Industry perspective - Peer reviewed

FLOW CHEMISTRY

Markus Nobis

Dominique M. Roberge

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).

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

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

Figure 1. Ozone in the organic synthesis (5, 8, 9-14).

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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 = 200400kJ/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 (Tad = 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.

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 kla 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 gastoliquid 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

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 40C) 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.

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. chimica oggi/Chemistry Today - vol 29 n 1 January/February 2011

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with highly diluted reactant feeds that ozone. During development, scale up are not economical viable. To increase and implementation, the process was the liquid volume ratio a re-circulation optimized to produce 0.5 t of product loop is required. A proper engineered per day in continuous mode. Using on loop reactor enables excellent the newly developed process, Lonza has interphase mass transfer via proper been able to manufacture commercial Figure 6. Ton-scale example of ozonolysis for the mixing elements under controlled conversion of chrysanthemic acid. quantities of the intermediate. pressure drop (vide supra). By feeding substrate in and pulling product out, the loop reactor can be ACKNOWLEDGEMENT operated continuously with the principle of a mixed flow reactor. Surprisingly, under depleted substrate and elevated product The industrial application of ozonolysis at Lonza was made conditions the ozonolysis often remains very selective and overpossible thanks to a team of talented persons: Tiziano Zaupa, oxidation is not observed; full continuous operations can be Anton Zenklusen, Detlef Roederer, and Eberhard Irle. achieved. If this is not the case, the reactor can also be operated semi-batch-wise with an appropriate dosage of ozone to control REFERENCES AND NOTES the reaction. The reaction temperature has to be kept below the flash point of the solvent. This is a pre-requisite that must be 1. Hollemann, Wiberg, 101.Aufl., Lehrbuch der anorganischen Chemie, enforced via technical measures. The gas-liquid reaction zone de Gruyter, Berlin, New York, 514ff (1995). must be very efficient to ensure the nearly complete consumption 2. CRC handbook of Chemistry and Physics, pp. 8-23, 87Ed. CRC of ozone because that could influence the flash point of solvents. press, Boca Raton (2006). Lonza has performed extensive studies with an external safety 3. Abwasserreinigung durch Ozon. Verfahrensberichte zur physikalischinstitute to understand ozone flash-point variations. This chemischen Behandlung von Abwssern. 8. Bericht. Frankfurt: Verband der Chemischen Industrie (1978). understanding, coupled with experience and technical know4. Ozon in der Wasseraufbereitung; Begriffe Reaktionen, how, is critical to the successful and safe operation of ozonolysis Anwendungsmglichkeiten. Technische Mitteilung. Merkblatt W reactions, which has only been mastered by a few companies.
5. 225. DVGW Regelwerk. R.T. Morrison, R.N. Boyd, Lehrbuch der organischen Chemie. 3. Aufl. Weinheim u.a.: Verl. Chemie, S. 436 ff (1986). Organikum, Verlag VEB, 16. Aufl., 346f (1986). D.M. Roberge, M. Gottsponer et al., Chem. Today, 27, pp. 8-11 (2009). L. Bailey, Ozonation in Organic Chemisty, Academic Press, New York (1978). B. Souza, J.Org. Chem., 25, p. 108 (1960). M. Diaper, Can. J. Chem., 38, p. 1976 (1960). L. Bailey, J. Am. Chem. Soc., 89, p. 4473 (1967). S.L. Regen, C. Koteel, J. Am. Chem. Soc., 99, pp. 3837-3838 (1977). E.v. Rudloff, Can. J. Chem., 43, pp. 1784-1791 (1965). Fieser & Fieser, Reagents for Organic Syntheses, 1, John Wiley & Sons, pp. 809-819 (1967). W. Petersen, J. Jaenichen et al., Verfahren zur Herstellung von 4--Methoxybenzoesure aus pflanzlichem Anethol und dessen Verwendung in kosmetischen oder dermatologischen Produkten sowie Lebensmitteln, EP 2 060 556 A1 (2007).

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 for the conversion of the chrysanthemic acid with ChimicaOggiAd_5.pdf 12/16/2010 10:14:21 AM

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Center for Process Analytical Chemistry

Rome Workshop

March 21-24, 2011

www.cpac.washington.edu

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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).

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