Diels-Alder reactions of myrcene using intensified continuous-flow reactors

Article abstract of DOI:10.3762/bjoc.13.15

This work describes the Diels-Alder reaction of the naturally occurring substituted butadiene, myrcene, with a range of different naturally occurring and synthetic dienophiles. The synthesis of the Diels-Alder adduct from myrcene and acrylic acid, containing surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of the final product per day. This continuous-flow approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times.

Full text of DOI:10.3762/bjoc.13.15

Diels–Alder reactions of myrcene using intensified
continuous-flow reactors
Christian H. Hornung*, Miguel Á. Álvarez-Diéguez, Thomas M. Kohl
and John Tsanaktsidis
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 120–126.
CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169,
Australia
doi:10.3762/bjoc.13.15
Received: 22 September 2016
Accepted: 02 January 2017
Published: 19 January 2017
Email:
Christian H. Hornung* - christian.hornung@csiro.au
* Corresponding author
This article is part of the Thematic Series "Automated chemical
synthesis".
Keywords:
continuous processing; flow chemistry; renewable feedstock;
surfactant
Guest Editor: I. R. Baxendale
© 2017 Hornung et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
This work describes the Diels–Alder reaction of the naturally occurring substituted butadiene, myrcene, with a range of different
naturally occurring and synthetic dienophiles. The synthesis of the Diels–Alder adduct from myrcene and acrylic acid, containing
surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of
the final product per day. This continuous-flow approach provides a facile alternative scale-up route to conventional batch process-
ing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times.
Introduction
Over the past years, great attention has been devoted to finding foremost in the fragrance and flavor industries, but also in the
alternative, renewable feedstocks to fossil oil for the production pharmaceutical and chemical industries [1-3]. Myrcene is a
of fuel and industrial chemicals. Especially, high value added naturally occurring, acyclic monoterpene which is used industri-
products from fine chemicals, specialty chemicals or the phar- ally for the manufacture of flavoring substances and fragrances;
maceuticals sector allow for a ‘drop-in’ replacement of existing, in research it is used as a model compound for a series of differ-
fossil resources based synthesis routes with economic alterna- ent reactions and in the synthesis of complex natural products,
tives based on renewable sources. Besides chemical platforms including several pheromones [3]. Myrcene is a colorless oil
based on sugar, lignin or fatty acid containing feedstocks, and exists as two isomers, the synthetic α-myrcene, containing
terpenes present another plant derived feedstock which is of an isopropenyl group, and the naturally occurring β-myrcene
great interest for a variety of industrial applications, first and (which will be referred to in the following only as “myrcene”
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Beilstein J. Org. Chem. 2017, 13, 120–126.
(1), see Scheme 1, vide infra). It can be found in significant The emergence of compact continuous-flow reactors has begun
quantities (up to 39%) in the essential oils of several plants, to transform the way chemical synthesis is conducted in
such as wild thyme [4], ylang-ylang [5], bay leaf [6], juniper research laboratories and small manufacturing over the past few
berries [7], lemongrass [8], or parsley [9], and in smaller per- years [14-21]. In several applications, where reaction times are
centages (<5%) in hops [3], celery [3], dill [9], rosemary [3], short and heat management is important, intensified continuous
tarragon [10] and nutmeg [3] to name but a few. A review by processes inside tubular or plate-type flow reactors can success-
Behr and Johnen [3] describes the manufacture of myrcene fully replace batch methodologies classically carried out in
from other terpenes, as well as several synthetic routes based on stirred glass vessels. We have demonstrated the benefits of this
this versatile and reactive starting material to form alcohols, superior heat management in previous work looking at exother-
esters, amines, chlorides, dimers, polymers and even complex mic radical polymerizations in continuous flow [22,23]. Over
natural products, amongst others. At present myrcene (1) is the past years, Diels–Alder reactions of isoprene using laborato-
manufactured industrially from turpentine; the distillate of pine ry-scale flow reactors were studied by different research groups
resin [3]. One of the main components of turpentine is β-pinene, [24,25]. A continuous-flow reactor can offer a range of benefits
from which myrcene can be synthesized upon thermal isomeri- over batch processing, with the enhanced heat and mass transfer
zation at temperatures between 400 and 600 °C. This was first arguable being one of the most important. In many cases in-
described by Goldblatt and Palkin in 1947 [11]. Myrcene is a creased control over the process and improvements in product
very versatile molecule that can act as the starting material for quality are the result. Herein, we describe the synthesis of
several valuable compounds. The industrial production of a several Diels–Alder adducts made from myrcene (1) and a
series of top-selling flavors and fragrances are based on series of dienophiles, which contain carboxylic acids, esters or
myrcene, such as geraniol, nerol, linalool, menthol, citral, acid anhydrides. In particular, the reaction of myrcene (1) with
citronellol or citronellal [3]. The terminal diene moiety present acrylic acid (2b) was investigated in detail, through batch and
in myrcene allows for a reaction with a suitable dienophile continuous-flow methods. The intensified flow process presents
following the Diels–Alder reaction mechanism. Dahill et al. a more compact and efficient alternative to classic batch manu-
describe the synthesis of the Diels–Alder adduct of myrcene facture for the production of Diels–Alder adduct surfactants
and acrylonitrile for the use as an odorant in the perfume from myrcene.
industry [12]. A series of Diels–Alder reactions of myrcene (1)
and another sesquiterpene, farnesene, with various dienophiles Results and Discussion
have been reported by Tabor et al. [13] for the use as solvents The solution-phase Diels–Alder reactions presented herein
and surfactants.
follow the general reaction pathway shown in Scheme 1. The
Scheme 1: Diels–Alder reaction of myrcene (1), with various dienophiles 2.
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Beilstein J. Org. Chem. 2017, 13, 120–126.
conjugated diene myrcene (1) was reacted with a series of of the acrylic acid–myrcene system. Table 2 presents a set of
dienophiles 2 to form the Diels–Alder adducts 3.
experiments using this system, at different process conditions
and in different solvents; samples were analyzed over time in
Before investigating this reaction for continuous-flow process- order to establish kinetic profiles of these reactions. Figure 1
ing, we first undertook a series of batch experiments to explore shows the kinetic profiles of the reactions presented in Table 2.
the reactivity of the different dienophiles shown in Scheme 1.
These experiments were carried out on a batch microwave- All reactions followed an expected trend, asymptotically
reactor system (see experimental section) at temperatures be- approaching full conversion with increasing reaction time.
tween 100 and 140 °C, and the results are presented in Table 1. While both EtOAc and toluene produced similarly fast kinetic
data with conversions around 95% after 40 to 60 min toluene
was preferred due to its higher boiling point. Figure 1b shows
Table 1: Reagents, reaction conditions and results for small scale
batch reaction of myrcene with various dienophiles.
the influence of temperature and the ratio of starting materials.
These experiments also showed trends as were expected. Values
for the reaction rate constant, k, calculated from these experi-
ments, are presented in Table 2 and are within expected limits
when compared to literature values. More details on the deriva-
tion of the k values and the literature references can be found in
Supporting Information File 1. After the Diels–Alder reaction
was optimized in batch on a small scale (typically 2 mL reac-
tion volume) the process was scaled-up first on a Vapourtec
R2/R4 tubular flow reactor to a reaction volume of typically
20 mL and then on a Chemtrix Plantrix® MR260 plate flow
reactor to a reaction volume of typically 200 mL (see also ex-
perimental section). The results from these continuous-flow ex-
periments are shown in Table 3.
entry dienophile solventa
T
reaction conversion
[°C]
time
[%]b
1.1
1.2
1.3
1.4
1.5
1.6
1.7
2a
2b
2c
2d
2e
2f
THF
100
5 min
1 h
90
98
70
97
93
96
48
toluene 140
iPrOH 140
10 h
10 h
10 h
5 h
neat
neat
neat
neat
140
140
120
140
2g
10 h
aEntries 1.1 to 1.3 were reacted with an initial myrcene concentration,
cMYR,0, of 2.8 mol/L; all entries were reacted with a myrcene to dieno-
phile ratio, R, of 0.9; bconversions were calculated based on NMR.
Maleic anhydride (2a) proved to be the most reactive of the The 10-times scale-up in the tubular flow reactor and the
dienophiles used in this study with reaction completion occur- 100 times scale-up in the plate flow reactor resulted in similar,
ring after a few minutes at 100 °C. Other activated dienophiles if not slightly higher conversions than the batch experiments
such as acrylic acid (2b) and ethyl acrylate (2f) reached high (see Figure 2). The two continuous reactors produced high-
conversions in excess of 90% after 1 to 5 h and the maleates 2d quality material at steady state conditions. The reaction profile
and 2e required up to 10 h reaction time at 140 °C to reach near- in the plate flow reactor was quantified by taking samples at the
completion. The slowest reactions were observed using itaconic outlet of the reactor over the entire duration of one experiment.
acid (2c) and the PEG containing acrylate 2g. Acrylic acid (2b) These profiles are very uniform with steep fronts and tails and a
was selected for further study given our interest in products flat steady state region, suggesting that the residence time distri-
with surfactant properties, and the preferable reaction kinetics bution inside the reactor is narrow and close to plug flow. One
Table 2: Solvents, reaction conditions, conversions and reaction rate constants, k, for small scale batch reactions of myrcene (1) with acrylic acid
(2b); for further details on derivation of k values see Supporting Information File 1.
entry
solvent
cMYR,0
R [–]b
T [°C]
reaction time [h]
conversion [%]c
k × 103
[mol L−1]a
[L mol−1 s−1]d
2.1
2.2
2.3
2.4
2.5
2.6
2.7
EtOAc
EtOAc
2.8
2.8
2.8
2.8
2.8
2.9
2.9
0.9
0.9
0.9
0.9
0.9
1.1
1.2
120
140
100
120
140
160
160
2
2
2
2
2
1
1
92
99
0.53
3.44
0.27
1.14
4.75
27.05
–
toluene
toluene
toluene
toluene
toluene
84
95
99
~100
~100
aInitial myrcene concentration; bratio of myrcene to acrylic acid; cconversions were calculated based on NMR; dk was derived from kinetic studies
plotted in Figure 1 for entries 2.1 to 2.6, as in these experiments R was close to 1 (between 0.9 and 1.1).
122

Beilstein J. Org. Chem. 2017, 13, 120–126.
Figure 1: Kinetic studies of the Diels–Alder reaction between myrcene (1) and acrylic acid (2b); a) for different solvents and temperatures, ratio of
myrcene to acrylic acid: 0.9; b) for different starting material ratios and temperatures, solvent: toluene.
Table 3: Solvents, reaction conditions and results for the continuous-flow reaction of myrcene (1) with acrylic acid (2b) in a tubular flow reactor
(reactor volume: 20 mL) and a plate flow reactor (reactor volume: 105 mL); all entries were reacted with a myrcene to dienophile ratio, R, of 0.9, and
cMYR,0 of 2.8 mol/L.
entry
reactor
solvent
R [–]
T [°C]
residence time [min]
conversion [%]a
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
tubular
tubular
tubular
tubular
tubular
plate
EtOAc
EtOAc
EtOAc
toluene
toluene
toluene
toluene
toluene
toluene
0.9
0.9
0.9
0.9
0.9
0.9
0.9
1.1
1.1
140
140
140
120
140
112
130
140
160
20
30
40
40
40
40
40
40
30
75
95
99
93
99
85
plate
93
plate
~100
99
plate
aConversions were calculated based on NMR.
of these profiles is shown in Figure S4 (Supporting Information unknown; it only occurred in the stainless steel reactor and not
File 1). The fastest conditions investigated herein were 30 min in the PFA tubing of the Vapourtec R-series flow reactor or the
in the plate reactor at 160 °C giving 99% conversion of 2b and silicon carbide module of the plate flow reactor. Hence, it was
a yield of 94% of a semi-crystalline product (Table 3, entry postulated that a metal catalyzed polymerisation on the stain-
3.9). As part of the scale-up investigations, we also performed less steel reactor tubes might have occurred, however, this
the Diels–Alder reaction of myrcene (1) and 2b in a 6 mm i.d. could not be confirmed. Further details on these observations
stainless steel tubular flow reactor with a reaction volume of can be found in Supporting Information File 1.
108 mL. A few minutes after start of the reaction, however, we
observed a pressure increase in the reactor which was caused by Using 13C NMR an approximate ratio of the two isomers, 3-3
fouling occurring in the reactor entrance section and ultimately and 3-4 (see Figure 2), was calculated for the continuous-flow
led to complete blockage of the tube at this point. This is reactions performed between 140 and 160 °C (see Table 3). The
believed to be caused by a side reaction of 2b and myrcene (1) amount of Diels–Alder adduct with the carboxylic acid located
forming polymeric material, which built up on the metal walls in the 3-substituted position, 3-3, was always larger than the
of the reactor, ultimately leading to the complete blockage. The 4-substitituted adduct, 3-4, with an average 3-3/3-4 ratio of 7:3
mechanism and circumstances of this side-reaction are (3-substituited adduct was between 68 and 71%).
123

Beilstein J. Org. Chem. 2017, 13, 120–126.
Figure 2: Comparison of conversions in three different reactors for the Diels–Alder reaction of myrcene (1) with acrylic acid (2b) in toluene; the reac-
tion forms two isomers, 3-3 and 3-4; reaction temperature for these experiments: 120, 130 or 140 °C, reaction time: 40 min; photographic images of a
tubular reactor coil of the Vapourtec R2/R4 flow reactor [26] and of the plate reactor module of the Chemtrix Plantrix® MR260 [27].
For Table 3, entry 3.9, the yield of the semi-crystalline product 2b. The results were promising and showed that the product
after solvent removal was 94%. The production capacity (PC) was able to stabilize emulsions for several hours compared to
and the space time yield (S.T.Y.) can be calculated based on the several seconds or minutes in the control experiments without
amount of isolated product, mP, using Equations 1 and 2.
the Diels–Alder adduct. Further details on these surfactant tests
are presented in Supporting Information File 1.
Conclusion
(1)
(2)
We have investigated the Diels–Alder reaction of myrcene (1)
with a range of different dienophiles at temperatures between
100 and 160 °C. The Diels–Alder reaction of myrcene (1) with
acrylic acid (2b), yielding a carboxylic acid containing surfac-
tant, was scaled-up in a plate-type continuous-flow reactor and
a batch stirred tank. The use of continuous-flow processing
allows for an efficient synthesis of large quantities of the
Diels–Alder adduct and we managed to scale-up the reaction of
myrcene (1) with acrylic acid (2b) inside the 105 mL flow
reactor to a throughput of 2.79 kg of the final product per day.
The small dimensions of the fluidic channels inside the tubular
and the plate-type flow reactors ensured that heat and mass
transfer were efficient and fast, and that the reaction could be
operated under ‘quasi isothermal’ conditions (i.e., with negli-
gible deviations from the set temperature in the entire bulk reac-
tion volume of the reactor). This resulted in a much more
uniform reaction profile than in batch stirred tanks, allowing for
Here, is the total volumetric flow rate through the reactor, VSS
the combined volume of both stock solutions and VR the volume
of the flow reactor. Running the plate reactor at 160 °C
(Table 3, entry 3.9), we managed to achieve a production
capacity of 116.3 g/h, which equates to an S.T.Y. of
1.11 kg L−1 h−1. Parallel to the scale-up in the plate flow
reactor, we also scaled up the process in batch to a 6 L scale
using a jacketed stirred tank reactor. Here, the reaction was run
for ~10 h at 100 °C in order to reach completion, compared to
only 30 min at 160 °C in continuous flow.
Preliminary experiments were carried out looking at the surfac- a much shorter reaction time than classically applied in batch
tant properties of the Diels–Alder adduct of myrcene (1) and operations.
124

Beilstein J. Org. Chem. 2017, 13, 120–126.
Experimental
the other containing 2b (8.58 g, 119.06 mmol), in EtOAc
Materials and analysis
(7.75 mL). The two solutions were continuously mixed in a
The reactants myrcene (1, 90% purity), maleic anhydride (2a), T-piece and then fed into a Vapourtec R2/R4 flow reactor set-
acrylic acid (2b), itaconic acid (2c), dimethyl maleate (2d), up [26], consisting of two 1.0 mm i.d. perfluoroalkoxy alkane
ethyl acrylate (2f) and poly(ethylene glycol) methyl ether acry- (PFA) reactor coil modules in series (10 mL each – total reactor
late (PEGA, 2g) were obtained from Sigma-Aldrich; bis(2- volume: 20 mL). The pump flow rate of the myrcene solution
ethylhexyl) maleate was provided by TriTech Lubricants. The was set to 0.3 mL∙min−1, the pump flow rate of the acrylic acid
solvents tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, solution was set to 0.2 mL∙min−1. This resulted in a total flow
dichloromethane (DCM) and isopropanol (iPrOH) were ob- rate of 0.5 mL∙min−1 and a mean hydraulic residence time of
tained from Merck KGaA. All reagents and solvents were used 40 min inside the two PFA reactor coils (the mean hydraulic
without further purification.
residence time is defined as ‘flow rate/reactor volume’). The
reaction was conducted at 140 °C. The product, a transparent,
Reaction conversions were calculated from 1H NMR spectra, faintly yellow solution, was collected at the reactor outlet, after
which were recorded on a Bruker AC-400 spectrometer in passing through a 75 psi back-pressure regulator. From this
deuterated chloroform (from Cambridge Isotope Laboratories solution, the reaction conversion was determined by 1H NMR.
Inc.). Conversion calculations were based on clearly identifi- Afterwards, the solvent was evaporated under reduced pressure
able and non-convoluted peaks of remaining starting material to yield a yellow semi-crystalline paste. Detailed reaction condi-
and generated product. The residual solvent peak at δ = tions and reagent compositions for each experiment in the
7.26 ppm was used as an internal reference. Product composi- tubular flow reactor can be found in Table 3.
tions were analyzed by GC–FID and GC–MS; details for both
Continuous-flow Diels–Alder reaction using a
can be found in Supporting Information File 1. The GC–FID
results were also used to confirm NMR conversions and to Chemtrix MR260 flow reactor
calculate GC-based yields.
The following procedure is typical for the preparation of the
Diels–Alder adduct of myrcene (1) and acrylic acid (2b) in a
Batch Diels–Alder reaction
silicon carbide plate-type flow reactor. Two reactant solutions
The following procedure is typical for the preparation of the were prepared, one containing myrcene (208.2 g of myrcene
Diels–Alder adduct of myrcene (1) and a series of different stock solution with a 90% purity, 1.375 mol of myrcene) in tol-
dienophiles. A reactant solution of myrcene (1, 811 mg of uene (21.2 mL), and the other containing 2b (90.1 g,
myrcene stock solution with a 90% purity, 5.36 mmol of 1.250 mol), in toluene (80.1 mL). The two feed solutions were
myrcene), 2b (429 mg, 5.95 mmol), in EtOAc (0.49 mL), was pumped using two Teledyne Isco D-series dual syringe pumps
premixed and filled into a sealed microwave vial. The reaction (100 DX, with Hastelloy™ syringes) and were continuously
was conducted in a laboratory microwave reactor (Biotage Initi- mixed in a T-piece. After mixing, the combined starting materi-
ator) at 140 °C with a reaction time of 2 h. A transparent, faintly al solution was fed into a Chemtrix Plantrix® MR260 [27]
yellow solution was obtained after reaction, from which the plate-type flow reactor. This plate flow reactor configuration
conversion was determined by 1H NMR. The solvent was evap- consisted of a series of 3M™ silicon carbide microstructured
orated under reduced pressure to yield a yellow semi-crys- plates (see also Figures S2 and S3 in Supporting Information
talline paste. Detailed reaction conditions and reagent composi- File 1), which was thermally regulated by a Lauda Integral XT
tions for each batch experiment can be found in Table 1 and 150 heater/chiller unit. The total reactor volume was 105 mL.
Table 2. For kinetic studies, small samples of the reaction mix- An SSI Prep 100 dual piston pump with PEEK pump heads was
ture for 1H NMR were withdrawn through the septum of the used to flush the reactor before and after the reaction with tolu-
microwave reactor glass vial using a syringe. For this the micro- ene. The pump flow rate of the myrcene solution was set to
wave reaction was stopped at various points in time over the 2.21 mL∙min−1, the pump flow rate of the acrylic acid solution
course of the reaction, namely at 20, 40, 60 and 120 min.
was set to 1.30 mL∙min−1. This resulted in a total flow rate of
3.51 mL∙min−1 and a reaction time of 30 min inside the plate
flow reactor. The reaction was conducted at 160 °C. The prod-
uct, a transparent, faintly yellow solution, was collected at the
Continuous-flow Diels–Alder reaction using a
Vapourtec R2/R4 flow reactor
The following procedure is typical for the preparation of the reactor outlet, after passing through a stainless steel Swagelok®
Diels–Alder adduct of myrcene (1) and acrylic acid (2b) in a R3A series adjustable high pressure valve. This valve was used
tubular flow reactor. Two reactant solutions were prepared, one as a back pressure regulator, in order to set the pressure inside
containing myrcene (16.22 g of myrcene stock solution with a the reactor to between 8 and 10 bar (116 to 145 psi) during
90% purity, 107.16 mmol of myrcene) in EtOAc (1.98 mL), and operation. From the resulting product solution, the reaction
125

Beilstein J. Org. Chem. 2017, 13, 120–126.
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vent was evaporated under reduced pressure to yield a yellow
semi-crystalline paste. Detailed reaction conditions and reagent
compositions for each experiment in the plate-type flow reactor
can be found in Table 3.
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Supporting Information File 1
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doi:10.1039/C1GC16022B
Analysis procedures, calculation of k-values, reactor
performance profiles, reactor fouling, emulsion stabilizing
properties, copies of 1H and 13C NMR and of GC-FID
spectra.
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doi:10.3184/174751912X13311365798808
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Acknowledgements
23.Hornung, C. H.; Guerrero-Sanchez, C.; Brasholz, M.; Saubern, S.;
Chiefari, J.; Moad, G.; Rizzardo, E.; Thang, S. H.
The authors thank Charlotte Wiles from Chemtrix BV for
helpful discussions and Matthew Waterford and Stuart Littler
for assistance with the operation of the Chemtrix Plantrix®
MR260 reactor.
Org. Process Res. Dev. 2011, 15, 593. doi:10.1021/op1003314
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