Structural Chemistry

, Volume 30, Issue 1, pp 75–83 | Cite as

How difficult are anion-molecule SNAr reactions of unactivated arenes in the gas phase, dimethyl sulfoxide, and methanol solvents?

  • Daniela R. Silva
  • Josefredo R. PliegoJr.Email author
Original Research


Nucleophilic substitution on the aromatic ring (SNAr) is a very important reaction for organic transformations. This kind of reaction is usually difficult to take place, requiring organometallic catalysis or activation of the ring by electron withdrawing groups to turn the nucleophilic attack possible. In this work, the relative importance of intrinsic gas phase barrier and the solvent effect on several SNAr reactions using theoretical calculations were investigated. The reactions of the anions OH, CN, and CH3O and the enolates CH3COCH2 and CH3COCHCOCH3 with bromobenzene and (o, m, p)-methoxy bromobenzene in methanol and dimethyl sulfoxide as solvents were considered. The OH and CH3O ions are highly reactive in the gas phase. However, the solvent effect induces a high activation barrier in solution, turning the reaction difficult, although feasible. The CN and CH3COCHCOCH3 ions have high activation barriers even in the gas phase. The interesting CH3COCH2 ion has a moderate barrier in the gas phase, although the free energy barrier in DMSO solution reaches 33 kcal mol−1. Our analysis suggests that decreasing the solvent effect, arylation of enolates with unactivated arenes could become possible.


Aromatic nucleophilic substitution Formation of carbon-carbon bond Solvent effect Regioselectivity Enolate 



The authors thank the support of the agencies CNPq, FAPEMIG, and CAPES.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    CulKin DA, Hartwig JF (2003) Palladium-catalyzed α-alylation of carbonyl compounds and nitriles. Acc Chem Res 36:234CrossRefGoogle Scholar
  2. 2.
    O’Reilly ME, Johnson SI, Nielsen RJ, Goddard WA, Gunnoe TB (2016) Transition-metal-mediated nucleophilic aromatic substitution with acids. Organometallics 35:2053–2056CrossRefGoogle Scholar
  3. 3.
    Isley NA, Linstadt RTH, Kelly SM, Gallou F, Lipshutz BH (2015) Nucleophilic aromatic substitution reactions in water enabled by micellar catalysis. Org Lett 17:4734–4737CrossRefGoogle Scholar
  4. 4.
    Burke AJ, Marques CS (2015) α-arylation processes, catalytic arylation methods: from the academic lab to industrial processes. Wiley-VCH, Place Published, Weinheim, pp 377–435Google Scholar
  5. 5.
    Danikiewicz W, Zimnicka M (2016) Negative ion gas-phase chemistry of arenes. Mass Spectrom Rev 35:123–146CrossRefGoogle Scholar
  6. 6.
    Walton JW, Williams JMJ (2015) Catalytic SNAr of unactivated aryl chlorides. Chem Commun 51:2786–2789CrossRefGoogle Scholar
  7. 7.
    Wendt MD, Kunzer AR (2010) Ortho-selectivity in SNAr substitutions of 2,4-dihaloaromatic compounds. Reactions with anionic nucleophiles. Tetrahedron Lett 51:3041–3044CrossRefGoogle Scholar
  8. 8.
    Neumann CN, Hooker JM, Ritter T (2016) Concerted nucleophilic aromatic substitution with 19F and 18Fᅟ. Nature 534:369–373CrossRefGoogle Scholar
  9. 9.
    Błaziak K, Danikiewicz W, Mąkosza M (2016) How does nucleophilic aromatic substitution really proceed in nitroarenes? Computational prediction and experimental verification. J Am Chem Soc 138:7276–7281CrossRefGoogle Scholar
  10. 10.
    Liljenberg M, Brinck T, Herschend B, Rein T, Tomasi S, Svensson M (2012) Predicting regioselectivity in nucleophilic aromatic substitution. J. Org. Chem. 77:3262–3269CrossRefGoogle Scholar
  11. 11.
    Fernández I, Frenking G, Uggerud E (2010) Rate-determining factors in nucleophilic aromatic substitution reactions. J. Org. Chem. 75:2971–2980CrossRefGoogle Scholar
  12. 12.
    Glukhovtsev MN, Bach RD, Laiter S (1997) Single-step and multistep mechanisms of aromatic nucleophilic substitution of halobenzenes and halonitrobenzenes with halide anions: ab initio computational study. J. Org. Chem. 62:4036–4046CrossRefGoogle Scholar
  13. 13.
    Błaziak K, Mąkosza M, Danikiewicz W (2015) Competition between nucleophilic substitution of halogen (SNAr) versus substitution of hydrogen (SNArH)—a mass spectrometry and computational study. Chem Eur J 21:6048–6051CrossRefGoogle Scholar
  14. 14.
    Pliego JR, Pilo-Veloso D (2008) Effects of ion-pairing and hydration on the SNAr reaction of the F- with p-chlorobenzonitrile in aprotic solvents. Phys Chem Chem Phys 10:1118–1124CrossRefGoogle Scholar
  15. 15.
    Hartwig JF (2006) Discovery and understanding of transition-metal-catalyzed aromatic substitution reactions. Synlett No 9:1283–1294CrossRefGoogle Scholar
  16. 16.
    Giroldo T, Xavier LA, Riveros JM (2004) An unusually fast nucleophilic aromatic displacement reaction: the gas-phase reaction of fluoride ions with nitrobenzene. Angew Chem Int Ed 43:3588–3590CrossRefGoogle Scholar
  17. 17.
    Sun H, DiMagno SG (2006) Room-temperature nucleophilic aromatic fluorination: experimental and theoretical studies. Angew Chem Int Ed 45:2720–2725CrossRefGoogle Scholar
  18. 18.
    Alarcon-Esposito J, Tapia RA, Contreras R, Campodonico PR (2015) Changes in the SNAr reaction mechanism brought about by preferential solvation. RSC Adv 5:99322–99328CrossRefGoogle Scholar
  19. 19.
    Acevedo O, Jorgensen WL (2004) Solvent effects and mechanism for a nucleophilic aromatic substitution from QM/MM simulations. Org Lett 6:2881–2884CrossRefGoogle Scholar
  20. 20.
    Park S, Lee S (2010) Effects of ion and protic solvent on nucleophilic aromatic substitution (SNAr) reactions. Bull Kor Chem Soc 31:2571CrossRefGoogle Scholar
  21. 21.
    Shelk NB, Ghorpade R, Pratap A, Tak V, Acharya BN (2015) SNAr reaction in aqueous medium in the presence of mixed organic and inorganic bases. RSC Adv 5:31226–31230CrossRefGoogle Scholar
  22. 22.
    Gazitúa M, Tapia RA, Contreras R, Campodónico PR (2014) Mechanistic pathways of aromatic nucleophilic substitution in conventional solvents and ionic liquids. New J Chem 38:2611–2618CrossRefGoogle Scholar
  23. 23.
    Wang X, Salaski EJ, Berger DM, Powell D (2009) Dramatic effect of solvent hydrogen bond basicity on the regiochemistry of SNAr reactions of electron-deficient polyfluoroarenes. Org Lett 11:5662–5664CrossRefGoogle Scholar
  24. 24.
    Valvi A, Tiwari S (2017) Concentration-dependent solvent effect on the SNAr reaction between 1-fluoro-2,4-dinitrobenzene and morpholine. J Phys Org Chem 30:e3615CrossRefGoogle Scholar
  25. 25.
    Alarcón-Espósito J, Contreras R, Tapia RA, Campodónico PR (2016) Gutmann's donor numbers correctly assess the effect of the solvent on the kinetics of SNAr reactions in ionic liquids. Chem Eur J 22:13347–13351CrossRefGoogle Scholar
  26. 26.
    Tanner EEL, Hawker RR, Yau HM, Croft AK, Harper JB (2013) Probing the importance of ionic liquid structure: a general ionic liquid effect on an SNAr process. Org Biomol Chem 11:7516–7521CrossRefGoogle Scholar
  27. 27.
    Xu X, Zhang Q, Muller RP, Goddard III WA (2005) An extended hybrid density functional (X3LYP) with improved descriptions of nonbond interactions and thermodynamic properties of molecular systems. J Chem Phys 122:014105–014114CrossRefGoogle Scholar
  28. 28.
    Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3093CrossRefGoogle Scholar
  29. 29.
    Su P, Li H (2009) Continuous and smooth potential energy surface for conductorlike screening solvation model using fixed points with variable areas. J Chem Phys 130:074109–074113CrossRefGoogle Scholar
  30. 30.
    Silva CM, Dias IC, Pliego JR (2015) The role of ammonia oxide in the reaction of hydroxylamine with carboxylic esters. Org. Biomol. Chem. 13:6217–6224CrossRefGoogle Scholar
  31. 31.
    Zhao Y, Truhlar DG (2008) Exploring the limit of accuracy of the global hybrid meta density functional for main-group thermochemistry, kinetics, and noncovalent interactions. J Chem Theory Comput 4:1849–1868CrossRefGoogle Scholar
  32. 32.
    Weigend F, Ahlrichs R (2005) Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: design and assessment of accuracy. Phys Chem Chem Phys 7:3297–3305CrossRefGoogle Scholar
  33. 33.
    Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396CrossRefGoogle Scholar
  34. 34.
    Pliego JR, Riveros JM (2002) Parametrization of the PCM model for calculating solvation free energy of anions in dimethyl sulfoxide solutions. Chem Phys Lett 355:543–546CrossRefGoogle Scholar
  35. 35.
    Silva NM, Deglmann P, Pliego JR (2016) CMIRS solvation model for methanol: parametrization, testing, and comparison with SMD, SM8, and COSMO-RS. J Phys Chem B 120:12660–12668CrossRefGoogle Scholar
  36. 36.
    Miguel ELM, Santos CIL, Silva CM, Pliego JR (2016) How accurate is the SMD model for predicting free energy barriers for nucleophilic substitution reactions in polar protic and dipolar aprotic solvents? J Braz Chem Soc 27:2055–2061Google Scholar
  37. 37.
    Westphal E, Pliego JR (2007) Ab initio , density functional theory and continuum solvation model prediction of the product ratio of the SN2 reaction of NO2- with CH3CH2Cl and CH3CH2Br in DMSO solution. J Phys Chem A 111:10068–10074CrossRefGoogle Scholar
  38. 38.
    Pliego JR, Piló-Veloso D (2007) Chemoselective nucleophilic fluorination induced by selective solvation of the SN2 transition state. J Phys Chem B 111:1752–1758CrossRefGoogle Scholar
  39. 39.
    Tondo DW, Pliego JR (2005) Modeling protic to dipolar aprotic solvent rate acceleration and leaving group effects in S N 2 reactions: a theoretical study of the reaction of acetate ion with ethyl halides in aqueous and dimethyl sulfoxide solutions. J Phys Chem A 109:507–511CrossRefGoogle Scholar
  40. 40.
    Almerindo GI, Pliego JR (2005) Ab initio study of the S N 2 and E2 mechanisms in the reaction between the cyanide ion and ethyl chloride in dimethyl sulfoxide solution. Org Lett 7:1821–1823CrossRefGoogle Scholar
  41. 41.
    Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su S, Windus TL, Dupuis M, Montgomery JA (1993) General atomic and molecular electronic structure system. J Comput Chem 14:1347–1363CrossRefGoogle Scholar
  42. 42.
    Guedira NE, Beugelmans R (1992) Ambident behavior of ketone enolate anions in SNAr substitutions on fluorobenzonitrile substrates. J Org Chem 57:5577–5585CrossRefGoogle Scholar
  43. 43.
    Freriks IL, De Koning LJ, Nibbering NMM (1991) Gas-phase ambident reactivity of acyclic enolate anions. J Am Chem Soc 113:9119–9124CrossRefGoogle Scholar
  44. 44.
    Ingemann S, Nibbering NMM, Sullivan SA, DePuy CH (1982) Nucleophilic aromatic substitution in the gas phase: the importance of fluoride ion-molecule complexes formed in gas-phase reactions between nucleophiles and some alkyl pentafluorophenyl ethers. J Am Chem Soc 104:6520–6527CrossRefGoogle Scholar
  45. 45.
    Cram DJ, Rickborn B, Knox GR (1960) Effect of solvent on rate of base-catalyzed proton abstraction from carbon. J Am Chem Soc 82:6412–6413CrossRefGoogle Scholar
  46. 46.
    Smith MB, March J (2007) Advanced organic chemistry: reactions, mechanism and structure, 6th. Wiley, HobokenGoogle Scholar
  47. 47.
    Eanes AD, Noin DO, Kebede MK, Gronert S (2014) Nucleophilic aromatic substitution with dianions: reactions driven by the release of coulomb repulsion. J Am Soc Mass Spectrom 25:10–17CrossRefGoogle Scholar
  48. 48.
    Carvalho NF, Pliego JR (2016) Theoretical design and calculation of a crown ether phase-transfer-catalyst scaffold for nucleophilic fluorination merging two catalytic concepts. J. Org. Chem. 81:8455–8463CrossRefGoogle Scholar
  49. 49.
    Pliego Jr JR (2011) Chemical reactions inside structured nano-environment: SN2 vs. E2 reactions for the F- + CH3CH2Cl system. Phys Chem Chem Phys 13:779–782CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departamento de Ciências NaturaisUniversidade Federal de São João Del ReiSão João Del ReiBrazil

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