Hydantoins and Mercaptoimidazoles: Vibrational Spectroscopy as a Probe of Structure and Reactivity in Different Environments, from the Isolated Molecule to Polymorphs

  • Rui FaustoEmail author
  • Gulce O. Ildiz
  • Elisa M. Brás
  • Bernardo A. Nogueira
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 26)


In this chapter, we highlight the power of vibrational spectroscopy as central technique to investigate the structure and reactivity of two relevant families of nitrogen-containing heterocyclic molecules: hydantoins and mercaptoimidazoles. Infrared spectroscopy is used in connection with the matrix isolation technique to investigate the structures of the isolated molecules and their photochemistry, while both infrared and Raman spectroscopies, supplemented by thermodynamics, microscopy, and diffraction techniques, are used to investigate neat condensed phases of the compounds and transitions between these phases. The experimental studies are supported by extensive computational studies, which include several approaches for detailed analysis of the electron density.



This investigation has been performed within the Project PTDC/QEQ-QFI/3284/2014–POCI-01-0145-FEDER-016617, funded by the Portuguese “Fundação para a Ciência e a Tecnologia” (FCT) and FEDER/COMPETE 2020-EU. The Coimbra Chemistry Centre (CQC) is supported by FCT, through the project UI0313/QUI/2013, also cofunded by FEDER/COMPETE 2020-EU. E.M.B. and B.A.N. thank FCT for the grant CCMAR/BI/0013/2017, within Project PTDC/MAR-BIO/4132/2014, and the Ph.D. grant SFRH/BD/129852/2017, respectively. R.F. and G.O.I. acknowledge the financial support through the project MATIS–Materiais e Tecnologias Industriais Sustentáveis (FCT and CENTRO-01-0145-FEDER-000014).


  1. 1.
    Whittle E, Dows DA, Pimentel GC (1954) Matrix isolation method for the experimental study of unstable species. J Chem Phys 22:1943–1944CrossRefGoogle Scholar
  2. 2.
    Norman I, Porter G (1954) Trapped atoms and radicals in a glass ‘cage’. Nature 174:508–509CrossRefGoogle Scholar
  3. 3.
    Holler TP, Ruan F, Spaltenstein A, Hopkins PB (1989) Total synthesis of marine mercaptohistidines: ovothiols A, B, and C. J Org Chem 54:4570–4575CrossRefGoogle Scholar
  4. 4.
    Hand CE, Honek JF (2005) Biological chemistry of naturally occurring thiols of microbial and marine origin. J Nat Prod 68:293–308CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Zoete V, Vezin H, Bailly F, Vergoten G, Catteau J-P, Bernier J-L (2000) 4-mercaptoimidazoles derived from the naturally occurring antioxidant ovothiols 2. Computational and experimental approach of the radical scavenging mechanism. Free Rad Res 32:525–533CrossRefGoogle Scholar
  6. 6.
    Crépin A, Wattier N, Petit S, Bischoff L, Fruit C, Marsais F (2009) Aminoacid-derived mercaptoimidazoles. Org Biomol Chem 7:128–134CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Nagasaka A, Hidaka H (1976) Effect of antithyroid agents 6-propyl-2-thiouracil and l-methyl-2-mercaptoimidazole on human thyroid iodide peroxidase. J Clin Endocrinol Metab 43:152–158CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Heath H, Toennies G (1958) The preparation and properties of ergothioneine disulphide. Biochem J 68:204–210CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Phan H, Lekin K, Winter SM, Oakley RT, Shatruk M (2013) Photoinduced solid state conversion of a radical σ-dimer to a π-radical pair. J Am Chem Soc 135:15674–15677CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Matsuzaki H, Fujita W, Awaga K, Okamoto H (2003) Photoinduced phase transition in an organic radical crystal with room-temperature optical and magnetic bistability. Phys Rev Lett 91:017403CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Brás EM, Fausto R (2018) An insight into methimazole phototautomerism: Central role of the thiyl radical and effect of benzo substitution. J Mol Struct. (in press)CrossRefGoogle Scholar
  12. 12.
    Brás EM, Fausto R (2018) Controlled light-driven switching in 2-thiobenzimidazole. J Photoch Photobio A 357:185–192CrossRefGoogle Scholar
  13. 13.
    Arunan E, Desiraju GR, Klein RA, Sadlej J, Scheiner S, Alkorta I, Clary DC, Crabtree RH, Dannenberg JJ, Hobza P, Kjaergaard HG, Legon AC, Mennucci B, Nesbitt DJ (2011) Definition of the hydrogen bond. Pure Appl Chem 83:1637–1641CrossRefGoogle Scholar
  14. 14.
    Lodochnikova OA, Bodrov AV, Saifina AF, Nikitina LE, Litvinov IA (2013) A new polymorph of methimazole: Single crystal and powder X-ray diffraction study. J Struct Chem 54:140–147CrossRefGoogle Scholar
  15. 15.
    Khan H, Badshah A, Shaheen F, Giek C, Qureshi RA (2008) 1-methyl-1H-benzimidazole-2(3H)-thione. Acta Cryst E 64:o1141CrossRefGoogle Scholar
  16. 16.
    Form GR, Raper ES, Downie TC (1976) The crystal and molecular structure of 2-mereaptobenzimidazole. Acta Cryst B 32:345–348CrossRefGoogle Scholar
  17. 17.
    Block SS (2003) Disinfection, sterilization and preservation, 4th edn. Lea & Febiger Inc., Philadelphia, USAGoogle Scholar
  18. 18.
    Kumar CSA, Kavitha CV, Vinaya K, Prasad SBB, Thimmegowda NR, Chandrappa S, Raghavan SC, Rangappa KS (2009) Synthesis and in vitro cytotoxic evaluation of novel diazaspiro bicyclo hydantoin derivatives in human leukemia cells: a SAR study. Invest New Drugs 27:327–337CrossRefGoogle Scholar
  19. 19.
    Kavitha CV, Nambiar M, Kumar CSA, Choudhary B, Muniyappa K, Rangappa KS, Raghavan SC (2009) Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells. Biochem Pharmacol 77:348–363CrossRefGoogle Scholar
  20. 20.
    Sarges R, Schnur RC, Belletire JL, Peterson MJ (1988) Spiro hydantoin aldose reductase inhibitors. J Med Chem 31:230–243CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Yang K, Tang Y, Iczkowski KA (2010) Phenyl-methylene hydantoins alter CD44-specific ligand binding of benign and malignant prostate cells and suppress CD44 isoform expression. Am J Transl Res 2:88–94PubMedPubMedCentralGoogle Scholar
  22. 22.
    Park HS, Choi HJ, Shin HS, Lee SK, Park MS (2007) Synthesis and characterization of novel hydantoins as potential COX-2 inhibitors: 1,5-Diarylhydantoins. Bull Korean Chem Soc 28:751–757CrossRefGoogle Scholar
  23. 23.
    Comber RN, Reynolds RC, Friedrich JD, Manguikian RA, Buckheit RW, Truss JW, Shannon WM, Secrist JA (1992) 5,5-disubstituted hydantoins: syntheses and anti-HIV activity. J Med Chem 35:3567–3572CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Cruz-Cabeza AJ, Schwalbe CH (2012) Observed and predicted hydrogen bond motifs in crystal structures of hydantoins, dihydrouracils and uracils. New J Chem 36:1347–1354CrossRefGoogle Scholar
  25. 25.
    Faris WM, Safi ZS (2014) Theoretical investigation of tautomerism stability of hydantoin in the gas phase and in the solution. Orient J Chem 30:1045–1054CrossRefGoogle Scholar
  26. 26.
    Ildiz GO, Nunes CM, Fausto R (2013) Matrix isolation infrared spectra and photochemistry of hydantoin. J Phys Chem A 117:726–734CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Ildiz GO, Boz I, Unsalan O (2012) FTIR spectroscopic and quantum chemical studies on hydantoin. Opt Spectrosc 112:665–670CrossRefGoogle Scholar
  28. 28.
    Nogueira BA, Ildiz GO, Canotilho J, Eusébio MES, Fausto R (2014) Molecular structure, infrared spectra, photochemistry, and thermal properties of 1-methylhydantoin. J Phys Chem A 118:5994–6008CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Nogueira BA, Ildiz GO, Henriques MSC, Paixão JA, Fausto R (2017) Structural and spectroscopic characterization of the second polymorph of 1-methylhydantoin. J Mol Struct 1148:111–118CrossRefGoogle Scholar
  30. 30.
    Nogueira BA, Ildiz GO, Canotilho J, Eusébio MES, Henriques MSC, Paixão JA, Fausto R (2017) 5-methylhydantoin: from isolated molecules in a low-temperature argon matrix to solid state polymorphs characterization. J Phys Chem A 121:5267–5279CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Rosado MTS, Lopes Jesus AJ, Reva ID, Fausto R, Redinha JS (2009) Conformational cooling dynamics in matrix-isolated 1,3-butanediol. J Phys Chem A 113:7499–7507CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Reva ID, Lopes Jesus AJ, Rosado MTS, Fausto R, Eusébio ME, Redinha JS (2006) Stepwise conformational cooling towards a single isomeric state in the four internal rotors system 1,2-butanediol. Phys Chem Chem Phys 8:5339–5349CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Reva I, Nowak MJ, Lapinski L, Fausto R (2015) Hydrogen atom transfer reactions in thiophenol: photogeneration of two new thione isomers. Phys Chem Chem Phys 17:4888–4898CrossRefPubMedCentralGoogle Scholar
  34. 34.
    Rostkowska H, Lapinski L, Khvorostov A, Nowak MJ (2003) Photochemical double-proton-transfer reactions in 2,6-dithiopurine. A matrix isolation study. J Phys Chem A 107:804–809CrossRefGoogle Scholar
  35. 35.
    Chmura B, Rode MF, Sobolewski AJ, Lapinski L, Nowak MJ (2008) A computational study on the mechanism of intramolecular oxo–hydroxy phototautomerism driven by repulsive πσ* state. J Phys Chem A 112:13655–13661CrossRefPubMedCentralGoogle Scholar
  36. 36.
    Bazargani MF, Talavat L, Naderi S, Khavasi HR (2011) 2-[(1H-Imidazol-2-yl)disulfanyl]-1H-imidazole. Acta Cryst E 67:o2585 CrossRefGoogle Scholar
  37. 37.
    Steed KM, Steed JW (2015) Packing problems: high Z′ -crystal structures and their relationship to cocrystals, inclusion compounds, and polymorphism. Chem Rev 115:2895–2933CrossRefGoogle Scholar
  38. 38.
    Rozenberg MS (1996) IR spectra and hydrogen bond energies of crystalline acid salts of carboxylic acids. Spectrochim Acta A 52:1559–1563CrossRefGoogle Scholar
  39. 39.
    Rozenberg MS, Shoham G, Reva I, Fausto R (2004) Low temperature FTIR spectroscopy and hydrogen bonding in cytosine polycrystals. Spectrochim Acta A 60:463–470CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Rui Fausto
    • 1
    Email author
  • Gulce O. Ildiz
    • 1
    • 2
  • Elisa M. Brás
    • 1
  • Bernardo A. Nogueira
    • 1
  1. 1.CQC, Department of ChemistryUniversity of CoimbraCoimbraPortugal
  2. 2.Department of Physics, Faculty of Sciences and LettersIstanbul Kultur UniversityIstanbulTurkey

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