Highly efficient biphasic ozonolysis of alkenes using a high-throughput film-shear flow reactor

Article abstract of DOI:10.1016/j.tetlet.2016.02.042

A new method for ozonolysis of alkenes using a continuous flow film-shear reactor was developed. The reactor uses a shearing microfluidic mixing chamber to provide biphasic mixing of an organic phase and aqueous phase with ozone gas. The H₂O acts as an in situ reducing agent for the carbonyl oxide intermediate, providing ketones and aldehydes directly from the reaction mixture. Flow rates of up to 1.0 mmol/min (alkene) with an ozone reaction efficiency of >70% were achieved. Aryl conjugated olefins reacted to form carbonyl species in good yields on a multi-gram scale; however, alkyl olefins reacted with ozone to predominantly form secondary ozonides. The discrepancy in product distributions between alkyl and aryl olefins likely originates from the electronic stability of the carbonyl oxide intermediate, which is longer lived for aryl derivatives due to conjugation.

Full text of DOI:10.1016/j.tetlet.2016.02.042

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient biphasic ozonolysis of alkenes using
a high-throughput film-shear flow reactor
Alexander J. Kendall, Justin T. Barry, Daniel T. Seidenkranz, Ajay Ryerson, Colin Hiatt, Chase A. Salazar,
⇑
Dillon J. Bryant, David R. Tyler
University of Oregon, Department of Chemistry and Biochemistry, 1253 University of Oregon, Eugene, OR 97403, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for ozonolysis of alkenes using a continuous flow film-shear reactor was developed. The
reactor uses a shearing microfluidic mixing chamber to provide biphasic mixing of an organic phase and
aqueous phase with ozone gas. The H2O acts as an in situ reducing agent for the carbonyl oxide interme-
diate, providing ketones and aldehydes directly from the reaction mixture. Flow rates of up to 1.0 mmol/
min (alkene) with an ozone reaction efficiency of >70% were achieved. Aryl conjugated olefins reacted to
form carbonyl species in good yields on a multi-gram scale; however, alkyl olefins reacted with ozone to
predominantly form secondary ozonides. The discrepancy in product distributions between alkyl and aryl
olefins likely originates from the electronic stability of the carbonyl oxide intermediate, which is longer
lived for aryl derivatives due to conjugation.
Received 12 January 2016
Revised 10 February 2016
Accepted 11 February 2016
Available online xxxx
Keywords:
Ozonolysis
Flow chemistry
Secondary ozonide
Carbonyl oxide
Film-shear reactor
Ó 2016 Elsevier Ltd. All rights reserved.
The use of ozone to oxidize alkenes (ozonolysis) is a powerful
tool in modern organic chemistry.1–3 Ozone has many advantages
over other common strong oxidants: high atom economy, absence
of metals or hyper-valent iodine, and the straightforward synthesis
of ozone from O2. These factors make ozonolysis ideal for many
industrial processes.4 However, the use of ozonolysis both industri-
ally and in research labs is limited because of the cryogenic tem-
peratures (À40 °C) typically required, dangerous intermediates
and byproducts that are produced stoichiometrically, and the
necessity of a secondary reduction step (using Me2S, PPh3, Pt/H2,
BH3, NaBH4, Zn/HOAc, LiAlH4, etc.) to form ketones, aldehydes, or
alcohols.3 Several approaches have been developed to address
these inherent drawbacks. Flow chemistry has been used to mini-
mize the concentration of dangerous intermediates and cryogenic
temperatures; however, the reactions still require a secondary
quench step of the reaction mixture.5–10 Another approach, pio-
neered by Dussault et al., prevents secondary ozonide (SOZ) forma-
tion using an in situ reduction of the carbonyl oxide intermediate
with water as the reductant (Fig. 1).11,12 This approach allows for
a single-step reaction using ozone and water to oxidize alkenes
into aldehydes and ketones directly while avoiding a secondary
step and strong reducing agents that may be incompatible with
the rest of the molecule. Batch reactions and water-miscible polar
organic solvents (containing 5% water) were used by Dussault and
coworkers, limiting the usefulness of this method for large scale
syntheses. Also, when a biphasic system using phase transfer catal-
ysis was attempted, in situ water reduction was never observed.14
To expand the approach of in situ carbonyl oxide reduction with
water, while taking advantage of the safety and scalability of flow
ozonolysis, we developed a high-throughput, flow method using a
SynthetronTM S3T1 film-shear reactor.15 A film-shear reactor is a
device with a rotating disk (the rotor) placed at an adjustable dis-
tance 20–300 lm from a stationary disk (the stator). The rotor
spins at speeds up to 104 rpm, and two streams containing the
reactants are introduced between the two disks. Contact of the
reactants within the narrow gap results in intense shear with con-
sequent intimate mixing of the reactants.
As shown in Figure 2, the reaction system is comprised of a
plug-flow organic/aqueous mixture that is sheared in the reaction
chamber with ozone. The shear force increases the interface of H2O
and the organic phase.16–20 In addition, the mass-transport of
ozone into solution benefits from the reactor microfluidics and
shear mixing.21–23 Upon exiting the reactor, the reaction mixture
self-separates, with the desired products in the organic phase
and H2O2 in the aqueous phase.
Preliminary optimizations using isoeugenol found that EtOAc
was an excellent solvent and that quantitative conversion to vanil-
lin was achieved at a molar flow rate of 1.0 mmol/min (S.I. Fig. S2).
This molar flow rate is approximately eight times faster than has
been previously reported in more conventional microfluidic sys-
tems.24 It is also notable that the residence time in the reactor is
⇑
Corresponding author.
E-mail address: dtyler@uoregon.edu (D.R. Tyler).
http://dx.doi.org/10.1016/j.tetlet.2016.02.042
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kendall, A. J.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.02.042

2
A. J. Kendall et al. / Tetrahedron Letters xxx (2016) xxx–xxx
secondary
ozonide (SOZ)
predominantly aldehyde or ketone products were observed. We
were then able to run six substrates on the gram/multi-gram scale
with good yields of the aldehyde or ketone (Table 1). Note that no
secondary quench was used before these isolations. These results
demonstrate several important attributes of our ozonolysis
method: (1) it can effectively mix biphasic media to react the car-
bonyl oxide with water during ozonolysis, (2) it is scalable to
multi-gram reaction scale while retaining good yields, (3) aldehy-
des and ketones can be directly attained from alkenes in flow with-
out a secondary quench step, and (4) reaction times of <10 s.
To further understand the reaction profile with the aryl sub-
strates, we screened an additional four aryl alkenes to determine
the ratio of SOZ to carbonyl (Table 2). These data help determine
how effective the in situ water reduction is for each substrate. In
addition, 1-decene was screened under a variety of conditions
(Table 3). The aryl alkenes afforded much higher ratios of carbonyl
to SOZ compared to alkyl alkenes. In fact, the dominant product of
the reaction with 1-decene was SOZ under a variety of conditions
(Table 3). (Even with aqueous oxidants, various acids, phase trans-
fer catalysts, and alcohol solvents, SOZ was the predominant
product.)
Traditional
Ozonolysis
O
O
R3
R2
R1
O
O
O
R1
R2
R3
O
O
O3
O
O
R1
H2O
+
H2O2
R1 R2
R2
R3
R3
O
O
+
primary
ozonide
Dussault
2008
carbonyl
oxide
R1 R2
R3
carbonyl
products
Figure 1. Criegee mechanism13 of ozonolysis showing traditional ozonolysis
product pathway (top route) and the Dussault modification11 of in situ H2O
reduction (bottom route).
The discrepancy between the alkyl and aryl alkene ozonolysis
products is likely due to a difference in the stabilities of the
Table 2
Product distributions for ozonolysis of aryl alkenes26
Figure 2. General setup of biphasic ozonolysis using the film-shear reactor. A more
detailed diagram of the reactor setup is provided in Supplemental information (S.I.)
Figure S1.
R1
R2
R1 R2
Film-shear
reactor
O
O
O
+
O3
+
O
R3
EtOAc : H2O
Ar
R3
Ar
R3
10 mL/min : 10 mL/min
Ar
Table 1
Gram/multi-gram scale ozonolysis of aryl alkenes26
Entry
1
Substrate
Ratio of carbonyl:SOZa
>99:1
R1 R2
Film-shear
O
reactor
CH3
CH3
+
O3
EtOAc : H2O
10 mL/min : 10 mL/min
R3
Ar
R3
H3CO
HO
Ar
Entry
1
Substrate
Product
Yielda (%)
49
CH3
O
H3CO
HO
2
>99:1
H3CO
HO
H3CO
CH3
O
3
4
5
7.6:1
33:1
2.8:1
2
81
H3CO
H3CO
O
3
4
72
64
O
O
6
7
3.4:1
3.5:1
O
O
5
6
79
35
a
Isolated yields.
8
9
3.6:1
1:1.8
8 s. Even with a very short residence time, ozone reacted with
greater than 70% efficiency (1.4 equiv of O3 per 1.0 equiv of isoeu-
genol, see S.I.).
10
1:17
The substrate scope of the film-shear ozonolysis system was
determined next. When aryl conjugated alkenes were screened
a
Determined by 1H NMR from the crude reaction mixture.
Please cite this article in press as: Kendall, A. J.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.02.042

A. J. Kendall et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 3
Screening conditions for alkyl olefin ozonolysis
O
O
O
CH2
Film-shear
reactor
O
O
+
O3
+
100 mM
Entry
Phases
Aqueous
Additivesa
Flow ratesb (mL/min)
Shear RPM (Â1000)
Conversionc (%)
Yieldc (%)
Aldehyde
Organic
Organic
Aqueous
SOZ
1
2
3
4
5
6
7
8
EtOAc
EtOAc
EtOAc
H2O
H2O
H2O
H2O
0.1 M H2SO4(aq)
1.0 M H2SO4(aq)
H2O
H2O
H2O
—
—
—
—
—
—
10
15
20
10
10
10
10
10
10
10
10
80
80
80
80
80
80
10
10
10
10
10
2.0
2.0
2.0
2.0
3.6
3.6
3.6
3.6
3.6
3.6
3.6
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
10
8
7
11
10
4
11
1
38
37
36
38
35
41
44
36
65
40
42
Hexanes
Hexanes
Hexanes
Hexanes
Hexanes
Hexanes
Hexanes
Hexanes
3 equiv TEABr
50% MeOH
3 equiv TBABr
50% EtOH
9
10
11
13
3
3
H2O
0.1 M H2SO4(aq)
50% EtOH
a
b
c
TEABr = tetraethylammonium bromide.
See Experimental section and S.I. Figure S1 for details on method.
As determined by 1H NMR with 1,1,2,2-tetrachloroethane or hexamethyl benzene as an internal standard.
chamber. Alkyl olefins likely produce a carbonyl oxide intermedi-
ate that is too short lived to effectively react with water, preferring
the formation of SOZs. The longer lifetimes of aryl conjugated car-
bonyl oxides are responsible for the excellent selectivity and reac-
tivity of aryl conjugated olefins, which generally prefer carbonyl
products from aryl alkenes without any secondary quench with
scalable (multi-gram) flow chemistry.
O
H
O
H
O
H
O
H
O
O
O
O
=
Figure 3. Resonance stabilization of aryl conjugated carbonyl oxide.
We are currently using this method to investigate aryl alkyne
ozonolysis, as well as stoichiometric ozone delivery to multi-olefin
substrates.
carbonyl oxide intermediates. Although the rate-determining step
in ozonolysis is the initial attack of the alkene on the ozone, the
nature of the intermediates that follow determine which product
(s) form. It is likely that the lifetime of the carbonyl oxide (10À3
–
Acknowledgments
10À5 s)25 plays a dominant role in product distributions observed
in these cases. For alkyl carbonyl oxides, rearrangement to SOZ is
preferred due to the short lifetime of the carbonyl oxide interme-
diate. However, with aryl conjugated alkenes, benzylic resonance
stabilization (Fig. 3) of the carbonyl oxide may contribute to a
more persistent intermediate, allowing enough time for the inter-
mediate to react with water, thus making the product-determining
step favor carbonyl products. This rationale also explains the large
bias for isoeugenol and anethole (Table 2, entries 1 and 2) toward
carbonyl products over SOZs, because they have electron rich aryl
rings that provide additional stabilization of the delocalized cation
of the carbonyl oxide intermediate.
We gratefully acknowledge the NSF (GRFP DGE-8029517) for
financial support. We would also like to thank Dr. Jeffrey Raber
for advice and insightful discussions.
Supplementary data
Supplementary data (the reactor setup, experimental proce-
dures, spectroscopic data, and additional references) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2016.02.042.
Most of the aryl alkenes in Table 2 have a ratio biasing strongly
toward aldehyde or ketone as products. Notably, cyclic alkenes
(entries 8–10) are more prone to form SOZs with decreasing
degrees of freedom (from entries 8 to 10) for the corresponding
carbonyl oxide intermediate. The tethered carbonyl and carbonyl
oxide pair favor SOZ formation if there is a strong enough entropic
bias preferring intramolecular reaction (leading to SOZ) over inter-
molecular reduction (leading to carbonyl products directly). Nota-
bly, phenanthrene (Table 2, entry 8) still produces a majority of
carbonyl products even though it is a tethered alkene.
References and notes
1. Ishmuratov, G. Y.; Legostaeva, Y. V.; Garifullina, L. R.; Botsman, L. P.; Yakovleva,
M. P.; Tolstikov, G. A. Chem. Nat. Compd. 2015, 51, 199–219.
2. Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem. Rev. 2006, 106, 2990–3001.
3. Bailey, P. S. In Ozonation in Organic Chemistry: Olefinic Compounds; Academic
Press: New York, 1978; Vol. 1,
4. Anderson, N. G. Practical Process Research and Development, 2nd ed.; Academic
Press: New York, 2012.
5. Ayman Allian In Managing Hazardous Reactions and Compounds in Process
Chemistry In ACS Symposium Series; American Chemical Society, 2014; Vol.
1181, pp 353–382.
In conclusion, we have developed a method for flow ozonolysis
using a film-shear reactor. H2O acts as a mild in situ reductant of
the carbonyl oxide intermediate, yielding ketones and aldehydes
directly. This flow reactor has a molar flow rate eight times faster
than previously reported flow ozonolysis systems and is currently
only limited by the rate of ozone production, with reaction times of
8 s. The excellent reaction rates and molar flow rates are attributed
to superb mixing of the reactants within the film-shear reaction
6. Irfan, M.; Glasnov, T. N.; Kappe, C. O. Org. Lett. 2011, 13, 984–987.
7. Allian, A. D.; Richter, S. M.; Kallemeyn, J. M.; Robbins, T. A.; Kishore, V. Org.
Process Res. Dev. 2011, 15, 91–97.
8. O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596–1598.
9. Hübner, S.; Bentrup, U.; Budde, U.; Lovis, K.; Dietrich, T.; Freitag, A.; Küpper, L.;
Jähnisch, K. Org. Process Res. Dev. 2009, 13, 952–960.
10. Bogdan, A.; McQuade, D. T. Beilstein J. Org. Chem. 2009, 5.
11. Schiaffo, C. E.; Dussault, P. H. J. Org. Chem. 2008, 73, 4688–4690.
12. Willand-Charnley, R.; Dussault, P. H. J. Org. Chem. 2013, 78, 42–47.
13. Criegee, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 745–752.
Please cite this article in press as: Kendall, A. J.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.02.042

4
A. J. Kendall et al. / Tetrahedron Letters xxx (2016) xxx–xxx
14. Schiaffo, C. I. An Improved Procedure for Alkene Ozonolysis. II. Exploring a New
Structural Paradigm for Peroxide Antimalarials; University of Nebraska-Lincoln:
Lincoln, NE, 2011.
15. Kinetichem, Inc. http://kinetichem.com/ (accessed Jan 3, 2016).
16. Fox, B. R.; Brinich, B. L.; Male, J. L.; Hubbard, R. L.; Siddiqui, M. N.; Saleh, T. A.;
Tyler, D. R. Fuel 2015, 156, 142–147.
17. Ghanem, A.; Lemenand, T.; Della Valle, D.; Peerhossaini, H. Chem. Eng. Res. Des.
2014, 92, 205–228.
18. Boodhoo, K. In Process Intensification for Green Chemistry; Boodhoo, K., Harvey,
A., Eds.; John Wiley & Sons, 2013; pp 59–90.
25. Bunnelle, W. H. Chem. Rev. 1991, 91, 335–362.
26. Standard ozonolysis procedure. The syringe pumps and the film-shear reactor
were primed by running 50 mL EtOAc at 10 mL/min and 50 mL deionized H2O
at 10 ml/min with the rotor running at 2000 RPM. This procedure was repeated
with pure oxygen also flowing at 0.8 L/min The film-shear reaction chamber
was cooled to 0 °C with a recirculator. Both a 0.10 M solution of alkene in
EtOAc at 0 °C and deionized water at 0 °C were pumped into a ‘T’ valve (10 mL/
min each) generating the plug-flow mixture that entered the film-shear
reactor. Ozone was sparged through the reaction chamber at 0.8 L/min. A
product flask was primed with 2 mol equiv of a sodium sulfite solution to
quench any hydrogen peroxide produced. The resulting product mixture was
19. Hampton, P. D.; Whealon, M. D.; Roberts, L. M.; Yaeger, A. A.; Boydson, R. Org.
Process Res. Dev. 2008, 12, 946–949.
collected in
a fume hood (CAUTION! residual ozone, formaldehyde, and
20. Holl, Richard. TCE 2003, 742, 32–34.
21. Sun, B.; Gao, M.; Arowo, M.; Wang, J.; Chen, J.; Meng, H.; Shao, L. Ind. Eng. Chem.
Res. 2014, 53, 19071–19076.
22. Steinfeldt, N.; Abdallah, R.; Dingerdissen, U.; Jähnisch, K. Org. Process Res. Dev.
2007, 11, 1025–1031.
23. Wada, Y.; Schmidt, M. A.; Jensen, K. F. Ind. Eng. Chem. Res. 2006, 45, 8036–8042.
24. Roydhouse, M. D.; Motherwell, W. B.; Constantinou, A.; Gavriilidis, A.; Wheeler,
R.; Down, K.; Campbell, I. RSC Adv. 2013, 3, 5076–5082.
hydrogen peroxide may be present as an aerosol; perform only in a well
ventilated hood). The pH was adjusted to 3 using 3 M HCl(aq). The two resulting
layers were separated. The aqueous layer was washed three times with 15 mL
of EtOAc, then the organic layers were combined, dried over Na2SO4, filtered,
and the solvent was removed under vacuum. The products were purified as
noted in Supplemental information.
Please cite this article in press as: Kendall, A. J.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.02.042