SNAr Reaction in other common molecular solvents

Mechanism + Description

As per N-based dipolar aprotic solvents

General comments

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.

Esters
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.

Alcohols
Isopropyl alcohol, i- BuOH t-BuOH, isoamyl alcohol have been used, but some less hindered alcohols can act as nuclophiles in SNAr reactions.

Ethers
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.

Aromatics
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
Liquid ammonia has been proposed as an alternative to dipolar aprotic solvents for SNAr reactions

DOE/PCA
Design of experiments (DOE) and principal component analysis (PCA) have been used to select non toxic solvents to replace dipolar aprotic solvents 

 

Key references

Org. Biomol. Chem., 2016, 14, 2373-2384 The application of design of experiments (DoE) to reaction optimisation and solvent selection

Org. Process Res. Dev., 2017, 21,  114–124 Methodology for Replacing Dipolar Aprotic Solvents Used in API Processing with Safe Hydrogen-Bond Donor and Acceptor Solvent-Pair Mixtures

Tet. Lett., 1996 Vol. 37, 6439-6442 Regioselective nucleophilic substitutions of fluorobenzene derivatives

J. Am. Chem. Soc. 2000, 122, 712-713 Preparation of Tertiary Benzylic Nitriles from Aryl Fluorides

Eur. J. Org. Chem. 2012, 7048–7052 Regioselective Preparation of 3-Alkoxy-4,5-difluoroanilines by SNAr

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

J. Org. Chem. 2006, 71, 2170-2172 Novel Synthesis of Desymmetrized Resorcinol Derivatives:  Aryl Fluoride Displacement on Deactivated Substrates

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

RSC Adv., 2015, 5, 7035-7048 Effective, transition metal free and selective C-F activation under mild conditions

J. Org. Chem. 2011, 76, 1425-1435 Liquid Ammonia as a Dipolar Aprotic Solvent for Aliphatic Nucleophilic Substitution Reactions

J. Org. Chem. 2011, 76, 3286-3295.  The kinetics and mechanisms of aromatic nucleophilic substitution reactions in liquid ammonia

Chem. Commun., 2014,50, 9650-9652 Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents

Beilstein J. Org. Chem. 2016, 12, 2005–2011 Scope and limitations of a DMF bio-alternative within Sonogashira cross-coupling and Cacchi-type annulation

 

 

Relevant scale up examples in DMSO with Scheme

Org. Process Res. Dev. 2017, 21,  387–398

Org. Process Res. Dev., 2011, 15, 1073–1080

Org. Process Res. Dev. 2012, 16, 1805−1810

Org. Process Res. Dev., 2016 20,  1191–1202

Org. Process Res. Dev. 2012, 16, 220−224

Org. Process Res. Dev. 2008, 12, 575–583

Org. Process Res. Dev. 2017, 21, 208−217

Org. Process Res. Dev., 2014, 18,  912–918

Org. Process Res. Dev. 2011, 15, 688–692

Org. Process Res. Dev. 2017, 21, 1320−1325

Org. Process Res. Dev., 2018, 22 (3), pp 344–350

Org. Process Res. Dev., 2018, 22, 409-419

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