Mr Sandman, Bring Me A Dream

Written by John Studley – June 13th, 2024. Aryl diazonium salts are a mainstay of organic and industrial chemistry. A recent review by Mo and Wang in Chemical Reviews gives a detailed summary of their properties and applications.1a,b Discovered in 1858 by Johann Peter Griefs, these versatile intermediates are prepared by low temperature reaction of an aniline with nitrosonium (NO+) ions, formed through acidic degradation of nitrite-based reagents such as sodium (NaNO2) or isoamyl nitrite. The use of sodium nitrite in organic synthesis was recently reviewed.1c They have limited thermal stability above 5°C, introducing safety issues-particularly on large scale- and as a result are usually generated and reacted in situ. There are several reports of explosions and incidents involving processing of these materials.2 A useful summary on safe preparation and handling was published in a recent editorial by Fairlamb and Firth in Organic Letters.2a Another paper by Browne et al in the OPRD journal compares the thermal stability of various diazonium salts (by DSC), and looks at structure-thermal activity relationships.2b Small changes in the synthetic protocol, small quantities of impurities, and mechanical force can result in unexpected detonations, and every new aryldiazonium salt should be considered dangerous and explosive until proven otherwise.2 Continuous flow processing has been used to attenuate the risk of batch processing. A review by Yu and Su et al describes recent advances in aromatic diazotisation and diazonium salts in continuous flow.3a

The conversion of aryl diazonium salts to aryl halides was first described by the Swiss chemist Traugott Sandmeyer 25 years later in 1884. This important industrial process involves oxidative addition of the diazonium salt to a d10 metal such as Cu(I), loss of nitrogen gas and formation of chlorides, bromides and iodides (Figure 1). The reaction can be carried out without copper to generate C-CF3/CF2, C-CN, C-S, and C-OH bonds.4 Methodology for trifluormethylation via a Sandmeyer reaction, developed in the research groups of Wang,  Gooben and Fu, has been reviewed by Browne.4c  A paper by Boyston et al describes efficient transposition of a Sandmeyer reaction from batch to flow.3b Tetrafluoroborate salts of diazonium ions are used industrially in the conceptually similar Balz-Schiemann reaction, used to prepare aryl fluorides.5 I myself have run large scale Schiemann reactions. Thermal decomposition of one particular BF4 salt (with a meta-carboxylic acid group) resulted in a violent decomposition. Luckily for me I was heating it in a melting point tube.

Figure 1: Original Sandmeyer process

The use of sodium nitrate (and nitrate esters) instead of nitrite in diazotisation chemistry has until now not been used synthetically because of the high kinetic stability of the former toward reduction. A recent paper by the Ritter group in Science has changed this paradigm.6 Under traditional acidic conditions, nitrates generate nitronium (NO2+) ions (rather than nitrosonium cations, NO+) and arene nitration is the preferred pathway (Figure 2).

Figure 2: Nitration v’s diazotisation

To achieve diazotization using nitrate (oxidation state +5), a reductive pathway, in the absence of acid, is required to generate NO+ (oxidation state +3). In the reductive process, single electron reduction to nitrogen dioxide (NO2, oxidation state +4) occurs. This is present in equilibrium with N2O4, disproportionation of which produces the key nitrosating agent NO+. Rate-limiting reduction of nitrate using thiosulfate or halo-cuprates ensures that the diazonium species is transient and does not accumulate due to rapid conversion to the aryl halide (Figure 3). From a process safety perspective this offers a significant advantage over traditional approaches in which the diazonium is generated stoichiometrically. The lower cost of nitrate and the environmentally benign nature of the by-products (N2 and H2O) also tick the box from a scale-up perspective. The reaction is carried out at a higher temperature than traditional diazonium salt formation (refluxing acetonitrile rather that <0°C).

Figure 3: Diazoniums as transient intermediates, preventing accumulation

Optimisation of the reaction conditions -depending on the halide you wish to introduce- is described in detail, with nitrate slats and esters being used interchangeably. For chlorination, 2-ethylhexyl nitrate (TBAC (tetrabutylammonium chloride)/CuCl/acetonitrile/reflux, 16hrs) in the presence of a radical scavenger (2-methyl-2-butene) was adopted. Use of acetonitrile as solvent reduced the formation of protodeaminated by-products. Bromination and iodination gave higher yields using nitrate salts (TABNO3 /KNO3). Dibromoethane and diiodoethane were used as sources of halide ions in the presence of Na2S2O5.5H2O. CuBr was used in the bromination reaction, however deaminative iodination could be carried in the absence of copper. Mechanistic studies, including the use of labelled 15N, confirmed the intermediacy of aryldiazonium salts. DFT calculations were carried out elaborate nitrate reduction pathways. In fact the main bulk of the text is related to detailed mechanistic studies. Interestingly thiosulfate alone cannot reduce NO3 below 140°C, so a chemically competent reductant must be formed in situ, presumably from S2O32-.

There are plenty of example reactions in the paper, including both anilines and aminoheterocycles. A couple of highlights from compounds used in the pharma industry include structural modification of the HIV protease inhibitor darunavirand, the anti-malaria drug sulfadoxin and the nonsteroidal antiandrogen nilutamide, and the from the agrochemical industry the herbicide chloridazon (Figure 4).

Figure 4: Example substrates

The paper concludes with reference to improved safety, particularly with substrates containing energetic functional groups. Diazonium species are very useful synthetic intermediates and this modern approach to their formation and processing without accumulation I’m sure will be of great interest to the synthetic community.

See you next time.

References:

  1. a) Recent development of aryl diazonium chemistry for the derivatization of aromatic compounds: J. Wang et al, Chem. Rev. 2021, 121, 5741–5829; b) Recent applications of arene diazonium salts in organic synthesis: J. Wang & G. Dong et al, Org. Biomol. Chem. 2013, 11, 1582-1593; c) Applications of sodium nitrite in organic synthesis: S. Batra et al, Eur. J. Org. Chem. 2019, 38, 6424-6451
  2. a) A need for caution in the preparation and application of synthetically versatile aryl diazonium tetrafluoroborate salts: I. Fairlamb et al, Org. Lett. 2020, 22, 7057-7059; b) Comparison of the thermal stabilities of diazonium salts and their corresponding triazenes: D. Browne et al, Org. Process Res. Dev. 2020, 24, 2336-2341; c) Reactive chemical hazards of diazonium salts: M. Sheng et al, Journal of Loss Prevention in the Process Industries, 2015, 38, 114-118; d) Thermal analysis of arenediazonium tetrafluoroborate salts: stability and hazardous evaluation: C. R. D. Correia et al, Process safety and hazard evaluation, 2023, 177, 69-81; e) Runaway reaction during production of an azo dye intermediate: S. Partington et al, IChemE Symposium Series 2001, No. 148, 81-93
  3. a) Efficient transposition of the Sandmeyer reaction from batch to continuous process: F. Buron et al, Org. Process Res. Dev. 2017, 21, 44-51 b) Revisiting aromatic diazotization and aryl diazonium salts in continuous flow: highlighted research during 2001–2021: Z. Yu et al, React. Chem. Eng., 2022, 7, 1247
  4. a) Recent trends in the chemistry of the Sandmeyer reaction: a review: A. F. Zahoor et al, Mol. Diversity 2022, 26, 1837-1873; b) Renaissance of Sandmeyer-type reactions: conversion of aromatic C-N bonds into C-X bonds (X=B, Sn, P or CF3): J. Wang et al, Acc. Chem. Res. 2018, 51, 496-506; c) The trifluoromethylating Sandmeyer reaction: A method for transforming C-N to C-CF3: D. Browne, Angew. Chem. Int. Ed. 2014, 53, 1482-1484
  5. Revisiting the Balz–Schiemann reaction of aryldiazonium tetrafluoroborate in different solvents under catalyst- and additive-free conditions: C. P. Zhang et al, ACS Omega 2021, 6, 21595–21603
  6. Nitrate reduction enables safer aryldiazonium chemistry: T. Ritter et al, Science 2024, 384, 446-452