Mastering ozonolysis: production from laboratory to ton scale in ...

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FLOW CHEMISTRY
Mastering ozonolysis:
production from laboratory
to ton scale in continuous flow
MARKUS NOBIS, DOMINIQUE M. ROBERGE
Lonza AG, Visp, 3930, Switzerland
KEYWORDS: Ozone, Ozonolysis, Oxidation, Scale-up, Microreactor
Technology, Microreactors, Continuous Flow Processes,
Green Chemistry, Sustainability
ABSTRACT: In most cases, ozonolysis is more sustainable and cost
effective for the oxidative treatment of organic unsaturated
compounds than other oxidation technologies. To enable the
scalability of this challenging gas-liquid oxidation process, Lonza
has developed a novel approach that combines microreactors,
a bench-scale reactor, and a large scale production reactor.
The approach also includes laboratory feasibility studies
and technical transfer - with hazard evaluations and safety
assessments - to successful large scale manufacturing.
INTRODUCTION
Ozone is a colourless gas that has an oxidation potential similar to
chlorine. Ozone is characterized and identified by the very
characteristic smell of fresh, spring rain when diluted. Based on its
high reactivity (1, 2), the gas is a well-known oxidation agent for
various applications, from waste water treatment (3) to potable
water purification (4). In organic synthesis, ozone is well known for
the cleavage of olefinic double bonds (unsaturated compounds)
and oxidation (5, 6, 8) performed at extremely low temperatures (in
general cryogenic). It is mainly known for generating high energetic,
unstable reaction products called ozonides (decomposition energy:
200-400 kJ/mol), which tend to decompose under sudden heat
evolution and have to be treated directly under oxidative or
reductive conditions. Reactions with ozone are characterized by
high atom efficiency of the oxidizing reagent where 66 mol% of the
molecule is directly used in the reaction compared to other
oxidation systems. Moreover, ozone is an environmentally friendly
reagent that forms oxygen as direct side product from the
ozonolysis. It is therefore a green and sustainable oxidation agent.
Based on the fact that it generates carbonyl compounds, ozonolysis
can be described as a technology platform that allows access to a
broad range of oxygen-containing substances (Figure 1).
CURRENT STATE
In industrial chemical applications, the use of ozonolysis has
come and gone in waves due to the difficulty in handling ozone;
most industrial scientists today have experience with ozone
through their university studies. Nevertheless, other stoichiometric
methods for double bond oxidation based on heavy metals –
chimica oggi/Chemistry Today - vol 29 n 1 January/February 2011
Markus Nobis
such as the well known permanganese salts, or chromic acid (6)
– are preferred over ozonolysis due to their ease of
implementation. In addition to being atom inefficient, these salts
pose severe challenge in cGMP applications. For example, in
cosmetic ingredients, residual traces of metal are intolerable and
require complex purification methods (15). Those issues are
overcome by the application of ozone in continuous flow/semibatch
production. The subsequent eco-friendly post-treatment of
the ozonide creates the desired product.
Ozonolysis remains hampered by critical concerns over safety
and technical implementation. Those issues include:
1. The high-energy potential of the ozonides, in the worst
case, leading to explosions.
2. Challenging gas-liquid mass transfer limited process with
high exothermy.
3. Operation of flammable organic solvents in the presence
of air/oxygen. Ozone is up to 15 wt% diluted in these gases
and leads to a very high gas-liquid volume ratio for
stoichiometric operation. Moreover, the manner in which
the flash point of organic solvents is affected by ozone is
difficult to predict. There is also the possible formation of
aerosols during the ozonolysis, which become a challenge
while approaching the endpoint of the conversion.
Despite these concerns, there is a huge safety advantage in
not having to retain oxidant stock since ozone has to be
generated on-site during its application.
SAFE HANDLING OF OZONIDES
Based on decades of experience with chemical process
scale-up (7), Lonza has developed a concrete method for
Figure 1. Ozone in the organic synthesis (5, 8, 9-14).
Industry perspective - Peer reviewed
Dominique M. Roberge

safely evaluating and implementing technical processes. This
includes a Routine Safety Assessment of the process:
• Reaction calorimetric measurements (RC-1) (monitoring
of the whole process, including downstream processing).
• DSC measurements on starting materials, intermediary
compounds and products from the process.
Spectroscopic Methodologies:
• The handling of the primary product from conversion of
ozone with an olefinic substance requires precautions that
are very similar to the handling and processing of peroxides
with regard to the decomposition (E = 200–400kJ/mol).
• UV measurements for the determination of the ozone
consumption (ozone efficiency).
Table 1 shows typical RC-1 results for an ozonolysis reaction and a
following quench reaction. Clearly, the ozonolysis is highly
exothermic with a theoretical adiabatic temperature rise of more
than 386 K However, the mass transfer, fully controls the reaction,
leading to no heat accumulation and a reaction controlled by
the dosage of ozone (Note: the dosage can be interrupted at
any time). On the other hand, the quench reaction is less
exothermic (ΔT ad = 127 K) but a heat accumulation of 100
percent is observed. In case of lost control, it is imperative to
reduce this amount to its maximum possible limit.
Table 1. Typical heat characteristic of an ozonolysis process.
The key to controlling the handling of primary-generated
ozonides is embedding the ozonolysis in the required downstream
processing via a continuous process. Continuous operation
enables one to keep the stock of ozonides to its minimum and to
further process them once generated. In addition, the ozonolysis
should be performed in a confined area. This is accomplished at
Lonza by a dedicated laboratory and a bunker for large-scale
applications since ozone is a toxic gas.
CONTROL OF THE GAS-LIQUID MASS TRANSFER PROCESS
The safe implementation of ozonolysis at technical scale with a
throughput up to 8.5 Kg ozone/hour requires the perfect control of
the gas-liquid mass transfer process. Indeed, this process is
achieved on a small scale by using a gas-liquid loop reactor
integrated with a micro venturi injector. Knowledge of the process
conditions at laboratory scale with a throughput of 50 g ozone/
hour is the key to generating most of the criteria for later handling
at technical scale. The full picture of ozonolysis at laboratory scale
is carried out by applying a highly modular laboratory loop reactor
(150-1000 mL, T: -70 to 40°C) as depicted in Figure 2.
The loop-system consists of 4 main parts:
• Injector for Ozone / residence time module (conversion of
the substrate to the Ozonide)
• Gas/liquid separation / Heat transfer device (separation
of the gas phase from reaction solution)
• Pump (pulsation free)
• Ozone analyzer equipment (balance of the Ozone,
determination of reaction efficiency)
Determining the reaction criteria of an ozonolysis process can be
seen as a package that enables one to show the safe
implementation of the process at technical scale (Figure 3). The
development can be divided into four major parts, which are each
crucial for the safe handling of the process at technical scale.
FLOW CHEMISTRY
Figure 2. Schematic representation of the laboratory reactor.
Figure 3. The implementation scenarios for ozonolysis.
If the ozonolysis part of the process must be studied further,
Lonza is able to implement an additional scale-up step that
allows one to handle the ozonolysis in a kilogramscale.
The unit is an integral scale down of the plant
system, and it integrates the Sulzer SMV TM mixer
elements (Figure 4). These elements are then
combined in a shell-and-tube heat-exchange module
for isothermal operations. These mixing elements have
predictable k l a values (mass transfer coefficient) and
can be scaled-up in a straightforward manner.
The system depicted in Figure 5 is an exact scaled down version
of the final production reactor (scale factor of ca 1:500).
Formation of aerosol and operation with flammable solvents
The operation of ozonolysis in a classic plug flow manner would
lead to a huge imbalance of gas–to–liquid volume, resulting, in the
worst case, to a very critical situation: the dryness of ozonides (i.e.
solvent evaporation). Such operating conditions are only possible
Figure 4. Sulzer SMV static mixer elements for the laboratory from different
perspectives.
Figure 5. Lonza bench-scale unit that is an exact scale down the plant
system.
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with highly diluted reactant feeds that
are not economical viable. To increase
the liquid volume ratio a re-circulation
loop is required. A proper engineered
loop reactor enables excellent
interphase mass transfer via proper
mixing elements under controlled
pressure drop (vide supra). By feeding
substrate in and pulling product out, the loop reactor can be
operated continuously with the principle of a mixed flow reactor.
Surprisingly, under depleted substrate and elevated product
conditions the ozonolysis often remains very selective and overoxidation
is not observed; full continuous operations can be
achieved. If this is not the case, the reactor can also be operated
semi-batch-wise with an appropriate dosage of ozone to control
the reaction. The reaction temperature has to be kept below the
flash point of the solvent. This is a pre-requisite that must be
enforced via technical measures. The gas-liquid reaction zone
must be very efficient to ensure the nearly complete consumption
of ozone because that could influence the flash point of solvents.
Lonza has performed extensive studies with an external safety
institute to understand ozone flash-point variations. This
understanding, coupled with experience and technical knowhow,
is critical to the successful and safe operation of ozonolysis
reactions, which has only been mastered by a few companies.
CONCLUSION
The above-mentioned aspects are essential for the safe
development and scale up of ozonolysis processes. Lonza has
repeatedly proven its ability to meet all these requirements for
successful implementation at technical scale. Moreover, Lonza
provides flexibility and time-savings by starting with pre-developed
processes (also at large scale) based on our experience in scaling
up processes from grams to tons. Lonza has undertaken each step
outlined above for the development of production processes that
have ozonolysis as a core step. For example, below is an ozonolysis
reaction developed for a chrysanthemum acid ester and its
corresponding aldehyde: A continuous process was developed for
the production of an insecticide key intermediate. It uses a 450 L
loop reactor ChimicaOggiAd_5.pdf for the conversion 12/16/2010 10:14:21 of AMthe
chrysanthemic acid with
chimica oggi/Chemistry Today - vol 29 n 1 January/February 2011
Figure 6. Ton-scale example of ozonolysis for the
conversion of chrysanthemic acid.
ACKNOWLEDGEMENT
ozone. During development, scale up
and implementation, the process was
optimized to produce 0.5 t of product
per day in continuous mode. Using on
the newly developed process, Lonza has
been able to manufacture commercial
quantities of the intermediate.
The industrial application of ozonolysis at Lonza was made
possible thanks to a team of talented persons: Tiziano Zaupa,
Anton Zenklusen, Detlef Roederer, and Eberhard Irle.
REFERENCES AND NOTES
1. Hollemann, Wiberg, 101.Aufl., Lehrbuch der anorganischen Chemie,
de Gruyter, Berlin, New York, 514ff (1995).
2. CRC handbook of Chemistry and Physics, pp. 8-23, 87Ed. CRC
press, Boca Raton (2006).
3. Abwasserreinigung durch Ozon. Verfahrensberichte zur physikalischchemischen
Behandlung von Abwässern. 8. Bericht. Frankfurt: Verband
der Chemischen Industrie (1978).
4. Ozon in der Wasseraufbereitung; Begriffe Reaktionen,
Anwendungsmöglichkeiten. Technische Mitteilung. Merkblatt W
225. DVGW Regelwerk.
5. R.T. Morrison, R.N. Boyd, Lehrbuch der organischen Chemie. 3.
Aufl. Weinheim u.a.: Verl. Chemie, S. 436 ff (1986).
6. Organikum, Verlag VEB, 16. Aufl., 346f (1986).
7. D.M. Roberge, M. Gottsponer et al., Chem. Today, 27, pp. 8-11
(2009).
8. L. Bailey, Ozonation in Organic Chemisty, Academic Press, New
York (1978).
9. B. Souza, J.Org. Chem., 25, p. 108 (1960).
10. M. Diaper, Can. J. Chem., 38, p. 1976 (1960).
11. L. Bailey, J. Am. Chem. Soc., 89, p. 4473 (1967).
12. S.L. Regen, C. Koteel, J. Am. Chem. Soc., 99, pp. 3837-3838 (1977).
13. E.v. Rudloff, Can. J. Chem., 43, pp. 1784-1791 (1965).
14. Fieser & Fieser, Reagents for Organic Syntheses, 1, John Wiley &
Sons, pp. 809-819 (1967).
15. W. Petersen, J. Jaenichen et al., Verfahren zur Herstellung von
4--Methoxybenzoesäure aus pflanzlichem Anethol und dessen
Verwendung in kosmetischen oder dermatologischen Produkten
sowie Lebensmitteln, EP 2 060 556 A1 (2007).
Center for Process Analytical Chemistry
Rome Workshop
March 21-24, 2011
www.cpac.washington.edu
The Center for Process Analytical Chemistry (CPAC) Rome Workshop is an annual forum to present
and discuss advances in continuous unit operations and measurement sciences linked to improved
process control incorporating Quality by Design (QbD) approaches.
The workshop will be held in Rome, Italy to bring together a group of international scientists and
engineers of similar expertise for presentations and discussions in the areas of
Micro-Instrumentation, Process Intensi�cation and new technical advances in Chemical and
Biological Processes, including emerging applications for NeSSI (New Sampling/Sensor Initiative).