O-Cubeâ„¢ Application Note - ThalesNano

O-Cube Application Note
Safe and Fast
Ozonolysis Using the
O-Cube
Continuous Flow
Reactor
INTRODUCTION
Ozonolysis is a fundamentally important oxidation
reaction, which has never been fully adopted due to the
safety concerns with performing the process. Its main
importance stems from the fact that you can selectively
oxidize double or triple bonds to form hydroxyl groups,
aldehydes, or carboxylic acids in the presence of other
oxidizable groups (Figure 1). Other conventional oxidative
methods are not so selective, are slower to react, require
addition of water or need purification to eliminate side
products leading to lower yields or need the use of
metal catalysts [1]. Compared to other methodologies,
ozonolysis is considered as a greener way of oxidation
[2]. Ozonolysis has been used frequently in major drug
syntheses such as (+)-Artemisinin, Indolizidine 251F, and
D,L-Camptothecin and with finechemical syntheses such
as L-Isoxazolylalanine and Prostaglandin endoperoxides.
FLOW OZONOLYSIS
In order to overcome the difficulties associated with
ozonolysis, such as dangerous workup of the potentially
explosive ozonide, use of low temperature, and
complicated setting up of ozonizer equipment, ThalesNano
has developed the O-Cube ozonolysis flow reactor. The
O-Cube system is a compact instrument dedicated for
performing ozonolysis and low temperature reactions.
The O-Cube reactor is safer and more efficient than
standard batch equipment due to the small reactor
volume and precise temperature control. The compact
manner of the O-Cube reactor allows chemists to carry
out the formation and reductive or oxidative cleavage of
the secondary ozonide in one instrument.
GENERAL PROCEDURE
The O-Cube reactor generates ozone via a continuous
flow of oxygen gas from a cylinder and an internal
ozonizer. The ozone is mixed with a continuous stream
of precooled starting material, controlled using two
syringe pumps. The gas/liquid mixture is then pumped
into a cooled reaction zone, which may be cooled down
to a temperature of -25 °C. The volume of the reactor
tubing is 10 cm 3 . After passing through the cooler, the
formed ozonide mixes with the quench reagent solution,
supplied by two separate syringe pumps. The quenching
is performed in a secondary cooler before eluting into a
collection vial. All the reaction conditions, such as flow
rates of starting material and quenching agent, reaction
temperature and ozone amount (%), were previously set
on the touch screen panel of the instrument.
Figure 1: Mechanism of ozonolysis reaction

RESULTS OF ALKENE OZONOLYSIS
Prof. Kappe’s group at University of Graz converted
different alkenes to the corresponding aldehydes/ketones
[3] (Scheme 1.) by reacting 0.05 M of starting materials
with ozone (concentration of 5%) in the O-Cube reactor
resulting in isolated yields of 72-90%, which were found to
be comparable to the published batch ozonolysis results.
As the two steps of the reaction process were carried
out in the same reactor unit, the only process needed
to obtain the 100 – 215 mg products within the 40 mins
reaction time was the evaporation of solvent. Peroxide
strips were used to make sure there was no ozonide and
ozone remaining in the reaction mixture.
RESULTS OF AMINE GROUP OZONOLYSIS
Adopting the same reaction conditions from the alkene
ozonolysis, an alkyl amine was oxidised to the nitro form.
After ozonolysis the ozonide was quenched to result in the
desired 1-nitrooctane with a 73% yield (117 mg) within 40
mins.
RESULTS OF THIOANISOLE OZONOLYSIS
Oxidation reactions of thioethers often lead to the sulfone
due to the fast oxidation of sulfoxide intermediate.
Under flow conditions, by altering the reactions
conditions (ozone concentration and the nature of
quenching agent), both the sulfoxide and sulfone could
be selectively synthesized in high yield, 84 and 87%
respectively, after a simple work-up procedure. With
the sulfone synthesis, the only method necessary to
obtain the product was the evaporation of solvent after
making sure there was no ozonide and ozone remaining in
the reaction solution. Further data of the two representative
reactions can be found in Scheme 3.
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O-Cube Application Note
1.) MeOH, 25 °C, 1 mL/min, 0.05 M, 3% ozone 90%
2.) NaBH 4 /MeOH, 25 °C, 0.7 mL/min
1.) Me 2 CO, 25 °C, 1 mL/min, 0.05 M, 3% ozone 84%
2.) 5% H 2 O/Me 2 CO, 25 °C, 0.7 mL/min
Scheme 1: Ozonolysis of alkene groups followed by reductive quenching
1.) EtOAc, 25 °C, 1 mL/min, 0.05 M, 10% ozone (3 equ.) 73%
2.) 1.5 M H 2 O 2 /CHCl 3 , 25 °C, 0.5 mL/min
Scheme 2: Ozonolysis of amine groups followed by oxidative quenching
1.) Ozonolysis: MeOH, 25 °C, 1 mL/min, ozone: 1 equ.
Reductive quenching: 0.1 M NaBH 4 /MeOH, 25 °C, 0.7 mL/min
2.) Ozonolysis: MeOH, 25 °C, 0.5 mL/min, ozone: 4 equ.
Oxidative quenching: 5 M H 2 O 2 /MeOH, 10 °C, 0.5 mL/min
Scheme 3: Reaction conditions and results of thioanisole ozonolysis
REFERENCES
[1] (a) Bailey, P. S.; Chem. Rev., 1958, 58, 925-1010; (b) Baley, P. S.; Ozonization in Organic Chemistry, Olefinic
Compounds; 1978; 1; (c) Bailey, P. S.; Ozonation in Organic Chemistry, Academic: San Diego; Chem. Abstr.; 1982, 2;
312-319; (d) Razumovskij, S. D.; Zaikov, G. E.; Ozone and Its reaction with Organic Compounds; Elsevier: Amsterdam; 1984
[2] Pluim, H.; Dyer-Smith, P.; Exner, M.; Chimica Oggi/Chemistry Today; 2011; 29(1); 59-62
[3] Irfan, M.; Glasnov, N. T.; Kappe, O. C.; Organic Letters; 2011; 13(5); 984-987
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