SNAr Reaction in other common molecular solvents
Mechanism + Description
As per N-based dipolar aprotic solvents
While dipolar aprotics are commonly used as solvents of first choice for SNAr reactions, many will take place in a range of solvents with better toxicity profiles. This is especially the case where more reactive electrophile/nucleophilepairs are used as reactants. Indeed, where the arene/heteroaromatic has two displaceable leaving groups, the use of a dipolar aprotic solvent often results in over reaction.
Some SNAr reactions can take place in esters like EtOAc , i-PrOAc, but if strong bases like NaOH, NaH, LDA, LHMDS, or alkoxides are needed, esters are not compatible.
Isopropyl alcohol, i- BuOH t-BuOH, isoamyl alcohol have been used, but some less hindered alcohols can act as nuclophiles in SNAr reactions.
Glymes, THF, 2-Me-THF and dimethylisosorbide have all been used as solvents for SNAr reactions. Diglyme and related ethers have been identified as having reprotoxic properties and should be avoided if possible. 2-MeTHF has a much better LCA profile than THF, and is manufactured from biorenewable carbon sources. Dihydrolevoglucosenone (Cyrene) is promoted as a replacement dipolar aprotic solvent, but is unstable in the presence of bases, so may not be suitable for most SNAr chemistry.
Solvents like toluene are occasionally utilised as solvents in SNAr reactions. Occasionally small amounts of dipolar aprotic solvents are used as additives to increase reaction rate.
Liquid ammonia has been proposed as an alternative to dipolar aprotic solvents for SNAr reactions
Design of experiments (DOE) and principal component analysis (PCA) have been used to select non toxic solvents to replace dipolar aprotic solvents
Journal of Polymer Science: Part A: Polymer Chemistry, 2004, Vol. 42, 6353–6363. Thianthrene as an activating group for the synthesis of poly(aryl ether thianthrene)s by nucleophilic aromatic substitution
Eur. J. Org. Chem. 2012, 6940–6952 Effects of the Pyridine 3-Substituent on Regioselectivity in the Nucleophilic Aromatic Substitution Reaction of 3-Substituted 2,6-Dichloropyridines with 1-Methylpiperazine Studied by a Chemical Design Strategy
Relevant scale up examples in DMSO with Scheme