Improving the efficiency of the Diels-Alder process by using flow chemistry and zeolite catalysis

Article abstract of DOI:10.1039/c6gc02334g

The industrial application of the Diels-Alder reaction for the atom-efficient synthesis of (hetero)cyclic compounds constitutes an important challenge. Safety and purity concerns, related to the instability of the polymerization prone diene and/or dienophile, limit the scalability of the production capacity of Diels-Alder products in a batch mode. To tackle these problems, the use of a high-pressure continuous microreactor process was considered. In order to increase the yields and the selectivity towards the endo-isomer, commercially available zeolites were used as a heterogeneous catalyst in a microscale packed bed reactor. As a result, a high conversion (≥95%) and endo-selectivity (89:11) were reached for the reaction of cyclopentadiene and methyl acrylate, using a 1:1 stoichiometry. A throughput of 0.87 g h^-1 during at least 7 h was reached, corresponding to a 3.5 times higher catalytic productivity and a 14 times higher production of Diels-Alder adducts in comparison to the heterogeneous lab-scale batch process. Catalyst deactivation was hardly observed within this time frame. Moreover, complete regeneration of the zeolite was demonstrated using a straightforward calcination procedure.

Full text of DOI:10.1039/c6gc02334g

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Improving the efficiency of the Diels-Alder process by using
flow chemistry and zeolite catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
S. Seghers,a L. Protasova,b S. Mullens,b J. W. Thybaut,c C. V. Stevens*a
DOI: 10.1039/x0xx00000x
The industrial application of the Diels-Alder reaction for the atom-efficient synthesis of (hetero)cyclic compounds
constitutes an important challenge. Safety and purity concerns, related to the instability of the polymerization prone diene
and/or dienophile, limit the scalability of the production capacity of Diels-Alder products in a batch mode. To tackle these
problems, the use of a high-pressure continuous microreactor process was considered. In order to increase the yields and
the selectivity towards the endo-isomer, commercially available zeolites were used as a heterogeneous catalyst in a
microscale packed bed reactor. As a result, a high conversion (≥95%) and endo-selectivity (89:11) was reached for the
reaction of cyclopentadiene and methyl acrylate, using a 1:1 stoichiometry. A throughput of 0.87 g/h during at least 7 h
was reached, corresponding to a 3.5 times higher catalytic productivity and a 14 times higher production of Diels-Alder
adducts in comparison to the heterogeneous lab-scale batch process. Catalyst deactivation was hardly observed within this
time frame. Moreover, complete regeneration of the zeolite was demonstrated using a straightforward calcination
procedure.
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1 Introduction
H
H
OHC
H
CHO
The Diels-Alder (DA) reaction is universally acknowledged for
its rapid, atom-efficient and clean access to molecular
complexity on small scale. This reaction involves a [4+2]-
cycloaddition between a diene and a dienophile, introducing
two new σ-bonds as indicated in red in Scheme 1.1 This
enables one of the most efficient routes towards six-
membered compounds. Controlling the stereo-, regio-, and
enantioselectivity is essential for the synthesis of complex
natural products and pharmaceuticals. Typically, a mixture of
endo- and exo-isomers is obtained (Scheme 1). The endo
products, however, are mostly obtained as the major products
due to favorable secondary orbital interactions.1, 2 Despite its
wide use at research level, problems associated with reactivity,
selectivity and scale-up still have to be overcome for Diels-
Alder reactions. The core problems are the instability of the
reagents, the required stoichiometric excess of reagent, the
exothermic behavior of the main and side reactions, poor
selectivity, extreme reaction times and temperatures, as well
as the use of (toxic) catalysts.3
H
endo approach (kinetics)
racemic mixture
H
CHO
H
H
H
CHO
exo approach (thermodynamics)
racemic mixture
Scheme 1 Stereoselectivity of the Diels-Alder reaction
Indeed, the industrial use of one of the most popular
transformations for organic chemists is limited due to safety
and purity concerns. Due to competing, rapid and uncontrolled
polymerization with a potentially explosive character, the
scale-up of the DA reaction constitutes an important challenge
in view of industrial application. Process engineers tend to
consider the DA reaction by definition in the field of non-
scalable transformations and, in many cases, refuse chemical
routes featuring the DA reaction as a key step.3, 4 For instance,
of the top 200 pharmaceutical products by US retail sales in
2010, only one marketed drug is produced industrially using
the DA reaction.3, 5, 6 Buprenorphine is a potent narcotic and is
additionally used to treat opioid addiction.7 The synthesis from
thebaine or oripavine includes a DA reaction step with methyl
vinyl ketone (MVK) as dienophile (Scheme 2).8 Although little is
known about DA reactions on industrial scale, Funel and Abele
recently published a review containing a limited number of
industrial
relevant
DA
reactions.3
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HO
MeO
MeO
O
MVK
O
O
N
NMe
O
NMe
MeO
HO
buprenorphine
MeO
MeO
O
thebaine
Scheme 2 Buprenorphine synthesis from thebaine8
In view of the aim of our research group to facilitate solid catalyst and the electron withdrawing group of the
challenging reactions in flow,9 microreactor technology (MRT) dienophile reduces the LUMO’s energy. This provides a better
11g, 11i
is believed to be able to overcome the previously described overlap with the HOMO of the diene.1,
Moreover,
problems. As a consequence of its small dimensions, the microporous or mesoporous structures also exhibit spatial
reaction environment can be controlled meticulously. The confinement of the reagents, even directing the product
desired reaction time, temperature and, due to efficient selectivity in the one or the other direction.11e, 11f, 12 The use of
mixing properties, stoichiometry can exactly be set. A fast, safe zeolites in combination with MRT is much less investigated.15
and low cost increase of the production capacity constitutes However, some research groups have performed reactions by
the key element to address the DA reaction in a continuous combining microreactors and acid catalysis by zeolites:
flow set-up. Moreover, the combination with heterogeneous dehydration of methanol to dimethylether,16 benzylation of
catalysis tends to be a perfect match as the immobilization of a benzene with benzyl alcohol,17 Knoevenagel condensation and
solid catalyst in
recuperation of the catalyst and the work-up of the product.10
a
microreactor simplifies both the the epoxidation of 1-pentene.18, 19
In this work, the reaction between cyclopentadiene (CPD), by
DA reactions are known to be catalyzed by Lewis or Brønsted far the most popular diene for DA reactions, and methyl
acids. The replacement of homogeneous catalysts, such as acrylate (MA), both reactive and polymerization prone
AlCl3, HF or H2SO4, by heterogeneous analogues, is of great substrates, was chosen as the generic reaction to optimize the
interest. In addition to concerns about health, safety and DA reaction under continuous flow conditions (Scheme 3).
corrosion, the use of homogeneous catalysts is also Among the commercially available zeolites (e.g. (US)Y, ZSM-5,
accompanied by high costs for work-up and disposal of waste Beta and Mordenite), zeolite Y and Beta type catalysts have
streams. Being solid acids, zeolites, often metal-doped or - the largest pore diameter and surface area.20 The subtype
exchanged, and mesoporous silica derived catalysts are Ultrastable Y (USY) is obtained after a dedicated dealumination
extensively investigated for DA reactions.11, 12 Zeolites consist treatment.21 In general, the large pore zeolite types USY and
of SiO4 and AlO4 tetrahedra as elementary building blocks in Beta are most often used as a solid acid catalyst in organic
well-ordered 3D structures. Within the cavities, both Brønsted synthesis.12, 22 H-USY was selected as a starting point for this
and Lewis acid sites are present.13, 14 The use of such solid acid analysis, however, a batch screening of different commercially
catalysts enhances the conversion and the selectivity to the available
endo-isomer, as the interaction between the acid sites of the
zeolites
was
carried
out.
endo-products (rac.)
major
COOMe
COOMe
OMe
USY-Zeolite
Endo-DA
flow
O
COOMe
exo-products (rac.)
minor
CPD
MA
COOMe
Exo-DA
Scheme 3 Target reaction to develop a continuous flow and heterogeneously catalyzed DA process
Being a hot topic in organic chemistry, the DA reaction has maximizing the yields and the endo/exo-selectivity.11j, 23, 24, 25
already been extensively studied considering a wide variety of Although some research aims at inversing this selectivity e.g.
26
(expensive) ionic liquids and Lewis acid catalysts, focusing on through the use of a bulky Lewis acid catalyst,2a, in most
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cases the maximal formation of the typical major endo-adduct importance.29 More recently, Chiroli et al. described
is desired. As the exo-isomer is generally obtained after continuous flow Diels-Alder reaction using chiral
a
a
isomerisation from an endo/exo-mixture under basic organocatalyst on a silica support. The yield varied from 55 to
conditions,27 also this research project is directed towards the 95% and an endo/exo-selectivity of 45:55 was obtained at
endo-isomer and thus the maximization of the inherent room temperature. However, an excess of 7 equivalents of
selectivity of a (catalyzed) Diels-Alder reaction. With regard to cyclopentadiene was used and the need of long residence
the reaction of cyclopentadiene and methyl acrylate, in many times (up to 25h) leads to low space-time yields (0.0024
publications, yields are up to 90% and higher, albeit obtained mmol/g/min).30
on a small scale and often requiring an excess of CPD and long
reaction times.11j, 24, 25 Mostly, the batch processes are limited
2 Experimental
27c
to an endo/exo-selectivity of about 80:20.24,
Still, some
research groups report an excellent selectivity of 90:10 and
even higher.11j, 25 In conclusion, the objectives to be achieved
can be set at a yield of at least 90% and a selectivity of 90:10
to be able to compete with the majority of the reported batch
investigations.
2.1 Materials
All reagents and solvents were purchased from Sigma-Aldrich
Belgium, except for the zeolite materials CBV 500 (Si/Al-ratio
2.6), CBV 720 (Si/Al-ratio 15), CBV 760 (Si/Al-ratio 30), CBV
3024E (Si/Al-ratio 15), CBV 21A (Si/Al-ratio 10) and CP814E*
(Si/Al-ratio 12.5), which were obtained from Zeolyst
International.20 The zeolite powder was pelletized under a 10
ton press and sieved to obtain the 125-200 µm particle
fraction. Dichloromethane was dried by distillation from
calcium hydride, while tetrahydrofuran (THF) and toluene
were distilled from sodium and benzophenone prior to use.
Ethyl acetate and acetonitrile were dried over molecular
sieves. Extra dry 2-methyl THF (stabilized, AcroSeal®) was
purchased from ACROS Organics and was used without any
further drying step. Cyclopentadiene was obtained by cracking
and distillation of dicyclopentadiene before each experiment.
The used zeolite material was characterised using N2-sorption
and thermogravimetric analysis (Table 1). These results show a
significantly higher specific surface area (SSA) and pore volume
of H-Beta. The analysed H-USY and H-Beta species contain a
comparable water content of about 10 to 15 wt%. Additionally,
the acid properties of the commercially available zeolite
powders were measured using NH3-TPD (Table 2).
The DA cycloaddition has been performed using MRT before,
mainly taking advantage of the excellent heat transfer,
pressurized conditions and the rapid optimization ability.28 In
an attempt to produce aromatics from a renewable feedstock,
Cheng and Hubert reported the production of mixtures of
aromatic compounds using gas-phase DA type reactions
between different furanic species and olefins over a ZSM-5
catalyst in
a continuous flow fixed-bed reactor at a
temperature range of 450-600 °C.11b In another paper the DA
reaction between cyclopentadiene and crotonaldehyde was
performed using a solid Lewis acid in a microreactor set-up.
This solid acid consisted of aluminium oxide functionalized
silica monoliths. Dichloromethane was used as a solvent at a
reactor temperature of 37 °C. Conversions of 15 to 80% were
reached. The optimized contact time was determined to be 9.4
min, resulting in 72% conversion, an endo/exo-distribution of
90:10 and a productivity of 0.033 mmol/g/min. Although this
work shows promising results, there is still room for
improvement in terms of conversion, productivity and
scalability, especially using acrylates in view of their industrial
Table 1 Overview of the default properties of the commercially available zeolites
Zeolite
type
Product
codea
SSAb,c
(m2/g)
104
Pore volumec
(cm3/g)
0.24
Pore radiic
(Å)
19.5
Water contentd
Shape
(wt%)
14
14
H-USY
H-USY
H-Beta
H-Beta
CBV 720
CBV 720
CP814E*
CP814E*
powder
pellets
powder
pellets
109
177
0.38
0.88
19.2
18.2
12
12
155
0.87
18.1
a Zeolyst International
b Specific Surface Area
c Determined using N2-sorption
d Determined using thermogravimetric analysis
Table 2 Acid properties of the commercially available zeolites using NH3-TPDa
c
c
d
e
Tl,max
(°C)
262
282
236
322
253
264
Th,max
CAS
(10-2 mol/kg)
ΔHd
Zeolite type
Product codeb
Si/Al
(°C)
498
482
423
579
471
638
(kJ/mol)
110
99
H-Y
H-USY
H-USY
CBV 500
CBV 720
CBV 760
CP814E*
CBV 3024E
CBV 21A
2.6
15
179
47
39
39
78
96
30
69
H-Beta
H-ZSM-5
H-Mordenite
a Ammonia Temperature Programmed Desorption
12.5
15
116
139
176
10
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b Zeolyst International
c Low- and high temperature maximum, respectively corresponding to the weak and strong acid sites
d Acid site concentration
e Heat of desorption of ammonia
2.2 Microreactor device
ratio of the catalyst bed mass, respectively the molar amount
of acid sites (AS), to the corresponding molar reagent flow
rate.
The X-Cube™ flow reactor is commercially available by
ThalesNano and is shown in Figure 1. The reagent solutions are
pumped in the stainless steel tubing by means of two high
pressure (HPLC) pumps. Each pump can deliver a 0.1-3 mL/min
flow rate. In the employed set-up, a single reagent solution
and corresponding pump were used. The reagent solution was
placed under a N2-pressure, using a pressurisation module of
the commercially available Africa flow system (Syrris). The
tubing was connected to the insulated CatCart® (Catalyst
Cartridge). In the commercial system, two cartridges can be
used in parallel. These cartridges can be mounted and
dismounted easily and can be heated from 20 to 200 °C in 5 °C
intervals, separately. For all experiments, only one CatCart®
was used after a manual fill with zeolite material (loading: 370
mg CBV 720; 350 mg CBV 760; 340 mg CP814E*). Finally, the
mixture was pumped to the pressure sensor and the back
pressure regulator, to which the outlet is connected. The
reactor pressure can be set per 5 bar, up to a maximum of 150
bar. A schematic representation of the X-Cube™ flow reactor is
given in Figure 2. The reactor was rinsed with (dry)
dichloromethane and subsequently with the reagent solution
at 100 °C and 30 bar before start-up, as the catalyst initially
catalyst mass
ST (kg cat . s/ mol substrate) =
molar flow rate reagent
catalyst mass . AS density
SiT (mol AS . s/ mol substrate) =
molar flow rate reagent
3 Results and Discussion
3.1 Batch solvent screening
In order to develop a sustainable production process, a
thoughtful solvent choice has to be made. A key example of a
green solvent is without doubt water. The Diels-Alder reaction
is an important example of an organic reaction which can be
accelerated using water as a solvent.31, 32, 33 However, taking a
look at the application of the Diels-Alder reaction in organic
synthesis, hardly shows any reaction that is not performed in
either a chlorinated or an aromatic solvent.34,
35
A quick
showed
a
high activity towards cyclopentadiene
database search demonstrates that dichloromethane is by far
the utmost used solvent for the cycloaddition of CPD and MA.
Toluene and hexane are located on respectively the second
and third place. Additionally, this reaction has been evaluated
in a wide variety of ionic liquids.36 To the best of our
knowledge, only four papers report the performance of this
reaction in water.33b, 37 By stirring MA and 2 equiv. of CPD at
room temperature in water for 72 h, the end product was
obtained in 89% yield and a endo/exo-distribution of 87:13.37a
Unfortunately, combining water as a solvent and a zeolite
catalyst is not an option, as both reagents and, if any, end
products accumulate inside the catalyst pore system.
polymerisation. A full experiment description can be found in
the Supporting Information.
Thus, the evaluation of the DA reaction between CPD and MA
(Scheme 3) was initiated in batch in various organic solvents in
order to determine the catalyst potential and the solvent of
choice. Thermogravimetric analysis of the zeolites showed a
water content of about 10 to 15 wt% (Table 1). In order to
remove loosely bound water molecules, the zeolite material
was kept for 24 h in the oven at 100 °C prior to its use. This
Figure 1 Set-up for the continuous flow Diels-Alder process (left) using a zeolite filled
CatCart® (right)
pin
pout
constitutes
calcinations or other high temperature and/or vacuum
a
milder zeolite activation compared to
A
M1
M2
treatments found in literature.11a-c,
Among the evaluated
11e-j
dry solvents, i.e. dichloromethane (DCM), THF, 2-methyl THF,
ethyl acetate and acetonitrile, the highest conversion and
endo/exo-selectivity was obtained in dry DCM (Table 3).
Although the conversion was higher in dry toluene at reflux
temperature, dichloromethane was chosen for optimization of
the reaction in a continuous flow device. As a 3 times lower
reflux temperature in dichloromethane still results in more
than half of the conversion in toluene and a significantly higher
endo-selectivity, it was envisaged that dichloromethane had
more potential to speed up the reaction and to lead to high
conversions and selectivity. In batch, however, even in the
Figure 2 Schematic representation of X-Cube™ flow reactor in the used set-up (M =
Mixer)
2.3 Analysis
The conversion of methyl acrylate to the end product was
determined by integration of the methoxy-signals of MA (3.76
ppm), the endo-adduct (3.62 ppm) and the exo-adduct (3.69
1
ppm) in the H-NMR spectrum of the crude reaction mixtures.
The space-time (ST) and site-time (SiT) were obtained as the
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presence of a high catalyst loading (30 wt%), a mere 43% conversion
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was
reached
after
3.5
h.
Table 3 Overview of the obtained results of the batch Diels-Alder reaction between 0.1 M CPD and 1 equiv. MA at reflux temperature of the used solvent. An oven-conditioned
USY type zeolite was used as a catalyst (CBV 720, Si/Al 15, 780 m2/g)
1H-NMR
MA (%) EPb (%)
Loading RTa
Endoc
(%)
Solvent
(wt%)
(h)
dry DCM
dry DCM
dry DCM
dry DCM
dry THF
0
0
2
3.5
2
3.5
2
2
2
2
2
94
90
64
57
85
77
87
82
36
6
79
79
92
92
73
71
74
81
73
10
36
43
15
23
13
18
59
30
30
30
30
30
30
30
dry 2-methyl THF
dry EtOAc
dry MeCN
dry toluene
a Reaction time
b End product (both endo- and exo-isomers)
c Percentage of endo-isomer in the final DA product
3.2 Batch catalyst screening
comparable amount of acid sites, their strength and
accessibility can be influenced by the catalyst architecture.
Using H-ZSM-5 and H-Mordenite catalysts, low conversions
were obtained. Finally, the highest conversion was observed
using a H-Beta catalyst with an analogous Si/Al-ratio, which
could be ascribed to the higher specific surface area and pore
volume, as well as to the acid strength of the sites (Table 1 and
2).39 The high maximum temperature corresponding to the
strong acid sites, indicates that, despite the lower amount of
acid sites, their strength is higher compared to the CBV 720
material. The most promising zeolite H-USY and H-Beta species
were applied as a catalyst under continuous flow conditions.
In a next phase of this study, different commercially available
zeolite types were evaluated in batch mode (Table 4). Among
the H-(US)Y family, species with a varying Si/Al-ratio were
evaluated. In this way, the best suited balance between the
amount of acid sites and the acid site strength was
investigated within a specific zeolite framework.38 CBV 720
(Si/Al 15) exhibited the highest conversion. An even higher
Si/Al-ratio only resulted in a slightly lower conversion and a
similar selectivity. Next, the influence of zeolite structure was
considered and other zeolite types with a similar Si/Al-ratio
were evaluated. Although these materials possess
a
Table 4 Overview of the obtained results of the batch Diels-Alder reaction between 0.1 M CPD and 1 equiv. MA in dry dichloromethane for 2 h at reflux temperature. Oven-
conditioned zeolite material was used as a catalyst in a 30 wt% loading
1H-NMR
MA (%) EPb (%)
Endoc
(%)
Zeolite type
Product codea
Si/Al
H-Y
H-USY
H-USY
CBV 500
CBV 720
CBV 760
CBV 3024E
CBV 21A
CP814E*
2.6
15
30
15
10
12.5
82
64
73
89
95
42
18
36
27
11
5
90
92
91
86
83
90
H-ZSM-5
H-Mordenite
H-Beta
58
a Zeolyst International
b End product (both endo- and exo-isomers)
c Percentage of endo-isomer in the final DA product
3.3 Dilute continuous flow experiments
catalyst bed (CatCart®, see Materials and Methods) was too
high (>100 bar) when commercial zeolite powder was used. To
avoid this, after a pelletizing, breaking and sieving pre-
treatment, a 125-200 µm fraction was used for all flow
experiments resulting in a maximum pressure drop below 5
bar. An overview of the presented flow configuration can be
found in Scheme 4. One starting solution was prepared,
containing 0.5 M of both reagents. This was stored at 0 °C and
placed under a N2-pressure, to ensure a good pump stability
and to avoid system pressure fluctuations. As it has been
stated before that Diels-Alder reactions are known to benefit
from pressurized conditions, the continuous flow experiments
were performed in a high temperature and high pressure
In addition to the problematic scalability, only a moderate
conversion was reached in batch. Therefore, the development
of a continuous flow process was considered. The proper use
of a high catalyst loading, a high pressure environment and
efficient radial mixing, as it occurs in ideal plug flow, inherently
related to the proposed microreactor device, is expected to
lead to an improved result. The batch experiments revealed
that dichloromethane was the solvent of choice. For
continuous flow experiments, the pressure drop over the
system depends on the solvent viscosity, catalyst, system set-
up and the pump speed. As indicated by the preliminary flow
experiments, the generated pressure drop over the packed
environment
(100
°C,
30
bar).
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100 °C
OMe
O
O
OMe
Exo-DA
30 bar
CPD
MA
O
OMe
Dry CH2Cl2, 0°C, N2-P
CatCart X-Cube
Endo-DA
Scheme 4 The continuous flow Diels-Alder process using a zeolite USY catalyst bed
Analogous to the preliminary batch experiments, the zeolite be applied to reach a high and stable conversion using a H-
catalyst was conditioned prior to its use, however, in the Beta catalyst or a H-USY species with a doubled Si/Al-ratio,
continuous flow configuration this drying was performed in respectively with
a space-time of 390 and 420 kg
situ. The CatCart® was packed with zeolite USY, after physical catalyst.s/mol CPD (Table 5 entries 7 and 8). The better
pre-treatment, and subsequently dried by a N2 flush of 1 h performance of CBV 760 catalyst in comparison to CBV 720 in
over the heated cartridge at 200 °C. A conversion of MA to the flow is different from the results obtained in batch (Table 4
end product of 85% was observed, which decreased to 70% and Table 5 entries 2 and 7). This can be ascribed to the
after 6 h (Table 5 entry 1). Additionally, the catalyst was improvements made in the condition procedure of the
evaluated without any conditioning procedure (Table 5 entry catalyst. Next, attempts were made to increase the flow rate
2). In this way, a conversion of 95% was reached, decreasing to without affecting the high conversion (Table 5 entries 9 and
81% after 6 h. Quite remarkably, the USY zeolite was thus 10). The optimal balance between conversion and throughput
found to be more active towards acid catalysis without any was found at a contact time of 1.8 min, corresponding to 195
drying step. Innumerable examples can be found in literature kg catalyst.s/mol CPD (Table 5 entry 9). Moreover, in contrast
of acid catalyzed reactions which require a calcination step or to the H-USY catalyst, the H-Beta catalyzed continuous flow
a high temperature and/or a vacuum step to activate these process in dichloromethane without pre-drying did not show a
aluminosilicate catalysts.11a-c, 11e-j, 40
drop in conversion within a 7 h time frame (Table 5 entries 6
and 11). These reaction conditions were selected for the
optimal Diels-Alder continuous flow process. Based on the
experimental results at a flow rate of 0.3 mL/min, deactivation
is expected to be observed starting 9 h after process start-up
(Table 5 entry 10).
Adjusting the dienophile to diene ratio, it was found that a
small excess of dienophile (1.2 equiv.) resulted in a nearly
quantitative conversion and high selectivity to the endo
product, as well as a high stability of the process, which were
the main goals of the present work (Table 5 entry 4). The
process was monitored during 7 h. Noteworthy, the contact Because of the volatility of the reagents and the solvent, the
time (CT), which equals the retention time in the catalyst bed, end products were isolated as a mixture of endo and exo
was barely 3.5 min. This corresponds to a space-time of 444 kg products in
a nearly quantitative yield via mild rotary
catalyst.s/mol CPD. Repetition of these process conditions evaporation. Upon evaporation with mild heating, a product
showed that the conversion remained at least 94% during the loss, mainly of the endo-isomer, was observed. The purity of
first 7 hours after start-up. In the resulting DA mixture, a the obtained mixture of DA products was verified using GC(-
selectivity of 88% endo isomer was observed. In comparison, MS) and was found to be ≥ 95%. Under the optimal process
when an excess of CPD was used, a fast deactivation of the conditions, the Diels-Alder products were isolated in a 94%
catalyst bed was observed (70% after 4 h, see Table 5 entry 3). yield, a 89% selectivity towards the endo isomer and a GC-
Doubling the flow rate, corresponding to a contact time of 1.8 purity of 97% (Table 5 entry 11). A calculated throughput of
min and a space-time of 222 kg catalyst.s/mol CPD, or using 0.87 g/h over 7 h was reached, corresponding to a space-time
dichloromethane without pre-drying (Table 5, entries 5 and 6), yield of 0.29 mmol/g/min. This implies a respectively 9 and 121
both gave rise to a comparably high conversion initially, but a times higher space-time yield in comparison to the published
fast drop in conversion afterwards. It indicates that the continuous flow procedures of Sachse et al. and Chiroli et
performance achieved with the higher space-time corresponds al.29,30 Noteworthy, our results were obtained using just a 1:1
with the establishment of thermodynamic equilibrium.
stoichiometric ratio of diene and dienophile and a contact time
of 1.8 min with the catalyst bed.
Based on the batch screening of catalysts, other promising
zeolite catalysts were identified for evaluation under
continuous flow conditions. A 1:1 CPD:MA stoichiometry could
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Table 5 Results of the continuous flow Diels-Alder process using a zeolite catalyst bed (dry dichloromethane, ξa = 0.35 mL, P = 30 bar, T = 100 °C)
1H-NMR
EP (%)
Zeoliteb,c
type
FR CT
(mL/min) (min)
Equiv. [CPD]
MA
[MA]
(M)
Timed
(h)
Endo
(%)
Entry
1e
Si/Al
15
(M)
1
85
70
95
88
83
81
92
81
70
96
98
99
99
98
98
96
95
95
95
95
80
68
62
93
96
99
96
93
84
80
93
93
93
93
93
93
92
93
94
94
94
94
94
94
95
95
88
86
89
89
88
87
89
88
87
88
88
88
88
88
88
88
89
90
89
89
89
88
88
87
88
87
88
88
87
87
88
88
88
89
89
89
89
87
88
88
88
88
89
88
88
89
H-USY
H-USY
0.1
0.1
3.5
3.5
1
0.5
0.5
0.5
6
1
1-5.5
2
3
15
15
1
0.5
0.6
5.5
5.5-6.5
1
H-USY
H-USY
0.1
0.1
3.5
3.5
0.8
0.5
0.6
1-4
4
1
2
3
4
5
15
15
15
30
1.2
1.2
1.2
1
0.5
0.5
0.5
0.5
4
5
6
7
1
2
3
H-USY
H-USY
H-USY
0.2
0.1
0.1
1.8
3.5
3.5
0.6
0.6
0.5
4
5
6
7
1
2
3
6f
4
5
6
7
1
2
3
7
4
5
6
7
1
2
3
8
9
H-Beta
H-Beta
12.5
12.5
0.1
0.2
3.5
1.8
1
1
0.5
0.5
0.5
0.5
4
5
6
7
1
2
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Journal Name
3
4
95
95
95
93
93
95
95
94
91
87
85
94
94
95
94
94
93
92
89
89
89
89
89
88
89
88
89
89
89
89
89
89
89
89
89
89
5
6
7
0.7
1
2
10
H-Beta
H-Beta
12.5
12.5
0.3
0.2
1.2
1.8
1
1
0.5
0.5
0.5
0.5
3
4
5
1
2
3
11f
4
5
6
7
a Void fraction in the catalyst bed, estimated value: 40% of total volume
b The catalyst was used without any drying procedure, unless specified otherwise
c The corresponding zeolite product code, as obtained from Zeolyst International, can be seen in Table 1 and Table 4
d Time since start-up of the process
e The catalyst was conditioned by a 1 h N2 flush over the cartridge at 200 °C
f Dichloromethane was not dried before use
In an attempt to avoid the use of harmful dichloromethane, Unfortunately, in case of toluene or acetonitrile as a solvent,
the second and third best solvent, as it was determined using a both the conversion and the selectivity towards the endo
batch solvent screening (Table 3), were also evaluated under isomer were significantly lower in comparison to the use of
the optimized continuous flow conditions (Table 6). dichloromethane.
Table 6 Results of the continuous flow Diels-Alder process using a H-Beta catalyst bed, without any drying procedure (CP814E*, Si/Al 12.5, ξa = 0.35 mL, P = 30 bar, T = 100 °C).
1H-NMR
EP (%)
FR CT
(mL/min) (min)
Equiv. [CPD] [MA] Timeb
Endo
(%)
Entry
Solvent
MA
(M)
0.5
(M)
0.5
(h)
1
2
3
4
5
6
7
1
2
3
4
5
6
7
66
64
62
61
59
57
55
84
87
86
85
83
81
79
83
84
83
84
84
83
83
86
84
86
85
86
84
85
1
Acetonitrile
0.1
0.1
3.5
1
2
Toluene
3.5
1
0.5
0.5
a Void fraction in the catalyst bed, estimated value: 40% of total volume
b Time since start-up of the process
1
3.4 Neat continuous flow experiments
of the cyclopentadiene dimer (about 6%) was observed on H-
NMR as a side-product.
Finally, an effort was made to eliminate the need for solvent
and thus the use of undiluted reagents was evaluated. To
avoid any uncontrollable reaction in the reagent reservoir, the
choice was made to handle two separate reagent streams. This
configuration entails a slight excess of cyclopentadiene (1.1
equiv.). Despite the higher throughput, a lower conversion and
selectivity were obtained (Table 7). Moreover, a small fraction
Table 7 Conditions and results of the neat continuous flow Diels-Alder process using a
zeolite USY catalyst bed (FR1 = FR2 = 0.1 mL/min, 1.1 equiv. CPD, ξ = 0.35 mL, CT = 1.8
min, P = 30 bar, T = 100 °C, CBV 720)
1H-NMR
EP (%)
Timeb
(h)
Endo
(%)
Entry
8 | J. Name., 2012, 00, 1-3
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3.5 Batch confirmation of the observed trends
1
3.5
1
85
85
86
70
69
70
1a
2
In order to get a full comparison, the batch experiments were
repeated using the non-dried zeolite material, which lead to an
increase of the conversion (Table 8). To get insight in the
influence of the pelletizing pre-treatment, comparative batch
experiments were carried out. For both the H-USY and the
H-Beta catalyst, the powder and the pelletized form showed a
comparable conversion and selectivity, although in case of the
H-Beta species a larger difference was observed in favour of
the powder form (Table 8 entries 2, 3, 5 and 6). The deposition
of cyclopentadiene on the catalyst surface was determined for
the changing CPD:MA ratio, which should theoretically equal
one at every moment of the experiment. The deviation of this
ratio from one can be ascribed to the deposition of
cyclopentadiene (polymers) on the catalyst bed. This process
leads to a biased view of the conversion of CPD to the end
products from 1H-NMR and is accompanied by a decreased
CPD:MA ratio. In each batch experiment, the deposition of CPD
amounted to 17-30% approximately. For comparison, also in
flow a continuous deposition of CPD on the catalyst surface
was observed (1-6%). In batch, it appears that the conversion
benefits from the drying of the solvent (Table 8 entries 2, 4, 5
and 7). The continuous flow experiment using the H-USY
catalyst indicates that without the pre-drying of
dichloromethane a sudden accelerated decline in conversion
can be observed (Table 5 entry 6). However, this was not seen
within a 7 h time frame when the H-Beta catalyst was used
a The catalyst was conditioned by a 1 h N2 flush
over the cartridge at 200 °C
b Time since start-up of the process
Presumably, the neat DA reaction mainly takes place in the
bulk phase and not on the catalyst surface. This could explain
the decreased selectivity, why no deactivation of the catalyst
bed was observed and why conditioning of the catalyst did not
influence the outcome of the reaction. This was easily verified
by calculation knowing the acidity of the catalyst. The acid site
concentration of CBV 720 was determined using NH3-TPD to be
0.47 mmol H+/g. Taking into account the internal
concentration of MA, the limiting reagent, of 5.5M, it appears
that there is a catalyst loading of 9 mol% in the CatCart® or a
site-time of 9.5 mol acid sites.s/mol MA. Therefore, knowing
that the reaction also proceeds, albeit non-selective, without
catalyst, the catalyst loading is too low, leading to a non-
catalyzed and thus non-selective background reaction. As a
result, the high conversion but low endo-selectivity can be
explained by the high temperature and pressure conditions. In
comparison, under diluted continuous flow conditions (Table 5
entry 4), this catalyst loading is 99 mol%, corresponding to a
site-time of 208.7 mol acid sites.s/mol CPD. These calculations
were performed under the assumption that the physical pre-
treatment does not affect the amount of acid sites, nor their
accessibility.
(Table
5
entry
11).
Table 8 Overview of the obtained results of the batch Diels-Alder reaction between 0.1 M CPD and 1 equiv. MA at reflux temperature. Non-dried zeolite was used as a catalyst in a
30 wt% loading. Conversions are reported as observed on integration of 1H-NMR of the crude reaction mixtures (RT = 3.5 h)
1H-NMR
Zeolite
Typea
Catalyst
form
Endo
(%)
CPD deposition
(mmol/g)
Entry
Si/Al
Solvent
MA (%)
EP (%)
1
2
3
4
5
6
7
no
-
15
15
15
12.5
12.5
12.5
- dry DCM
pelletized dry DCM
powder dry DCM
pelletized DCM
pelletized dry DCM
90
47
46
56
36
30
38
10
53
54
44
64
70
62
79
92
92
92
92
89
91
-
H-USY
H-USY
H-USY
H-Beta
H-Beta
H-Beta
13 (26%)
15 (29%)
15 (30%)
11 (23%)
11 (21%)
9 (17%)
powder
pelletized
dry DCM
DCM
a The corresponding zeolite product code, as obtained from Zeolyst International, can be seen in Table 1
In flow, a high loading and a continuous recuperation of the considered. Therefore, to demonstrate the reactivation of the
catalyst results in a high catalytic productivity. Assuming that a catalyst, an excess of cyclopentadiene was used to accelerate
batch process is stopped at 70% conversion after 3.5 h (Table 8 the deposition (Figure 3 process 1). As can be seen from Table
entry 6) as from then on hardly any change in conversion was 5 entry 3 and Table 9 process 1, a small excess of CPD leads to
observed, a catalytic productivity of 5.3 g EP/g H-Beta could be a fast drop in conversion. Next, after the loss of conversion
obtained. In contrast, the 7 h flow process, as presented in and selectivity, the challenge remained to regenerate the
Table 5 entry 11, has a catalytic productivity of 18.7 g EP/g H- catalyst’s activity. In a first attempt, a 4 h high vacuum
Beta. Moreover, this productivity is a minimal value, as the treatment at 150 °C was carried out, after a continuous flow
catalyst deactivation was not monitored to its boundaries. ethanol rinse. Subsequently, a continuous flow process under
Evaluating both the lab-scale batch and continuous process at the optimized conditions was evaluated (Figure 3 process 2).
3.5 h, the flow process has a 14 times higher production of The obtained conversion and selectivity, however, were
Diels-Alder end products (0.87 g/h).
unsatisfying (Table 9 process 2). Thus, a more severe
reactivation procedure was performed. Again a continuous
flow rinse of ethanol was performed after which the zeolite
was calcined for 5 h at 500 °C. In this way, the catalyst was
reactivated and a high conversion and endo-selectivity was
observed again under the optimized continuous flow
3.6 Spent catalyst characterisation and regeneration
Although hardly any deactivation of the used zeolite was
observed within a 7 h time frame under the optimized
conditions, the regeneration advantage of zeolite catalysis was
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conditions (Figure 3 and Table 9, process 3). A mixture of end In addition to our work, sieve analysis was carried out on used
pelletized zeolite, which revealed attrition of small zeolite
particles upon reaction (Table 10).
products was isolated in a 92% yield, with a GC-purity of 99%.
Table 10 Influence of the process on the particle distribution through sieve analysis
Particle
distribution (%)
Zeolite
type
Si/Ala
Condition
<125
µm
16
125-
200 µm
84
H-USY
H-USY
H-Beta
15
15
after reaction
after regeneration
and reaction
13
18
87
82
Figure 3 Process conditions of the regeneration experiments of the used zeolite USY
Table 9 Overview of the obtained conversions and endo-selectivity for the regeneration
12.5
after reaction
a The corresponding product code can be seen in Table 1
1H-NMR
EP (%)
3.7 Expansion to other derivatives
Timea
(h)
Endo
(%)
Process
To demonstrate the versatile performance of this process,
alternative dienophiles were evaluated (Table 11). Isolation was
performed using mild rotary evaporation. Methyl vinyl ketone
(MVK) gave rise to an excellent yield and selectivity towards the
endo-isomer. Although this selectivity was slightly lower in case
acrolein (AL) was used, a high yield of Diels-Alder products was
obtained. In order to get a high conversion with acrylonitrile (AN) as
a dienophile, the temperature was raised to 200 °C. Finally,
dimethyl acetylene dicarboxylate (DMAD) also lead to an excellent
1
4
1
2
2
6
92
70
57
59
94
94
89
87
85
85
89
89
1
2
3
a Time since start-up of the process
conversion
for
7
hours.
Table 11 Results of the continuous flow Diels-Alder process of cyclopentadiene and alternative dienophiles using a zeolite catalyst bed (dichloromethane, [CPD] =0.5M, [DP] = 0.5
M, ξa = 0.35 mL, FR = 0,2 mL/min, RT = 1.8 min, P = 30 bar, T = 100 °C)
Endo
(%)
Dienophile
Timea (h)
Conversionb (%)
Yieldc (%)
94 (97)
1
7
1
7
1
7
1
7
1
7
94
92
89
MA
100
100
98d
98d
84e
82e
86
99 (97)
92 (100)
84 (96)
60f
89
78
54
-
MVK
AL
AN
90
DMAD
a Time since start-up of the process
b The conversion was determined by integration of the signals of dienophile and end product(s) in
the 1H-NMR spectrum of the crude reaction mixtures, unless specified otherwise
c GC-purity is indicated between brackets
d
The conversion was determined by integration of the signals of diene and end product(s) in the
1H-NMR spectrum of the crude reaction mixtures
e T = 200 °C
f After distillation
high conversion (≥92%) and selectivity towards the endo-
isomer (89:11) was obtained in just 1.8 min contact time in the
packed catalyst bed. Moreover, a 1:1 stoichiometry diene to
dienophile was applied. These values are similar to some of
the best small scale batch procedures and thus the safely
Conclusions
An efficient continuous flow process was developed for the
Diels-Alder reaction of cyclopentadiene and methyl acrylate.
Using zeolite H-Beta catalysis and high pressure conditions, a
10 | J. Name., 2012, 00, 1-3
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scalable continuous flow process can compete with previously 10. (a) A. Pohar and I. Plazl, Chemical and Biochemical Engineering
developed batch processes, as these often require an excess of Quarterly, 2009, 23, 537-544; (b) P. Watts and C. Wiles, Journal of
cyclopentadiene, long reaction times, (toxic) Lewis acid Chemical Research, 2012, 181-193; (c) J. Wegner, S. Ceylan and A.
catalyst or expensive ionic liquids. The process was monitored Kirschning, Chem. Commun., 2011, 47, 4583-4592.
during 7 h and a calculated throughput of 0.87 g/h was 11. (a) C. Bernardon, B. Louis, V. Beneteau and P. Pale,
reached, corresponding to
a 3.5 times higher catalytic Chempluschem, 2013, 78, 1134-1141; (b) Y.-T. Cheng and G. W.
productivity and a 14 times higher production of Diels-Alder Huber, Green Chemistry, 2012, 14, 3114-3125; (c) J. M. Fraile, J. I.
adducts in comparison to the small scale batch process. In Garcia, D. Gracia, J. A. Mayoral, T. Tarnai and F. Figueras, J. Mol.
contrast to various literature examples, the zeolite material Catal. A-Chem., 1997, 121, 97-102; (d) S. Ghosh and N. L. Bauld, J.
was found more active in acid catalysis without any drying Catal., 1985, 95, 300-304; (e) M. V. Gomez, A. Cantin, A. Corma and
step. Afterwards, the end products could be isolated in a A. de la Hoz, J. Mol. Catal. A-Chem., 2005, 240, 16-21; (f) S. Imachi
straightforward manner in high yields. The use of neat reagent and M. Onaka, Tetrahedron Lett., 2004, 45, 4943-4946; (g) T. Kugita,
streams was also evaluated, but resulted into a slightly M. Ezawa, T. Owada, Y. Tomita, S. Namba, N. Hashimoto and M.
decreased conversion and a significant loss of endo-selectivity. Onaka, Micropor. Mesopor. Mat., 2001, 44, 531-536; (h) T. Kugita, S.
The regeneration of the used zeolite catalyst was performed K. Jana, T. Owada, N. Hashimoto, M. Onaka and S. Namba, Appl.
using a 5 h calcination step at 500 °C. Finally, the versatility of Catal. A-Gen., 2003, 245, 353-362; (i) G. Mashayekhi, M. Ghandi, F.
this process was demonstrated as alternative dienophiles were Farzaneh, M. Shahidzadeh and H. M. Najafi, J. Mol. Catal. A-Chem.,
evaluated, leading to high yields.
2007, 264, 220-226; (j) M. Onaka, N. Hashimoto, Y. Kitabata and R.
Yamasaki, Appl. Catal. A-Gen., 2003, 241, 307-317; (k) J. K. Park, S.
W. Kim, T. Hyeon and B. M. Kim, Tetrahedron-Asymmetry, 2001, 12
,
Acknowledgements
2931-2935; (l) M. Zendehdel, N. F. Far and Z. Gaykani, Journal of
Inclusion Phenomena and Macrocyclic Chemistry, 2005, 53, 47-49.
12. D. E. De Vos and P. A. Jacobs, Micropor. Mesopor. Mat., 2005,
82, 293-304.
13. J. Weitkamp, Solid State Ionics, 2000, 131, 175-188.
14. A. F. Masters and T. Maschmeyer, Micropor. Mesopor. Mat.,
2011, 142, 423-438.
Financial support for this research from the Fund for Scientific
Research Flanders (FWO Vlaanderen) and VITO (Vlaamse
Instelling voor Technologisch Onderzoek) and BOF (Bijzonder
Onderzoeksfonds) of Ghent University is gratefully
acknowledged.
15. (a) A. Gavriilidis, P. Angeli, E. Cao, K. K. Yeong and Y. S. S. Wan,
Chem. Eng. Res. Des., 2002, 80, 3-30; (b) Y. S. S. Wan, J. L. H. Chau,
Notes and references
A. Gavriilidis and K. L. Yeung, Micropor. Mesopor. Mat., 2001, 42
,
1. P. Wothers, N. Greeves, S. Warren and J. Clayden, ed. Oxford
University Press, 2001, pp 907-924.
157-175.
16. (a) Y. Liu, S. Podila, D. L. Nguyen, D. Edouard, P. Nguyen, C.
Pham, M. J. Ledoux and P. H. Cuong, Appl. Catal. A-Gen., 2011, 409
2. (a) M. Hatano, T. Mizuno, A. Izumiseki, R. Usami, T. Asai, M.
Akakura and K. Ishihara, Angew. Chem.-Int. Edit., 2011, 50, 12189-
12192; (b) M. K. Kesharwani and B. Ganguly, Croatica Chemica Acta,
2009, 82, 291-298; (c) J.-H. Zhou, B. Jiang, F.-F. Meng, Y.-H. Xu and
T.-P. Loh, Org. Lett., 2015, 17, 4432-4435.
3. J. A. Funel and S. Abele, Angew. Chem.-Int. Edit., 2013, 52
3822-3863.
4. V. Casson, T. Snee and G. Maschio, J. Hazard. Mater., 2014, 270
45-52.
5. N. A. McGrath, M. Brichacek and J. T. Njardarson, J. Chem.
Educ., 2010, 87, 1348-1349.
6. J. T. Njardarson http://njardarson.lab.arizona.edu/content/top-
pharmaceuticals-poster (accessed 01/02/2016).
7. N. D. Campbell and A. M. Lovell, In Addiction Reviews, ed. G. R.
Uhl, Blackwell Science Publ, Oxford, 2012, Vol. 1248, pp 124-139.
8. (a) A. Machara, L. Werner, M. A. Endoma-Arias, D. P. Cox and T.
Hudlicky, Advanced Synthesis & Catalysis, 2012, 354, 613-626; (b) L.
Werner, A. Machara, D. R. Adams, D. P. Cox and T. Hudlicky, Journal
of Organic Chemistry, 2011, 76, 4628-4634.
,
113-121; (b) Q. Tang, H. Xu, Y. Y. Zheng, J. F. Wang, H. S. Li and J.
Zhang, Appl. Catal. A-Gen., 2012, 413, 36-42.
17. N. Candu, M. Florea, S. M. Coman and V. I. Parvulescu, Appl.
Catal. A-Gen., 2011, 393, 206-214.
18. G. C. Zhang, X. F. Zhang, J. Lv, H. O. Liu, J. S. Qiu and K. L. Yeung,
Catal. Today, 2012, 193, 221-225.
19. Y. S. S. Wan, J. L. H. Chau, A. Gavriilidis and K. L. Yeung, Chem.
Commun., 2002, 878-879.
20. http://zeolyst.com/our-products.aspx (accessed 20/11/2015).
21. (a) W. Lutz, Advances in Materials Science and Engineering,
2014; (b) V. Patzelova, A. Zukal and J. Kloubek, Chemical Papers-
Chemicke Zvesti, 1985, 39, 361-367; (c) Z. M. Yan, M. A. Ding, J. Q.
Zhuang, X. C. Liu, X. M. Liu, X. W. Han, X. H. Bao, F. X. Chang, L. Xu
and Z. M. Liu, J. Mol. Catal. A-Chem., 2003, 194, 153-167.
22. (a) A. Corma and H. Garcia, Catal. Today, 1997, 38, 257-308; (b)
,
,
S. E. Sen, S. M. Smith and K. A. Sullivan, Tetrahedron, 1999, 55
,
12657-12698.
23. D. Nakashima and H. Yamamoto, Org. Lett., 2005,
7, 1251-1253.
9. (a) D. R. J. Acke and C. V. Stevens, Green Chemistry, 2007, 9,
24. (a) I. H. Chen, J. N. Young and S. J. Yu, Tetrahedron, 2004, 60
,
386-390; (b) A. Cukalovic, J.-C. R. Monbaliu and C. Stevens, In
Synthesis of Heterocycles via Multicomponent Reactions I, ed. R. V.
A. Orru and E. Ruijter, Springer Berlin Heidelberg, 2010, Vol. 23, pp
161-198; (c) T. S. Heugebaert, C. V. Stevens and C. O. Kappe,
11903-11909; (b) J. R. Harjani, R. D. Singer, M. T. Garcia and P. J.
Scammells, Green Chemistry, 2009, 11, 83-90; (c) G. Imperato, E.
Eibler, J. Niedermaier and B. Konig, Chem. Commun., 2005, 1170-
1172; (d) E. Janus, I. Goc-Maciejewska, M. Lozynski and J. Pernak,
Tetrahedron Lett., 2006, 47, 4079-4083; (e) I. Lopez, G. Silvero, M. J.
Arevalo, R. Babiano, J. C. Palacios and J. L. Bravo, Tetrahedron,
2007, 63, 2901-2906; (f) D. Sarma and A. Kumar, Appl. Catal. A-
Gen., 2008, 335, 1-6; (g) G. H. Tao, L. He, W. S. Liu, L. Xu, W. Xiong,
ChemSusChem, 2015,
8, 1648-51; (d) F. E. A. Van Waes, J.
Drabowicz, A. Cukalovic and C. V. Stevens, Green Chemistry, 2012,
14, 2776-2779; (e) F. E. A. Van Waes, S. Seghers, W. Dermaut, B.
Cappuyns and C. V. Stevens, Journal of Flow Chemistry, 2014, 4,
118-124.
T. Wang and Y. Kou, Green Chemistry, 2006, 8, 639-646; (h) X. P. Xu,
This journal is © The Royal Society of Chemistry 20xx
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Page 12 of 13
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ARTICLE
Journal Name
M. T. Ma, Y. M. Yao, Y. Zhang and Q. Shen, European Journal of 30. (a) V. Chiroli, M. Benaglia, F. Cozzi, A. Puglisi, R. Annunziata and
Inorganic Chemistry, 2005, 676-684. G. Celentano, Org. Lett., 2013, 15, 3590-3593; (b) V. Chiroli, M.
25. (a) K. Erfurt, I. Wandzik, K. Walczak, K. Matuszek and A. Benaglia, A. Puglisi, R. Porta, R. P. Jumde and A. Mandoli, Green
Chrobok, Green Chemistry, 2014, 16, 3508-3514; (b) V. Escande, T. Chemistry, 2014, 16, 2798-2806.
K. Olszewski and C. Grison, Comptes Rendus Chimie, 2014, 17, 731- 31. S. W. Breeden, J. H. Clark, D. J. Macquarrie and J. R. Sherwood,
737; (c) A. Kumar and S. S. Pawar, Journal of Organic Chemistry, In Green Techniques for Organic Synthesis and Medicinal Chemistry,
2007, 72, 8111-8114; (d) B. Mathieu, L. de Fays and L. Ghosez, ed. W. Zhang and B. W. Cue, Wiley, 2012, pp 243-262.
Tetrahedron Lett., 2000, 41, 9561-9564; (e) K. Mori, T. Hara, T. 32. J. Clayden, N. Greeves and S. Warren, In Organic Chemistry, ed.
Mizugaki, K. Ebitani and K. Kaneda, Journal of the American Oxford University Press, 2012, pp 877-908.
Chemical Society, 2003, 125, 11460-11461; (f) W. Stefaniak, E. Janus 33. (a) R. Breslow and U. Maitra, Tetrahedron Lett., 1984, 25, 1239-
and E. Milchert, Catalysis Letters, 2011, 141, 742-747; (g) Z. Tang, B. 1240; (b) R. Breslow, U. Maitra and D. Rideout, Tetrahedron Lett.,
Mathieu, B. Tinant, G. Dive and L. Ghosez, Tetrahedron, 2007, 63
8449-8462.
,
1983, 24, 1901-1904; (c) P. A. Grieco, P. Garner and Z.-m. He,
Tetrahedron Lett., 1983, 24, 1897-1900; (d) D. C. Rideout and R.
26. (a) K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, Journal of Breslow, Journal of the American Chemical Society, 1980, 102, 7816-
the American Chemical Society, 2000, 122, 4243-4244; (b) A. Barba, 7817; (e) R. B. Woodward and H. Baer, Journal of the American
S. Barroso, G. Blay, L. Cardona, M. Melegari and J. R. Pedro, Synlett, Chemical Society, 1948, 70, 1161-1166.
2011, 1592-1596; (c) S. Erol and I. Dogan, Tetrahedron, 2013, 69
,
34. K. C. Nicolaou, S. A. Snyder, T. Montagnon and G.
1337-1344; (d) M. Hatano and K. Ishihara, Chem. Commun., 2012, Vassilikogiannakis, Angewandte Chemie (International ed. in
48, 4273-4283; (e) K. Ishihara and K. Nakano, Journal of the English), 2002, 41, 1668-98.
American Chemical Society, 2005, 127, 10504-10505; (f) Z. J. Jia, Q. 35. K.-i. Takao, R. Munakata and K.-i. Tadano, Chemical Reviews,
Zhou, Q. Q. Zhou, P. Q. Chen and Y. C. Chen, Angew. Chem.-Int. 2005, 105, 4779-4807.
Edit., 2011, 50, 8638-8641; (g) T. Kano, Y. Tanaka and K. Maruoka, 36. https://scifinder.cas.org/ (accessed 08/08/2016).
Org. Lett., 2006,
Yamamoto, Journal of the American Chemical Society, 1994, 116
12115-12116; (i) S. C. Pellegrinet and R. A. Spanevello, Org. Lett., 1989, 30, 1785-1788; (c) A. Manna and A. Kumar, The Journal of
2000, , 1073-1076; (j) W. R. Roush and B. B. Brown, Journal of Physical Chemistry A, 2013, 117, 2446-2454.
Organic Chemistry, 1992, 57, 3380-3387; (k) J. H. Zhou, B. Jiang, F. F. 38. M. J. Remy, D. Stanica, G. Poncelet, E. J. P. Feijen, P. J. Grobet, J.
Meng, Y. H. Xu and T. P. Loh, Org. Lett., 2015, 17, 4432-4435. A. Martens and P. A. Jacobs, Journal of Physical Chemistry, 1996,
27. (a) M. Kanao, A. Otake, K. Tsuchiya and K. Ogino, Int. J. Org. 100, 12440-12447.
Chem., 2012, , 26-30; (b) P. Klein, M. Thyes, M. Grosse and K. M. 39. A. Funez, J. W. Thybaut, G. B. Marin, P. Sanchez, A. De Lucas and
Weber, 2002 ; (c) A. Okamoto, M. S. Snow and D. R. Arnold, J. L. Valverde, Appl. Catal. A-Gen., 2008, 349, 29-39.
Tetrahedron, 1986, 42, 6175-6187. 40. (a) P. Botella, A. Corma, M. T. Navarro, F. Rey and G. Sastre, J.
8
, 2687-2689; (h) K. Maruoka, H. Imoto and H. 37. (a) M. J. Diego-Castro and H. C. Hailes, Tetrahedron Lett., 1998,
,
39, 2211-2214; (b) D. A. Jaeger and C. E. Tucker, Tetrahedron Lett.,
2
2
28. (a) S. Abele, S. Hock, G. Schmidt, J. A. Funel and R. Marti, Org. Catal., 2003, 217, 406-416; (b) L. Cerveny, K. Mikulcova and J. Cejka,
Process Res. Dev., 2012, 16, 1114-1120; (b) F. Benito-Lopez, A. J. Appl. Catal. A-Gen., 2002, 223, 65-72; (c) M. G. Cutrufello, I. Ferino,
Mettelalj, R. J. M. Egberink, A. H. Velders, R. M. Tiggelaar, H. R. Monaci, E. Rombi, V. Solinas, R. Magnoux and A. Guisnet, Appl.
Gardeniers, D. N. Reinhoudt and W. Verboom, Chim. Oggi-Chem. Catal. A-Gen., 2003, 241, 91-111; (d) X. C. Hu, G. K. Chuah and S.
Today, 2010, 28, 56-59; (c) M. Rasheed and T. Wirth, Chim. Oggi- Jaenicke, Micropor. Mesopor. Mat., 2002, 53, 153-161; (e) N.
Chem. Today, 2011, 29, 53-55.
Srinivas, A. P. Singh, A. V. Ramaswamy, A. Finiels and P. Moreau,
29. A. Sachse, V. Hulea, A. Finiels, B. Coq, F. Fajula and A. Catalysis Letters, 2002, 80, 181-186; (f) G. Takeuchi, Y. Shimoura
Galarneau, J. Catal., 2012, 287, 62-67.
and T. Hara, Appl. Catal. A-Gen., 1996, 137, 87-91; (g) J. Wang, J.-N.
Park, Y.-K. Park and C. W. Lee, J. Catal., 2003, 220, 265-272.
12 | J. Name., 2012, 00, 1-3
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Green Chemistry
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DOI: 10.1039/C6GC02334G
Improving the efficiency of the Diels-Alder process by using flow
chemistry and zeolite catalysis
S. Seghers, L. Protasova, S. Mullens, J. W. Thybaut, C. V. Stevens