p-Cymene as Solvent for Olefin Metathesis: Matching Efficiency and Sustainability

Article abstract of DOI:10.1002/cssc.201700116

The underexploited biorenewable p-cymene is employed as a solvent for the metathesis of various substrates. p-Cymene is a nontoxic compound that can be obtained in large amounts as a side product of the cellulose and citrus industry. For the cross-metathesis of estragole with methyl acrylate, this solvent prevents the consecutive double-bond isomerization of the product and affords the best yield of all solvents tested. Undesired consecutive isomerization is a major challenge for many substrates in olefin metathesis, including pharmaceutical precursors, and the use of p-cymene as a solvent may be a way to prevent it. This solvent results in a better metathesis performance than toluene for the three substrates tested in this work, matching its performance for two other substrates.

Full text of DOI:10.1002/cssc.201700116

Accepted Article
Title: p-cymene as a solvent for olefin metathesis: matching efficiency
and sustainability
Authors: Eduardo N. dos Santos, Artur V. Granato, and Alexandra G.
Santos
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To be cited as: ChemSusChem 10.1002/cssc.201700116
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p-cymene as solvent for olefin metathesis: matching efficiency
and sustainability
Artur V. Granato,[a] Alexandra G. Santos,[a] and Eduardo N. dos Santos*[a]
The underexploited, biorenewable, p-cymene is employed as
a solvent for the metathesis of various substrates. p-cymene is a
nontoxic compound that can be obtained in large amounts from
side product of cellulose and citrus industry. For the cross-
metathesis of estragole with methyl acrylate, this solvent
prevents the consecutive double-bond isomerization of the
product and gives the best yield of all solvents tested. Undesired
once ubiquitous in C-C double bond metathesis, are now
classified as hazardous or very hazardous in a recent
rank.[14] Toluene has been used as an alternative, because
it is considerably less problematic than the chlorinated
ones, while still efficient. However, toluene is produced from
fossil sources, compromising its sustainable utilization.
Perhaps surprising is the fact that p-cymene has not
yet been reported as an alternative solvent for Ru-catalyzed
C-C double bond metathesis, since it acts as a ligand in
consecutive isomerization is
a major problem for many
substrates in olefin metathesis, including pharmaceutical
precursors, and the use of p-cymene as solvent may be a way to
prevent it. This solvent presented a better performance for
metathesis than toluene for three substrates tested in this work,
matching its performance for other two substrates.
various
ruthenium(II)
complexes,
including
some
metathesis pre-catalysts.[15-17] Therefore, a stabilizing effect
for such kind of catalyst could be forecasted. p-cymene is a
naturally occurring compound present in significant
amounts in various essential oils, notably in those from
Thymus gender, and is considered to be nontoxic.[18] Its
acute oral LD50 in rats is 4.75 g/Kg (for comparison, the
acute oral LD50 in rats of toluene ranges from 2.6 to 7.5
g/Kg).[19] Nowadays, the large-scale production of p-cymene
relies on petrochemicals, but Clark et al.[20,21] have recently
acknowledged its potential as a renewable solvent, once it
can be readily obtained from renewable sources also
available in large scale.[22,23] The aromatization of d-
limonene obtained from citrus industry produces p-cymene
in high yields[22] and the potential for this route may reach
500,000 ton/year.[24]
Introduction
Olefin metathesis has become a major tool in modern
organic chemistry. It is widely employed in petrochemistry,[1]
and since the development of well-defined Schrock and
Grubbs catalysts, it has also been used in fine chemicals
and pharmaceutical industry.[2,3] The commercial availability
of various robust pre-catalysts as exemplified in Figure 1
helped to disseminate the use of this methodology in
academia and in industry. An outstanding application of
metathesis is in bio-refineries, in which triglycerides from
plants are transformed into olefins and unsaturated esters
that find applications both as “drop in” and new chemicals.[4]
Although in some cases it is possible to run this
reaction in neat substrates,[5-7] for most applications the use
of a solvent is mandatory. In line with the global tendency of
the chemical industry to use solvents that cause less
environmental impact;[8] various potentially greener solvents
have been employed for C-C double bond metathesis, e.g.
Ph
Cl
SIMes
Ph
Cl
SI-iPr
O iPr
Cl
PCy3
Cl
O iPr
Cl
PCy3
Cl
Cl
Ru
Ru
Cl
SI-iPr
Ru
Ru
H-II'
SIMes
G-II
H-II
G-II'
Pri-O
NH
Ph
O
Ph
water,[9]
ionic
liquids,[10]
methyl-THF,[11]
organic
PPh3
Cl
O iPr
Cl
SI-iPr
Cl
SIMes
PCy3
Cl
Cl
SI-iPr
Ru
Ru
Ind-II'
Ru
carbonates,[12] among others. A tentative green solvent
guide specifically for metathesis has been recently
published.[13] The chlorinated solvents, very efficient and
Cl
Ind-II
M73
(SI-iPr)
(SIMes)
[a]
MSc. A. V. Granato, MSc. A. G. Santos, Prof. E. N. dos Santos
Chemistry Department
N
N
N
N
Federal University of Minas Gerais
Av. Antônio Carlos, 6627
31270-901 Belo Horizonte (Brazil)
E-mail: nicolau@ufmg.br
Figure 1. Selection of commercial ruthenium catalysts.
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10.1002/cssc.201700116
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double-bond isomerization, a process that is detrimental to
good yields of the primarily formed cross-metathesis
products (Scheme 1). For example, Bruneau et al.[12]
described the analogous cross-metathesis of eugenol with
methyl acrylate employing various Ru-ylidene catalysts. In
toluene with 2 mol% of H-II (Figure 1) at 80 oC, the
isomerization products reached 54%. In dimethylcarbonate
(DMC), the isomerization products reached 43% even at
room temperature. The addition of 1,4-benzoquinone (5
mol% related to catalyst) resulted in considerable reduction
in isomerization activity (9%) and allowed up to 78% of
isolated yield of the cross-metathesis product. Broadly
speaking, isomerization is a major problem for several
substrates used in metathesis processes.[31-33] Remarkable
examples are reported in the pharmaceutical development
for the ring closing metathesis (RCM) of terminal dienes to
produce antiviral macrocycles.[2] Besides the selectivity
loss, in some cases the isomerization products result in
Fischer-type carbenes that inhibit the metathesis activity.[37]
In order to choose the initial conditions for this work,
An even more promising renewable starting material
for this solvent is a mixture known as industrial dipentene, a
cheap co-product of the Kraft cellulose process generated
worldwide in million ton scale.[23] Industrial dipentene has
racemic limonene as the major constituent, along with other
p-menthenic monoterpenes. These components can be
readily converted to p-cymene by aromatization with the
additional bonus of green hydrogen co-production.[25] Thus,
p-cymene has an enormous potential to be a sustainable
alternative to aromatic solvents such as benzene or toluene
and its production employing bio-renewable starting
materials is expected to increase. Pursuing greener routes
for fine chemicals synthesis,[26] we have been interested in
aggregating the complexity generated by nature in direct
catalytic routes to chemicals used by the cosmetic industry.
In a recent example, we have developed a one-step
synthesis of the commercial fragrance Canthoxal® by the
hydroformylation of the naturally occurring estragole,
employing water as a solvent in a recyclable biphasic
system.[27] We have also established a route to produce
octyl methoxycinnamate, a major UV-A filter used in
sunscreen lotions, by the ruthenium-catalyzed cross-
metathesis of the naturally occurring anethole with the
commodity chemical 2-ethylhexyl acrylate.[28] More
generally, the cross-metathesis of natural products with
acrylates is an excellent approach to the synthesis of
monomers, polymers[29,30] or fine chemicals.[12,28,31-33]
In this work we compared the performance of traditional
solvents, as well as other solvents regarded as greener
alternatives, with p-cymene in the challenging cross-
metathesis of naturally occurring propenylbenzenes with
acrylates.
some reaction employing 1,2-dichloroethane as solvent
were examined. Considering that 1 is prone to give self-
metathesis and that for acrylates this tendency is much
smaller,[38] the latter was used in a four-fold molar excess to
maximize the cross-metathesis of 1. The increase in
catalyst
concentration
seems
to
accelerate
its
decomposition process, with the consequent increase in the
rate of isomerization (Table 1, entries 1-9). The best
compromise among yields and selectivity was chosen: a
solvent volume of 4 mL and a catalyst amount of 2.5x10-3
mmol (0.5 mol % relative to 1). The presence of ethene is
detrimental to the lifetime of the catalysts due to the
formation of unstable Ru-methylidene species.[39] The use
of argon flow during the reaction helps to eliminate light
olefins and leads to better yields (Table 1, entry 7 vs. 10)
and was adopted as standard in this work. Lower
temperatures reduce the consecutive isomerization, but at
the expense of the reaction rate (Table 1, entry 12 vs. 10
Results and Discussion
The cross-metathesis of methyl acrylate with estragole
(1), a naturally occurring allylbenzene that can be obtained
as a co-product in the Kraft cellulose process, was chosen
as a test reaction. This is a particularly challenging reaction
because the cross-metathesis may be followed by the C-C
o
and 11). The best yield was obtained at 70 C, which was
the temperature adopted to carry out the subsequent
studies.
OMe
OMe
OMe
OMe
OMe
OMe
6
5
1
2
3
4
Ru dec.
Ru cat.
Ru cat.
MeO
MeO
+
+
+
+
+
O
OMe
O
O
OMe
OMe
OMe
Isomerization
O
O
Undesired
Cross-Metathesis
Substrate
Isomerization
Self-Metathesis
Cross-Metathesis
Ru dec.
Scheme 1. Cross-metathesis of estragole (1) with methyl acrylate.
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10.1002/cssc.201700116
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obtained from bio-renewable sources, the selectivity for 2
raises to 90%, but the conversion is considerably reduced.
Employing the renewable[14] dimethylcarbonate (DMC),
entry 5, the consecutive isomerization reaches 20%, which
impacts negatively the yield. Diethylcarbonate (DEC), entry
6, gives slightly better results, in agreement with the
previous work employing the analogous eugenol as
substrate.[12] The best results were obtained employing p-
cymene (p-CYM) as solvent (entry 7): the conversion
reached 95% and the consecutive isomerization was
practically suppressed. This finding suggests that p-cymene
is a very promising solvent for C-C double-bond metathesis
because it reduces the undesired isomerization.
It is also noteworthy that, among the solvents examined,
p-cymene (99%, Sigma-Aldrich) has the lowest
specification level or was submitted to the simplest pre-
treatment. Me-THF, THF, and 1,2-dichloroethane were
anhydrous, packed under inert atmosphere by the supplier
(Aldrich Sure-seal solvents). Diethyl carbonate and dimethyl
carbonate were distilled and stored over 4Å molecular
sieves under argon, while p-cymene was only distilled
under vacuum and stored under argon. We also compared
the performance of the distilled p-cymene against p-
cymene, from a recently opened bottle, only bubbled with
argon for 10 min, without distillation or any further
treatment, for the cross-metathesis of 1 with methyl-
acrylate. The results were very similar, suggesting that
even vacuum distillation is unnecessary. The GC analysis
(see Figure S19 in the supporting information) of p-cymene
as received indicates that it is quite pure (99,97% based on
GC-FID area integration). Typically deleterious impurities
such as water, acids, bases or even peroxides, if present,
do not prevent it to perform better than alternative solvents
of higher specification levels.
In order to verify the generality of the beneficial effects
of p-cymene, the commercial catalysts shown in Figure 1
were tested in the cross-metathesis of 1 with methyl
acrylate in this solvent and the results are presented in
Table 3. It is noteworthy that in p-cymene the consecutive
isomerization is almost suppressed for all catalysts tested.
It is also worthwhile mentioning that the cheaper versions of
second-generation catalysts Ind-II and G-II give good yields
even at low loading (0.5%) of catalyst for this challenging
reaction. The system employing G-II as pre-catalyst (entry
2, Table 3) presented a higher isomerization activity, which
suggests its faster decomposition. This effect could be
forecasted considering the deleterious effect of the leaving
PCy3 in the cross-metathesis with acrylates demonstrated
by Fogg[40]. Thus, it is surprising that Ind-II matches the
output of H-II for this reaction, and this suggests that the
ylidene ligand installed in the pre-catalyst may play a role in
the pathways of decomposition promoted by PCy3. As
expected, the influence of modifying ligand (NHC) is more
significant than the leaving ligands (PCy3, PPh3, Isopropyl
ether moiety) or the reactive ylidene ligands (benzylidene,
Table 1. Cross-metathesis of estragole (1) with methyl acrylate
using H-II.[a]
Product
Yield
2
distribution [%][b]
VSolvent
[mL]
Conv.[b]
[%]
H-II
[mmol]
Entry
[%][b]
2
3
4
6
1
2
3
4
5
6
7
8
none
2
4
26
57
80
75
12
38
78
80
91
86
58
90
78 16
70 14 12
6
0
4
2
0
0
3
2
2
7
1
0
1
20
40
64
63
11
33
66
64
59
78
56
79
5.0x10-3
80
84
94
88
85
80
65
91
96
88
8
8
2
2
1
8
9
2
3
1
10
8
4
10
6.2x10-4
1.2x10-3
2.5x10-3
5.0x10-3
1.0x10-2
7
12
10
19
6
1
10
4
4
9
10[c]
11[c,d]
12[c,e]
2.5x10-3
[a] estragole (1) (78 µL, 0.50 mmol); methyl acrylate (181 µL, 2.0 mmol); H-II;
dichloroethane; 50°C; 4 h.
[b] determined by gas chromatography, based on 1
[c] argon swept system
[d] 30°C
[e] 70°C
For a greener process, not only should the solvent be
safe from the operational, health, and environmental
viewpoint,[14] but also should be obtained from renewable
sources[26] and should allow good yields for the product in a
specific process.[13] In Table 2, a comparison among
various solvents under the previously selected reaction
conditions is shown. If the reaction is carried in neat
substrates (entry 1), the conversion is low and the
selectivity for the cross-metathesis product 2 is poor. Not
only is the primary product 2 consecutively isomerized to 4,
but also the substrate is isomerized to 5, leading to the
formation of the cross-metathesis product 6. Employing the
usually efficient, but hazardous[14] 1,2-dichoroethane (DCE)
as solvent, entry 2, the conversion increases considerably,
but c.a. 10% of 2 is consecutively isomerized to 4. The use
of the less hazardous toluene (TOL), entry 3, leads to
similar results. In entry 4, employing methyl THF (Me-THF)
Table 2. Cross-metathesis of estragole (1) with methyl acrylate:
solvent variation.[a]
Product
Yield
distribution [%]
Conv.
[%]
Entry
Solvent [b]
2
[%][c]
2
3
4
6
1
2
3
4
5
6
7
none
DCE
TOL
Me-THF
DMC
DEC
37
90
88
81
86
90
95
68
88
92
90
77
84
98
2
1
0
2
1
1
1
25
10
8
5
1
0
2
2
1
0
25
79
81
73
66
76
93
6
20
14
1
p-CYM
[a] estragole (1) (78 µL, 0.50 mmol); methyl acrylate (181 µL, 2.0 mmol); H-II
(1.56 mg, 2.5x10-3 mmol); solvent (if any, 4.0 mL); 70 °C; 4 h.
[b] DCE: 1,2-dichloroethane; TOL: toluene; Me-THF: 2-methyltetra
hydrofurane; DMC: dimethylcarbonate; DEC: diethylcarbonate; p-CYM: p-
cymene;
indenylidene, isopropoxybenzylidene).
The catalysts
bearing the bulkier SI-iPr (c.f. Ind-II’, G-II’, M73) are more
prone to give self-metathesis product 3 than the ones
[c] determined by gas chromatography, based on 1
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10.1002/cssc.201700116
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FULL PAPER
isomerization process, which is superior to the best solvent
reported (toluene). One can speculate that p-cymene can
trap unsaturated ruthenium species responsible for
isomerization to form saturated η6-p-cymene bounded
ruthenium species. Other reasons such as Ru-hydride
trapping by diene impurities of p-cymene cannot be ruled
out. Regardless the accuracy of the explanation, p-cymene
has proved to be a useful solvent in C-C double-bond
metathesis.
In a previous work[28] we established a route to the
synthesis of cinnamate derivatives through the cross-
metathesis of propenylbenzenes obtained from renewable
sources and commodity acrylates. Some of the products
are known for their anti-inflammatory activity, and the cross-
metathesis of trans-anethole (5) with 2-ethylhexyl acrylate
(Scheme 2) leads in one step to octyl methoxycinnamate
(7), a UV-A filter largely used in sunscreen lotions. trans-
Table 3. Cross-metathesis of estragole (1) with methyl acrylate:
catalyst variation in p-cymene.[a]
Product
distribution [%]
Yield
2
Conv.
[%]
Entry
Catalyst[b]
[%][c]
2
3
1
1
1
30
6
4
1
8
2
1
2
2
3
6
0
0
0
0
0
0
0
1
2
3
4
5
6
7
H-II
G-II
95
92
95
70
78
76
85
98
91
97
69
92
75
84
93
84
92
48
72
57
71
Ind-II
Ind-II’
G-II’
M73
H-II’
22
13
[a] estragole (1) (78 µL, 0.50 mmol); methyl acrylate (181 µL, 2.0 mmol);
catalyst (1.56 mg, 2.5x10-3 mmol); p-cymene (4.0 mL); 70oC; 4 h.
[b] for structures, see Fig. 1
[c] determined by gas chromatography, based on 1
bearing the SIMes as ligand (H-II, G-II, Ind-II). For the
catalysts containing the bulkier SI-iPr ligand, the homo
coupling of two allyl fragments of 1 result in less steric
hindrance than the hetero coupling of the allyl fragment of 1
and the vinyl fragment of the acrylate. As a consequence,
the contribution of the self-metathesis is higher than for the
catalysts bearing the SIMes ligand.
anethole is
a representative example of a naturally
occurring propenylbenzene and is largely employed in
chemical industry.
The former studies were carried employing the 1,2-
dichloroethane as solvent, which is now classified as
hazardous.[14] In this work, a set of solvents considered
more benign was tested for the same reaction, and the
results are presented in Table 4. In entry 1 the results in
DCE are presented under similar conditions to the previous
work. In entry 2 a further excess of 2-ethylhexyl acrylate
was employed to make up the reaction volume and avoid
the use of additional solvents. The conversion and yield
were lower than in DCE, indicating that the use of a solvent
is beneficial and therefore a set of less hazardous solvents
was then examined. When toluene is employed, entry 3, the
results are better than in neat acrylate and the yield for 7
reaches 93%. Employing the more polar and renewable
methyl-THF, entry 4, conversion is good, but a significant
amount of self-metathesis product 9 is observed. The use
of DMC or DEC seems to be inappropriate for this particular
reaction, since neither the conversion nor the yields are
good. The fact that 8 is not transformed into 7 or 9 under
It is well accepted in literature that isomerization during
metathesis is due to ruthenium species that arises from
decomposition of the metathesis catalyst, although there
are some questions about the nature of these species.
Fogg
et
al.[35]
demonstrated
that
RuCl(CO)(H)(PCy3)(SIMes)], which was once considered to
be responsible for parallel isomerization, is not kinetically
competent to account for the isomerization during the self-
[36]
metathesis of estragole. Nelson and Percy
suggest that
lack in isomerization activity of this species is due to the low
lability of the PCy3 ligand, but the 14e
[RuCl(CO)(H)(SIMes)] species is very active for
isomerization and can be formed directly from ruthenium-
methylidene species present in the metathesis catalytic
cycles of terminal C-C double-bond. The authors also
demonstrated that there is a clear solvent effect on the rate
of isomerization, which increases in the order toluene <
chloroform ~ benzene < dichloromethane. It is, therefore,
outstanding the capacity of p-cymene to reduce the
these reaction conditions suggests
a
fast catalyst
deactivation. The results employing p-cymene as solvent
are presented in entry 7. Although slightly inferior than
toluene (c.f. entry 3 vs. 7), the yield is still in the range
OMe
O
O
O
O
O
O
9
+
7
Ru cat.
+
+
+
MeO
MeO
MeO
MeO
8
5
Undesired
Cross-Metathesis
Cross-Metathesis
Self-Metathesis
Scheme 2. Cross-metathesis of anethole (5) with 2-ethylhexyl acrylate.
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10.1002/cssc.201700116
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FULL PAPER
which contains a unprotected phenol group, with cis- cis-
1,4-diacetoxy-2-butene the relative improvement in yield
was 36% (Table 5, entry 2). For the RCM of 15, the yield
was essentially the same in both solvents. Thus, p-cymene
presented a better performance as a solvent for metathesis
for three out of five substrates tested in this work, and
matches the performance of toluene for remaining two
substrates.
Table 4. Cross-metathesis of anethole (5) with 2-ethylhexyl
acrylate.[a]
Product
distribution [%]
Yield
7
Conv.
[%]
Entry
Solvent[b]
[%][c]
7
8
1
4
1
1
19
22
2
9
1
5
DCE
Neat[d]
TOL
Me-THF
DMC
100
87
99
99
69
76
99
97
91
94
81
55
54
91
97
79
93
80
38
41
90
1
2
3
4
5
6
7
5
18
26
24
7
DEC
p-CYM
Conclusions
[a] anethole (5) (75 µL, 0.5 mmol); 2-ethyhexyl acrylate (416 µL, 2.0 mmol);
H-II (1.56 mg, 2.5x10-3 mmol); solvent (if any, 2.5 mL); 70oC, 4 h.
[b] DCE: 1,2-dichloroethane; TOL: toluene; Me-THF: 2-methyltetrahydro-
furane; DMC: dimethyl carbonate; DEC: diethyl carbonate; p-CYM: p-
cymene;
We demonstrated that p-cymene is an excellent
alternative solvent for the cross-metathesis of estragole
with methyl acrylate. It is outstanding that this solvent
prevents the consecutive double-bond isomerization of the
cross-metathesis product. Taking into account that
isomerization is a major problem in olefin metathesis, p-
cymene has an enormous potential to replace the
hazardous 1,2-dichloroethane or the non-renewable toluene
in olefin metathesis. Although a careful global analysis must
be carried out for each application taking into account, e.g.,
the costs for solvent recycling, p-cymene seems to be a
promising candidate to replace toluene as a greener
alternative in metathesis since it is apparently less toxic, it
can be obtained from renewable sources and it matches or
surpasses the performance of toluene for the substrates
studied in this article.
[c] determined by gas chromatography, based on 5
[d] extra 2-ethyhexyl acrylate (2.5 mL)
considered acceptable for a green process.[13] Due to its
potential to be obtained from renewable sources, p-cymene
seems to be the most sustainable solvent alternative
among the examined solvents for this transformation.
In order to verify the generality of the utility of p-cymene
as a solvent for metathesis, we tested this solvent with
other substrates. Toluene is a suitable solvent to use as a
benchmark, because it is presently among the most
employed solvents for this reaction. We tested the cross
metathesis of trans-anethole (5) and isoeugenol (12) with a
different class of counter-part, namely cis-1,4-diacetoxy-2-
butene, as well as the ring-closing metathesis (RCM) of
N,N-diallyacetamide (15), and the results are presented in
Table 5. The relative improvement in yield for p-cymene in
the cross-metathesis of 5 with cis-1,4-diacetoxy-2-butene
was 12% (Table 5, entry 1). For the cross-metathesis of 12,
Table 5. Comparative study of cross-metathesis and RCM in toluene or p-cymene.
Yield
[%][d]
Catalyst
[mol%]
Entry
1[a]
Reactants
Main Product
toluene
55
p-cymene
CO2Me
CO2Me
+
Ind-II
(1.0 mol%)
5
11
67
MeO2C
MeO
MeO
CO2Me
MeO
HO
MeO
HO
CO2Me
+
Ind-II
(1.0 mol%)
2[b]
64
92
87
94
12
14
MeO2C
O
O
N
GII
3[c]
N
16
15
(0.25 mol%)
[a] anethole (5) (75 µL, 0.50 mmol); cis-1,4-diacetoxy-2-butene (336 µL, 2.0 mmol); Ind-II (4.75 mg, 5.0x10-3 mmol); solvent (2.5 mL); 70 °C; 4 h.
[b] isoeugenol (12) (76 µL, 0.50 mmol); cis-1,4-diacetoxy-2-butene (336 µL, 2.0 mmol); Ind-II (4.75 mg, 5.0x10-3 mmol); solvent (2.5 mL); 70 °C; 4 h.
[c] N-N-diallylacetamide (15) (78 µL, 0.50 mmol); G-II (1.1 mg, 1.25x10-3 mmol); solvent (4.0 mL); 40 °C, 30 min.
[d] determined by gas chromatography, based on substrate.
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10.1002/cssc.201700116
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(30 m length, 250 µm internal diameter) and a flame ionization
detector (FID) at 320 °C. For the quantification of the products of
the cross-metathesis of estragole with methyl acrylate the
temperature program was: 50 °C for 5.0 min, heating at 15
°C/min to 280 °C and isotherm for 5.0 min. For the cross
metathesis of trans-anethole with 2-ethylhexyl acrylate the
temperature program was: 50 °C for 3 min, heating at 10 °C/min
to 310 °C and isotherm for 5 min. For the cross-metathesis
reactions with cis-1,4-diacetoxy-2-butene the temperature
program was: 50 °C for 2 min, heating at 10 °C/min to 310 °C
and isotherm for 5 min (see Supporting Information S13). For
the ring-closing metathesis reaction of N,N-diallylacetamide the
products quantification was made by gas chromatography (GC)
employing p-xylene as the internal standard on Shimadzu
GC2010 Plus apparatus with an auto-sampler, using an inlet
split ratio of 50:1, an inlet temperature of 230 °C, and H2 (UHP
grade) as carrier gas, a polar Rtx®-Wax column (30 m length,
250 µm internal diameter) and a flame ionization detector (FID)
at 230 °C. The temperature program was: 50 °C for 3 min,
heating at 20 °C/min to 230 °C and isotherm for 5 min (see
Supporting Information S17). The qualitative analysis of the
products was made by mass spectrometry on a Shimadzu
GC2010/QP2010-GC/MS apparatus employing an electron
impact detector at 70 eV (see Supporting Information). The GC
conditions were identical to GC/FID, except for the carrier gas
(helium). The major products were also separated by
preparative thin layer chromatography in silica using
hexane/ethyl acetate as eluent and identified by 1H-Nuclear
Magnetic Resonance (1H-NMR) and 13C-Nuclear Magnetic
Experimental Section
General procedures
Except otherwise specified, all reactions were carried out in an
argon-filled glovebox (MBraun) and all chemicals were
purchased from Sigma-Aldrich. Anhydrous Sure-seal solvents,
dichloroethane, methyl-THF and THF were used as received.
Diethyl carbonate and dimethyl carbonate were distilled under
argon and stored over 4A molecular sieves. p-cymene was
distilled in a Kugelrohr distillation apparatus at 50 °C and 10-1
mbar, collected under argon and stored in the glove box.
Estragole (98%) and trans-anethole (99%) were passed through
a neutral alumina column and bubbled with argon for 10 minutes
before use. Methyl acrylate (99%) and 2-ethylhexyl acrylate
(98%) were degassed by three freeze-pump-thaw cycles, and
stored under argon at -19 °C. The catalysts G-II (CAS 246047-
72-3), G-II’ (CAS 373640-75-6), H-II (CAS 301224-40-8), H-II’
(CAS 635679-24-2) were purchased from Sigma-Aldrich and the
catalysts Ind-II (CAS 536724-67-1), Ind-II’ (1307233-23-3), and
M73 (1025728-57-7) were kindly donated by UMICORE.
Protocols for metathesis reactions
The reactions were carried out in a HEL7 reactor, which
allow seven tests in parallel. Each well has a 20 mL glass insert,
a
PTFE-coated magnetic stirring bar and an individual
condenser tip with a customized PTFE gasket to prevent cross-
contamination. The reactor was degased and introduced in the
glove box. Each glass insert was loaded with estragole (76 mg,
0.50 mmol), p-xylene (54 mg, 0.50 mmol), methyl acrylate (173
mg, 2.0 mmol), solvent (4.0 mL) and catalyst (2.5x10-3 mol, 0.5
mol%). The reactor was sealed, taken out of the glove box,
introduced in a pre-heated aluminum block that reached 1/3 of
its length and temperature of the block was kept at 70oC by a
PID controller. The overhead of the reactor was cooled by a
circulating mixture of water/ethyleneglycol at 5 °C, and swept
with a steady argon flow. Under these conditions, no cross-
contamination was observed. After 4 hours the reactor was
opened to air and a 0.50 mL sample was taken of each vial,
diluted with 1.0 mL of untreated dichloroethane and analyzed by
gas chromatography (GC). For the cross-metathesis of trans-
anethole with 2-ethylhexyl acrylate, each glass insert was
loaded with anethole (74 mg, 0.50 mmol), 2-ethylhexyl acrylate
(368 mg, 2.0 mmol), solvent (2.5 mL) and catalyst (2.5x10-3 mol,
0.5 mol%). After 4 hours the reactor was opened to air and p-
xylene (54 mg, 0.50 mmol) was added in each vial. For GC
analysis, 0.10 mL sample was taken of each vial and diluted with
1.0 mL untreated dichloroethane.
Resonance (13C-NMR) on
a Brucker 400 MHz NanoBay
spectrometer at 298K, and referenced to the residual proton
signals of the deuterated solvent. Signals are reported in ppm,
relative to TMS (1H) at 0 ppm (see Supporting Information).
Acknowledgements
This work was funded by CNPq (Edital Universal and
INCT-Catálise) and FAPEMIG. UMICORE is thanked for
the generous gift of Ind-II, Ind-II’, and M73.
Keywords: homogenous catalysis • metathesis • renewable
resources• solvent •
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p-cymene, which can be produced
from rejects of cellulose and citrus
industry, is an excellent solvent for
Ru-catalysed metathesis of various
substrates. It prevents the undesired
Artur V. Granato, Alexandra G. Santos
and Eduardo N. dos Santos*
Page No. – Page No.
p-cymene as solvent for
olefin metathesis: matching
efficiency and sustainability
consecutive
double-bond
isomerization and delivers better
yields as compared to other bio-
renewable solvents.
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