The Theoretical and Experimental Study of DiazomethaneStyrene [3+2]-Cycloadditions

Authors

  • Serhii I. Shuvakin Enamine Ltd.; Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine
  • Serhii P. Ivonin Enamine Ltd.; Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine

DOI:

https://doi.org/10.24959/ophcj.25.326552

Keywords:

diazomethane, styrene, pyrazoline, cycloaddition, DFT calculations

Abstract

Pyrazolines are an important class of heterocyclic compounds known for their biological activities, making them attractive objects for medicinal chemistry. This study investigated the regioselective [3+2]-cycloaddition of diazomethane with para-substituted styrenes featuring electron-withdrawing (EWG) and electron-donating (EDG) groups. Experimental results have demonstrated that the electronic properties of substituents significantly affect the reaction efficiency and regioselectivity, as well as the product stability. At the same time, EWG provided lower activation barriers and higher reaction yields. Calculations performed by the density functional theory (DFT) method confirmed the experimental data allowing us to understand in detail the reaction mechanism, activation energy values, and thermodynamic parameters. This integrated experimental and theoretical approach improves understanding of the effects of substituents, contributing to the rational design of substituted pyrazolines.

Supporting Agency

  • The work was supported by the National Research Foundation of Ukraine (grant No. 0124U003838).

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References

  1. Shaaban, M. R.; Mayhoub, A. S.; Farag, A. M. Recent Advances in the Therapeutic Applications of Pyrazolines. Expert Opinion on Therapeutic Patents 2012, 22 (3), 253 – 291. https://doi.org/10.1517/13543776.2012.667403.
    | |
  2. Auwers, K.; König, F. Über Den Aufbau von Pyrazolin-carbonsäureestern. Justus Liebigs Ann. Chem. 1932, 496 (1), 27 – 51. https://doi.org/10.1002/jlac.19324960103.
  3. Westermann, T.; Mleczko, L. Heat Management in Microreactors for Fast Exothermic Organic Syntheses—First Design Principles. Org. Process Res. Dev. 2016, 20 (2), 487 – 494. https://doi.org/10.1021/acs.oprd.5b00205.
    |
  4. Kemsley, J. FIRM FINED FOR CHEMIST’S DEATH: SAFETY: Sepracor Canada Admits Lack of Lab Ventilation in Worker Fatality Case. Chem. Eng. News Archive 2011, 89 (19), 15. https://doi.org/10.1021/cen-v089n019.p015.
  5. Pendiukh, V. V.; Yakovleva, H. V.; Stadniy, I. A.; Pashenko, A. E.; Rusanov, E. B.; Grabovaya, N. V.; Kolotilov, S. V.; Rozhenko, A. B.; Ryabukhin, S. V.; Volochnyuk, D. M. Practical Synthetic Method for Amino Acid-Derived Diazoketones Shelf-Stable Reagents for Organic Synthesis. Org. Process Res. Dev. 2024, 28 (1), 165 – 176. https://doi.org/10.1021/acs.oprd.3c00230.
    |
  6. Bastide, J.; Henri-Rousseau, O.; Aspart-Pascot, L. Cycloaddition des diazoalcanes sur les alcenes et alcynes disubstitues. Tetrahedron 1974, 30 (18), 3355 – 3363. https://doi.org/10.1016/S0040-4020(01)97513-1.
    |
  7. Sammakia, T.; Ramazanov, I. R.; Yaroslavova, A. V. Diazomethane, CAS No. 334-88-3. In Encyclopedia of Reagents for Organic Synthesis; 2021; pp 1 – 12. https://doi.org/10.1002/047084289X.rd017.pub2.
  8. Jmol: An Open-Source Java Viewer for Chemical Structures in 3D; Jmol Development Team; https://jmol.sourceforge.net/ (accessed Nov 28, 2024).
  9. Canepa, P.; Hanson, R. M.; Ugliengo, P.; Alfredsson, M. J-ICE : A New Jmol Interface for Handling and Visualizing Crystallographic and Electronic Properties. J Appl Crystallogr 2011, 44 (1), 225 – 229. https://doi.org/10.1107/S0021889810049411.
    |
  10. Neese, F. The ORCA Program System. WIREs Comput Mol Sci 2012, 2 (1), 73 – 78. https://doi.org/10.1002/wcms.81.
    |
  11. Neese, F. Software Update: The ORCA Program System, Version 4.0. WIREs Comput Mol Sci 2018, 8 (1), e1327. https://doi.org/10.1002/wcms.1327.
    |
  12. Becke, A. D. Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Phys. Rev. A 1988, 38 (6), 3098 – 3100. https://doi.org/10.1103/PhysRevA.38.3098.
    | |
  13. Perdew, J. P. Density-Functional Approximation for the Correlation Energy of the Inhomogeneous Electron Gas. Phys. Rev. B 1986, 33 (12), 8822 – 8824. https://doi.org/10.1103/PhysRevB.33.8822.
    | |
  14. Whitten, J. L. Coulombic Potential Energy Integrals and Approximations. The Journal of Chemical Physics 1973, 58 (10), 4496 – 4501. https://doi.org/10.1063/1.1679012.
    |
  15. Dunlap, B. I.; Connolly, J. W. D.; Sabin, J. R. On Some Approximations in Applications of X α Theory. The Journal of Chemical Physics 1979, 71 (8), 3396 – 3402. https://doi.org/10.1063/1.438728.
    |
  16. Vahtras, O.; Almlöf, J.; Feyereisen, M. W. Integral Approximations for LCAO-SCF Calculations. Chemical Physics Letters 1993, 213 (5 – 6), 514 – 518. https://doi.org/10.1016/0009-2614(93)89151-7.
    |
  17. Eichkorn, K.; Treutler, O.; Öhm, H.; Häser, M.; Ahlrichs, R. Auxiliary Basis Sets to Approximate Coulomb Potentials. Chemical Physics Letters 1995, 240 (4), 283 – 290. https://doi.org/10.1016/0009-2614(95)00621-A.
    |
  18. Zhao, Y.; Truhlar, D. G. 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 Account 2008, 120 (1 – 3), 215 – 241. https://doi.org/10.1007/s00214-007-0310-x.
    |
  19. Schäfer, A.; Huber, C.; Ahlrichs, R. Fully Optimized Contracted Gaussian Basis Sets of Triple Zeta Valence Quality for Atoms Li to Kr. The Journal of Chemical Physics 1994, 100 (8), 5829 – 5835. https://doi.org/10.1063/1.467146.
    |
  20. Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient, Approximate and Parallel Hartree–Fock and Hybrid DFT Calculations. A ‘Chain-of-Spheres’ Algorithm for the Hartree–Fock Exchange. Chemical Physics 2009, 356 (1 – 3), 98 – 109. https://doi.org/10.1016/j.chemphys.2008.10.036.
    |
  21. Cammi, R.; Mennucci, B.; Tomasi, J. Fast Evaluation of Geometries and Properties of Excited Molecules in Solution: A Tamm-Dancoff Model with Application to 4-Dimethylaminobenzonitrile. J. Phys. Chem. A 2000, 104 (23), 5631 – 5637. https://doi.org/10.1021/jp000156l.
    |
  22. Schäfer, A.; Horn, H.; Ahlrichs, R. Fully Optimized Contracted Gaussian Basis Sets for Atoms Li to Kr. The Journal of Chemical Physics 1992, 97 (4), 2571 – 2577. https://doi.org/10.1063/1.463096.
    |

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Published

2025-05-15

How to Cite

(1)
Shuvakin, S. I.; Ivonin, S. P. The Theoretical and Experimental Study of DiazomethaneStyrene [3+2]-Cycloadditions. J. Org. Pharm. Chem. 2025, 23, 49-55.

Issue

Vol. 23 No. 1 (2025)

Section

Original Researches

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