Organocatalyzed epoxidation of alkenes in continuous flow using a multi-jet oscillating disk reactor

Article abstract of DOI:10.1002/cssc.201100262

The times are changing: A batch process, the Minisci epoxidation, is transformed into a continuous-flow protocol for the selective aerobic radical epoxidation of alkenes. The use of a novel reactor type allows to considerably shorten reactor residence times. Experimental results suggest that two different reaction mechanisms exist for the oxidation: one for the batch conditions and a different one for flow synthesis protocol. Copyright

Full text of DOI:10.1002/cssc.201100262

DOI: 10.1002/cssc.201100262
Organocatalyzed Epoxidation of Alkenes in Continuous Flow using a Multi-
Jet Oscillating Disk Reactor
[
a, c]
[b]
[c]
[a, b]
Raffaele Spaccini,
Lucia Liguori, Carlo Punta, and Hans-Renꢀ Bjørsvik*
Several epoxidation reactions and methods have been report-
[
1]
ed in the literature, and the majority of these are based on
transition metal catalysis. Examples include the Mukaiyama ep-
[
2,3]
[4]
oxidation,
Sharpless epoxidation, and Jacobsen–Katsuki
[
5]
epoxidation. Even though such transition metal-catalyzed
processes offer several advantages, a serious disadvantage
exists if the epoxide is to be used in the preparation of phar-
maceuticals, nutraceuticals, or other food and feed additives:
the need for an extensive purification of the synthesized target
[
10]
Scheme 1. The Minisci epoxidation process.
[6]
product. Guidelines from The European Medicines Agency
with a-olefins and cyclic olefins, producing the corresponding
epoxides in excellent yields and selectivities, while internal acy-
clic olefins were proven to be unreactive.
state that the oral permitted exposure to, for example, palladi-
um and nickel in pharmaceutical ingredients should be
À1
À1
À1
À1
<
2.6 mg kg day and 20 mg kg day, respectively. Devel-
Even though the Minisci epoxidation can be said to be a
green and economical process, it also suffers from a disadvant-
age from an industrial point of view: its low relative efficiency
owing to long batch reactor residence times (24–48 h). To
overcome this major drawback, we initialized a project for
technology transfer, development, and optimization to realize
an aerobic epoxidation catalyzed by NHPI (3) under continu-
ous-flow conditions by means of a new technology: the multi-
Pd
Ni
oping protocols that meet these requirements can be a chal-
lenging task, but this can usually be solved by means of classi-
cal purification methods. These often involve several consecu-
tive purification steps and/or a combination of several meth-
ods. A new, emerging technology known as organic solvent
[
7]
nanofiltration can also be applied, without the need of sever-
al repeating steps. However, processing in this manner increas-
es costs and decreases throughput and yield. Competitive or-
ganic processes that do not require the use of any transition
metals in order to operate exist, but from an industrial point of
view these also suffer from a drawback, namely the need for
long reactor residence times to reach suitable product yields.
This of course limits the efficiency and throughput of the pro-
cess.
[
11a]
jet oscillating disk (MJOD) reactor.
During recent years, we
have in our laboratories at the University of Bergen and at
Fluens Synthesis designed, manufactured, developed, and in-
vestigated an approach for flow organic synthesis that has re-
sulted in this novel reactor platform. A detailed account of the
[11b]
MJOD reactor technology was recently disclosed by us,
but
a short description of the MJOD reactor technology follows
here.
The epoxidation of alkenes via aerobic oxidation with an al-
dehyde as a co-reagent has been reported by Kaneda and col-
A 3D drawing of the MJOD reactor that includes the input
section, reactor body, output section, and oscillator section is
shown in Figure 1. A process flowchart for the experiments dis-
closed herein is given in Figure 2. The right-hand side of
Figure 1 shows a transparent top-down view of the input sec-
tion, together with a small section of the reactor zone. The
MJOD unit is placed in the center of the reactor tube. The
outer shell of the reactor body forms a ring-shaped room that
encapsulates the whole length of the reactor tube. This room
is used for circulating a heating or cooling fluid. Due to the ad-
vantageous reactor net volume versus the heating/cooling sur-
face ratio of the reactor tube, an exceptionally good heat
transfer capacity is achieved. A variable-frequency and varia-
ble-amplitude oscillator is used for the vertical “piston move-
ment” of the MJOD unit. An electric motor connected to a cam
mechanism is used to power the up–down movement of the
MJOD assembly. In addition, the cam assembly provides con-
trol of the amplitude by linear translation of the cam assembly
to a predefined position (i.e., the distance to the motor shaft).
Frequencies in the range of f=1–10 Hz and amplitudes in the
range of A=0.5–15 mm can be achieved by adjusting the
motor speed and the cam assembly. Various types of feeding
[
8a]
[8b]
laborators,
Lassila and collaborators,
and Beak and Jar-
[
8c]
boe. The Shi epoxidation gives access to epoxides starting
from various alkenes using a fructose-derived organocatalyst
[
9]
with Oxone as the terminal oxidant. Minisci and co-workers
disclosed an organocatalyzed epoxidation (Scheme 1) in which
olefins 1 are treated with acetaldehyde 2 under an oxygen at-
mosphere in the presence of N-hydroxyphthalimide (NHPI) 3
[10]
as catalyst, to obtain epoxides 4 in good to excellent yields.
The Minisci epoxidation was demonstrated to operate superbly
[a] Dr. R. Spaccini, Prof. Dr. H.-R. Bjørsvik
Department of Chemistry
University of Bergen
Allꢀgaten 41, 5007 Bergen (Norway)
Fax: (+47)55 58 94 90
E-mail: hans.bjorsvik@kj.uib.no
[b] Dr. L. Liguori, Prof. Dr. H.-R. Bjørsvik
Fluens Synthesis
Thormøhlensgate 55, 5008 Bergen (Norway)
[c] Dr. R. Spaccini, Dr. C. Punta
Dipartimento di Chimica, Materiali e Ingegneria Chimica, “Giulio Natta”
Politecnico di Milano
Via Mancinelli 7, 20131 Milano (Italy)
ChemSusChem 2012, 5, 261 – 265
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
261

the reactor body. The post-reaction mixture is collected at the
output section at the top of the reactor tube, close to the os-
cillator section. When the reaction mixture passes through the
nozzles, extremely good mixing of the components is achieved
by the oscillation of the disks. This study reveals that this is
also the case for a two-phase systems, such as a gas/liquid
one. The heating and temperature are controlled by a circula-
tion pump connected to the heating/cooling circuit of the
MJOD reactor body.
Investigations of the MJOD reactor system in our laboratory
have demonstrated an excellent heat and mass transfer capaci-
ty for the system, usually concomitant with a substantially in-
creased reaction rate. With these results in hand, we supposed
that the reactor system could substantially improve the effi-
ciency of the Minisci epoxidation, and set out to reinvestigate
the epoxidation protocol under MJOD continuous-flow condi-
tions.
Figure 1. 3D model of the MJOD reactor. The right-hand side of the figure
shows the input section and a transparent of the reactor zone section, with
the ring room for the heat transfer liquid and the tubular reactor with MJOD
units placed in its center. The left-hand side shows a complete reactor body,
comprising the input section, reactor body, output section, and oscillator
unit.
An MJOD millireactor with a net volume of ca. 51 mL (L=
1500 mm, i.d. 10 mm) furnished with N=80 four-jet disks
(d =2 mm), forming 79 inter-disk cavities (V
ꢀ0.65 mL)
jet
cavity
was used for all experiments described herein. The cross sec-
tion of the four-jet disk corresponds to the cross section of the
tubular reactor, similar to the piston head of an engine (see
Figure 1). Four reagent inlet lines were used, three of which
were connected to precision piston- or syringe-feeding pumps.
The fourth input line was connected to a pressurized gas tank
containing molecular oxygen. The O flow was adjusted to a
2
pressure slightly above atmospheric pressure. A process flow-
chart for the set-up is shown in Figure 2. The ring-room encap-
sulating the reactor tube was used to circulate water that was
heated and regulated by a thermostat (temperatures were se-
lected in the range T=20–608C). The oscillator (i.e., the cam
mechanism) was tuned to provide oscillations with an ampli-
tude A=5 mm and a frequency f=1–3 Hz.
A series of olefins were investigated in the MJOD reactor
system described above. The results are summarized in Table 1.
It is evident that the epoxidation process runs with high con-
versions and yields. Moreover, the process is substantially ac-
celerated, shortening the residence time from 24–48 h (batch
process) to only 1–4 h. Using continuous-flow conditions it ap-
pears that NHPI plays a key role for both the initiation and
propagation steps of the radical chain (Scheme 2). Initially we
explored three different olefins: octene, decene, and dode-
cene, in the presence of 10mol% NHPI at a reaction tempera-
ture T=608C and a residence time t=1 h. Subsequently we re-
duced the quantity of the organocatalyst NHPI to 5mol% and
2.5mol%. Figure 3 is a summary of these initial experiments.
The results obtained under continuous-flow conditions
showed different reactivity and selectivity compared to the re-
Figure 2. Process flowchart of the MJOD millireactor system, used to reinves-
tigate the Minisci epoxidation in continuous-flow conditions. The MJOD
system comprised a millireactor body (L=1500 mm, d=10 mm) with a
MJOD unit assembly of 80 disks, three feeding pumps with associated reser-
voirs, one input section and one output section equipped with an oscillator
(amplitude A=5 mm, and frequency f=3 Hz). The reactor body was heated
by means of a heat exchanger, circulating water in the jacketed millireactor
body.
pumps can be used to feed the substrate, reagents, catalysts,
and solvents into the MJOD reactor through the feeding chan-
nels of the input section, which is located at the bottom of the
vertically placed reactor body. The various reagents and sub-
strate are continuously pumped into the reactor tube via the
input section, which implies that the reaction mixture is
pushed upwards in the reactor tube (in a plug flow fashion).
The reaction mixture successively passes upwards through the
jets of the MJOD disks, from one reaction cavity to the next
cavity. Together with the up–down movements of the disks,
the tightening of the cross section (the small jets in the disks)
leads to changes in the rate of liquid flow, which creates an
very good mixing of the liquid and gas that streams upward in
[10]
sults achieved using batch conditions. In particular, while in-
ternal acyclic olefins were unreactive under the reported batch
conditions, the corresponding epoxides were achieved in high
yields and selectivities when the MJOD reactor technology was
used (Table 1, entry 9).
In the specific case of limonene, the stereochemistry for the
NHPI-catalyzed aerobic epoxidation was also different, that is,
the batch mode provided a cis/trans ratio of 67:33, while the
2
62
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ChemSusChem 2012, 5, 261 – 265

ing reagent. The acyl peroxyl
radical adds directly to the olefin
double bond, which subsequent-
ly decomposes to produce the
epoxide and carbon dioxide and
the methyl radical. The reported
mechanism is supported by the
observed selectivity under batch
conditions, which excludes the
involvement of peracetic acid in
the epoxidation step.
[
a]
Table 1. Continuous-flow epoxidation of olefins by aerobic oxidation of acetaldehyde, catalyzed by NHPI.
[
b]
[c]
[d]
Entry
Olefin
Product epoxide(s)
t
Yield
[%]
Conversion
[%]
Selectivity
[%]
[
h]
1
2
1
2
1
2
1
30
54
72
80
77
30
54
72
80
77
100
100
100
100
100
3
4
1
1
48
25
74
64
34
The peracetic acid must be
produced in situ, in competition
with the addition of the olefin,
by fast acyl peroxyl hydrogen
5
6
1
32
32
100
2
4
42
99
42
99
100
100
abstraction
from
NHPI
(
Scheme 2). In fact, even though
1
33
ca. 33
ca. 100
we could not determine k2 for
2
4
36
31
45
47
80
65
this reaction, we expect a value
4
À1 À1
higher than 10 m s , as we
have measured a value of 7.2ꢂ
7
8
1
32
32
100
3
À1 À1
10 m
s
for the hydrogen ab-
4
1
4
1
73
26
38
8
91
34
50
80
76
76
34
straction from NHPI by tBuOO·
radical, and the reaction in
À1
Scheme 2 is about 5 kcalmol
more
exothermic
(1 cal=
4.184 J). Nevertheless, according
4
1
12
81
34
90
to the observed selectivity under
batch conditions, reaction of
9
90
peracetic acid with NHPI has to
[
a] General procedure: olefin (5 mmol), acetaldehyde (15 mmol), and NHPI (0.5 mmol, 10%) were mixed in ace-
be faster than the epoxidation
tonitrile (10 mL) and pumped into the MJOD reactor system at T=608C. was is introduced to the MJOD reactor
at normal atmosphere (1 atm; time shown in the Table). The epoxides were isolated and purified by flash chro-
matography and characterized by NMR and MS. Spectra were compared to those of authentic samples or data
of alkenes. The absence of reac-
tivity for internal olefins can
[
13]
previously disclosed in the literature. [b] Isolated yield. [c] Calculated as mmol(epoxide)/mmol(olefin)ꢂ100%.
d] Calculated based on conversion and yield of product.
most probably be attributed to a
[
simple steric effect, which inhib-
its the insertion of the acyl per-
oxyl radical on the double bond. In fact, although peracetic
acid is actually formed in situ by fast acyl peroxyl hydrogen ab-
4
straction from NHPI (k >10 , Scheme 2), it undergoes mole-
2
Scheme 2. Acyl peroxyl hydrogen abstraction from NHPI.
continuous-flow mode provided the opposite stereochemistry,
with a cis/trans ratio of 40:60, and an additional diepoxide in a
yield of 25% (Table 1, entry 4). These results suggest that two
different mechanisms operate for the epoxidation: one for the
batch mode and another for the continuous flow mode. The
proposed mechanism for the batch-mode procedure is out-
lined in Figure 4. In the initiation step, NHPI undergoes mole-
cule-induced homolysis by the presence of the in situ generat-
ed peracetic acid, leading to the formation of the correspond-
[
12]
ing pthalimido N-oxyl (PINO) radical. PINO plays a key role in
the promotion of the free radical process as it performs a fast
hydrogen abstraction from acetaldehyde. The corresponding
acyl radical adds to molecular oxygen, affording the acyl per-
oxyl radical that appears to be the actual operating epoxidiz-
Figure 3. Influence of the quantity of the NHPI organocatalyst on the epoxi-
dation. Several 1-alkenes (octene, decene, and dodecene) were treated at
T=608C, with an MJOD reactor residence time t=1 h.
ChemSusChem 2012, 5, 261 – 265
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
263

In summary, this study reports an improved Minisci epoxida-
tion process suitable for olefins. The improved process is
based on the original batch protocol, redesigned and redevel-
oped for continuous-flow conditions by using the novel multi-
jet oscillating disk (MJOD( reactor technology. While the batch
protocol requires a residence time of 24–48 h, the continuous-
flow process only requires a residence time of 1–4 h for the
same substrates. Without any further optimization of the
through flow, the flow protocol possesses a capacity of
À1
1
mLmin containing 5 mmol substrate. With a yield of 80%
and using one MJOD reactor system as described in this
report, this corresponds to a production capacity on the order
À1
of 80 gday . The reaction mechanism in continuous flow ap-
pears to be different from the mechanism that operates in re-
actions carried out according to batch protocols, but both
mechanisms seem to involve NHPI as catalyst (Figure 4).
Figure 4. Proposed reaction mechanism for the Minisci epoxidation.
Experimental Section
Starting materials, reagents, and solvents were purchased commer-
cially and used without further purification. GLC analyses were per-
formed on a capillary gas chromatograph equipped with a fused
silica column (L=25 m, i.d. 0.20 mm, film thickness 0.33 mm) at a
helium pressure of 200 kPa, splitless/split injector, and a flame ioni-
zation detector. Mass spectra were acquired on a GC-MS instru-
ment, using a gas chromatograph equipped with fused silica
column (L=30 m, 0.25 mm i.d., 0.25 mm film thickness) and helium
cule-induced homolysis with another NHPI molecule too fast
(see mechanism in Figure 4) to be involved in the direct epoxi-
dation of the olefin.
On the contrary, the higher reactivity of internal olefins and
the different stereochemistry of limonene, observed when con-
ducting the NHPI-catalyzed aerobic oxidation using the MJOD
reactor, are typical for epoxidations performed with peracids.
This indicates that in this case peracetic acid, generated in situ
1
as carrier gas. Structure control H NMR spectra were recorded on
a NMR spectrometer operating at 400 MHz. Chemical shifts were
referenced to internal TMS.
(Scheme 2), is the operating epoxidation reagent in the NHPI-
catalyzed aerobic epoxidation process. In addition to convert-
ing the alkene to epoxide, one equivalent of acetic acid is pro-
duced as a co-product as outlined in the proposed reaction
mechanism (Scheme 3).
Synthetic procedure. The alkene (5 mmol) was dissolved in CH CN
3
(4 mL) and transferred to reservoir #1 (Vtotal ꢀ5 mL). N-hydroxyph-
thalimide (1–10% w/w) was dissolved in CH CN (6 mL) and heated
3
at 608C under good stirring until the organocatalyst was dissolved
whereof the solution was cooled at room temperature and acetal-
dehyde (0.85 mL) was added. This mixture was transferred to the
reservoir #2 (Vtotal ꢀ7 mL). Reservoir #3 was filled with pure solvent,
acetonitrile. The oxygen gas flow was adjusted carefully using a
À1
bubble glass to achieve 1–2 bubbles s. Note that a too vigorous-
ly bubbling of oxygen results in a flush-off of the organic compo-
nents, especially the low boiling component such as acetaldehyde.
Control of the oxygen flow should be performed on the inlet at
the input section of the reactor. The reactor residence times was
regulated by adjusting the flow rate of the feeding pumps.
Scheme 3. Epoxidation of olefins by peracetic acid.
Residence time of 1 h. The flow rate of pump #1 was tuned to pro-
À1
vide a rate of 0.46 mLmin and the flow rate of pump #2 was
À1
tuned to provide 0.64 mLmin. The feeding pumps #1 & #2 was
Excellent mass transfer can be achieved by using the MJOD
reactor, which facilitates interaction between (1) gas and liquid
phase, and (2) the compounds present in the liquid phase,
which gives rise to an augmented production of peracid as
well as an extended contact between the in situ produced per-
acid and the olefin. The overall result is that the epoxidation
process is accelerated considerably, providing high conversions
and yields in substantially shorter residence times. This new
continuous-flow epoxidation process has been successfully ap-
plied to other useful natural olefins (Table 1, entries 5–8), af-
fording the corresponding epoxides with good yields and very
high selectivity.
run until the two reservoirs were emptied, then switched off at the
same time as pump#3 was switched on to feed the pure solvent at
À1
a rate of 1.1 mLmin until a volume of ꢀ10 mL, corresponding to
the total volume of the reacting mixture was collected in the re-
ceiving reservoir.
Residence time of 2 h. The flow rate of pump #1 was adjusted to a
rate of 0.92 mLmin and the flow rate of feeding pump #2 was
adjusted to 0.54 mLmin. The pumps #1 & #2 were run until the
reservoirs was emptied, then the pump #3 was switched on to
À1
À1
À1
feed the pure solvent at a rate of 0.55 mLmin until a volume of
ꢀ10 mL, corresponding to the total volume of the reacting mix-
ture was collected in the receiving reservoir.
2
64
www.chemsuschem.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2012, 5, 261 – 265

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Acknowledgements
We thank the Fluens Synthesis Company for providing an MJOD
reactor system. The University of Bergen is acknowledged for fi-
nancial support of the present study. Politecnico di Milano is ac-
knowledged for a travel grant to R.S.
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