S_NAr Solvents and Reagents

General Overview

The synthesis of C-N/O/S bonds is one of the most common synthetic operations in the pharma industry. One of the most common routes to aromatic Csp²-N/O/S bonds is the S_NAr reaction. This reaction type probably represents 15-20% of all C-N/O/S bonds constructed in pharmaceutical synthesis. Typically, a neutral or anionic nucleophile displaces a leaving group on a aryl or heteroaryl electrophile generating the product and a metal salt or acidic species. Often a base is added to create an anion nucleophile, or to remove any acidic species generated. Typically aryl fluorides or heteroaryl chlorides/bromides are employed as electrophiles although other leaving groups like nitro or sulfonate are occasionally encountered.

While aryl fluorides are common substrates for S_NAr reactions, often aryl and especially heteroaryl fluorides, are the desired product. A version of the S_NAr reaction, the Halex process, delivers aryl / heteroaryl fluorides by nucleophilic displacement of chloride using an excess of inorganic fluoride ions in a high boiling solvent.

Typically S_NAr reactions are intermolecular between an electrophile and a nucleophile, but can be used in an intramolecular sense for the construction of fused heterocycles.

As a general rule, the learnings around substituting in  greener solvents for use in SNAr reactions as described in this reagent guide can be directly transcribed to S_N2 reactions- another very common and widely used methodology for the  construction Csp³-N/O/S bonds where common H4XX dipolar aprotic solvents are also historically widely used.

This guide covers simple SNAr reactions and not related reactions that produce similar or identical products like Vicarious Nucleophilic Substitution (VNS) or Buchwald-Hartwig/Ullmann metal catalysed reactions involving insertion of a metal catalyst in the Csp2-halogen bond/leaving group as the initial step in the substitution process.

Green Criteria for S_NAr Reactions

1. Solvents should be chosen to minimise any potential safety and environmental impact.
2. If possible H340/341/H360/H361 labelled dipolar aprotic or ethereal solvents should be avoided/substituted.
3. Newer/neoteric replacements for older dipolar aprotic solvents may have insufficient data to truly evaluate vs. older solvents
4. If a dipolar aprotic solvent has to be used, minimise amounts used or see the dipolar aprotic can be diluted with a more benign solvent
5. Reagents should be selected to minimise safety issues. Large molar excesses of reagents should be avoided if possible
6. Care should be taken to assess the ability of fluoride anions or HF to damage reactors and other process equipment

General literature reviews on S_NAr reactions

Chem. Rev., 1951, 49 (2), pp 273–412 Aromatic Nucleophilic Substitution Reactions

Angew. Chem. Int. Ed. 2013, 52, 8214–8264 Introduction of Fluorine and Fluorine-Containing Functional Groups

Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques Nucleophilic Aromatic Substitution

Org. Process Res. Dev., 2015, 19, 740-747 Survey of Solvent Usage in Papers Published in Organic Process Research & Development 1997–2012

Chemistry – A European Journal (2014), 20(19), 5536-5545 Reactions of Nucleophiles with Nitroarenes: Multifacial and Versatile Electrophiles

Synthesis 2010(11): 1804–1821. C–F Bond Formation for the Synthesis of Aryl Fluorides

Russian Chemical Reviews (2003), 72(8), 681-703. Nucleophilic substitution of the nitro group, fluorine and chlorine in aromatic compounds