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Selectivity in the Wittig reaction within the ab initio static and metadynamics approaches

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Abstract

Car–Parrinello molecular dynamics and metadynamics were carried out for salt-free Wittig reaction of non-stabilized, semi-stabilized and stabilized ylides and correlated to static quantum calculation at PBE/6-31G(d, p), including continuum solvation. The Grimme’s dispersion correction approach (DFT-D) was employed throughout the study for both methods. The aim of the present investigations is to reformulate in details than has been possible hitherto, the reaction path and introduce all the stable and metastable states in the Wittig reaction, using ab-initio molecular dynamics tools. In what follows, we show that in the calculated free energy surface, betaine appears at the beginning of the reaction followed by oxaphosphetane for all ylides. The betaine has a higher energy and short life time than oxaphosphetane. It is found that increasing the ylide stability extends the reaction onset time and reduces the overall reaction time. The metadynamics trajectory (metatrajectory) shows the early formation of the C–C bond followed by the P–O bonding formation and simultaneous breaking of the P–C and C–O bond. Within this process, a high E selectivity for all ylides is observed. The metadynamics analysis encompasses all possible energy reaction coordinates; this property provides a more detailed mechanistic picture. Comparison with static calculations demonstrates the potential of the metadynamics approach in the conformational and geometric analysis of the cycloaddition and the cycloelimination processes.

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References

  1. Wittig G, Geissler G (1953) Zur Reaktionsweise des Pentaphenyl-phosphors und einiger Derivate. Eur J Org Chem 580(1):44–57

    CAS  Google Scholar 

  2. Wittig G, Schöllkopf U (1954) Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien (I. Mitteil). Chem Ber 87(9):1318–1330

    Article  Google Scholar 

  3. Heravi MM et al (2020) Applications of Wittig reaction in the total synthesis of natural macrolides. ChemistrySelect 5(31):9654–9690

    Article  CAS  Google Scholar 

  4. Edgar M et al (2019) Benchtop NMR spectroscopy and spectral analysis of the cis-and trans-stilbene products of the Wittig reaction. J Chem Educ 96(9):1938–1947

    Article  CAS  Google Scholar 

  5. Heravi MM et al (2019) Recent advances in the applications of Wittig reaction in the total synthesis of natural products containing lactone, pyrone, and lactam as a scaffold. Mon Chem Chem Mon 150:1365–1407

    Article  CAS  Google Scholar 

  6. Mlakić M et al (2022) Synthesis of new heterocyclic resveratrol analogues in milli-and microreactors: Intensification of the Wittig reaction. J Flow Chem 12(4):429–440

    Article  Google Scholar 

  7. Zhou R et al (2010) Wittig olefination between phosphine, aldehyde, and allylic carbonate: a general method for stereoselective synthesis of trisubstituted 1, 3-dienes with highly variable substituents. Org Lett 12(5):976–979

    Article  CAS  PubMed  Google Scholar 

  8. Xu S et al (2010) Stereoselective synthesis of 1, 2, 3, 4-tetrasubstituted dienes from allenoates and aldehydes: an observation of phosphine-induced chemoselectivity. Org Lett 12(15):3556–3559

    Article  CAS  PubMed  Google Scholar 

  9. Ghosh A et al (2010) Wittig-selectivity in mixed ketones: exploring 1, 3-interaction and enolization. Tetrahedron 66(1):164–171

    Article  CAS  Google Scholar 

  10. Robiette R et al (2006) Reactivity and selectivity in the Wittig reaction: a computational study. J Am Chem Soc 128(7):2394–2409

    Article  CAS  PubMed  Google Scholar 

  11. Harvey JN (2010) Ab initio transition state theory for polar reactions in solution. Faraday Discuss 145:487–505

    Article  CAS  Google Scholar 

  12. Robiette R et al (2005) On the origin of high E selectivity in the Wittig reaction of stabilized ylides: importance of dipole−dipole interactions. J Am Chem Soc 127(39):13468–13469

    Article  CAS  PubMed  Google Scholar 

  13. Stepien M (2013) Anomalous stereoselectivity in the Wittig reaction: the role of steric interactions. J Org Chem 78(18):9512–9516

    Article  CAS  PubMed  Google Scholar 

  14. Jarwal N, Thankachan PP (2017) Theoretical study of the Wittig, aza-Wittig and arsa-Wittig reactions of Me 3 P=XH ylide (X=CH, N and As) with cyclic ketones in the gas phase and solution phase. Comput Theor Chem 114:65–76

    Article  Google Scholar 

  15. Jarwal N, Thankachan PP (2015) Theoretical study of the Wittig reaction of cyclic ketones with phosphorus ylide. J Mol Model 21(4):87

    Article  PubMed  Google Scholar 

  16. Ayub K, Ludwig R (2016) Gas hydrates model for the mechanistic investigation of the Wittig reaction “on water.” RSC Adv 6(28):23448–23458

    Article  CAS  Google Scholar 

  17. Jarwal N, Meena JS, Thankachan PP (2016) The E/Z selectivity in gas phase Wittig reaction of non-stabilized, semi-stabilized and stabilized Me 3 P and Ph 3 P phosphorus ylides with monocyclic ketone: a computational study. Comput Theor Chem 1093:29–39

    Article  CAS  Google Scholar 

  18. Adda A et al (2018) Ab initio static and metadynamics investigations of the Wittig reaction. Theoret Chem Acc 137(7):94

    Article  Google Scholar 

  19. Farfán P, Gomez S, Restrepo A (2019) On the origins of stereoselectivity in the Wittig reaction. Chem Phys Lett 728:153–155

    Article  Google Scholar 

  20. Farfán P, Gómez S, Restrepo A (2019) Dissection of the mechanism of the Wittig reaction. J Org Chem 84(22):14644–14658

    Article  PubMed  Google Scholar 

  21. Chamorro E et al (2020) A close look to the oxaphosphetane formation along the Wittig reaction: A [2+ 2] cycloaddition? J Org Chem 85:6675–6686

    Article  CAS  PubMed  Google Scholar 

  22. Chen Z et al (2014) Isotope effects, dynamic matching, and solvent dynamics in a Wittig reaction. Betaines as bypassed intermediates. J Am Chem Soc 136(38):13122–13125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Byrne PA, Gilheany DG (2013) The modern interpretation of the Wittig reaction mechanism. Chem Soc Rev 42(16):6670–6696

    Article  CAS  PubMed  Google Scholar 

  24. Takeda T (2004) Modern carbonyl olefination-methods and applications. Synthesis 2004(09):1532–1532

    Article  Google Scholar 

  25. Vedejs E, Peterson M (1994) Stereochemistry and mechanism in the Wittig reaction. Top Stereochem 21:1–157

    Article  CAS  Google Scholar 

  26. Kolodiazhnyi OI (2008) Phosphorus ylides: chemistry and applications in organic synthesis. John Wiley & Sons, Hoboken

    Google Scholar 

  27. Leyssens T, Peeters D (2008) Negative hyperconjugation in phosphorus stabilized carbanions. J Org Chem 73(7):2725–2730

    Article  CAS  PubMed  Google Scholar 

  28. Chesnut D (2003) Atoms-in-molecules and electron localization function study of the phosphoryl bond. J Phys Chem A 107(21):4307–4313

    Article  CAS  Google Scholar 

  29. Dobado J et al (1998) Chemical bonding in hypervalent molecules revised. Application of the atoms in molecules theory to Y3 X and Y3 XZ (Y=H or CH3; X=N, P or As; Z=O or S) compounds. J Am Chem Soc 120(33):8461–8471

    Article  CAS  Google Scholar 

  30. Kocher N et al (2004) Metal coordination to the formal P=N bond of an iminophosphorane and charge-density evidence against hypervalent phosphorus (V). Chem A Eur J 10(15):3622–3631

    Article  CAS  Google Scholar 

  31. Byrne PA (2013) Investigation of reactions involving pentacoordinate intermediates: the mechanism of the Wittig reaction. Springer Science & Business Media, Berlin

    Google Scholar 

  32. Vedejs E, Snoble K (1973) Direct observation of oxaphosphetanes from typical Wittig reactions. J Am Chem Soc 95(17):5778–5780

    Article  CAS  Google Scholar 

  33. Vedejs E, Meier G, Snoble K (1981) Low-temperature characterization of the intermediates in the Wittig reaction. J Am Chem Soc 103(10):2823–2831

    Article  CAS  Google Scholar 

  34. Vedejs E, Marth CF (1989) Oxaphosphetane pseudorotation: rates and mechanistic significance in the Wittig reaction. J Am Chem Soc 111(4):1519–1520

    Article  CAS  Google Scholar 

  35. Reitz AB, Mutter MS, Maryanoff BE (1984) Observation of cis and trans oxaphosphetanes in the Wittig reaction by high-field phosphorus-31 NMR spectroscopy. J Am Chem Soc 106(6):1873–1875

    Article  CAS  Google Scholar 

  36. Maryanoff BE et al (1986) Stereochemistry and mechanism of the Wittig reaction. Diasteromeric reaction intermediates and analysis of the reaction course. J Am Chem Soc 108(24):7664–7678

    Article  CAS  PubMed  Google Scholar 

  37. Bangerter F et al (1998) Observation of pseudorotamers of two unconstrained Wittig intermediates, (3 RS, 4 SR)-and (3 RS, 4 RS)-4-Cyclohexyl-2-ethyl-3, 4-dimethyl-2, 2-diphenyl-1, 2λ5-oxaphosphetane, by dynamic 31P NMR spectroscopy: line-shape analyses, conformations, and decomposition kinetics. J Am Chem Soc 120(41):10653–10659

    Article  CAS  Google Scholar 

  38. Appel M, Blaurock S, Berger S (2002) A Wittig reaction with 2-furyl substituents at the phosphorus atom: improved (Z) selectivity and isolation of a stable oxaphosphetane intermediate. Eur J Org Chem 2002(7):1143–1148

    Article  Google Scholar 

  39. Vedejs E, Fleck TJ (1989) Kinetic (not equilibrium) factors are dominant in Wittig reactions of conjugated ylides. J Am Chem Soc 111(15):5861–5871

    Article  CAS  Google Scholar 

  40. Vedejs E, Peterson M (1996) Advances in carbanion chemistry. Jai Press Inc., Greenwich, pp 1–85

    Google Scholar 

  41. Laio A, Parrinello M (2002) Escaping free-energy minima. Proc Natl Acad Sci 99(20):12562–12566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. CPMD, Copyright IBM Corp. (1990–2013) and Copyright MPI für Festkörperforschung, Stuttgart (1997–2001), http://www.cpmd.org/

  43. Troullier N, Martins JL (1991) Efficient pseudopotentials for plane-wave calculations. Phys Rev B 43(3):1993

    Article  CAS  Google Scholar 

  44. Perdew JP, Burke K, Ernzerhof M (1997) Generalized gradient approximation made simple [Phys. Rev. Lett. 77, 3865 (1996)]. Phys Rev Lett 78(7):1396

    Article  CAS  Google Scholar 

  45. Grimme S (2006) Semiempirical GGA-type density functional constructed with a long-range dispersion correction. J Comput Chem 27(15):1787–1799

    Article  CAS  PubMed  Google Scholar 

  46. Nosé S (1984) A unified formulation of the constant temperature molecular dynamics methods. J Chem Phys 81(1):511–519

    Article  Google Scholar 

  47. Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31(3):1695

    Article  CAS  Google Scholar 

  48. Frisch MJ et al (2009) Gaussian 09, Revision. D 01. Gaussian. Inc., Wallingford

    Google Scholar 

  49. Hariharan PC, Pople JA (1973) The influence of polarization functions on molecular orbital hydrogenation energies. Theor Chem Acc Theory Comput Model (Theor Chim Acta) 28(3):213–222

    Article  CAS  Google Scholar 

  50. Cossi M et al (2002) New developments in the polarizable continuum model for quantum mechanical and classical calculations on molecules in solution. J Chem Phys 117(1):43–54

    Article  CAS  Google Scholar 

  51. Mari F, Lahti P, McEwen W (1992) A theoretical study of the Wittig olefination reaction: MNDO-PM3 treatment of the Wittig half-reaction of unstabilized ylides and aldehydes. J Am Chem Soc 114(3):813–821

    Article  CAS  Google Scholar 

  52. Marí F, Lahti PM, McEwen WE (1991) Molecular modeling of the Wittig olefination reaction: part 2: A molecular orbital approach at the MNDO-PM3 level. Heteroat Chem 2(2):265–276

    Article  Google Scholar 

  53. Vedejs E, Marth C (1988) Mechanism of the Wittig reaction: the role of substituents at phosphorus. J Am Chem Soc 110(12):3948–3958

    Article  CAS  Google Scholar 

  54. Vedejs E, Marth C, Ruggeri R (1988) Substituent effects and the Wittig mechanism: the case of stereospecific oxaphosphetane decomposition. J Am Chem Soc 110(12):3940–3948

    Article  CAS  Google Scholar 

  55. Schlosser M, Schaub B (1982) Cis selectivity of salt-free Wittig reactions: a" Leeward Approach" of the aldehyde at the origin? J Am Chem Soc 104(21):5821–5823

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are deeply grateful to the University of Oran (Algeria) for computing resources, storage and computer time used on Haytham at the UCI (Unité de Calcul Intensif), and to the University of Reims Champagne Ardennes (URCA, France) for computing resources and computer time used on Romeo calculator and Al-Farabi Cluster of the Ecole Nationale Polytechnique Oran-Maurice Audin.

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  1. LCPM, Chemistry Department, Faculty of Sciences, University of Oran 1, Ahmed Benbella, 31000, Es-Senia, Oran, Algeria

    Abdelghani Adda, Ratiba Hadjadj Aoul, Hayat Sediki & Abdelghani Mohamed Krallafa

  2. Research Centre in Analytical Chemistry and Physics (CRAPC), Algiers RP, BP 248, 16004, Algiers, Algeria

    Abdelghani Adda & Moussa Sehailia

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  1. Abdelghani Adda
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AA: Calculation , Text-Presentation, Analysis, Graph & Tables, Discussion HS: Calculation, Graph & Tables SM: Calculation, Graph & Tables RHA: Calculation, Analysis AMK: Text-Presentation, Analysis, Graph & Tables, Discussion All authors reviewed the manuscript before submission.

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Adda, A., Aoul, R.H., Sediki, H. et al. Selectivity in the Wittig reaction within the ab initio static and metadynamics approaches. Theor Chem Acc 142, 102 (2023). https://doi.org/10.1007/s00214-023-03029-1

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