.53 (m, 2H, c), 1.77 (p, J = 6.7 Hz,
4H, b), 2.71 (dd, J = 5.0, 2.6 Hz, 1H, g), 2.85 (m, 1H, h), 3.35
(m, 1H, f), 3.79 (s, 3H, Me), 3.80, (s, 3H, Me), 3.87 (dd,
J = 11.4, 6.7 Hz, 1H, d), 4.26 (t, J = 6.3 Hz, 4H, a), 4.38 (dd,
J = 11.3, 2.6 Hz, 1H, e), 4.62 (d, J = 5.3 Hz, 2H, d′), 5.28 (dd,
J = 10.5, 1.4 Hz, 1H, g′) 5.40 (qd, J = 17.3, 1.6 Hz, 1H, f′), 6.05
(tdd, J = 5.3, 10.6, 16.0 Hz, 1H, e′), 7.01 (d, J = 8.5 Hz, 2H,
H-5), 7.43 (dd, J = 5.0, 2.0 Hz, 2H, H-2), 7.52 (d, J = 8.5 Hz,
2H, H-6) ppm. [C27H32O9 + H+]: 501.0.
Allyl-3(allyloxy)-4,5-bis(oxiran-2-ylmethoxy)benzoate 5a, 5a′.
1
Colourless oil. H NMR (500 MHz, DMSO-d6) δ = 2.62 (ddd,
J = 5.0, 2.6, 1.1 Hz, 1H, e), 2.76 (m, 2H, d), 2.84, (m, 1H, e′),
3.29 (ddd, J = 6.6, 3.9, 2.8 Hz, 1H, c), 3.36 (dq, J = 5.0, 2.5 Hz,
1H, c′), 3.91 (m, 2H, a) 4.26 (td, J = 11.7, 2.8 Hz, 1H, b′),
4.44 (dd, J = 11.3, 2.3 Hz, 1H, b), 4.66 (d, J = 5.0, 2H, f), 4.79
(td, J = 5.3, 1.4 Hz, 2H, f′), 5.28 (m, 2H, i,i′), 5.41 (m, 2H, h,h′),
6.05 (m, 2H, g,g′), 7.26 (s, 2H, H-2 and H-6) ppm. [C19H22O7 +
H+]: 363.0.
Pentane-1,5-diyl bis(3-methoxy-4-(oxiran-2-ylmethoxy)benzo-
ate) 11. White solid. H NMR (500 MHz, DMSO-d6) δ = 1.52
Product with three epoxy groups 6 (a, b, b′, c). Yellow oil.
1H NMR (500 MHz, DMSO-d6) δ = [2.76 (m, 3H), 2.84 (dd,
J = 9.3, 4.4 Hz, 3H), epoxy ring CH2], 3.32 (m, 3H, epoxy ring
CH), [3.91 (m), 4.08 (m), 4.26 (dt, J = 11.7 Hz, 2.8), 4.44 (dd,
J = 11.3, 2.0 Hz), 6H, epoxy CH2O], [4.57 (d, J = 5.7 Hz), 4.64
(m), 4.80 (d, J = 5.3 Hz), 2H, allylic CH2O], [5.28 (m, 1H), 5.41
(dd, J = 17.3, 2.0 Hz, 1H), 6.05 (m, 1H), allylic double bond],
[7.27 (s, 1H), 7.30 (s, 1H), aromatic H] ppm. [C19H22O8 + H+]:
379.0.
1
(m, 2H, c), 1.77 (m, 4H, b), 2.71 (dd, J = 5.0, 2.6 Hz, 2H, g),
2.85 (m, 2H, h), 3.36 (ddd, J = 6.9, 5.4, 2.8 Hz, 2H, f), 3.80, (s,
6H, Me), 3.88 (dd, J = 11.4, 6.7 Hz, 2H, d), 4.26 (t, J = 6.4 Hz,
4H, a), 4.38 (dd, J = 11.4, 2.9 Hz, 2H, e), 7.02 (d, J = 8.5 Hz,
2H, H-5), 7.44 (d, J = 2.0 Hz, 2H, H-2), 7.52 (dd, J = 8.5,
2.0 Hz, 2H, H-6) ppm. [C27H32O10 + H+]: 517.0.
Acknowledgements
3,4,5-Triglycidylether glycidyl benzoate 7. Yellow oil.
1H NMR (500 MHz, CDCl3) δ = [2.72 (m, 2H), 2.80 (m, 2H),
2.84 (t, J = 4.6 Hz, 1H), 2.92 (q, J = 4.9 Hz, 3H), epoxy ring
CH2], [3.34 (dd, J = 5.8, 3.0 Hz, 1H), 3.40 (bs., 3H), epoxy ring
CH], [4.03 (m, 2H), 4.07 (dd, J = 12.0, 6.9 Hz, 1H), 4.13 (dd,
J = 12.4, 6.6 Hz, 1H), 4.36 (m, 3H), 4.66 (dd, J = 12.2, 2.8 Hz,
1H), epoxy CH2O], 7.36 (s, 2H, aromatic H) ppm. 13C NMR
(125 MHz, methanol-d4) δ = 43.25 (a), 43.41 (d, 2C), 43.67 (g),
48.86 (b), 49.52 (e, 2C), 50.00 (h), 65.35 (c), 70.00 (f, 2C),
73.90 (i), 108.30 (2, 2C), 124.41 (1), 141.43 (4), 151.70 (3, 2C),
164.80 (CvO) ppm. [C19H22O9 + H+]: 395.1.
This work was supported by department CEPIA (INRA,
France). The authors are grateful to Christine Le Guernevé
(SPO, INRA, France) for her help on NMR analyses.
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