Reactivity of pyrazole derivatives with halomethanes: A DFT theoretical study

  • Monia Chebbi
  • Youssef ArfaouiEmail author
Original Paper


The N-alkylation reaction of pyrazole derivatives with halomethanes was studied using density functional theory (DFT). The hybrid method B3LYP was employed, along with an ECP basis set such as LANL2DZ for halogen atoms (X = Cl, Br, I) and the 6–311 + G(d,p) basis set for all other atoms. In order to predict the specific site at which the pyrazole derivatives interact with halomethanes, local reactivity descriptors such as the Fukui functions were calculated. Detailed analysis of transition-state energies showed that alkylation occurred at the nitrogen atom N2 in the pyrazole derivatives, in agreement with the chemical reactivity results. The reaction mechanisms were elucidated by performing intrinsic reaction coordinate (IRC) calculations that considered the effects of the solvent and the species of halogen in the halomethane.


N-alkylation Pyrazoles Halomethanes Density functional theory Theoretical mechanism Reactivity 


  1. 1.
    Adnan AB, Hayam MAA, Yasser SAG, Alaa El-Din AB, Azza B (2008) Synthesisand biological evaluation of some thiazolyl and thiadiazolylderivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur J Med Chem 43(3):456–463.
  2. 2.
    Güniz Küçükgüzel Ş, Sevim R, Habibe E, Muammer K, Cevdet Ekinci A, Aylin V (2000) Synthesis, characterization and pharmacological properties of some 4-arylhydrazono-2-pyrazoline-5-one derivatives obtained from heterocyclic amines. Eur J Med Chem 35(7–8):761–771. CrossRefPubMedGoogle Scholar
  3. 3.
    Padmaja A, Payani T, Dinneswara Reddy G, Padmavathi V (2009) Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles, isoxazoles, pyrimidine and thioxopyrimidine derivatives. Eur J Med Chem 44(11):4557–4566. CrossRefPubMedGoogle Scholar
  4. 4.
    Venkat Ragavan R, Vijayakumar V, Suchetha Kumari N (2010) Synthesis and antimicrobial activities of novel 1,5-diaryl pyrazoles. Eur J Med Chem 45(3):1173–1180. CrossRefPubMedGoogle Scholar
  5. 5.
    Petra Č, Giang VT, Viktor M, André L, Soňa J, Marica T (2005) Utilization of 2-ethoxymethylene-3-oxobutanenitrile in the synthesis of heterocycles possessing biological activity. Tetrahedron 61(23):5379–5387Google Scholar
  6. 6.
    El-borai MA, Rizk HF, Abd-Aal MF, El-Deeb IY (2012) Synthesis of pyrazolo[3,4-b]pyridines under microwave irradiation in multicomponent reactions and their antitumor and antimicrobial activities. Eur J Med Chem 48:92–96.
  7. 7.
    Ronghui L et al (2007) Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents. Bioorg Med Chem Lett 17(15):4297–4302.
  8. 8.
    Bertrand C, Partick T, Christophe M, Aline P, Jacques C (2002) Synthesis and hypoglycemic evaluation of substituted pyrazole-4-carboxylic acids. Bioorg Med Chem Lett 12(16):2105–2108CrossRefGoogle Scholar
  9. 9.
    Govindarajulu B, Hui-Ming Y, Shyh-Ming Y, Jim-Min F (2004) Carbazolothiophene-2-carboxylic acid derivatives as endothelin receptor antagonists. Bioorg Med Chem Lett 14(5):1229–1234. CrossRefGoogle Scholar
  10. 10.
    Ashish KT, Anil M (2001) Synthesis and anti-inflammatory activities of N 4,N 5-disubstituted-3-methyl-1H-pyrazolo[3,4-c]pyridazines. Bioorg Med Chem 9(3):715–718.
  11. 11.
    Ka Young L, Jeong Mi K, Jae Nyoung K (2003) Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from Baylis–Hillman adducts. Tetrahedron Lett 44(35):6737–6740. CrossRefGoogle Scholar
  12. 12.
    Genin MJ, Biles C, Keiser BJ, Poppe SM, Swaney SM, Tarpley WG, Yagi Y, Romero DL (2000) Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives. J Med Chem 43(5):1034–1040CrossRefPubMedGoogle Scholar
  13. 13.
    Cheng GC (1969) Some pyrimidines of biological and medicinal interest. Prog Med Chem 6:37–147Google Scholar
  14. 14.
    Rajender SV (1999) Solvent-free organic syntheses using supported reagents and microwave irradiation. Green Chem 1:43–55.
  15. 15.
    Attarian OS, Matsoyan SG, Martirosyan SS (2005) Synthesis of N-vinylpyrazoles. Chem Heterocycl Compd 41(4):452–455Google Scholar
  16. 16.
    Attaryana OS, Baltayana AO, Sagatelyanb RE, Takmazyanb KTS (2008) Synthesis of 1-(2-aminoethyl) pyrazoles under phase-transfer catalysis. Russ J Gen Chem 78(1):136–138Google Scholar
  17. 17.
    Juan AA et al (2014) Structure–activity relationships (SAR) and structure–kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists. III: The role of a hydrogen-bond acceptor in long receptor residence times. Bioorg Med Chem Lett 24(21):5127–5133.
  18. 18.
    Goikhman R, Jacques TL, Sames D (2009) C-H bonds as ubiquitous functionality: a general approach to complex arylated pyrazoles via sequential regioselective C-arylation and N-alkylation enabled by SEM-group transposition. J Am Chem Soc 131(8):3042–3048CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Shiguang P, Jinhua L, Huanrong L, Zhenyu W, Xingwei G, Zhiping L (2010) Iron-catalyzed N-alkylation of azoles via oxidation of C-H bond adjacent to an oxygen atom. Org Lett 12(9):1932–1935CrossRefGoogle Scholar
  20. 20.
    Vanessa M, Josefina P, Vicenc B, Josep R (2005) Regioselective formation of N-alkyl-3,5-pyrazole derived ligands. A synthetic and computational study. Tetrahedron 61(52):12377–12385.
  21. 21.
    Khon W, Becke AD, Parr RG (1996) Density functional theory of electronic structure. J Phys Chem 100(31):12974–12980CrossRefGoogle Scholar
  22. 22.
    Frisch MJ et al (2009) Gaussian 09. Gaussian, Inc., WallingfordGoogle Scholar
  23. 23.
    Monia C, Hammouda C, Hedi M, Youssef A (2017) Theoretical and experimental study of the reaction of 2-guanidinobenzimidazole on a series of meta-substituted benzaldehydes. Chem Res Chin Univ 33(5):765–772CrossRefGoogle Scholar
  24. 24.
    Youssef A, Mohamed LE, Néji B (2013) Theoretical investigations on the mechanistic pathway of the thermal rearrangement of substituted N-acyl-2,2-dimethylaziridines. J Mol Model 19(10):4603–4612.
  25. 25.
    Chandra AK, Nguyen MT (2002) Use of local softness for the interpretation of reaction mechanisms. Int J Mol Sci 3(4):310–323CrossRefGoogle Scholar
  26. 26.
    Nazari F, Zali FR (2007). Density functional study of the relative reactivity of the carbonyl group in substituted cyclohexanone. J Mol Struct (THEOCHEM) 817(1–3):11–18.
  27. 27.
    Fukui K, Yonezawa T, Nagata C, Shingu H (1954) Molecular orbital theory of orientation in aromatic, heteroaromatic, and other conjugated molecules. J Chem Phys 22(8):1433–1442. CrossRefGoogle Scholar
  28. 28.
    Pearson RG (1976) Symmetry rules for chemical reactions. Wiley-Interscience, New YorkGoogle Scholar
  29. 29.
    Fukui K, Yonezawa T, Shingu H (1952) A molecular orbital theory of reactivity in aromatic hydrocarbons. J Chem Phys 20(4):722–725. CrossRefGoogle Scholar
  30. 30.
    Nakanishi W, Nakamoto T, Hayashi S, Sasamori T, Tokitoh N (2007) Atoms-in-molecules analysis of extended hypervalent five-center, six-electron (5c-6e) C2Z2O interactions at the 1,8,9-positions of anthraquinone and 9-methoxyanthracene systems. Chem Eur J 13(1):255–268Google Scholar
  31. 31.
    Nagao Y, Hirata T, Goto S, Sano S, Kakehi A, Iizuka K, Shiro M (1998) Intramolecularnonbonded S···O interaction recognized in (acylimino) thiadiazoline derivatives as angiotensin II receptor antagonists and related compounds. J Am Chem Soc 120(13):3104–3110. CrossRefGoogle Scholar
  32. 32.
    Burling FT, Goldstein BM (1992) Computational studies of nonbonded sulfur–oxygen and selenium–oxygen interactions in the thiazole and selenazole nucleosides. J Am Chem Soc 114(7):2313–2320.
  33. 33.
    Xin Guo X, Liu YW, Li QZ, Li WZ, Cheng JB (2015) Competition and cooperativity between tetrel bond and chalcogen bond in complexes involving F2CX (X = Se and Te). Chem Phys Lett 620(20):7–12. CrossRefGoogle Scholar
  34. 34.
    Weizhou W, Baoming J, Yu Z (2009) Chalcogen bond: a sister noncovalent bond to halogen bond. J Phys Chem A 113(28):8132–8135. CrossRefGoogle Scholar
  35. 35.
    Qing-Zhong L et al (2012) Competition of chalcogen bond, halogen bond, and hydrogen bond in SCS__HOX and SeCSe__HOX (X = Cl and Br) complexes. Comput Theor Chem 980:56–61. CrossRefGoogle Scholar
  36. 36.
    Upendra A, Steve S (2014) Effects of charge and substituent on the S···N chalcogen bond. J Phys Chem A 118(17):3183–3192. CrossRefGoogle Scholar
  37. 37.
    Luis Miguel A, Steve S (2014) Complexation of n SO2 molecules (n = 1, 2, 3) with formaldehyde and thioformaldehyde. J Chem Phys 140:1–10.
  38. 38.
    Cristina WN, Gilson Z, João BTR (2004) Organoselenium and organotellurium compounds: toxicology and pharmacology. Chem Rev 104(12):6255–6286. CrossRefGoogle Scholar
  39. 39.
    Qing-Zhong L et al (2012) Prediction and characterization of a chalcogen–hydride interaction with metal hybrids as an electron donor in F2CS–HM and F2CSe–HM (M = Li, Na, BeH, MgH, MgCH) complexes. Phys Chem Chem Phys 14(9):3025–3030.
  40. 40.
    Brezgunova ME et al (2013) Chalcogen bonding: experimental and theoretical determinations from electron density analysis. Geometrical preferences driven by electrophilic–nucleophilic interactions. Cryst Growth Des 13(8):3283–3289. CrossRefGoogle Scholar
  41. 41.
    Chi-Rung L, Ting-Hua T, Likey C, Chih-Chieh W, Yu W (2004) Topological analysis of charge density in heptasulfur imide (S7NH) from isolated molecule to solid. J Phys Chem Solids 65:1957–1966. CrossRefGoogle Scholar
  42. 42.
    Politzer P, Murray JS, Concha MC (2002) The complementary roles of molecular surface electrostatic potentials and average local ionization energies with respect to electrophilic processes. Int J Quantum Chem 88(1):19–27. CrossRefGoogle Scholar
  43. 43.
    Naray-Szabo G, Ferenczy GG (1995) Molecular electrostatics. Chem Rev 95(4):829–847. CrossRefGoogle Scholar
  44. 44.
    Murray JS, Politzer P (1998) Statistical analysis of the molecular surface electrostatic potential: an approach to describing noncovalent interactions in condensed phases. Theochem 425(1–2):107–114. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of Sciences, Laboratory of Physical Chemistry of Condensed MaterialsUniversity of Tunis El ManarTunisTunisia

Personalised recommendations