Unveiling the molecular mechanisms of the cycloaddition reactions of aryl hetaryl thioketones and C,N-disubstituted nitrilimines


Many synthetic routes to constructing biologically active heterocyclic compounds are made feasible through the (3 + 2) cycloaddition (32CA) reactions. Due to a large number of possible combinations of several heteroatoms from either the three-atom components (TACs) or the ethylene derivatives, the potential of the 32CA reactions in heterocyclic syntheses is versatile. Herein, the cycloaddition reaction of thiophene-2-carbothialdehyde derivatives and C,N-disubstituted nitrilimines have been studied through density functional theory (DFT) calculations at the B3LYP/6-311G(d,p) level of theory. In the present study, a one-step 32CA and two-step (4 + 3) cycloaddition (43CA) reaction mechanisms involved in TACs reactions and ethylene derivative have been investigated. In all reactions considered, the one-step 32CA cycloaddition is preferred over the two-step 43CA. The TAC chemoselectively adds across the thiocarbonyl group present in the ethylene derivative in a 32CA fashion to form the corresponding cycloadduct. Analysis of the electrophilic \( {P}_K^{+} \) and nucleophilic \( {P}_K^{-} \) Parr functions at the various reaction centers in the ethylene derivative show that the TAC adds across the atomic centers with the largest Parr functions, which is in total agreement with the experimental observation. The selectivities observed in the titled reactions are kinetically controlled.

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  1. 1.

    Y. Lan, K.N. Houk, Mechanism and stereoselectivity of the stepwise 1 , 3-dipolar cycloadditions between a thiocarbonyl ylide and electron-deficient dipolarophiles : a computational investigation, (2010) 17921–17927

  2. 2.

    V. Nair, T.D. Suja, Intramolecular 1 , 3-dipolar cycloaddition reactions in targeted syntheses, (2018). https://doi.org/10.1016/j.tet.2007.09.065

  3. 3.

    G.C. Tron, T. Pirali, R.A. Billington, P.L. Canonico, G. Sorba, A.A. Genazzani, Click chemistry reactions in medicinal chemistry : applications of the 1 , 3-dipolar cycloaddition between azides and alkynes, 28 (2007) 278–308. https://doi.org/10.1002/med

  4. 4.

    G.B. Pipim, E. Opoku, R. Tia, E. Adei, Peri-, chemo-, regio-, stereo- and enantio-selectivities of 1,3-dipolar cycloaddition reaction of C,N-disubstituted nitrones with disubstituted 4-methylene-1,3-oxazol-5(4H)- one: a quantum mechanical study, J. Mol. Graph. Model. 97 (2020) 107542. https://doi.org/10.1016/j.jmgm.2020.107542

  5. 5.

    E. Opoku, G. Arhin, G.B. Pipim, A.H. Adams, R. Tia, E. Adei, Site-, enantio- and stereo-selectivities of the 1,3-dipolar cycloaddition reactions of oxanorbornadiene with C,N-disubstituted nitrones and dimethyl nitrilimines: a DFT mechanistic study, Theor. Chem. Accounts 139 (2020) 16. https://doi.org/10.1007/s00214-019-2529-8

  6. 6.

    Opoku E, Baffour Pipim G, Tia R, Adei E (2020) Mechanistic study of the tandem intramolecular (4 + 2)/intermolecular (3 + 2) cycloaddition reactions for the formation of polyaza- and polyisoxazolidine-steroids. J. Heterocycl. Chem. 57:1748–1758. https://doi.org/10.1002/jhet.3900

    CAS  Article  Google Scholar 

  7. 7.

    B. Donkor, E. Opoku, Formation of steroid-type skeletons: an ubiquitous natural product, Adv. J. Chem. Sect. B. 2020 (2020) 209–213. https://doi.org/10.22034/ajcb.2020.113671

  8. 8.

    D.H. Ess, K.N. Houk, Theory of 1 , 3-Dipolar cycloadditions : distortion / interaction and frontier molecular orbital models, (2008) 10187–10198

  9. 9.

    L. F. Gera, R. Huisgen, I. Kalwinsch, E. Langhals, X. Li, G. moston, K. Polborn, J. Rapp, W. Sicking, R. Sustmann, New thione chemistry, 1996

  10. 10.

    Mlostoń G, Urbaniak K, Gębicki K, Grzelak P, Heimgartner H (2014) Hetaryl thioketones: synthesis and selected reactions. Heteroat Chem 25(6):548–555. https://doi.org/10.1002/hc.21191

  11. 11.

    Huisgen R, Rapp J (1997) 1,3-dipolar cycloadditions, 98. The chemistry of thiocarbonyl S-sulfides. Tetrahedron. 53:939–960. https://doi.org/10.1016/S0040-4020(96)01068-X

    CAS  Article  Google Scholar 

  12. 12.

    Mlosto G, Grzelak P, Mikina M, Linden A (2015). Hetero-Diels – Alder reactions of hetaryl and aryl thioketones with acetylenic dienophiles. https://doi.org/10.3762/bjoc.11.63

  13. 13.

    Huisgen R, Sustmannt R (1999) Thiones as superdipolarophiles. Rates and equilibria of nitrone cycloadditions:9671–9678. https://doi.org/10.1021/ja00143a008

  14. 14.

    G. Mlosto, A. Linden, H. Heimgartner, Synthesis of ferrocenyl-substituted 1 , 3-dithiolanes via [ 3 + 2 ] -cycloadditions of ferrocenyl hetaryl thioketones with thiocarbonyl S -methanides, (2016) 1421–1427. https://doi.org/10.3762/bjoc.12.136

  15. 15.

    K. Shioji, Ã.A. Matsumoto, M. Takao, Y. Kurauchi, T. Shigetomi, Y. Yokomori, K. Okuma, Cycloadditions of 3 , 4-dihydro-2 H -pyrrole N -oxide with thioketones and a selenoketone, 80 (2007) 743–746. https://doi.org/10.1246/bcsj.80.743

  16. 16.

    A. Michalak, A. Fruzin, M. Jasin, G. Mloston, Tetrahedron : asymmetry stereoselective 1 , 3-dipolar cycloadditions of thioketones to carbohydrate-derived nitrones, 27 (2016) 973–979. https://doi.org/10.1016/j.tetasy.2016.08.007

  17. 17.

    Mlostoń G, Grzelak P, Hamera-Fałdyga R, Jasiński M, Pipiak P, Urbaniak K, Albrecht Ł, Hejmanowska J, Heimgartner H (2017) Aryl, hetaryl, and ferrocenyl thioketones as versatile building blocks for exploration in the organic chemistry of sulfur, phosphorus. Sulfur Silicon Relat. Elem. 192:204–211. https://doi.org/10.1080/10426507.2016.1252368

    CAS  Article  Google Scholar 

  18. 18.

    Jain AK, Sharma S, Vaidya A, Ravichandran V, Agrawal RK (2013) 1,3,4-thiadiazole and its derivatives: a review on recent progress in biological activities. Chem. Biol. Drug Des. 81:557–576. https://doi.org/10.1111/cbdd.12125

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    M. D. Hanwell, D. E. Curtis, D. C. Lonie, T. Vandermeersch, E. Zurek G. R. Hutchison; “Avogadro: an advanced semantic chemical editor, visualization, and analysis platform” J. Cheminformatics 2012, 4:17. https://doi.org/10.1186/1758-2946-4-17

  20. 20.

    M. Clark, R.D. Cramer, N. Van Opdenbosch, Validation of the general purpose tripos 5.2 force field, J. Comput. Chem. 10 (1989) 982–1012. https://doi.org/10.1002/jcc.540100804

  21. 21.

    Opoku E, Tia R, Adei E (2019) DFT mechanistic study on tandem sequential [4 + 2]/[3 + 2] addition reaction of cyclooctatetraene with functionalized acetylenes and nitrile imines. J. Phys. Org. Chem. 32:e3992. https://doi.org/10.1002/poc.3992

    CAS  Article  Google Scholar 

  22. 22.

    Opoku E, Tia R, Adei E (2019) Computational studies on [4 + 2] / [3 + 2] tandem sequential cycloaddition reactions of functionalized acetylenes with cyclopentadiene and diazoalkane for the formation of norbornene pyrazolines. J. Mol. Model. 25:168. https://doi.org/10.1007/s00894-019-4056-x

    Article  PubMed  Google Scholar 

  23. 23.

    Opoku E, Tia R, Adei E (2019) Quantum chemical studies on the mechanistic aspects of tandem sequential cycloaddition reactions of cyclooctatetraene with ester and nitrones. J. Mol. Graph. Model. 92:17–31. https://doi.org/10.1016/j.jmgm.2019.06.019

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Schlegel HB (1982) Optimization of equilibrium geometries and transition structures. J. Comput. Chem. 3:214–218. https://doi.org/10.1002/jcc.540030212

    CAS  Article  Google Scholar 

  25. 25.

    Kudin KN, Scuseria GE, Cancès E (2002) A black-box self-consistent field convergence algorithm: one step closer. J. Chem. Phys. 116:8255. https://doi.org/10.1063/1.1470195

    CAS  Article  Google Scholar 

  26. 26.

    Hratchian HP, Schlegel HB (2004) Accurate reaction paths using a hessian based predictor–corrector integrator. J. Chem. Phys. 120:9918–9924. https://doi.org/10.1063/1.1724823

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    H.P.H. and, H.B. Schlegel, Using Hessian Updating To Increase the Efficiency of a Hessian Based Predictor-Corrector Reaction Path Following Method, (2004). https://doi.org/10.1021/CT0499783

  28. 28.

    Arhin G, Adams AH, Opoku E, Tia R, Adei E (2019) 1, 3-Dipolar cycloaddition reactions of selected 1,3-dipoles with 7-isopropylidenenorbornadiene and follow-up thermolytic cleavage: a computational study. J. Mol. Graph. Model. 92:267–279. https://doi.org/10.1016/j.jmgm.2019.08.004

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    E. Opoku, R. Tia, E. Adei, [ 3 + 2 ] versus [ 2 + 2 ] Addition : a density functional theory study on the mechanistic aspects of transition metal-assisted formation of 1 , 2-dinitrosoalkanes, J. Chem. 2016 (2016) 10 pages. doi.org/10.1155/2016/4538696

  30. 30.

    Borketey JB, Opoku E, Tia R, Adei E (2020) The mechanisms of gallium-catalysed skeletal rearrangement of 1,6-enynes – insights from quantum mechanical computations. J. Mol. Graph. Model. 94:107476. https://doi.org/10.1016/j.jmgm.2019.107476

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    C.Y. Legault, C. Y. CYLview, (2009). http://www.cylview.org

  32. 32.

    Gaussian 16, Revision B.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2016

  33. 33.

    Houk KN, Beno BR, Nendel M, Black K, Yoo HY, Wilsey S, Lee JK (1997) Exploration of pericyclic reaction transition structures by quantum mechanical methods: competing concerted and stepwise mechanisms. J. Mol. Struct. THEOCHEM 398–399:169–179. https://doi.org/10.1016/S0166-1280(96)04970-6

    Article  Google Scholar 

  34. 34.

    Tirado-Rives J, Jorgensen WL (2008) Performance of B3LYP density functional methods for a large set of organic molecules. J. Chem. Theory Comput. 4:297–306. https://doi.org/10.1021/ct700248k

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Wheeler SE, Moran A, Pieniazek SN, Houk KN (2009) Accurate reaction enthalpies and sources of error in DFT thermochemistry for aldol, mannich, and α-aminoxylation reactions. J. Phys. Chem. A 113:10376–10384. https://doi.org/10.1021/jp9058565

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Spectus CON, Zhao Y, Truhlar DG (2008) Density functionals with broad applicability in chemistry. Acc. Chem. Res. 41:157–167. https://doi.org/10.1021/ar700111a

    CAS  Article  Google Scholar 

  37. 37.

    Domingo LR, Aurell MJ, Pérez P, Contreras R (2002) Quantitative characterization of the global electrophilicity power of common diene/dienophile pairs in Diels-Alder reactions. Tetrahedron. 58:4417–4423. https://doi.org/10.1016/S0040-4020(02)00410-6

    CAS  Article  Google Scholar 

  38. 38.

    R.G. Parr, L. v. Szentpály, S. Liu, Electrophilicity Index, J. Am. Chem. Soc. 121 (1999) 1922–1924. https://doi.org/10.1021/ja983494x

  39. 39.

    Koopmans T (1934) Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den Einzelnen Elektronen Eines Atoms. Physica. 1:104–113. https://doi.org/10.1016/S0031-8914(34)90011-2

    Article  Google Scholar 

  40. 40.

    Domingo LR, Pe P, Pérez P, Sáez JA (2013) Understanding the local reactivity in polar organic reactions through electrophilic and nucleophilic Parr functions. RSC Adv. 3:1486–1494. https://doi.org/10.1039/c2ra22886f

    CAS  Article  Google Scholar 

  41. 41.

    Jaramillo P, Domingo LR, Chamorro E, Pérez P (2008) A further exploration of a nucleophilicity index based on the gas-phase ionization potentials. J. Mol. Struct. THEOCHEM 865:68–72. https://doi.org/10.1016/j.theochem.2008.06.022

    CAS  Article  Google Scholar 

  42. 42.

    L.R. Domingo, E. Chamorro, P. Pérez, Understanding the reactivity of captodative ethylenes in polar cycloaddition reactions. A theoretical study , J. Org. Chem. 73 (2008) 4615–4624. https://doi.org/10.1021/jo800572a

  43. 43.

    Domingo LR (2014) A new C-C bond formation model based on the quantum chemical topology of electron density. RSC Adv. 4:32415–32428. https://doi.org/10.1039/c4ra04280h

    CAS  Article  Google Scholar 

  44. 44.

    Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor—acceptor viewpoint. Chem. Rev. 88:899–926. https://doi.org/10.1021/cr00088a005

    CAS  Article  Google Scholar 

  45. 45.

    Reed AE, Weinstock RB, Weinhold F (1985) Natural population analysis. J. Chem. Phys. 83:735–746. https://doi.org/10.1063/1.449486

    CAS  Article  Google Scholar 

  46. 46.

    Ranck JP (2001) Modern physical chemistry: a molecular approach. J. Chem. Educ. 78:1024. https://doi.org/10.1021/ed078p1024

    CAS  Article  Google Scholar 

  47. 47.

    L.R. Domingo, F. Ghodsi, M. Ríos-Gutiérrez, A molecular electron density theory study of the synthesis of spirobipyrazolines through the domino reaction of nitrilimines with allenoates, Molecules. 24 (2019). https://doi.org/10.3390/molecules24224159

  48. 48.

    Domingo LR, Ríos-Gutiérrez M, Pérez P (2020) A molecular electron density theory study of the participation of tetrazines in aza-Diels-Alder reactions. RSC Adv. 10:15394–15405. https://doi.org/10.1039/d0ra01548b

    CAS  Article  Google Scholar 

  49. 49.

    Domingo LR, Kula K, Ríos-Gutiérrez M (2020) Unveiling the reactivity of cyclic azomethine ylides in [3+2] cycloaddition reactions within the molecular electron density theory. European J. Org. Chem. 2020:5938–5948. https://doi.org/10.1002/ejoc.202000745

    CAS  Article  Google Scholar 

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This work was made possible in part by a grant of high performance computing resources from the South Africa’s Centre for High-Performance Computing.

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Koachie Health Systems (KHS) funded this project through the basic and computational sciences research fund (KHS/MQC/2640/2020).

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Pipim, G.B., Opoku, E. Unveiling the molecular mechanisms of the cycloaddition reactions of aryl hetaryl thioketones and C,N-disubstituted nitrilimines. J Mol Model 27, 84 (2021). https://doi.org/10.1007/s00894-021-04706-3

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  • Nitrilimines
  • Thioketones
  • Cycloadditions
  • Molecular mechanism