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Nitro Reduction

The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

In terms of atom economy the most efficient transformation is hydrogenation with a recyclable precious metal catalyst (PMC) or Nickel catalyst, preferably using gaseous H2 or transfer hydrogenation. The use of sulfur reagents is a cheap option, but can cause issues with odour and safety. Metal reductions have been used for a long time to reduce nitrobenzenes. These can use more environmentally acceptable metals like Fe, but can lead to issues removing metal from the product. Most nitro group reductions are very exothermic and need to be designed and scaled up with appropriate safety testing to ensure safe operability. The application of new technologies like flow processing and Process Analytical Technology (PAT) can remove some of the potential hazards involved in the large scale reduction of nitro compounds. Some references in this area are listed below.

Org. Process Res. Dev. 2011, 15, 1063 Discovery of a novel, efficient, and scalable route to bendamustine hydrochloride– a safety study included.

Org. Process Res. Dev. 1997, 1(5), 339 Kinetic and calorimetric considerations in the scale-up of the catalytic reduction of a substituted nitrobenzene. A reaction calorimetric investigation was conducted to assess proposed scale-up conditions for the batch-wise reduction. Heat evolution rates under these conditions were judged to be too large for safe plant operation with alternative processing conditions being investigated.

Org. Process Res. Dev. 2006, 10(3), 539 Scalable reactor design for pharmaceuticals and fine chemicals production. A comprehensive review of factors that inhibit scalability of fine chemicals and pharmaceuticals – including reduction of nitroarenes.

Org. Process Res. Dev. 2014, 18(11), 1427 Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

Org. Process Res. Dev., 2000, 4 (5), 357 The use of on-line mid-IR spectroscopy as a real-time monitoring tool for hydrogenation reactions is illustrated. The results show that this technique can be successfully used as an alternative to traditional off-line methods to monitor the reaction endpoint and the formation of impurities.

Org. Process Res. Dev., 2000, 4(6), 554 Rapid process development and scale-up using a multiple reactor system. This article presents case studies that show how computer control involving parallel synthesis in specially designed reactors, particularly on the 25−100 mL scale, can provide significant benefits to the development cycle of new synthetic compounds of commercial interest.

 

Green Criteria for NO2 reduction

  1. Reagents have no major toxicity or safety issues- catalytic reduction with H2 gas or transfer hydrogenation preferred over stoichiometric reagents
  2. Process has no major safety issues and the generation of hazardous waste is minimized and controlled
  3. Adequate consideration has been given to optimization of catalyst levels, recovery and any metal in the product API or effluent
  4. H2 gas pressure minimised
  5. Solvents should be chosen to minimize any potential impact.
  6. Use of hazardous reagents – (H2S) has been eliminated / minimized & effective abatement used.