Continuous flow ozonolysis in a laboratory scale reactor

Article abstract of DOI:10.1021/ol102984h

Several important types of ozonolysis reactions have been performed in a continuous flow device that is able to perform both the ozonolysis and quenching steps in flow mode. This technique allows safe and scalable ozonolysis reactions to be performed on a laboratory scale.(Figure Presented)

Full text of DOI:10.1021/ol102984h

ORGANIC
LETTERS
2011
Vol. 13, No. 5
984–987
Continuous Flow Ozonolysis in a
Laboratory Scale Reactor
Muhammad Irfan, Toma N. Glasnov, and C. Oliver Kappe*
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of
Chemistry, Karl-Franzens University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
oliver.kappe@uni-graz.at
Received December 14, 2010
ABSTRACT
Several important types of ozonolysis reactions have been performed in a continuous flow device that is able to perform both the ozonolysis and
quenching steps in flow mode. This technique allows safe and scalable ozonolysis reactions to be performed on a laboratory scale.
Ozonolysis has been extensively studied for several
according to the most widely accepted Criegee mechanism
for liquid-phase ozonolysis.3
€
decades after the apparently first report by Schonbein in
1855.1 Considered as a clean and efficient way of introduc-
ing oxygen-containing groups (alcohols, aldehydes, ke-
tones, or acids) by oxidative cleavage of C-C double
bonds, ozonolysis has become a common tool for synthetic
chemists in academic and industrial research laboratories.2
From the mechanistic standpoint, ozonolysis reactions
represent a sequence of 1,3-cylcoaddition-reversion steps
In the classical view of the reaction, the 1,3-cycloaddi-
tion of an ozone molecule to a C-C double bond leads to
the initial formation of a 1,2,3-trioxolane ring (primary
ozonide, “molozonide”). Subsequent ring cleavage results
in a highly reactive dipolar carbonyl oxide intermediate
and an aldehyde or a ketone, which then recombine to
provide a 1,2,4-trioxolane (secondary ozonide). Upon
oxidative or reductive cleavage (quenching) the latter
heterocycle can then be converted into aldehydes, ketones,
alcohols, or acids.2,3
€
(1) Schonbein., C. F. J. Prakt. Chem. 1855, 66, 282.
(2) (a) Bailey, P. S. Chem. Rev. 1958, 58, 925–1010. (b) Bailey, P. S.
Ozonolysis in Organic Chemistry; Academic Press: New York, 1978; Vol. 1.
(c) Odinokov, V. N.; Tolstikov, G. A. Russ. Chem. Rev. 1981, 50, 636–
656. (d) Bailey, P. S. Ozonolysis in Organic Chemistry; Academic Press:
New York, 1982; Vol. 2. (e) Bunnelle, W. H. Chem. Rev. 1991, 91, 335–
362. (f) Ishmuratov, G. Y.; Kharisov, R. Y.; Odinokov, V. N.; Tolstikov,
G. A. Russ. Chem. Rev. 1995, 64, 541–568. (g) Van Ornum, S. G.;
Champeau, R. M.; Pariza, R. Chem. Rev. 2006, 106, 2990–3001. (h)
Zvereva, T. I.; Kasradze, O. B.; Kazakova, O. B.; Kukovinets, O. S.
Russ. J. Org. Chem. 2010, 46, 1431–1451.
(3) (a) Murray, R. W. Acc. Chem. Res. 1968, 1, 313–320. (b) Criegee,
R. Angew. Chem., Int. Ed. 1975, 14, 745–751. (c) Kuczkowski, R. L. Acc.
Chem. Res. 1983, 16, 42–47. (d) Kuczkowski, R. L. Chem. Soc. Rev.
1992, 21, 79–83. (e) Schank, K. Helv. Chim. Acta 2004, 87, 2074–2083.
Although an intrinsically environmentally benign and
atom-efficient oxidation process compared to analogous
metal-mediated transformations, a major concern in ozo-
nolysis chemistry is safety,4 since the formed ozonides (and
peroxides) are unstable and potentially explosive. Further-
more, the subsequent quenching step to produce the final
products is generally an exothermic process, requiring
efficient temperature control. Arguably, given the hazard
(4) Kula, J. Chem. Health Saf. 1999, 6, 21–22.
r
10.1021/ol102984h
Published on Web 01/26/2011
2011 American Chemical Society

Table 1. Flow Ozonolysis of Selected Styrenes
Figure 1. Simplified schematic view of the O-Cube reactor.
of forming potentially explosive intermediates and con-
sidering the toxicityofO3 itself, traditionalbatch ozonolyis
reactions have little prospect of becoming fully integrated
into the arsenal of synthetically useful (and safe) labora-
tory procedures.5
Recently, continuous-flow processing and microreactor
technology have gained increased attention as valuable
alternatives to batch protocols.6,7 Dedicated flow reactors
have been employed successfully in the past for performing
highly exothermic reactions or in cases where hazardous
(explosive, toxic) reagents or intermediates are involved.6,7
The small reactor volumes and high heat transfer rates
characteristic of these devices can mitigate the risks nor-
mally experienced in a batch process.6,7 Therefore, the
concept of continuous flow ozonolysis appears tobe highly
attractive. In recent years, several dedicated flow/micro-
a Isolated yield.
reactor deviceshavebeendescribedin the literature, ableto
effectively perform ozonolysis reactions for specific appli-
cations.8-12 Nonetheless, the development of a general
purpose laboratory scale continuous flow ozonolysis sys-
tem is still in its infancy.
Herein we report a variety of ozonolysis reactions
performed in a dedicated commercially available flow
device. The flow ozonolysis reactor (O-Cube) is a compact
benchtop instrument suitable for atmospheric pressure
ozonolysis from -25 °C to room temperature at 0.2-
2.0 mL/min flow rates, capable of producing up to 10 g of
material per day (Figure 1).13
The instrument uses an O2 gas cylinder to supply an
inbuilt O3 generator with a continuous flow of O2 at a
maximum flow rate of 20 mL/min. The generated O3 is
quantified in an internal analyzer and passed through a
polytetrafluoroethylene (PTFE) frit to mix with a contin-
uous stream of dissolved substrate (A). The substrate flow
is maintained by two syringe pumps equipped with PTFE
heads. The stream of substrate is continuously cooled
before and after being mixed with O3. The cooled reaction
loop is a 4 mL (reaction volume) 1 mm i.d. PTFE tube
wrapped around a refrigeration unit. After passing
through the reaction loop, the formed ozonide mixes with
the quench reagent solution (B), supplied by two further
syringe pumps. Finally, the formed product is eluted into a
collection vial (CAUTION! As the formed ozonides and/or
peroxides are potentially explosive, the reaction mixture has
to besubjected to further workuponlyafter NEGATIVE test
with peroxide test strips).
(5) Despite this fact, industriallyimportant ozonolysisprocesses have
been carried out on considerable scale. For details, see: Caron, S.;
Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Chem.
Rev. 2006, 106, 2943–2989 and citations therein.
(6) Selected reviews on microreactor technology, see: (a) Fukuyama,
T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151–163. (b) Wiles,
C.; Watts, P. Eur. J. Org. Chem. 2008, 1655–1671. (c) Geyer, K.;
Gustafsson, T.; Seeberger, P. H. Synlett 2009, 2382–2391. (d) Hartman,
R. L.; Jensen, K. F. Lab Chip 2009, 9, 2495–2507. (e) McMullen, J. P.;
Jensen, K. F. Annu. Rev. Anal. Chem. 2010, 3, 19–42.
(7) (a) Wirth, T., Ed. Microreactors in Organic Synthesis; Wiley-VCH:
Weinheim, 2008. (b) Hessel, V., Schouten, J. C., Renken, A., Wang, Y.,
Yoshida, Y.-i., Eds. Handbook of Micro Reactors; Wiley-VCH: Weinheim,
2009. (c) Yoshida, J.-i. Flash Chemistry-Fast Organic Synthesis in
Microsystems; Wiley-VCH; Weinheim, 2008. (d) Luis, S. V., Garcia-
Verdugo, E., Eds. Chemical Reactions and Processes under Flow Condi-
tions; Royal Society of Chemistry: Cambridge, 2010.
(8) Wada, Y.; Schmidt, M. A.; Jensen, K. F. Ind. Eng. Chem. Res.
2006, 45, 8036–8042.
(9) (a) Steinfeldt, N.; Abdallah, R.; Dingerdissen, U.; Jahnisch, K.
€
€
Org. Process Res. Dev. 2007, 11, 1025–1031. (b) Hubner, S.; Bentrup, U.;
€
€
Budde, U.; Lovis, K.; Dietrich, T.; Freitag, A.; Kupper, L.; Jahnisch, K.
Org. Process Res. Dev. 2009, 13, 952–960. (c) Steinfeldt, N.; Bentrup, U.;
€
Jahnisch, K. Ind. Eng. Chem. Res. 2010, 49, 72–80.
In order to investigate the scope and potential of this
technology we have explored various common ozonolysis
(10) O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12,
1596–1598.
(11) (a) Pelletier, M. J.; Fabilli, M. L.; Moon, B. Appl. Spectrosc.
2007, 61, 1107–1115. (b) Pflieger, M.; Monod, A.; Wortham, H. Atmos.
Environ. 2009, 43, 5597–5603. (c) Pflieger, M.; Goriaux, M.; Temime-
Roussel, B.; Gligorovski, S.; Monod, A.; Wortham, H. Atmos. Chem.
(12) Allian, A. D.; Richter, S. M.; Kallemeyn, J. M.; Robbins, T. A.;
Kishore, V. Org. Process Res. Dev. 2011, 15, 91-97.
(13) For more details, see: http://www.thalesnano.com/products/
o-cube.
~
Phys. 2009, 9, 2215–2225. (d) Gomes, A. C.; Nunes, J. C.; Simoes,
R. M. S. J. Hazard. Mat. 2010, 178, 57–65.
Org. Lett., Vol. 13, No. 5, 2011
985

required is an extraction followed by solvent evapora-
tion, producing the desired products in >95% purity
(1H NMR, HPLC/GC-MS) and high yields.
Scheme 1. Flow Ozonolysis of Various Substrates
Similarly, 4-methoxybenzaldehyde 2d, after isolation
from the initial ozonolysis step 1d f 2d, could be further
oxidized to 4-methoxybenzoic acid with 1.5 equiv of O3 in
CHCl3 followed by an oxidative quench. In addition, when
using methanol as solvent, the ozonolysis of 4-fluoro-R-
methylstyrene (1b) resulted in the selective formation of
methyl 4-fluorobenzoate in 72% isolated yield (see Sup-
porting Information for details).
In another example, we were able to convert β-pinene (3)
into nopinone (4) in a single continuous-flow experiment
(Scheme 1a). Whereas the groups of Brown and Dumas
performed batch ozonolysis experiments at -78 °C in
order to obtain the nopinone structure after a Me2S
quench (83% and 85% yield),15 using the O-Cube reactor
allowed us to perform the oxidative process under ambient
conditions (25 °C) at a 1 mL/min flow rate toobtain nopin-
one (4) in 100% conversion and 70% isolated yield after
chromatograhpy, using H2O/acetone as quenching re-
agent (Scheme 1a). In addition to olefinic double bonds,
the ozonolysis of the terminal C-C triple bond in 1,1-
diphenylprop-2-yn-1-ol 5 (Scheme 1b) was also investi-
gated. In our hands, the ozonolysis of propynol 5 in CHCl3
did not lead to the expected glycolic acid 616 but to
diphenylketone 7 in 86% yield. The observed result can
be rationalized by the presence of ozone in the reaction
mixture, creating anoxidizing environment, able to rapidly
decarboxylate the in situ formed glycolic acid, thereby
forming diphenylketone 7 as observed previously by Hurd
and Christ for similar substrates.17
Inanotherapplication of the continuous flow ozonolysis
concept, we attempted the oxidative transformation of
octan-1-amine 8 (Scheme 1c) into the corresponding ni-
troalkane 10. Previous work by Bachman and Strawn has
confirmed that primary amines of type 8 can be subjected
to ozonolysis under batch conditions to provide nitro-
alkanes,18 and the Jensen group has reported the oxidation
8 f 9 with O3 in a multichannel microreactor.8 Adopting
operating conditions similar to those used during olefin
ozonlysis, a 0.05 M EtOAc solution of octan-1-amine 8
was subjected to flow ozonolysis in the O-Cube at room
temperature. Applying a 10% ozone concentration (∼3
equiv), complete consumption of the starting material was
experienced, providing 1-nitrooctane 9 in 73% yield after a
single pass through the instrument within 40 min. The
oxidation of thioanisole (10) appeared to be a somewhat
more demanding process, as it has been found that alipha-
tic/aromatic or aromatic/aromatic thioethers tend to react
relatively slowly or not at all with ozone (thioesters).19
While the formation of the sulfoxide proceeds relatively
processes in combination with either oxidative or reductive
quenching/workup steps. We initially examined the con-
tinuous flow ozonolysis of several styrenes (1a-d) as
model substrates.14
In a single pass through the continuous flow reactor,
solutions of 1a-d readily afforded the correspond-
ing aldehydes/ketones 2a-d in 72-90% isolated yield
(Table 1), comparable to the published batch ozonolysis
results.14 Typically, a 0.05 M stock solution of the corre-
sponding styrene 1a-d in methanol (MeOH) or acetone
(Me2CO) as solvent was passed through the ozonolysis
device at 0-25 °C using 5% ozone concentration (1.5
equiv) and a 0.7-1.0 mL/min flow rate.
The degree of conversion can easily be determined by
monitoring the composition of the reaction mixture after
being exposed to the ozonolysis conditions by HPLC or
GC-MS analysis. For all of the examples covered in this
manuscript, full conversion of the starting material was
achieved. Adjusting the proper settings on the instrument
(O3 concentration, temperature, and flow rate) allowed the
facile optimization of the reaction conditions in these and
related transformations (see Table S1 in the Supporting
Information for details). Using the above-described con-
ditions, typically 100-215 mg of product could be pro-
duced within a 40 min run.
A major advantage of the flow-through concept con-
cerns the handling of the excess ozone and ozonides (or
peroxides) present in the reaction mixture. In the current
system, the quenching step is performed immediately after
the substrate has left the ozonolysis coil, destroying any
excess O3 and transforming the ozonide intermediates
into the corresponding product. In the case of aldehydes/
ketones 2a-d (Table 1) the only remaining workup that is
(15) (a) Brown, H. C.; Weissman, S. A.; Perumal, P. T.; Dhokte, U. P.
J. Org. Chem. 1990, 55, 1217–1223. (b) Dumas, F.; Alencar, K.;
Mahuteau, J.; Barbero, M. J. L.; Miet, C.; Gerrd, F.; Vasconcellos,
L. A. A.; Costa, P. R. R. Tetrahedron: Asymmetry 1997, 8, 579–583.
(16) (a) Cannon, J. G.; Darko, L. L. J. Org. Chem. 1964, 29, 3419–
3420. (b) DeMore, W. B.; Lin., C.-L. J. Org. Chem. 1973, 38, 985–989.
(17) Hurd., C. D.; Christ, R. E. J. Org. Chem. 1936, 1, 141–145.
(18) Bachman, G. B.; Strawn, K. G. J. Org. Chem. 1968, 33, 313–315.
(14) (a) Wacek, A. V.; Eppinger, H. O. Chem. Ber. 1940, 73, 644–651.
(b) Keaveney, W. P.; Berger, M. G.; Pappas, J. J. J. Org. Chem. 1967, 32,
1537–1542. (c) Schiaffo, C. E.; Dussault, P. H. J. Org. Chem. 2008, 73,
4688–4690.
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Org. Lett., Vol. 13, No. 5, 2011

Table 2. Selectivities in the Flow Ozonolysis of Thioanisole (11)
conv % (GC-MS)
entry O3 (equiv) solvent step 1 (mL/min) temp (°C)
quenching solution
step 2 (mL/min) temp (°C)
10
11
12
1
2
3
4
5
6
7
8
1
2
2
2
2
2
2
4
MeOH
Me2CO
Me2CO
Me2CO
Me2CO
MeOH
MeOH
MeOH
1
25
25
0.1 M NaBH4/MeOH
0.05 M NaIO4/H2O
1 M H2O2/H2O
0.7
1
25
25
0
0
99a
82
57
22
12
0
0
18
43
78
88
68
86
99b
0.5
0.5
1
10
1
15
0
5
3 M H2O2/H2O
1
10
0
1
5
5 M H2O2/H2O
1
10
0
1
-10
-20
-20
5 M H2O2/MeOH
5 M H2O2/MeOH
5 M H2O2/MeOH
1
0
32
14
0
1
1
-10
-10
0
0.5
0.5
0
a Isolated yield 84%. b Isolated yield 87%.
slowly, the further oxidation steptothe sulfoneisknown to
be even more sluggish.19 Therefore, we investigated the
oxidation behavior of thioanisole (10) with ozone under
flow conditions. Initially, a 0.05 M solution of thioanisole
(10) in methanol was processed at 25 °C and 1 mL/min
flowrateapplying 5% O3 (1.0 equiv). Reductive quenching
with 0.1 M NaBH4 in MeOH at 25 °C followed by
extractive workup provided sulfoxide 11 in 84% isolated
product yield (Table 2, entry 1).
In order to access sulfone 12 the reductive quench was
replaced by anoxidative one (Table 2, entryies 2-8). Using
NaIO4 as oxidative reagent at 25 °C and 2 equiv of O3 in
acetone, full conversion based on consumption of sulfide
10 was achieved at a 0.5 mL/min flow rate in the ozonolysis
step. Analysis (GC-MS) of the obtained reaction mixture
showed predominant formation of sulfoxide 11 accompanied
by 18% of the desired sulfone 12 (Table 2, entry 2). Lower
temperatures and higher flow rates, as well as changing the
oxidative reagent to 5 M H2O2 in water as solvent led to an
improved sulfoxide/sulfone product distribution (Table 2,
entries 3-5) providing up to 88% selectivity for sulfone 12.
Ultimately, changing the reaction solvent to MeOH initially
did not seem promising (Table 2, entry 6); however, after
further optimization we were finally able to achieve quanti-
tative conversion of thioanisole 10 into the desired sulfone 12.
Under the optimized conditions for full conversion (Table 2,
entry 8) a preparative experiment provided 87% isolated
yield of sulfone 12 after a simple workup.
In conclusion, a novel continuous flow laboratory
scale ozonolysis instrument has been described. The flow
ozonolysis of aromatic/aliphatic olefins and an alkyne as
well as the oxidation of an amine into the corresponding
nitro-compound and the selective oxidation of an aromatic
thioether into the corresponding sulfoxide and sulfone
have been conducted successfully. In all of these processes,
the highly energetic ozonolysis and quenching reactions
were performed safely in flow format with excellent tem-
perature control, avoiding the inventory of the highly
unstable ozonide intermediates. The application of this
novel reactor for a range of more complex ozonolysis
reactions is currently in progress in our laboratories.
Acknowledgment. This work was supported by a grant
from the Christian Doppler Research Society (CDG). M.I.
thanks the Higher Education Commission of Pakistan for
a Ph.D. scholarship. We thank ThalesNano Nanotechnol-
ogy Inc. (Budapest, Hungary) for the provision of the
O-Cube ozonolysis reactor.
Supporting Information Available. Full experimental
details and spectral data (NMR, MS) for all transforma-
tions and compounds described. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Horner, L.; Schaefer, H.; Ludwig., W. Chem. Ber. 1958, 91,
75–81.
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