Synthetic toolbox: Flow chemistry

CHEM21 Case Study: Formation of N-chloramines in flow

This case study was provided by Dr Katherine Jolley during her time at the University of Leeds.

Amines, amides and nitrogen heterocycles are an important class of compounds being one of the most common structures present within pharmaceutical and biologically active compounds and are present in most of the top selling drugs e.g. Aripiprazole for the treatment of depression, Imatinib for the treatment of cancers and Telaprevir for the treatment of Hepatitis C.

The use of N-chloramines as reagents offers a convenient and atom efficient route to formation of key nitrogen functionalities including amines, amides and imines, however due to the hazards associated with the formation and reaction of chloramines[1][2] they are an underutilised class of reagents.

N-Chloramines are prepared by reaction of the amine precursor with an electrophilic chlorine source such as chlorine, N-chlorosuccinimide (NCS) or hypochlorite salts. Due to the exothermicity of N-chloramine formation and the instability of the products formed the reactions often require cooling or controlled addition of reagents.[2]  Despite its atom efficiency, use of chlorine gas is undesirable due to its toxicity, strong oxidising properties and it being difficult to handle and use. In addition, hydrochloric acid is produced as a byproduct of the reaction meaning additional processing is required for its neutralisation and removal after chloramine formation. NCS is frequently used for chloramine formation,[2][3][4] however the reaction is atom inefficient and removal of the succinimide by-product is required. Use of hypochlorites as chlorinating reagents is also common, although tBuOCl is an expensive and hazardous reagent and is thus less widely used. Recent reports of its formation in-situ to avoid the hazards associated with its use are inefficient with high levels of waste generated.[5] NaOCl is a more desirable reagent, being an inexpensive by-product of chlorine manufacture, however in some reports use of NaOCl in chloramine formation has  given low yields and can require long reaction times.[2][6][7]

Given the importance of amines and amides, the development of alternative, safer or more sustainable routes to their synthesis is a key field of research. Within the CHEM21 project, researchers have developed a continuous, biphasic process for formation of N-chloro-N,N-dialkylamines by reaction of amines with aqueous NaOCl with enhanced mixing by use of in-line static mixers.[8] Use of continuous flow methodology is beneficial to the reaction allowing:

  • Precise control of reaction parameters e.g. reaction time/temperature;
  • Improved heat transfer properties removing the need for external cooling of the reaction/reactor;
  • Limited volume of reagents reacting at any one time;
  • Increased productivity and consistency of product formation.

Use of NaOCl as the chlorinating agent is both economical and convenient and allows for a more atom efficient reaction than use of NCS or in-situ formation of tBuOCl. Use of biphasic reaction conditions also allows for facile separation of the product within the organic solvent from the water soluble NaOH by-product. Continuous phase separation by way of membrane separators is well known in the literature.[9]

Scheme 1: Comparison of CHEM21 continuous synthesis of chloramines[8] with previously published procedures.[5][10]

The methodology described allows safe and convenient formation of a range of N-chloro-N,N-dialkylamines without the need for purification or isolation of potentially hazardous or unstable products giving safe and efficient access to an underutilised class of reagents. The reactors used for the process are comprised of widely available generic equipment making the methodology accessible to all. Continuous separation of clean product solution from the reaction mixture also means that the process can easily be coupled to further processes for direct use of the chloramine products formed in subsequent reactions. The continuous reaction of chloramines to form more complex amine or amide products has also been investigated within the scope of this project and will be reported in due course.

  1. P. G. Urben, Bretherick's Handbook of Reactive Chemical Hazards, Academic Press (Elsevier), 7th edn., 2006.
  2. Science of Synthesis - Houben-Weyl Methods of Molecular Transformations: Compounds with one saturated carbon-heteroatom bond, (ed. D. Enders and E. Schaumann) vol. 40b, Thieme, Stuuttgart, 2008.
  3. G. Heuger, S. Kalsow and R. Göttlich, Copper(I) Catalysts for the Stereoselective Addition of N-Chloroamines to Double Bonds: A Diastereoselective Radical Cyclisation, European Journal of Organic Chemistry, 2002, 2002, 1848-1854.
  4. T. J. Barker and E. R. Jarvo, Umpolung Amination: Nickel-Catalyzed Coupling Reactions of N,N-Dialkyl-N-chloroamines with Diorganozinc Reagents, Journal of the American Chemical Society, 2009, 131, 15598-15599.
  5. Y. - L. Zhong, H. Zhou, D. R. Gauthier, J. Lee, D. Askin, U. H. Dolling and R. P. Volante, Practical and efficient synthesis of N-halo compounds, Tetrahedron Letters, 2005, 46, 1099-1101.
  6. S. J. Padegimas and P. Kovacic, Adamantanes and related compounds. V. endo-7-Aminomethylbicyclo[3.3.1]nonan-3-ones from rearrangement of 1-N-substituted N-haloadamantanamines by aluminum chloride, The Journal of Organic Chemistry, 1972, 37, 2672-2676.
  7. D. J. Pedder, H. M. Fales, T. Jaouni, M. Blum, J. MacConnell and R. M. Crewe, Constituents of the venom of a south african fire ant (solenopsis punctaticeps), Tetrahedron, 1976, 32, 2275-2279.
  8. A. J. Blacker and K. E. Jolley, Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso-scale flow reactors, Beilstein J. Org. Chem., 2015, 11, 2408–2417.
  9. A. Adamo, P. L. Heider, N. Weeranoppanant and K. F. Jensen, Membrane-Based, Liquid–Liquid Separator with Integrated Pressure Control, Industrial & Engineering Chemistry Research, 2013, 52, 10802-10808.
  10. J. Grandl, E. Sakr, F. Kotzyba-Hibert, F. Krieger, S. Bertrand, D. Bertrand, H. Vogel, M. Goeldner and R. Hovius, Fluorescent Epibatidine Agonists for Neuronal and Muscle-Type Nicotinic Acetylcholine Receptors, Angewandte Chemie International Edition, 2007, 46, 3505-3508.