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Improving the efficiency of the Diels–Alder

Cite this: Green Chem., 2017, 19, 237
process by using flow chemistry and zeolite
catalysis†
S. Seghers,a L. Protasova,b S. Mullens,b J. W. Thybautc and C. V. Stevens*a
Published on 25 October 2016. Downloaded on 6/8/2020 5:58:12 AM.

Received 21st August 2016,
Accepted 24th October 2016
DOI: 10.1039/c6gc02334g
www.rsc.org/greenchem
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.

1 Introduction
The Diels–Alder (DA) reaction is universally acknowledged for
its rapid, atom-efficient and clean access to molecular com-
plexity on a small scale. This reaction involves a [4 + 2]-cyclo-
addition 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 com-
pounds. 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 Scheme 1 Stereoselectivity of the Diels–Alder reaction.

mostly obtained as the major products due to favorable sec-

ondary orbital interactions.1,2 Despite its wide use at the
research level, problems associated with reactivity, selectivity
required stoichiometric excess of the reagent, the exothermic
and scale-up still have to be overcome for Diels–Alder reac-
behavior of the main and side reactions, poor selectivity,
tions. The core problems are the instability of the reagents, the
extreme reaction times and temperatures, as well as the use of
(toxic) catalysts.3
a
Indeed, the industrial use of one of the most popular trans-
SynBioC Research Group, Department of Sustainable Organic Chemistry and
Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,
formations for organic chemists is limited due to safety and
9000 Ghent, Belgium. E-mail: chris.stevens@ugent.be purity concerns. Due to competing, rapid and uncontrolled
b
VITO, Vlaamse Instelling voor Technologisch Onderzoek, Boeretang 200, 2400 Mol, polymerization with a potentially explosive character, the
Belgium scale-up of the DA reaction constitutes an important challenge
c
Laboratory for Chemical Technology, Department of Chemical Engineering and
in view of industrial application. Process engineers tend to
Technical Chemistry, Faculty of Engineering and Architecture, Ghent University,
Technologiepark 914, 9052 Ghent, Belgium
consider the DA reaction by definition in the field of non-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/ scalable transformations and, in many cases, refuse chemical
c6gc02334g routes featuring the DA reaction as a key step.3,4 For instance,

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Scheme 2 Buprenorphine synthesis from thebaine.8
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
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from thebaine or oripavine includes a DA reaction step with
methyl vinyl ketone (MVK) as a dienophile (Scheme 2).8
Although little is known about DA reactions on the industrial
scale, Funel and Abele recently published a review containing
a limited number of industrial relevant DA reactions.3
In view of the aim of our research group to facilitate chal-
lenging reactions in flow,9 microreactor technology (MRT) is
believed to be able to overcome the previously described pro-
blems. As a consequence of its small dimensions, the reaction
environment can be controlled meticulously. The desired reac-
tion time, temperature and, due to efficient mixing properties,
stoichiometry can exactly be set. A fast, safe and low cost
increase of the production capacity constitutes the key element
to address the DA reaction in a continuous flow set-up.
Moreover, the combination with heterogeneous catalysis tends
to be a perfect match as the immobilization of a solid catalyst
in a microreactor simplifies both the recuperation of the cata-
lyst and the work-up of the product.10
DA reactions are known to be catalyzed by Lewis or
Brønsted acids. The replacement of homogeneous catalysts,
such as AlCl3, HF or H2SO4, by heterogeneous analogues, is of
great interest. In addition to concerns about health, safety and
corrosion, the use of homogeneous catalysts is also
accompanied by high costs for work-up and disposal of waste
streams. Being solid acids, zeolites, often metal-doped or
-exchanged, and mesoporous silica derived catalysts are exten-
sively investigated for DA reactions.11,12 Zeolites consist of SiO4
and AlO4 tetrahedra as elementary building blocks in well-
ordered 3D structures. Within the cavities, both Brønsted and
Lewis acid sites are present.13,14 The use of such solid acid cata-
lysts enhances the conversion and the selectivity to the endo-
Scheme 3 Target reaction to develop a continuous flow and heterogeneously catalyzed DA process.
238 | Green Chem., 2017, 19, 237–248
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isomer, as the interaction between the acid sites of the solid cata-
lyst and the electron withdrawing group of the dienophile
reduces the LUMO’s energy. This provides a better overlap with
the HOMO of the diene.1,11g,i Moreover, microporous or meso-
porous structures also exhibit spatial confinement of the
reagents, even directing the product selectivity in the one or the
other direction.11e,f,12 The use of zeolites in combination with
MRT is much less investigated.15 However, some research groups
have performed reactions by combining microreactors and acid
catalysis by zeolites: dehydration of methanol to dimethylether,16
benzylation of benzene with benzyl alcohol,17 Knoevenagel con-
densation and the epoxidation of 1-pentene.18,19
In this work, the reaction between cyclopentadiene (CPD),
by far the most popular diene for DA reactions, and methyl
acrylate (MA), both reactive and polymerization prone sub-
strates, was chosen as the generic reaction to optimize the DA
reaction under continuous flow conditions (Scheme 3). Among
the commercially available zeolites (e.g. (US)Y, ZSM-5, Beta and
Mordenite), zeolite Y and Beta type catalysts have the largest
pore diameter and surface area.20 The subtype Ultrastable
Y (USY) is obtained after a dedicated dealumination treatment.21
In general, the large pore zeolite types USY and Beta are most
often used as a solid acid catalyst in organic synthesis.12,22
H-USY was selected as a starting point for this analysis,
however, a batch screening of different commercially available
zeolites was carried out.
Being a hot topic in organic chemistry, the DA reaction has
already been extensively studied considering a wide variety of
(expensive) ionic liquids and Lewis acid catalysts, focusing on
maximizing the yields and the endo/exo-selectivity.11j,23–25
Although some research aims at inversing this selectivity, e.g.
through the use of a bulky Lewis acid catalyst,2a,26 in most
cases the maximal formation of the typical major endo-adduct
is desired. As the exo-isomer is generally obtained after isomer-
isation from an endo/exo-mixture under basic conditions,27
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also this research project is directed towards the endo-isomer
and thus the maximization of the inherent selectivity of a (cata-
lyzed) Diels–Alder reaction. With regard to the reaction of cyclo-
pentadiene and methyl acrylate, in many publications, yields
are up to 90% and higher, albeit obtained on a small scale and
often requiring an excess of CPD and long reaction times.11j,24,25
Mostly, the batch processes are limited to an endo/exo-selectivity
of about 80 : 20.24,27c Still, some research groups report an excel-
lent 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.
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
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reaction using a chiral organocatalyst on a silica support. The
yield varied from 55 to 95% and an endo/exo-selectivity of
45 : 55 was obtained at room temperature. However, an excess
of 7 equivalents of cyclopentadiene was used and the need for
long residence times (up to 25 h) leads to low space–time
yields (0.0024 mmol g−1 min−1).30
2 Experimental
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*

an attempt to produce aromatics from a renewable feedstock,
Cheng and Huber reported the production of mixtures of aro-
matic 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 in the 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 con-
sisted of aluminium oxide functionalized silica monoliths.
Dichloromethane was used as a solvent at a reactor tempera-
ture of 37 °C. Conversions of 15 to 80% were reached. The opti-
mized contact time was determined to be 9.4 min, resulting in
72% conversion, an endo/exo-distribution of 90 : 10 and a pro-
ductivity of 0.033 mmol g−1 min−1. 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 importance.29 More
recently, Chiroli et al. described a continuous flow Diels–Alder
(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 a 125–200 µm particle fraction.
Dichloromethane was dried by distillation from calcium
hydride, while tetrahydrofuran (THF) and toluene were dis-
tilled 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 thermo-
gravimetric analysis (Table 1). These results show a signifi-
cantly 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).

Table 1 Overview of the default properties of the commercially available zeolites

Zeolite type Product codea Shape SSAb,c (m2 g−1) Pore volumec (cm3 g−1) Pore radiic (Å) Water contentd (wt%)

H-USY CBV 720 Powder 104 0.24 19.5 14

H-USY CBV 720 Pellets 109 0.38 19.2 14
H-Beta CP814E* Powder 177 0.88 18.2 12
H-Beta CP814E* Pellets 155 0.87 18.1 12
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

Zeolite type Product codeb Si/Al Tl,max c (°C) Th,max c (°C) CAS d (10−2 mol kg−1) ΔHd e (kJ mol−1)

H-Y CBV 500 2.6 262 498 179 110

H-USY CBV 720 15 282 482 47 99
H-USY CBV 760 30 236 423 39 69
H-Beta CP814E* 12.5 322 579 39 116
H-ZSM-5 CBV 3024E 15 253 471 78 139
H-Mordenite CBV 21A 10 264 638 96 176
a
Ammonia temperature programmed desorption. 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.

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2.2 Microreactor device
The X-Cube™ flow reactor is commercially available from
ThalesNano and is shown in Fig. 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−1 flow rate. In the employed set-up, a single reagent solu-
tion and the corresponding pump were used. The reagent solu-
tion 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
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CatCart® was used after a manual fill with the 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 Fig. 2. The reactor was rinsed with (dry) di-
chloromethane and subsequently with the reagent solution at
100 °C and 30 bar before start-up, as the catalyst initially
showed a high activity towards cyclopentadiene polymeris-
ation. A full experiment description can be found in the ESI.†
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 ppm) in the 1H-NMR spectrum of the crude reaction mix-
Fig. 1 Set-up for the continuous flow Diels–Alder process (left) using a
zeolite filled CatCart® (right).
Fig. 2 Schematic representation of the X-Cube™ flow reactor in the
used set-up (M = Mixer).
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tures. The space–time (ST) and site-time (SiT) were obtained as
the ratio of the catalyst bed mass, respectively the molar
amount of acid sites (AS), to the corresponding molar reagent
flow rate.
Catalyst mass
STðkg cats mol1 substrateÞ ¼
Molar flow rate reagent
Catalyst mass  AS density
SiTðmol ASs mol1 substrateÞ ¼
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.31–33 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 data-
base 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 have reported the performance of this reac-
tion 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 cata-
lyst is not an option, as both reagents and, if any, end products
accumulate inside the catalyst pore system.
Thus, the evaluation of the DA reaction between CPD and
MA (Scheme 3) was initiated in batch in various organic sol-
vents 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 an oven at 100 °C prior to its use.
This constitutes a milder zeolite activation compared to calci-
nations or other high temperature and/or vacuum treatments
found in the literature.11a–c,e–j Among the evaluated dry sol-
vents, i.e. dichloromethane (DCM), THF, 2-methyl THF, ethyl
acetate and acetonitrile, the highest conversion and endo/exo-
selectivity were obtained in dry DCM (Table 3). Although the
conversion was higher in dry toluene at reflux temperature, di-
chloromethane 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 con-
version 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 presence of a high
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Table 3 Overview of the obtained results of the batch Diels–Alder selectivity. Next, the influence of the zeolite structure was con-
reaction between 0.1 M CPD and 1 equiv. MA at reflux temperature of sidered and other zeolite types with a similar Si/Al-ratio were
the used solvent. An oven-conditioned USY type zeolite was used as a
evaluated. Although these materials possess a comparable
catalyst (CBV 720, Si/Al 15, 780 m2 g−1)
amount of acid sites, their strength and accessibility can be
1
H-NMR influenced by the catalyst architecture. Using H-ZSM-5 and
H-Mordenite catalysts, low conversions were obtained. Finally,
Loading RTa MA EPb endoc the highest conversion was observed using a H-Beta catalyst
Solvent (wt%) (h) (%) (%) (%)
with an analogous Si/Al-ratio, which could be ascribed to the
Dry DCM 0 2 94 6 79 higher specific surface area and pore volume, as well as to the
Dry DCM 0 3.5 90 10 79
Dry DCM 30 2 64 36 92 acid strength of the sites (Tables 1 and 2).39 The high
Dry DCM 30 3.5 57 43 92 maximum temperature corresponding to the strong acid sites
Dry THF 30 2 85 15 73 indicates that, despite the lower amount of acid sites, their
Dry 2-methyl THF 30 2 77 23 71
Dry EtOAc 30 2 87 13 74 strength is higher compared to the CBV 720 material. The
Dry MeCN 30 2 82 18 81 most promising zeolite H-USY and H-Beta species were
Dry toluene 30 2 36 59 73 applied as a catalyst under continuous flow conditions.
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a
Reaction time. b End product (both endo- and exo-isomers).
c
Percentage of the endo-isomer in the final DA product.
3.3 Dilute continuous flow experiments
In addition to the problematic scalability, only a moderate con-
catalyst loading (30 wt%), a mere 43% conversion was reached version was reached in batch. Therefore, the development of a
after 3.5 h. 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 an ideal plug flow, inher-
3.2 Batch catalyst screening
ently related to the proposed microreactor device, is expected
In the next phase of this study, different commercially avail- to lead to an improved result. The batch experiments revealed
able zeolite types were evaluated in the batch mode (Table 4). that dichloromethane was the solvent of choice. For continu-
Among the H-(US)Y family, species with a varying Si/Al-ratio ous flow experiments, the pressure drop over the system
were evaluated. In this way, the best suited balance between depends on the solvent viscosity, catalyst, system set-up and
the amount of acid sites and the acid site strength was investi- pump speed. As indicated by the preliminary flow experiments,
gated within a specific zeolite framework.38 CBV 720 (Si/Al 15) the generated pressure drop over the packed catalyst bed
exhibited the highest conversion. An even higher Si/Al-ratio (CatCart®, see Section 2.2) was too high (>100 bar) when
only resulted in a slightly lower conversion and a similar 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 result-
Table 4 Overview of the obtained results of the batch Diels–Alder ing in a maximum pressure drop below 5 bar. An overview of
reaction between 0.1 M CPD and 1 equiv. MA in dry dichloromethane for the presented flow configuration can be found in Scheme 4. A
2 h at reflux temperature. Oven-conditioned zeolite material was used
starting solution was prepared, containing 0.5 M of both
as a catalyst in a 30 wt% loading
reagents. This was stored at 0 °C and placed under a N2-
1
H-NMR pressure, to ensure a good pump stability and to avoid system
pressure fluctuations. As it has been stated before that Diels–
a
Zeolite type Product code Si/Al MA (%) EPb (%) endoc (%) Alder reactions are known to benefit from pressurized con-
H-Y CBV 500 2.6 82 18 90 ditions, the continuous flow experiments were performed in a
H-USY CBV 720 15 64 36 92 high temperature and high pressure environment (100 °C,
H-USY CBV 760 30 73 27 91
H-ZSM-5 CBV 3024E 15 89 11 86 30 bar).
H-Mordenite CBV 21A 10 95 5 83 Analogous to the preliminary batch experiments, the zeolite
H-Beta CP814E* 12.5 42 58 90 catalyst was conditioned prior to its use, however, in the con-
a
Zeolyst International. b End product (both endo- and exo-isomers). tinuous flow configuration this drying was performed in situ.
c
Percentage of the endo-isomer in the final DA product. The CatCart® was packed with zeolite USY, after physical

Scheme 4 The continuous flow Diels–Alder process using a zeolite USY catalyst bed.

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pre-treatment, and subsequently dried by a N2 flush of 1 h over
the heated cartridge at 200 °C. A conversion of MA to the end
product of 85% was observed, which decreased to 70% after
6 h (Table 5, entry 1). Additionally, the catalyst was evaluated
without any conditioning procedure (Table 5, entry 2). In this
way, a conversion of 95% was reached, decreasing to 81% after
6 h. Quite remarkably, the USY zeolite was thus found to be
more active towards acid catalysis without any drying step.
Innumerable examples can be found in the literature of acid
catalyzed reactions which require a calcination step or a high
temperature and/or a vacuum step to activate these alumino-
silicate catalysts.11a–c,e–j,40
On 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
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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 for 7 h. Noteworthily, the contact time
(CT), which equals the retention time in the catalyst bed, was
barely 3.5 min. This corresponds to a space–time of 444
kg cat·s mol−1 CPD. Repetition of these process conditions
showed that the conversion remained at least 94% during the
first 7 hours after start-up. In the resulting DA mixture, a
selectivity of 88% endo-isomer was observed. In comparison,
when an excess of CPD was used, a fast deactivation of the
catalyst bed was observed (70% after 4 h, see Table 5, entry 3).
Doubling the flow rate, corresponding to a contact time of
1.8 min and a space–time of 222 kg cat·s mol−1 CPD, or
using dichloromethane without pre-drying (Table 5, entries 5
and 6), both gave rise to a comparably high conversion
initially, but a fast drop in conversion afterwards. It indicates
that the performance achieved with the higher space–time
corresponds to the establishment of thermodynamic
equilibrium.
Based on the batch screening of catalysts, other promising
zeolite catalysts were identified for evaluation under continu-
ous flow conditions. A 1 : 1 CPD : MA stoichiometry could be
applied to reach a high and stable conversion using a H-Beta
catalyst or a H-USY species with a doubled Si/Al-ratio, respect-
ively with a space–time of 390 and 420 kg cat·s mol−1
CPD (Table 5, entries 7 and 8). The better performance of the
CBV 760 catalyst in comparison to CBV 720 in flow is different
from the results obtained in batch (Tables 4 and 5, entries 2
and 7). This can be ascribed to the improvements made in the
condition procedure of the catalyst. Next, attempts were made
to increase the flow rate without affecting the high conversion
(Table 5, entries 9 and 10). The optimal balance between con-
version and throughput was found at a contact time of
1.8 min, corresponding to 195 kg cat·s mol−1 CPD
(Table 5, entry 9). Moreover, in contrast to the H-USY catalyst,
the H-Beta catalyzed continuous flow process in dichloro-
methane without pre-drying did not show a drop in conversion
within a 7 h time frame (Table 5 entries 6 and 11). These reac-
tion conditions were selected for the optimal Diels–Alder con-
tinuous flow process. Based on the experimental results at a
flow rate of 0.3 mL min−1, deactivation is expected to be
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observed starting 9 h after the process start-up (Table 5,
entry 10).
Because of the volatility of the reagents and the solvent, the
end products were isolated as a mixture of endo and exo pro-
ducts in a nearly quantitative yield via mild rotary evaporation.
Upon evaporation with mild heating, a product loss, mainly of
the endo-isomer, was observed. The purity of the obtained
mixture of DA products was verified using GC(-MS) and was
found to be ≥95%. Under the optimal process conditions, the
Diels–Alder products were isolated in a 94% yield, a 89%
selectivity towards the endo-isomer and a GC-purity of 97%
(Table 5, entry 11). A calculated throughput of 0.87 g h−1 over
7 h was reached, corresponding to a space–time yield of
0.29 mmol g−1 min−1. This implies a respectively 9 and 121
times higher space–time yield in comparison to the published
continuous flow procedures of Sachse et al. and Chiroli
et al.29,30 Noteworthily, our results were obtained using just a
1 : 1 stoichiometric ratio of diene and dienophile and a contact
time of 1.8 min with the catalyst bed.
In an attempt to avoid the use of harmful dichloromethane,
the second and third best solvents, as it was determined using
a batch solvent screening (Table 3), were also evaluated under
the optimized continuous flow conditions (Table 6).
Unfortunately, in the case of toluene or acetonitrile as a
solvent, both the conversion and the selectivity towards the
endo-isomer were significantly lower in comparison to the use
of dichloromethane.
3.4 Neat continuous flow experiments
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 con-
figuration 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
of the cyclopentadiene dimer (about 6%) was observed on
1
H-NMR as a side-product.
Presumably, the neat DA reaction mainly takes place in the
bulk phase and not on the catalyst surface. This was easily veri-
fied by calculating the acid site concentration in the catalyst
bed. This was easily verified by calculating the known acidity
of the catalyst. The acid site concentration of CBV 720 was
determined using NH3-TPD to be 0.47 mmol H+ per g. Taking
into account the internal concentration of MA, the limiting
reagent, of 5.5 M, it appears that there is a catalyst loading of
9 mol% in the CatCart® or a site-time of 9.5 mol AS·s mol−1
MA. Therefore, knowing that the reaction also proceeds, albeit
non-selective, without the catalyst, the catalyst loading is too
low, leading to a non-catalyzed and thus non-selective back-
ground 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 AS·s mol−1
CPD. These calculations were performed under the assumption
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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)

1
H-NMR
Entry Zeolite typeb,c Si/Al FR (mL min−1) CT (min) Equiv. MA [CPD] (M) [MA] (M) Timed (h) EP (%) endo (%)
e
1 H-USY 15 0.1 3.5 1 0.5 0.5 1 85 88
6 70 86

2 H-USY 15 0.1 3.5 1 0.5 0.5 1 95 89

1–5.5 88 89
5.5 83 88
5.5–6.5 81 87

3 H-USY 15 0.1 3.5 0.8 0.6 0.5 1 92 89

1–4 81 88
4 70 87

4 H-USY 15 0.1 3.5 1.2 0.5 0.6 1 96 88

2 98 88
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3 99 88
4 99 88
5 98 88
6 98 88
7 96 88

5 H-USY 15 0.2 1.8 1.2 0.5 0.6 1 95 89

2 95 90
3 95 89
4 95 89
5 80 89
6 68 88
7 62 88

6f H-USY 15 0.1 3.5 1.2 0.5 0.6 1 93 87

2 96 88
3 99 87
4 96 88
5 93 88
6 84 87
7 80 87

7 H-USY 30 0.1 3.5 1 0.5 0.5 1 93 88

2 93 88
3 93 88
4 93 89
5 93 89
6 93 89
7 92 89

8 H-Beta 12.5 0.1 3.5 1 0.5 0.5 1 93 87

2 94 88
3 94 88
4 94 88
5 94 88
6 94 89
7 94 88

9 H-Beta 12.5 0.2 1.8 1 0.5 0.5 1 95 88

2 95 89
3 95 89
4 95 89
5 95 89
6 93 89
7 93 89

10 H-Beta 12.5 0.3 1.2 1 0.5 0.5 0.7 95 88

1 95 89
2 94 88
3 91 89
4 87 89
5 85 89

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Table 5 (Contd.)

1
H-NMR
Entry Zeolite typeb,c Si/Al FR (mL min−1) CT (min) Equiv. MA [CPD] (M) [MA] (M) Timed (h) EP (%) endo (%)
f
11 H-Beta 12.5 0.2 1.8 1 0.5 0.5 1 94 89
2 94 89
3 95 89
4 94 89
5 94 89
6 93 89
7 92 89
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 2. 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.

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,
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ξa = 0.35 mL, P = 30 bar, T = 100 °C)

1
H-NMR
Entry Solvent FR (mL min−1) CT (min) Equiv. MA [CPD] (M) [MA] (M) Timeb (h) EP (%) endo (%)

1 Acetonitrile 0.1 3.5 1 0.5 0.5 1 66 83

2 64 84
3 62 83
4 61 84
5 59 84
6 57 83
7 55 83

2 Toluene 0.1 3.5 1 0.5 0.5 1 84 86

2 87 84
3 86 86
4 85 85
5 83 86
6 81 84
7 79 85
a
Void fraction in the catalyst bed, estimated value: 40% of total volume. b Time since start-up of the process.

Table 7 Conditions and results of the neat continuous flow Diels–

the influence of the pelletizing pre-treatment, comparative
Alder process using a zeolite USY catalyst bed (FR1 = FR2 = 0.1 mL min−1,
1.1 equiv. CPD, ξ = 0.35 mL, CT = 1.8 min, P = 30 bar, T = 100 °C, batch experiments were carried out. For both the H-USY and
CBV 720) the H-Beta catalyst, the powder and the pelletized form
showed a comparable conversion and selectivity, although in
1
H-NMR the case of the H-Beta species a larger difference was observed
Entry Timeb (h) EP (%) endo (%)
in favour of the powder form (Table 8, entries 2, 3, 5 and 6).
a
1 1 85 70 The deposition of cyclopentadiene on the catalyst surface was
3.5 85 69 determined from the changing CPD : MA ratio, which should
2 1 86 70 theoretically equal one at every moment of the experiment.
a
The deviation of this ratio from one can be ascribed to the
The catalyst was conditioned by a 1 h N2 flush over the cartridge at deposition of cyclopentadiene ( polymers) on the catalyst bed.
200 °C. b Time since start-up of the process.
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 depo-
sition of CPD amounted to 17–30% approximately. For com-
that the physical pre-treatment does not affect the amount of
parison, also in flow a continuous deposition of CPD on the
acid sites, nor their accessibility.
catalyst surface was observed (1–6%). In batch, it appears that
the conversion benefits from the drying of the solvent
3.5 Batch confirmation of the observed trends (Table 8, entries 2, 4, 5 and 7). The continuous flow experi-
In order to obtain a full comparison, the batch experiments ment using the H-USY catalyst indicates that without the pre-
were repeated using the non-dried zeolite material, which lead drying of dichloromethane a sudden accelerated decline in
to an increase of the conversion (Table 8). To gain insight into conversion can be observed (Table 5, entry 6). However, this

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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)

1
H-NMR

Entry Zeolite typea Si/Al Catalyst form Solvent MA (%) EP (%) endo (%) CPD deposition (mmol g−1)

1 No — — Dry DCM 90 10 79 —
2 H-USY 15 Pelletized Dry DCM 47 53 92 13 (26%)
3 H-USY 15 Powder Dry DCM 46 54 92 15 (29%)
4 H-USY 15 Pelletized DCM 56 44 92 15 (30%)
5 H-Beta 12.5 Pelletized Dry DCM 36 64 92 11 (23%)
6 H-Beta 12.5 Powder Dry DCM 30 70 89 11 (21%)
7 H-Beta 12.5 Pelletized DCM 38 62 91 9 (17%)
a
The corresponding zeolite product code, as obtained from Zeolyst International, can be seen in Table 1.
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was not seen within a 7 h time frame when the H-Beta catalyst Table 9 Overview of the obtained conversions and endo-selectivity for
was used (Table 5, entry 11). the regeneration
In flow, a high loading and a continuous recuperation of 1
H-NMR
the catalyst results in a high catalytic productivity. Assuming Process Timea (h) EP (%) endo (%)
that a batch process is stopped at 70% conversion after 3.5 h
(Table 8, entry 6) as from then on hardly any change in conver- 1 1 92 89
4 70 87
sion was observed, a catalytic productivity of 5.3 g EP per g
H-Beta could be obtained. In contrast, the 7 h flow process, as 2 1 57 85
presented in Table 5, entry 11, has a catalytic productivity of 2 59 85
18.7 g EP per g H-Beta. Moreover, this productivity is a 3 2 94 89
minimal value, as the catalyst deactivation was not monitored 6 94 89
to its boundaries. Evaluating both the lab-scale batch and con- a
Time since start-up of the process.
tinuous processes at 3.5 h, the flow process has a 14 times
higher production of Diels–Alder end products (0.87 g h−1).
conditions was evaluated (Fig. 3, process 2). The obtained con-
3.6 Spent catalyst characterisation and regeneration
version and selectivity, however, were unsatisfying (Table 9,
Although hardly any deactivation of the used zeolite was process 2). Thus, a more severe reactivation procedure was per-
observed within a 7 h time frame under the optimized con- formed. Again a continuous flow rinse of ethanol was per-
ditions, the regeneration advantage of zeolite catalysis was formed after which the zeolite was calcined for 5 h at 500 °C.
considered. Therefore, to demonstrate the reactivation of the In this way, the catalyst was reactivated and a high conversion
catalyst, an excess of cyclopentadiene was used to accelerate and endo-selectivity was observed again under the optimized
the deposition (Fig. 3, process 1). As can be seen from Table 5, continuous flow conditions (Fig. 3 and Table 9, process 3). A
entry 3 and Table 9, process 1, a small excess of CPD leads to a mixture of end products was isolated in a 92% yield, with a
fast drop in conversion. Next, after the loss of conversion and GC-purity of 99%.
selectivity, the challenge remained to regenerate the catalyst’s In addition to our work, sieve analysis was carried out on
activity. In the first attempt, a 4 h high vacuum treatment at the used pelletized zeolite, which revealed attrition of small
150 °C was carried out, after a continuous flow ethanol rinse. zeolite particles upon reaction (Table 10).
Subsequently, a continuous flow process under the optimized

Table 10 Influence of the process on the particle distribution through

sieve analysis

Particle distribution
(%)
Zeolite
type Si/Ala Conditions <125 µm 125–200 µm

H-USY 15 After reaction 16 84

H-USY 15 After regeneration 13 87
and reaction
H-Beta 12.5 After reaction 18 82
Fig. 3 Process conditions of the regeneration experiments of the used
a
zeolite USY. The corresponding product code can be seen in Table 1.

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Table 11 Results of the continuous flow Diels–Alder process of cyclo- lyst or expensive ionic liquids. The process was monitored for
pentadiene and alternative dienophiles using a H-Beta catalyst bed 7 h and a calculated throughput of 0.87 g h−1 was reached,
(CP814E*, dichloromethane, [CPD] = 0.5 M, [DP] = 0.5 M, ξa = 0.35 mL,
corresponding to a 3.5 times higher catalytic productivity and
FR = 0.2 mL min−1, RT = 1.8 min, P = 30 bar, T = 100 °C)
a 14 times higher production of Diels–Alder adducts in com-
Timea Conversionb Yieldc endo parison to the small scale batch process. In contrast to various
Dienophile (h) (%) (%) (%) literature examples, the zeolite material was found to be more
1 94 94 (97) 89 active in acid catalysis without any drying step. Afterwards, the
7 92 end products could be isolated in a straightforward manner in
high yields. The use of neat reagent streams was also evalu-
ated, but resulted in a slightly decreased conversion and a sig-
1 100 99 (97) 89 nificant loss of endo-selectivity. The regeneration of the used
7 100
zeolite catalyst was performed using a 5 h calcination step at
500 °C. Finally, the versatility of this process was demonstrated
1 98d 92 (100) 78 as alternative dienophiles were evaluated, leading to high
7 98d yields.
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1 84e 84 (96) 54
82e
7
1 86 60 f
—
7 90
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
1
H-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.
3.7 Expansion to other derivatives
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 pro-
ducts was obtained. In order to obtain 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 conversion for 7 hours.
4 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
high conversion (≥92%) and selectivity towards the endo-
isomer (89 : 11) were 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 scal-
able continuous flow process can compete with previously
developed batch processes, as these often require an excess of
cyclopentadiene, long reaction times, a (toxic) Lewis acid cata-
Acknowledgements
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.
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