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Understanding the role of the trifluoromethyl group in reactivity and regioselectivity in [3+2] cycloaddition reactions of enol acetates with nitrones. A DFT study

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Abstract

The mechanism of the [3+2] cycloaddition (32CA) reaction of C-phenyl-N-methylnitrone with ethyl trifluoroacetoacetate has been theoretically studied at the MPWB1K/6-311G(d,p) level. This 32CA reaction, in which the enol form of the β-keto ester participates as the ethylene component, takes place with complete ortho regioselectivity and exo stereoselectivity. The presence of the CF3 group in the β-position in the enol acetate accelerates the 32CA reaction, but it does not modify the regioselectivity, which is controlled by the presence of the ester group. While ortho regioselectivity is reproduced by the MPWB1K calculations, the endo selectivity is not. The inclusion of solvent effects slightly decreases the reactivity but does not modify the gas phase selectivities. Analysis of the DFT global reactivity indices and the Parr functions in reagents provide a rationalization for the participation of ethyl trifluoroacetoacetate and the regioselectivity in this zw-type 32CA reaction.

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References

  1. Gothelf KV, Jorgensen KA (1999) Asymmetric catalysis of 1,3-dipolar cycloaddition reactions–the concepts of activation and induction of asymmetry. Chem Rev 82:327–350

    CAS  Google Scholar 

  2. Karlsson S, Hogberg HE (2001) Asymmetric 1,3-dipolar cycloadditions for the construction of enantiomerically pure heterocycles. A review. Org Prep Proced Int 33:105–172

    Article  Google Scholar 

  3. Piperno A, Giofre SV, Iannazzo D, Romeo R, Romeo G, Chiacchio U, Rescifina A, Piotrowska DG (2010) Synthesis of C-4’-truncated phosphonated carbocyclic 2’-Oxa-3’-azanucleosides as antiviral agents. J Org Chem 75:2798–2805

    Article  CAS  Google Scholar 

  4. Domingo LR, Sáez JA (2009) Understanding the mechanism of polar Diels–Alder reactions. Org Biomol Chem 7:3576–3583

    Article  CAS  Google Scholar 

  5. Domingo LR, Emamian SR (2014) Understanding the mechanisms of [3+2] cycloaddition reactions. The pseudoradical versus the zwitterionic mechanism. Tetrahedron 70:1267–1273

    Article  CAS  Google Scholar 

  6. Padwa A, Pearson WH (2002) Synthetic applications of 1,3-dipolar cycloaddition chemistry toward heterocycles and natural products, vol 59. Wiley, Hoboken

  7. Domingo LR, Aurell MJ, Pérez P (2014) A DFT analysis of the participation of TACs in zw-type [3+2] cycloaddition reactions. Tetrahedron 70:4519–4525

    Article  CAS  Google Scholar 

  8. Bravo P, Bruché L, Fronza G, Zecchi G (1992) A cycloadditive route to trifluoromethyl-substituted aminoalcohols. Tetrahedron 48:9775–9788

    Article  CAS  Google Scholar 

  9. Tanaka K, Mori T, Mitsuhashi K (1989) Novel ring transformation of 3-benzoylisoxazolidines into 2-hydroxydihydrofurans - N-O cleavage vs 1,3-dipolar cycloreversion. Chem Lett 18:1115–1118

    Article  Google Scholar 

  10. Bravo P, Bruché L, Crucianelli M, Farina A, Valdo Meille S, Merli A, Seresini P (1996) Asymmetric 1.3-Dipolar cycloadditions of nitrile oxides and nitrones with fluorosubstituted chiral vinyl sulfoxides. J Chem Res Synop 8:348–349

    Google Scholar 

  11. Tanaka K, Mitsuhashi K (1987) Synthesis of trifluoromethyl azoles using building-blocks. J Synth Org Chem Jpn 45:269–283

    Article  CAS  Google Scholar 

  12. Sobhi C, Nacereddine AK, Djerourou A, Aurell MJ, Domingo LR (2012) The role of the trifluoromethyl group in reactivity and selectivity in polarcycloaddition reactions. A DFT study. Tetrahedron 68:8457–8462

    Article  CAS  Google Scholar 

  13. BonnetDelpon D, Begue JP, Lequeux T, Ourevitch M (1996) Trifluoromethylalkenes in cycloaddition reactions. Tetrahedron 52:59–70

    Article  CAS  Google Scholar 

  14. Camps F, Coll J, Messeguer A, Roca A (1977) NMR-study of keto-enol equilibrium of ethyl gamma, gamma, gamma-trifluoroacetoacetate and its reaction with water and alcohols. Tetrahedron 33:1637–1640

    Article  Google Scholar 

  15. Zhao Y, Truhlar DG (2004) Hybrid meta density functional theory methods for thermochemistry, thermochemical kinetics, and noncovalent interactions: The MPW1B95 and MPWB1K models and comparative assessments for hydrogen bonding and van der Waals interactions. J Phys Chem A 108:6908–6918

    Article  CAS  Google Scholar 

  16. Hehre WJ, Radom L, Schleyer PR, Pople JA (1986) Ab initio molecular orbital theory, vol 33. Wiley, New York

    Google Scholar 

  17. Soto-Delgado J, Aizman A, Contreras R, Domingo LR (2012) On the catalytic effect of water in the intramolecular Diels–Alder reaction of quinone systems: a theoretical study. Molecules 17:13687–13703

    Article  CAS  Google Scholar 

  18. Rhyman L, Ramasami P, Joule JA, Saez JA, Domingo LR (2013) Understanding the formation of [3+2] and [2 + 4] cycloadducts in the Lewis acid catalysed reaction between methyl glyoxylate oxime and cyclopentadiene: a theoretical study. RSC Adv 3:447–457

    Article  CAS  Google Scholar 

  19. Domingo LR, Sáez JA, Arnó M (2014) A DFT study on the NHC catalysed Michael addition of enols to α, β-unsaturated acyl-azoliums. A base catalysed C–C bond-formation step. Org Biomol Chem 12:895–904

    Article  CAS  Google Scholar 

  20. Schlegel HB (1982) Optimization of equilibrium geometries and transition structures. J Comput Chem 3:214–218

    Article  CAS  Google Scholar 

  21. Schlegel HB (1995) Geometry optimization on potential energy surfaces. Mod Electron Struct Theory 2:459–500

    Article  CAS  Google Scholar 

  22. Tomasi J, Persico M (1994) Molecular-interactions in solution—an overview of methods based on continuous distributions of the solvent. Chem Rev 94:2027–2094

    Article  CAS  Google Scholar 

  23. Simkin B, Sheikhet II (1995) Quantum chemical and statistical theory of solutions: a computational approach. Horwood, London

    Google Scholar 

  24. Mennucci B, Cances E, Tomasi J (1997) Evaluation of solvent effects in isotropic and anisotropic dielectrics and in ionic solutions with a unified integral equation method: theoretical bases, computational implementation, and numerical applications. J Phys Chem B 101:10506–10517

    Article  CAS  Google Scholar 

  25. Cossi M, Barone V, Cammi R, Tomasi J (1996) Ab initio study of solvated molecules: a new implementation of the polarizable continuum model. Chem Phys Lett 255:327–335

    Article  CAS  Google Scholar 

  26. Barone V, Cossi M, Tomasi J (1998) Geometry optimization of molecular structures in solution by the polarizable continuum model. J Comput Chem 19:404–417

    Article  CAS  Google Scholar 

  27. Reed AE, Weinstock RB, Weinhold F (1985) Natural-population analysis. J Chem Phys 83:735–746

    Article  CAS  Google Scholar 

  28. Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem Rev 88:899–926

    Article  CAS  Google Scholar 

  29. Frisch M (2009) Gaussian 09, revision A. 02. Gaussian. Inc, Wallingford

    Google Scholar 

  30. Parr RG, Szentpály L, Liu S (1999) Electrophilicity index. J Am Chem Soc 121:1922–1924

    Article  CAS  Google Scholar 

  31. Parr RG, Pearson RG (1983) Absolute hardness: companion parameter to absolute electronegativity. J Am Chem Chem Soc 105:7512–7516

    Article  CAS  Google Scholar 

  32. Parr RG, Yang W (1989) Density functional theory of atoms and molecules. Oxford University Press, New York

    Google Scholar 

  33. Domingo LR, Chamorro E, Pérez P (2008) Understanding the reactivity of captodative ethylenes in polar cycloaddition reactions. A theoretical study. J Org Chem 73:4615–4624

    Article  CAS  Google Scholar 

  34. Domingo LR, Pérez P (2011) The nucleophilicity N index in organic chemistry. Org Biomol Chem 9:7168–7175

    Article  CAS  Google Scholar 

  35. Benchouk W, Mekelleche SM, Silvi B, Aurell MJ, Domingo LR (2011) Understanding the kinetic solvent effects on the 1,3-dipolar cycloaddition of benzonitrile N-oxide: a DFT study. J Phys Org Chem 24:611–618

    Article  CAS  Google Scholar 

  36. Domingo LR, Pérez P, Aurell MJ, Sáez JA (2012) Understanding the bond formation in hetero-Diels-Alder reactions. An ELF analysis of the reaction of nitroethylene with dimethylvinylamine. Curr Org Chem 16:2343–2351

    Article  CAS  Google Scholar 

  37. Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Accounts 120:215–241

    Article  CAS  Google Scholar 

  38. Chai J-D, Head-Gordon M (2008) Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections. Phys Chem Chem Phys 10:6615–6620

    Article  CAS  Google Scholar 

  39. Geerlings P, De Proft F, Langenaeker W (2003) Conceptual density functional theory. Chem Rev 103:1793–1873

    Article  CAS  Google Scholar 

  40. Ess DH, Jones GO, Houk KN (2006) Conceptual, qualitiative, and quantitative theories of 1,3-dipolar and Diels-Alder cycloadditions used in synthesis. Adv Synth Catal 348:2337–2361

    Article  CAS  Google Scholar 

  41. Domingo LR, Pérez P, Sáez JA (2013) Understanding the regioselectivity in hetero Diels-Alder reactions. An ELF analysis of the reaction between nitrosoethylene and 1-vinylpyrrolidine. Tetrahedron 69:107–114

    Article  CAS  Google Scholar 

  42. Domingo LR, Pérez P, Sáez JA (2013) Understanding the local reactivity in polar organic reactions through electrophilic and nucleophilic Parr functions. RSC Adv 3:1486–1494

    Article  CAS  Google Scholar 

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Acknowledgments

L.R.D thanks to Ministerio de Economía y Competitividad of the Spanish Government, project CTQ2013-45646-P, for financial support.

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Authors and Affiliations

  1. Synthesis and Biocatalysis Organic Laboratory, Chemistry Department, Faculty of Sciences, Badji Mokhtar University, Annaba, PB 12, 23000, Annaba, Algeria

    Hatem Layeb, Abdelmalek Khorief Nacereddine & Abdelhafid Djerourou

  2. Departamento de Química Orgánica, Universidad de Valencia, Dr. Moliner 50, 46100, Burjassot, Valencia, Spain

    Mar Ríos-Gutiérrez & Luis R. Domingo

Authors
  1. Hatem Layeb
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  2. Abdelmalek Khorief Nacereddine
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  3. Abdelhafid Djerourou
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  4. Mar Ríos-Gutiérrez
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  5. Luis R. Domingo
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Correspondence to Luis R. Domingo.

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Supporting information

MPWB1K/6-311G(d,p) total energies, and enthalpies, entropies, and Gibbs free energies, computed at 384.15 K and 1 atm in toluene, of the stationary points involved in the 32CA reaction between nitrone 20 and enol acetate 22. B3LYP, MPWB1K, M062X, ωB97X-D, and MP2 total energies and energetic differences between the stereoisomeric ortho TSs involved in the 32CA reaction of nitrone 20 with enol acetate 22. MPWB1K/6-311+G(d,p) total and relative gas phase energies of the stationary points involved in the 32CA reaction between nitrone 20 and enol acetate 22. MPWB1K/6-311+G(d,p) geometries of the TSs involved in the 32CA reaction of nitrone 20 with enol acetate 22. Top view of the geometries of the stereoisomeric ortho TSs involved in the 32CA reaction of nitrone 20 with enol acetate 22. MPWB1K/6-311G(d,p) total energies, enthalpies, entropies, and Gibbs free energies, computed at 384.15 K and 1 atm in toluene, of the stationary points involved in the 32CA reaction between nitrone 20 and enol acetate 24. Complete reference [29. (DOC 777 kb)

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Layeb, H., Nacereddine, A.K., Djerourou, A. et al. Understanding the role of the trifluoromethyl group in reactivity and regioselectivity in [3+2] cycloaddition reactions of enol acetates with nitrones. A DFT study. J Mol Model 21, 104 (2015). https://doi.org/10.1007/s00894-015-2658-5

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