Continuous-Flow Production of Alkyl Nitrites, Originally Designed by BIOS Chemicals

FLOW CHEMISTRY Industry Perspective ● Peer reviewed

Jean-Christophe M. Continuous-flow production Monbaliu of alkyl nitrites

JEAN-CHRISTOPHE M. MONBALIU1*, JEREMY JORDA2, BÉRENGÈRE CHEVALIER2, CHRISTIAN V. STEVENS1, BERNARD MORVAN3

*Corresponding author 1. Ghent University, SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Coupure links 653, Gent, B-9000, Belgium 2. CORNING S.A.S, Corning European Technology Center, Avenue de Valvins 7 bis, Avon, F-77210, France 3. BIOS Chemicals, Plateforme technologique DELTA Sud, Verniolle, F- 09340, France

the oxidation of olefins (6f, 7c). Recent publications reported ABSTRACT their use for the production of diazonium intermediates in the Alkyl nitrites are important building blocks for the chemical continuous production of synthesis of azo dyes (6c). and pharmaceutical industries. In this article, we report a case study for the continuous-flow production of alkyl nitrites, originally designed by BIOS Chemicals. The PREPARATION OF ALKYL NITRITES intrinsic advantages of a Corning® Advanced-Flow™ reactor system, including high versatility, high mixing, and Numerous methods have been developed at the lab scale heat-exchange efficiency under corrosive conditions, for preparing alkyl nitrites from alcohols: esterification with allowed the development of an economically viable and nitrous acid; transesterification from tert-butyl nitrite (8a) or from user-friendly process in a short period of time, leading to N-nitrosoamines (8b); and nitrosation with various nitrosating a throughput of 10t/year of processed material with high agents such as nitrosyl chloride (8c). Thiols and trimethylsilyl ethers purity (93-98 percent). can also be transformed in the corresponding nitrites (8d). Industrial processes can be divided into two categories: (a) 50 liquid phase processes and (b) vapour phase processes. Among liquid phase processes, alkyl nitrites are produced by ALKYL NITRITES: AN OVERVIEW OF THEIR APPLICATIONS reacting alcohols with nitrous acid in water or with different nitrogen oxides (NO, NO2, N2O4 and N2O3), eventually in rganic nitrites (RONO) are the esters of nitrous acid the presence of nitric acid or oxygen (9). These processes are generally characterized by laborious extraction of (HNO2). In particular, alkyl nitrites have been used for therapeutic applications for over a century. Amyl the processed alkyl nitrites and prolonged reaction times, O leading to undesired oxidation by-products. A distillation nitrite was used for treating angina pectoris by L. Burton in 1867 (1). RONO have remained over the years prominent step is generally required for further purification, increasing therapeutics (2) since they belong to a main class of nitrogen the industrial hazard and cost. The vapour process consists in oxide (NO) donors (3). Alkyl nitrites are also used in part for vaporizing an alcohol and NO2/NO in the presence of water. the treatment against poisoning with cyanhydric or sulfhydric These processes are characterized by very short contact times acid (4). However, chronic exposure to aliphatic nitrous esters between the chemicals (1-10s) at elevated temperatures has been reported to cause hypoxic condition in vital organs (>100°C) (10). The reported processes used counter flow, batch (5). or trickle bed reactors (11). These processes are generally In addition to their physiological use, alkyl nitrites have also reported as being strongly exothermic (12). been included as useful reagents for organic synthesis at the lab-scale. They are powerful agents for the nitrosation of a wide range of functional groups (6a), for reductive deamination of OBJECTIVES & CHEMISTRY aromatic derivatives (6b) and for the preparation of diazonium compounds (6c). The Barton reaction, i.e. the photocatalytic This work is aimed at the development of an economically cleavage of nitrous esters, has been extensively studied, even viable industrial process for the continuous production of under flow conditions (6d). Alkyl nitrites have also shown utility alkyl nitrites from commercially available alcohols under in azido peptide synthesis (6e) and are efficient reoxidizing flow conditions, with the final objective of processing 10 tons agents in catalytic Pd-based processes (6f). a year. The esterification of alcohols with nitrous acid is a Organic nitrites are also important industrial intermediates. rather straightforward reaction in liquid phase (Scheme 1). The Ube process (7a) is a striking example of their industrial Free nitrous acid is highly unstable and decomposes rapidly. potential: this oxidative carbonylation converts alkyl nitrites HONO has a higher stability in an aqueous media, while and carbon monoxide into dialkyloxalates, which are concentrated solutions are also unstable, leading to the useful intermediates as an alternative entry (non-petroleum formation of nitrogen oxides, essentially NO and NO2. dependent) to ethylene glycol. Accordingly, the best way to carry out this reaction is to Dialkylcarbonates were also prepared from lower RONO, generate in situ nitrous acid in the presence of an alcohol, at low temperatures. Nitrous acid is generated in solution by the carbon monoxide and a PdCl2-CuCl2 catalyst (7b). Alkyl nitrites Wacker-type reactions were successfully developed for reaction of a strong mineral acid and an alkyl nitrite.

chimica oggi/Chemistry Today - vol. 29 n. 3 May/June 2011 FLOW CHEMISTRY

In this project, hydrochloric acid (HCl) was selected to avoid Flow reactors are especially advantageous for industrial any oxidation of the parent alcohol, while working with HCl applications, as demonstrated by the increasing number of reports precluded the use of any metal part in contact with the flow in that area (13). Most notably, they offer easy scalability (scale- of chemicals. Sodium nitrite was selected as an appropriate out and numbering-up, Figure 1), adaptability to market demand source of nitrous acid. Additionally, the generation of sodium and particularly short transitions between R&D and production. chloride as a side product was found to offer a convenient In this case, the reactor equipment has been engineered and and efficient salting out procedure, allowing easy separation manufactured by Corning. The Corning® Advanced-Flow™ of the nitrous esters. reactors are made of glass fluidic modules (FMs) assembled with Beyond safety issues, efficient temperature control was critical appropriate connectors, tubing and support frames (Figure 2). to the salt solubility.

Scheme 1. Esterification of alcohols with nitrous acid.

FLOW REACTOR & PROCESS DESIGN

To prepare nitrous esters in high yield within short residence time, an efficient mass transfer and close control of reaction temperature are paramount to avoid a reckless run due to the Figure 1. An example (left) of scale-out: from Gen1 to Gen3 fluidic modules, the total processed throughput ranges from 10 to 200 kg/h. high exothermicity. After review of state-of-the-art techniques, An example (right) of numbering-up: several identical reactors it became obvious that flow reactors can contribute to the operated in parallel (production bank) give through as well. In all development of an efficient and versatile industrial process for the situations, identical performances in terms of heat exchange and preparation of nitrous esters of commercial interest. mixing efficiency are conserved.

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GEN1 reactor) with a minimum cooling of the reactor (18°C), while working under safe and environmental- friendly conditions. This provided an additional breakthrough by comparison with a classical batch process. Figure 2. Flow chart for the flow production of alkyl nitrites from alcohols. Feed A & B are aqueous solutions. The optimal control Pumps, valves, pressure and temperature sensors and auxiliaries have been omitted for clarity. of the operating parameters and the local stoichiometry In the illustrated project, FMs are GenI-type fluidic modules allowed the development of an atom-efficient process with (Figure 1). They can manage several unit operations such as minimal waste effluents. feeding, premixing, preheating, reagent mixing and provide different residence times depending on their relative position in the reactor, the number of inlets, and their internal design. ACKNOWLEDGMENTS Each FM is integrated with heat transfer, allowing a precise temperature control (Figure 2) along the whole reactor Jean-Christophe M. Monbaliu is Postdoctoral Fellow of the path. FM01&02 are used as pre-cooling and FM 03&04 are Research Foundation Flanders (FWO-Vlaanderen). integrated with highly efficient static mixing zones ensuring high mass transfer via a continuous mixing along the reaction path for residence time. REFERENCES AND NOTES The outlet of the reactor was connected to a continuous liquid-liquid decantation apparatus. The organic layer, 1. T.L. Brunton, Lancet, 2, pp. 97-98 (2009). essentially pure alkyl nitrite, was collected in a tank at -5°C 2. A.C. Nicolescu, J.N. Reynolds et al., Chem. Res. Toxicol., 17, pp. 185- and further washed in batch with saturated aqueous sodium 196 (2004). carbonate and brine. 3. B. Clement, J. Boucher et al., Biochem. Pharmacol., 58, pp. 439-445 The mother liquor, essentially containing the excess of (1999). 52 unreacted nitrous acid, was neutralized in a separate tank 4. T.J. Haley, J. Toxicol. Clin. Toxicol., 16, pp. 317-329 (1980). containing aqueous urea (14). Careful optimization was 5. S.M. Bradberry, R.M. Whittington et al., J. Toxicol. Clin. Toxicol., 32, carried out. In an example run, isopropanol was converted pp. 179-184 (1994). into its corresponding nitrite. Sodium nitrite and hydrochloric 6. a) For example: B. Akhlaghinia, E. Roohi, Lett. Org. Chem., 3, pp. acid were used in slight excess (1.03 and 1.05 equivalents, 220-224 (2006); b) For example: M.W. Pelter, L.S.W. Peler et al., J. respectively). Chem. Educ., 81, pp. 111-112 (2004); c) R. Fortt, R.C.R. Wootton, Optimal reaction conditions were achieved within few days A.J. de Mello, Org. Process Res. Dev., 7, pp. 762-768 (2003); d) A. and required a temperature of 18°C, instead of maximum Sugimoto, Y. Sumino et al., Tetrahedron Lett., 47, pp. 6197-6200 5°C mentioned in the literature. The steady-state was (2006); e) M. Joullié, K.M. Lassen, ARKIVOC, 8, pp.189-250 (2010); f) reached after 15 minutes. At the maximum flow rates tested S. Uchiumi, K. Ataka et al., J. Organomet. Chem., 576, pp. 279-289 (~200 mL/min), it was possible to decrease the reaction time (1999). down to 4.8 s. After downstream processing and washing 7. a) K. Nishimura, S. Uchiumi et al., Jpn. Kokai Tokkyo Koho JP 54- step, isopropyl nitrite was obtained in a purity of >98 percent 41813, 54-100312 (1979), US Patent 4229589, 4229591, Chem. Abstr., (HPLC) and the global conversion was >99 percent (90 91, p. 4958 (1979); b) N. Manada, K. Abe et al., Nippon Kagaku percent for batch process). Kaishi, 667 (1994), Chem. Abstr., 11, p. 204820 (1999); c) K. Nishimura, The reactor was operated continuously for 24 h with a high K. Mizutare et al., Jpn. Kokai Tokkyo Koho 03-14143, 04-089458, homogeneity of the production. In these conditions, a GEN1 Chem. Abstr., 115, p. 8100 (1991). reactor allows processing up to 10t/y total throughput. 8. a) M.P. Doyle, J.W. Terpstra et al., J. Org. Chem., 48, pp. 3379-338 Similar conditions were then used for the production of (1983); b) L. Garcia-Rio, J.R. Leis et al., Eur. J. Org. Chem., pp. 614- isobutyl nitrite which was obtained in 93 percent purity after 622 (2004); c) Williams, D.L. . Nitrosation, Cambridge University washing step. Press: Cambridge, pp. 150-172 (1988) and references cited therein; d) B. Akhlaghinia, E. Roohi, Lett. Org. Chem., 3, pp. 220-224 (2006). 9. For example: A.R., Doumaux, J.R. Nelson, US 2166698 (1987). CONCLUSION 10. See for example: A.R. Doumaux, M. Downey et al., US 4 353843 (1981). In conclusion, we have developed an economically viable 11. H. Wang, G. Li, Chem. Eng. J., 163, pp. 422-428 (2010). flow process for the production of alkyl nitrites. Our flow 12. See for example: K. Nishihira, S. Tanaka, EP 0911316 (2004). process allows the continuous manufacturing of alkyl nitrites 13. a) P. Watts, C. Wiles, Chim. Oggi-Chem. Today, 28, pp. 3-5 (2010); b) in high purity within very short reaction times (5s) regarding J.-C. Monbaliu, M. Winter et al., Chim. Oggi-Chem. Today, 28, pp. actual patented processes (e.g. the BASF process, patented 4-45 (2010); c) B. Chevalier, E.D. Lavric et al., Chim. Oggi-Chem. in 2008, claimed a reaction time of 40-60 min under flow Today, 26, pp. 1-4 (2008). conditions for the same conversion) (15). 14. A. Lasalle, C. Roizard et al., Ind. Eng. Chem. Res., 31, pp. 777-780 The highly efficient heat exchanger allows reaching large (1992). scale production of alkyl nitrites (10T/year process with 15. S. Kudis, R. Lochtman et al., US 7 314 948 (2008).

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