Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Nov 11;58(46):16368-16388.
doi: 10.1002/anie.201902216. Epub 2019 Sep 13.

Concerted Nucleophilic Aromatic Substitution Reactions

Simon Rohrbach  1 , Andrew J Smith  1 , Jia Hao Pang  2 , Darren L Poole  3 , Tell Tuttle  1 , Shunsuke Chiba  2 , John A Murphy  1
Affiliations
Review

Concerted Nucleophilic Aromatic Substitution Reactions

Simon Rohrbach et al. Angew Chem Int Ed Engl. .

Abstract

Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cSN Ar) rather than classical, two-step, SN Ar mechanisms. Whereas traditional SN Ar reactions require substantial activation of the aromatic ring by electron-withdrawing substituents, such activating groups are not mandatory in the concerted pathways.

Keywords: Meisenheimer complex; cSNAr mechanism; concerted reactions; nucleophilic aromatic substitution.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Classical two‐step mechanism for SNAr reactions.
Scheme 2
Scheme 2
Some known Meisenheimer intermediates.
Scheme 3
Scheme 3
Organolithium additions to pyridine, and re‐aromatisation.
Scheme 4
Scheme 4
Miller's studies of Hammett correlations.
Scheme 5
Scheme 5
Proposal for concerted SNAr reactions by Pierre et al.27
Scheme 6
Scheme 6
Some SNAr reactions provided Hammett correlations with low ρ‐values.
Scheme 7
Scheme 7
Substitutions of aryloxy‐substituted triazines.
Scheme 8
Scheme 8
Hydrolysis of protonated triazines.
Scheme 9
Scheme 9
Computational investigations of identity substitutions.
Scheme 10
Scheme 10
Concerted substitutions in 5,7‐dinitroquinazolin‐4‐one 51.
Scheme 11
Scheme 11
Low activation energy predicted in gas‐phase substitution.
Scheme 12
Scheme 12
Concerted mechanism proposed in displacements of 4‐pentafluorophenoxides.
Scheme 13
Scheme 13
No Meisenheimer intermediates were found in computational studies on displacements on pentachloropyridine.
Scheme 14
Scheme 14
Concerted substitution reactions studied by Stenlid and Brinck.48
Scheme 15
Scheme 15
Studies on the effect of ion‐pairing, explicit hydration and solvent polarity on the fluorodechlorination reaction.
Scheme 16
Scheme 16
Substitution reactions of bromomethoxybenzenes.
Scheme 17
Scheme 17
Gas‐phase reactivity with ammonia as nucleophile.
Scheme 18
Scheme 18
Reactivity in solution with ammonia as nucleophile.
Scheme 19
Scheme 19
Ritter's studies53, 54, 55, 56 on the deoxyfluorination of phenols.
Scheme 20
Scheme 20
Examples of deoxyfluorination by Sanford et al.
Figure 1
Figure 1
Energy profile for conversion of 112 to fluoroarene 115.
Scheme 21
Scheme 21
Intramolecular nucleophilic amination of methoxyarenes.
Scheme 22
Scheme 22
Intermolecular nucleophilic amination of methoxyarenes.
Figure 2
Figure 2
Free energy profile for the cyclisation of amide salt 142.
Scheme 23
Scheme 23
Sequential substitutions of methoxyarenes by amines.
Scheme 24
Scheme 24
Hydrodehalogenations effected by sodium hydride‐lithium iodide complex.
Figure 3
Figure 3
Free Energy profile for reaction of bromobenzene with solvated monomeric sodium hydride.
Scheme 25
Scheme 25
Stereo‐retention prevails in hydrodehalogenations of vinyl bromides.
Scheme 26
Scheme 26
Support for four‐centred transition state in the Pierre reaction.
Scheme 27
Scheme 27
Concerted displacements of halides from haloarenes by naked hydride ions are predicted from computation.
Scheme 28
Scheme 28
Products of hydrodefluorination from the study of Ogoshi et al. H indicates an H atom that has displaced F; only the major product isomer is shown in each case.
Scheme 29
Scheme 29
Proposed cycles for hydrodefluorination by TBAT (194) and a silane.
Scheme 30
Scheme 30
Phosphinodefluorination of aryl fluorides.
Figure 4
Figure 4
Energy profile of phosphinodefluorination reaction.
Scheme 31
Scheme 31
Products arising from silyldefluorination reactions.
Scheme 32
Scheme 32
Hartley's cSNAr route to phenanthridinium salts.
Scheme 33
Scheme 33
Carbon nucleophiles in cSNAr displacements (DCM: dichloromethane; AcOH: acetic acid).
Scheme 34
Scheme 34
A) Stereocontrol in Clayden's aryl transfer reactions; B) earlier aryl reactions showing nucleophilic substitution at the meta‐ position of a pyridine; C) vinyl transfer reactions.
Scheme 35
Scheme 35
Unexpected product 253, together with a proposal for its mechanism of formation.
Scheme 36
Scheme 36
The Julia–Kocieński reaction features concerted displacement at the tetrazole ring.
Scheme 37
Scheme 37
A stepwise mechanism was predicted for this Smiles rearrangement from computational studies.
Scheme 38
Scheme 38
Further examples of Smiles rearrangements where computational research predicts stepwise mechanisms.
Scheme 39
Scheme 39
The Newman–Kwart and related rearrangement reactions.
Scheme 40
Scheme 40
cSNAr reactions in the formation of dibenzothiophenes.
Scheme 41
Scheme 41
Substitution of perfluorophenylbenzenes by methanthiolate occurring through highly ordered transition states.
Scheme 42
Scheme 42
Thio‐dehalogenation of atrazine 305 occurs on the borderline between concerted and stepwise mechanisms.
Scheme 43
Scheme 43
Bio‐inspired substitution reactions.
Scheme 44
Scheme 44
cSNAr substitutions on arenes with a hypervalent iodine substituent.
Scheme 45
Scheme 45
Mechanistic studies on nucleophilic aromatic substitution reactions on hypervalent iodine substrates. (DCE: 1,2‐dichloroethane).
Scheme 46
Scheme 46
Free Energy profile for nucleophilic aromatic substitution reactions on hypervalent iodine substrates.
Scheme 47
Scheme 47
Aryl migration in iodonium ylides.
Scheme 48
Scheme 48
Substitution reactions of arendiazonium salts by water.
Scheme 49
Scheme 49
Recent remarkable displacements by magnesium nucleophiles.
Scheme 50
Scheme 50
Three reactions studied in depth by Jacobsen et al.
See this image and copyright information in PMC

References

    1. Smyth M. B., in March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 7 th ed., Wiley, Hoboken, 2013, Chap. 11, pp. 569–641, e-book ISBN: 9781118472217.
    1. Bunnett J. F., Zahler R. E., Chem. Rev. 1951, 49, 273–412.
    1. Terrier F., Modern Nucleophilic Aromatic Substitution, Wiley-VCH, Weinheim, 2013, e-book ISBN: 9783527656141.
    1. Błaziak K., Danikiewicz W., Mąkosza M., J. Am. Chem. Soc. 2016, 138, 7276–7281, and references therein. - PubMed
    1. Takikawa H., Nishii A., Sakai T., Suzuki K., Chem. Soc. Rev. 2018, 47, 8030–8056. - PubMed