FLOW CHEMISTRY Industry perspective

Continuous processes - sustainable manufacturing

JÖRG SCHRICKEL CABB AG, Düngerstrasse 81, 4133, Pratteln, Switzerland

remains small enough to control the reaction. Then, reactions can be KEYWORDS performed in a faster, safer and more selective way, with a reduction Sustainability; sustainable chlorination; continuous of materials and energy compared to batch reactions. In addition, processes; continuous chlorination; Verbund and recycling many chemical reactions are only possible in a continuous process system; Wolff-Kishner reduction. when side products are continuously removed and not available for side reactions or decompositions. It is no surprise that continuous processes are the number 1 topic in the pharmaceutical industry ABSTRACT where quality, safety and economics are the driving factors of development (2). In terms of sustainability or green chemistry (3) the Continuous processes are considered to support most important aspects for continuous reactions are lower energy sustainability in many ways. In general, continuous consumption, less waste production, less consumption of solvents processes require less energy, less materials and less and auxiliaries, safer processes and less exposure of chemicals (4), solvents. The heat exchange is better than in batch which is a benefi t for plant staff and the environment. Chlorinations reactions and therefore reactions can run in a more and sulfonations are generally not considered as sustainable precise and steady manner which may improve yield 22 reactions. This is due to the hazardous nature of the reagents which and selectivity: whereas batch processes involve a are used and often the chlorinated or sulfonated product represents continuous variation of temperature, pressure and other a hazard too. More importantly, in many of these reactions, large parameters. In addition, the smaller reaction volumes, volumes of waste are generated. compared to batch processes, can be conducted in Publications about “green” or sustainable chlorination methods a safer way and some processes are only possible as are rather scarce in literature and are rarely effi cient methods (5). continuous processes. In this article, different continuous Halogenated molecules are highly reactive but rarely natural, so processes are presented which support sustainability and that additional steps and transformations are necessary to produce which are based mostly on conventional multi-purpose the precursor. If this can be circumvented by other technologies, equipment. Examples are given for sustainable processes no halogenated precursors have to be used and no halogenated with a complete continuous production process from raw waste by-product is generated (6). On the other hand, chlorination material uptake until fi nal distilled product described. reactions in particular, often allow a shortcut in the synthesis and help to avoid the generation of waste. The reasons why chlorination and sulfonation reactions can be carried out in a much more sustainable INTRODUCTION way, is displayed in Figure 1. Specifi c technical requirements are necessary, which are given by CABB’s Verbund and recycling he term “fl ow chemistry” or “continuous fl ow chemistry” - system. At CABB, and trioxide are produced on-site although not limited in general to a certain volume - is usually and reagents like thionyl , sulfuryl chloride, chlorosulfonic Tassociated with microreactor technology and refers to acid and other chlorination and sulfonation reagents are relatively small volumes in continuous fl ow reactions. The principle manufactured from them and are either captively used or sold to benefi ts of microreactor technology are: the possibility to perform merchant markets. These reagents are used for further downstream critical reactions in a safe way, the ease of scalability from lab manufacturing of intermediates, Advanced Intermediates and up to commercial volumes and the possibility of using several Actives and thus form a vertical, integrated production system. In microreactors in parallel in order to obtain more product in a shorter most of these downstream manufacturing processes the off-gases

time. Characteristics of microreactor chemistry are: the excellent HCl and SO2 are generated. In the Verbund and recycling system heat exchange; the closed system; the possibility to pressurise the the off-gases are separated, purifi ed and completely recycled: in the microreactor and the easy automation. This leads to effi cient and case of it is fed back into the sulfur oxidation process

reproducible mixing and very precise reaction control. Reactions and is converted into SO3. The gas is absorbed in microreactors therefore are often cleaner with better yields and in water and concentrated and sold as high quality commercial less by-products compared to batch reactions (1). However there hydrochloric acid. No waste is generated. In conventional systems, are limitations of microreactor technology when using multi-phase without this specifi c recycling system, caustic scrubbers are used systems, e.g. suspensions. to absorb these off-gases to form aqueous, salt containing waste Most of the benefi ts apply to continuous processes in general - water. And this is usually where large amounts of waste are formed independent from the reactor size, as long as the critical reactor size and which make the process not sustainable - regardless of the

Chimica Oggi - Chemistry Today - vol. 31(3) May/June 2013 FLOW CHEMISTRY

Figure 2. Comparison of a batch and a continuous chlorination of a carboxylic acid with . Figure 1. The CABB Verbund and recycling system: a vertical, integrated production system with off-gas recycling can be measured by the following metrics (figure 4): fact that handling with hazardous substances is necessary. Due the PMI and the E-factor. to availability, handling and transportability most of chlorination The PMI is the Process Mass reactions are carried out with thionyl chloride or sulfuryl chloride, Intensity and defined as and to a lesser extend chlorosulfonic acid in the case of sulfonyl the ratio of the amount of . The chlorinated intermediates are then often converted incoming materials including Table 1. Demand of energy and into corresponding amides or sulfonamides especially within the solvents and water by the cooling water for a batch and pharmaceutical or agrochemical applications (7). Chlorination with amount of product which a continuous chlorination of a the above mentioned reagents creates large amounts of waste is formed. A PMI of “1” carboxylic acid. and - in addition - is based on hazardous reagents. Alternative would be for most chemical amide formation routes without the use of hazardous reagents reactions a good result. The are, however, even less economical as they generate even larger Environmental factor is the quotient of the amount of waste which is quantities of waste (8). formed by the amount of product which is formed (9).

CASE STUDY: BATCH AND CONTINUOUS CHLORINATION 23 The case study (Figure 2) shows the chlorination reaction of a carboxylic acid with thionyl chloride as it was carried out at commercial scale at CABB. The conventional reaction was carried out as a batch process (left) in a stirred reactor. This was compared with a continuous process (right) based on identical production volumes in a loop reactor. To simplify matters, the removal of the off-gases is not considered at this point, only the reaction part to compare the efficiency of the batch with the continuous process. The continuous chlorination reaction of a specific carboxylic acid is carried out in a loop reactor without solvent and with only a slight excess of thionyl chloride, calculated on the substrate. The amount of energies and cooling water for both processes are measured from consumption and the required resources of the continuous process are set as reference with all values at a 100% level (Table 1). A comparison of the required energies and cooling water shows a clear advantage for the continuous process: electricity, steam and cooling water are required in much less quantity compared to the batch process. In particular the temperature control of the batch reaction requires much more cooling and heating than the steady-state conditions of the continuous process. Hitherto the removal of the off-gases was not considered. In order to change only one parameter, the next comparison is based on the scrubber capacity of the batch process, taking into consideration that the continuous process is much more efficient. The same reaction as above is carried out in the multipurpose batch equipment with the conventional removal of the off-gases by a caustic scrubber system and, in comparison, by the Verbund and recycling system at CABB (Figure 3). The conventional way to dispose of the off-gases of the chlorination reaction, is the absorption in caustic soda, with the result, that large amounts of salt containing waste water is generated. In contrast, the Verbund and recycling system enables a complete recycling of SO2 and to completely convert the HCl into commercial hydrochloric acid (see also figure 1). The “greenness” of processes

Chimica Oggi - Chemistry Today - vol. 31(3) May/June 2013 FLOW CHEMISTRY

Here, a number close to “0” would be the desired target. As shown equipment which is used. It is then not the type of chemical reaction in table 2, the scrubber process needs more energy than the off- any more but the technical process description which leads to the gas removal in the Verbund and recycling system. In addition, a design of a process. In this way, the process for the Wolff-Kishner lot of caustic soda is necessary to absorb the hydrogen chloride reaction - depicted below - was developed, which represents a gas and the sulfur dioxide which are formed during the chlorination completely different kind of chemistry compared to the usually process and large volumes of waste water are formed containing applied core chemistries at CABB. salt load. In contrast, no caustic is needed and no waste water is generated in the Verbund and recycling system. The PMI, calculated from the used materials and obtained products, clearly CASE STUDY: CONTINUOUS WOLFF-KISHNER shows a three times higher value for the scrubber process than for REDUCTION the Verbund system which reflects the large volume of caustic soda which is needed for the scrubber absorption. The E-factor - as an The Wolff-Kishner reduction (figure 6) is a chemical method to indicator for the waste formation - shows an even larger difference reduce ketones and aldehydes to the corresponding . In between the two processes. As the sulfur dioxide is completely contrast to other reduction reactions, the alkanes are obtained in a recycled and the hydrochloric acid is a sales product, they are not regarded as waste and the E-factor is close to zero. In contrast, the salt containing waste water from the scrubber process has to be treated as waste and leads to a significantly higher E-factor (approx. 100 times higher).

CASE STUDY: CONTINUOUS CHLORINATION

The optimum efficiency can be obtained, if a set of independent continuous standard unit operations for different process steps is available, which can be combined in multi-purpose equipment for the manufacturing of different products. In an ideal way, a process may be designed as subsequent continuous processes - without Figure 3. Off-gas removal after thionyl chloride reaction by conventional bottlenecks - from raw material uptake up to the storage tank scrubber and by the Verbund and recycling system. of the final product. Figure 5 shows an example of a complete continuous process in multi-purpose (chlorination reaction and work-up on the right hand side) and dedicated equipment (off- gas removal and waste water oxidation on the left hand side). As an example it shows the chlorination reaction of a substrate with 24 thionyl chloride as chlorination reagent in subsequent standard unit operations as it is carried out at CABB. One additional argument for a continuous process is the possibility to remove reactants out of the reaction mixture, which in many cases helps to prevent the formation of by-products (10). In the case of chlorination reactions the formation of hydrogen chloride gas as a by-product may react Figure 4. Two metrics to determine the greenness of a chemical process. with sensitive substrates, like unsaturated molecules. In conventional batch reactions, the addition of a scavenger - often amines - is necessary and leads to the formation of amine hydrochloride salts, which cannot react any further with the substrate. In terms of sustainability this has however a negative impact on the PMI and E-factor values, as it needs additional products and leads to more waste water formation. In a continuous process, the gas can be removed from the reaction mixture without addition of a scavenger and any side reaction can be suppressed. During the chlorination reaction with thionyl chloride in slight excess in a loop reactor, the

formed off-gases HCl and SO2 are continuously removed, separated and purified and further processed (see also figure 1). After a given residence time the crude product is removed from the reaction mixture and fed into further continuous device for work-up. Resulting waste water is also processed in a dedicated plant. The crude product is then continuously distilled and stored as pure end product in storage tanks. From the dosage of the reactants to the final distilled product all process steps including off-gas recycling and waste water purification run in a continuous and sustainable way without any bottlenecks. The whole process can be separated into continuous

standard unit operations. Every Table 2. Comparison of different Figure 5. Complete continuous production process of single operation step can be defined methods of off-gas removal. continuous standard unit operations. for a type of reaction and the

Chimica Oggi - Chemistry Today - vol. 31(3) May/June 2013 of batch processes, product quality and yield are often superior in continuous processes. Chlorination reactions using thionyl chloride as reagent can be performed on a large commercial scale in a continuous way, saving energy and cooling water. If it can be Figure 6. Wolff-Kishner reduction of triacetone amine to combined with a recycling system, in which the off-gases HCl and tetramethylpiperidine SO2 are recycled and converted into commercial products, then the resulting waste formation can be reduced to a minimum, converting even chlorinations into almost sustainable processes. direct and selective way without the use of metal catalysts. Based The most efficient process is obtained when continuous standard on the knowledge of continuous processes CABB has constructed unit operations can be combined over the whole production a plant which is dedicated for Wolff-Kishner reductions. The biggest process, to build up a consistent process with maximum efficiency challenge for a commercial production is the fact that hydrazine is and without bottlenecks. This requires the sound understanding of used as a reagent and that large volumes of nitrogen are formed. the standard unit operations and if so, manufacturing problems In the lab or in small scale production like in microreactors this does of completely different chemistries can be solved, e.g. the Wolff- not create too many problems but in the commercial production Kishner reaction. where batch processes are used, some serious safety issues arise. Apart from more efficient production, continuous processes are mainly safer than batch processes. In the case of the Wolff-Kishner REFERENCES reduction, large volumes of nitrogen gas evolve during the reaction. In a batch process this can happen in a spontaneous way once the 1. Drobot M., Chemical Engineering World 46(12), 86-90 (2011) temperature is sufficient to trigger the reaction. As a consequence, 2. Jimenez-Gonzalez C., Poechlauer P., et al., Org. Process Res. Dev., the reaction cannot be controlled any more. In the case of the 15, 900-911 (2011) continuous process the reaction volumes can be kept small and, in 3. Anastas P.T., Warner J.C.: Principles of Green Chemistry, Chapter addition, the amount of intermediate, which releases the nitrogen 4, in Green Chemistry: Theory and Practice, Oxford University Press: gas, is small per time unit. The volume of nitrogen, which evolves New York (1998). continuously, is low and can be controlled and removed by 4. Sheldon R.A., Green Chemistry 7(5), 267-278 (2005) convection via the venting system in a safe way. 5. Smith K., Butters M., et al., Green Chemistry, 1(2), 83-90 (1999) 6. Anastas P., Eghbali N.,Chem. Soc. Rev., 39(1), 301-312 (2010), 7. Carey J.S., Laffan D., et al., Org. Biomol. Chem. 4, 2337-2347 (2006) 8. Constable D.J.C., Dunn P.J., et al., Green Chem., 9, 411-420 (2007) CONCLUSION 9. Sheldon R.: Introduction to green Chemistry, Organic Synthesis and Pharmaceuticals, Chapter 1, in: Green Chemistry in the Continuous processes are regarded as more sustainable than Pharmaceutical Industry, Edited by Dunn, P.J., Wells, A.S., Williams, batch processes for the generally lower demand for energy and M.T., Wiley-VCH Verlag Chemie GmbH & Co KGaA, Weinheim (2010) materials and also lower formation of waste. In addition, due to 10. Murzin D.Y., Leino R., Chemical Engineering, Research and Design, the steady state compared to the alternating parameter changes 86, 1002-1010 (2008).