Elucidating the origin of selectivity of [3 + 2]-cycloaddition reactions between thioketone and carbohydrate-derived nitrones by the DFT

  • Junxia Yang
  • Yan Zhang
  • Yongsheng Yang
  • Ying XueEmail author
Original Paper


The mechanism and origin of selectivity for [3 + 2]-cycloaddition (32CA) reactions between thioketone and carbohydrate-derived nitrones in THF were investigated by using the density functional theory (DFT) at the M06-2X/6-311+G(d,p)//M06-2X/6-31+G(d,p) level of theory combined with the solvation SMD model. The calculated results revealed that the 32CA reactions proceed through the asynchronous one-step manner. For the chemoselectivity in thioketone, the C=S bond as a dipolarophile attacking three-atom-component (TAC) nitrone in reactivity was more preferential than the C=O bond. The theoretical results also confirmed the stereoselectivity of two 32CA reactions of thioketone with carbohydrate-derived nitrones with the anti-form product being more favored than the syn-form product, and the predicted anti/syn product ratios are in agreement with the experimental ones in literature. Furthermore, the analysis of the conceptual density functional theory reactivity indices showed that the 32CA reactions have polar character. Weak noncovalent interaction and Parr function analyses are used to reveal the origin of the stereoselectivity.

Graphical abstract

[3 + 2]-cycloaddition reactions between thioketone and carbohydrate-derived nitrones


Thioketone Carbohydrate-derived nitrones [3 + 2]-cycloaddition reactions Selectivity DFT calculation 



This project has been supported by the National Natural Science Foundation of China (Grant No. 21573153).

Supplementary material

894_2019_4104_MOESM1_ESM.docx (217 kb)
ESM 1 (DOCX 217 kb)


  1. 1.
    Caramella P, Grunanger, P (1984) In: Padwa A (ed) 1,3-Dipolar cycloaddition chemistry, vol. 1. Wiley, New YorkGoogle Scholar
  2. 2.
    Grigg R (1987) Prototropic routes to 1,3-and 1,5-dipoles, and 1,2-ylides: applications to the synthesis of heterocyclic compounds. Chem Sov Rev 16:89–121CrossRefGoogle Scholar
  3. 3.
    Tsuge O, Kanemasa S (1989) Recent advances in azomethine ylide chemistry. Adv Heterocycl Chem 45:231–349Google Scholar
  4. 4.
    Padwa A, Pearson WH (Eds) (2003) Synthetic applications of 1, 3-dipolar cycloaddition chemistry toward heterocycles and natural products, vol. 59. Wiley, New YorkGoogle Scholar
  5. 5.
    Jørgensen KA (Ed) (2002) Cycloaddition reactions in organic synthesis. WileyGoogle Scholar
  6. 6.
    Curtius T (1883) Ueber die Einwirkung von salpetriger Säure auf salzsauren Glycocolläther. Ber Dtsch Chem Ges 16(2):2230–2231CrossRefGoogle Scholar
  7. 7.
    Huisgen R (1963) 1,3-dipolar cycloadditions. Past and future. Angew Chem Int Ed Engl 2(10):565–598CrossRefGoogle Scholar
  8. 8.
    Domingo LR, Aurell MJ, Arnó M, Sáez JA (2007) Toward an understanding of the acceleration of Diels−Alder reactions by a pseudo-intramolecular process achieved by molecular recognition. A DFT study. J Org Chem 72(11):4220–4227CrossRefGoogle Scholar
  9. 9.
    Jones GO, Houk KN (2008) Predictions of substituent effects in thermal azide 1, 3-dipolar cycloadditions: implications for dynamic combinatorial (reversible) and click (irreversible) chemistry. J Org Chem 73(4):1333–1342CrossRefGoogle Scholar
  10. 10.
    Huisgen R, Fisera L, Giera H, Sustmann R (1995) Thiones as superdipolarophiles. Rates and equilibria of nitrone cycloadditions to thioketones. J Am Chem Soc 117(38):9671–9678CrossRefGoogle Scholar
  11. 11.
    Huisgen R, Langhals E (2006) 1, 3-dipolar cycloadditions of diphenyldiazomethane to thioketones: rate measurements disclose thiones to be superdipolarophiles. Heteroatom Chem 17(5):433–442CrossRefGoogle Scholar
  12. 12.
    Huisgen R, Li X, Giera H, Langhals E (2001) Thiobenzophenone S-methylide’(=(diphenylmethylidenesulfonio) methanide), and C, C multiple bonds: cycloadditions and dipolarophilic reactivities. Helv Chim Acta 84(5):981–999CrossRefGoogle Scholar
  13. 13.
    Mlostoń G, Heimgartner H (2006) Targets in heterocyclic systems—chemistry and propertiesGoogle Scholar
  14. 14.
    Gothelf KV, Jørgensen KA (1998) Asymmetric 1, 3-dipolar cycloaddition reactions. Chem. Rev. 98(2):863–910CrossRefGoogle Scholar
  15. 15.
    Simonsen KB, Bayon P, Hazell RG, Gothelf KV, Jørgensen KA (1999) Catalytic enantioselective inverse-electron demand 1, 3-dipolar cycloaddition reactions of nitrones with alkenes. J Am Chem Soc 121(16):3845–3853CrossRefGoogle Scholar
  16. 16.
    Buchlovič M, Hebanová S, Potáček M (2012) 1,3-dipolar cycloadditions of new 2,5-bifunctionalized five-membered cyclic nitrones. Tetrahedron 68(14):3117–3122CrossRefGoogle Scholar
  17. 17.
    Ríos-Gutiérrez M, Domingo LR (2019) Unravelling the mysteries of the [3+2] cycloaddition reactions. Eur. J. Org. Chem. 2019(2-3):267–282CrossRefGoogle Scholar
  18. 18.
    Domingo LR, Ríos-Gutiérrez M, Pérez P (2018) A molecular electron density theory study of the reactivity and selectivities in [3+2] cycloaddition reactions of C, N-dialkyl nitrones with ethylene derivatives. J Org Chem 83(4):2182–2197CrossRefGoogle Scholar
  19. 19.
    Black SC, Watson KG (1973) Nitrones and oxaziridines. IX. Cycloaddition reactions of nitrones with thioketones and the thermal and photochemical properties of some resulting 1, 4, 2-oxathiazolidines. Aust. J. Chem. 26(11):2491–2504CrossRefGoogle Scholar
  20. 20.
    Mlostoń G, Michalak A, Fruziński A, Jasiński M (2016) Stereoselective 1, 3-dipolar cycloadditions of thioketones to carbohydrate-derived nitrones. Tetrahedron Asymmetry 27(19):973–979CrossRefGoogle Scholar
  21. 21.
    Nacereddine AK, Layeb H, Chafaa F, Yahia W, Djerourou A, Domingo LR (2015) A DFT study of the role of the Lewis acid catalysts in the [3+2] cycloaddition reaction of the electrophilic nitrone isomer of methyl glyoxylate oxime with nucleophilic cyclopentene. RSC Adv. 5(79):64098–64105CrossRefGoogle Scholar
  22. 22.
    Roca-López D, Polo V, Tejero T, Merino P (2015) Understanding bond formation in polar one-step reactions. Topological analyses of the reaction between nitrones and lithium ynolates. J Org Chem 80(8):4076–4083CrossRefGoogle Scholar
  23. 23.
    Çelebi-Ölçüm N, Lam YH, Richmond E, Ling KB, Smith AD, Houk KN (2011) Pericyclic Cascade with chirality transfer: reaction pathway and origin of enantioselectivity of the hetero-Claisen approach to oxindoles. Angew Chem Int Edit 50(48):11478–11482CrossRefGoogle Scholar
  24. 24.
    Emamian S (2015) Understanding the molecular mechanism in a regiospecific [3+ 2] cycloaddition reaction including C–O and C–S interactions: an ELF topological analysis. RSC Adv. 5(89):72959–72970CrossRefGoogle Scholar
  25. 25.
    Yang X, Yang Y, Rees RJ, Yang Q, Tian Z, Xue Y (2016) How dirhodium catalyst controls the enantioselectivity of [3+ 2]-cycloaddition between nitrone and vinyldiazoacetate: a density functional theory study. J Org Chem 81(17):8082–8086CrossRefGoogle Scholar
  26. 26.
    Zhang Y, Yang Y, Zhao J, Xue Y (2018) Mechanism and Diastereoselectivity of [3+ 3] cycloaddition between enol diazoacetate and azomethine imine catalyzed by dirhodium tetracarboxylate: a theoretical study. Eur J Org Chem 2018(24):3086–3094CrossRefGoogle Scholar
  27. 27.
    Ríos-Gutiérrez M, Darù A, Tejero T, Domingo LR, Merino P (2017) A molecular electron density theory study of the [3+ 2] cycloaddition reaction of nitrones with ketenes. Org Biomol Chem 15(7):1618–1627CrossRefGoogle Scholar
  28. 28.
    Domingo LR (2016) Molecular electron density theory: a modern view of reactivity in organic chemistry. Molecules 21(10):1319CrossRefGoogle Scholar
  29. 29.
    Geerlings P, De Proft F, Langenaeker W (2003) Conceptual density functional theory. Chem Rev 103(5):1793–1874CrossRefGoogle Scholar
  30. 30.
    Domingo LR (2014) A new C–C bond formation model based on the quantum chemical topology of electron density. RSC Adv 4(61):32415–32428CrossRefGoogle Scholar
  31. 31.
    Contreras-García J, Johnson ER, Keinan S, Chaudret R, Piquemal JP, Beratan DN, Yang W (2011) NCIPLOT: a program for plotting noncovalent interaction regions. J Chem Theory Comput 7(3):625–632CrossRefGoogle Scholar
  32. 32.
    Lande DN, Bhadane SA, Gejji SP (2017) Noncovalent interactions accompanying encapsulation of resorcinol within azacalix [4] pyridine macrocycle. J Phys Chem A 121(8):1814–1824CrossRefGoogle Scholar
  33. 33.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani, G; Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2013) Gaussian 09, revision D.01. Gaussian, Inc., WallingfordGoogle Scholar
  34. 34.
    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(1–3):215–241Google Scholar
  35. 35.
    Zhao Y, Truhlar DG (2008) Density functionals with broad applicability in chemistry. Accounts Chem Res 41(2):157–167CrossRefGoogle Scholar
  36. 36.
    Gonzalez C, Schlegel HB (1990) Reaction path following in mass-weighted internal coordinates. J Phys Chem 94(14):5523–5527CrossRefGoogle Scholar
  37. 37.
    Ribeiro RF, Marenich AV, Cramer CJ, Truhlar DG (2011) Use of solution-phase vibrational frequencies in continuum models for the free energy of solvation. J Phys Chem B 115(49):14556–14562CrossRefGoogle Scholar
  38. 38.
    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(18):6378–6396CrossRefGoogle Scholar
  39. 39.
    Domingo L, Ríos-Gutiérrez M, Pérez P (2016) Applications of the conceptual density functional theory indices to organic chemistry reactivity. Molecules 21(6):748CrossRefGoogle Scholar
  40. 40.
    Dennington R, Keith T, Millam J (2009) GaussView, version 5. Semichem Inc., Shawnee MissionGoogle Scholar
  41. 41.
    Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33(5):580–592CrossRefGoogle Scholar
  42. 42.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38CrossRefGoogle Scholar
  43. 43.
    Domingo LR, Pérez P, Sáez JA (2013) Understanding the local reactivity in polar organic reactions through electrophilic and nucleophilic Parr functions. RSC Adv 3(5):1486–1494CrossRefGoogle Scholar
  44. 44.
    Domingo LR, Saéz JA, Zaragozá RJ, Arnó M (2008) Understanding the participation of quadricyclane as nucleophile in polar [2σ+ 2σ+ 2π] cycloadditions toward electrophilic π molecules. J Org Chem 73(22):8791–8799CrossRefGoogle Scholar
  45. 45.
    Cao Y, Houk KN (2011) Computational assessment of 1,3-dipolar cycloadditions to graphene. J Mater Chem 21(5):1503–1508CrossRefGoogle Scholar
  46. 46.
    Domingo LR, Ríos-Gutiérrez M, Pérez P (2018) A molecular electron density theory study of the role of the copper metalation of azomethine ylides in [3+2] cycloaddition reactions. J Org Chem 83(18):10959–10973CrossRefGoogle Scholar
  47. 47.
    Johnson ER, Keinan S, Mori-Sanchez P, Contreras-García J, Cohen AJ, Yang W (2010) Revealing noncovalent interactions. J Am Chem Soc 132(18):6498–6506CrossRefGoogle Scholar
  48. 48.
    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(7):611–618CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of Chemistry, Key Lab of Green Chemistry and Technology in Ministry of EducationSichuan UniversityChengduPeople’s Republic of China

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