Journal of Molecular Modeling

, 24:309 | Cite as

Theoretical investigation of the regioselective ring opening of 2-methylaziridine. Lewis acid effect

  • Emna CherniEmail author
  • Khaled Essalah
  • Néji Besbes
  • Manef Abderrabba
  • Sameh Ayadi
Original Paper


The formation of substituted 1,2-diamines via the regiospecific nucleophilic ring opening of 2-methylaziridine with methylamine was performed by nucleophilic attack at aziridine carbon atoms. A detailed theoretical study was investigated by density functional theory (DFT) at the B3LYP level and second order Moller Plesset perturbation theory (MP2) by using the 6-311G(d,p) basis set. The third Grimme correction term (D3) was used to take into account weak interactions. Solvent effects were computed in methanol and dimethylsulfoxide using the polarizable continuum model (PCM). Emphasis was placed on the ring opening mechanisms of neutral aziridines and aziridinium ions obtained through N-complexation with the BF3 Lewis acid. Moreover, the effect of substituent groups on the regioselectivity of the ring opening was investigated. The nucleophilic attack was carried out via two pathways (frontside attack M1 and backside attack M2) where activation barriers proved the preference for ring opening through the backside attack at the C3 aziridine carbon atom. The obtained results showed that the frontside attack with methylamine takes place along a concerted mechanism that leads to formation of products through one transition state. However, the backside attack is carried via a stepwise process in which the methylamine attack takes place in an SN2 fashion where the leaving group is the ring nitrogen. It first conduces a ring opening considered as the rate-determining step followed by formation of a zwitterionic intermediate. This latter undergoes a rotation to allow the proton transfer step and finally leads to formation of the thermodynamic products.


Aziridine Ring opening Nitrogen inversion Activation energy 



The authors gratefully acknowledge the support provided by the Tunisian Ministry of Higher Education and Scientific Research and would like to thank Professor Bahoueddine Tangour for valuable insights and recommendations.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

894_2018_3833_MOESM1_ESM.pdf (1 mb)
ESM 1 (PDF 1.02 MB)


  1. 1.
    Sweeney JB (2002) Aziridines: epoxides’ ugly cousins? Chem Soc Rev 31:247–258CrossRefGoogle Scholar
  2. 2.
    Zwanenburg B, Holte PT (2001) The synthetic potential of three-membered ring aza-heterocycles. Top Curr Chem 216:93–124CrossRefGoogle Scholar
  3. 3.
    Budzisz E, Bobka R, Hauss A, Roedel JN, Wirth S, Lorenz IP, Rozalska B, WięckowskaSzakiel M, Krajewska U, Rozalski M (2012) Synthesis, structural characterization, antimicrobial and cytotoxic effects of aziridine, 2-aminoethylaziridine and azirine complexes of copper (II) and palladium (II). Dalton Trans 41:5925–5933CrossRefGoogle Scholar
  4. 4.
    Mao H, Jeong H, Yang J, Ha HJ, Yang JW (2018) Preparation of chiral contiguous epoxyaziridines and their regioselective ring-opening for drug synthese. Chem Eur J 24:2370–2374CrossRefGoogle Scholar
  5. 5.
    Noll DM, Mason TM, Miller PS (2006) Formation and repair of interstrand cross-links in DNA. Chem Rev 106:277–301CrossRefGoogle Scholar
  6. 6.
    Rajeshwari B, Kalaiselvan A, Senthilnathan D (2018) Ab initio and DFT investigations on the ring opening of aziridines using singlet unsaturated carbenes. J Chem Theory Comput 1126:1–6CrossRefGoogle Scholar
  7. 7.
    Phung C, Tantillo DJ, Hein J, Pinha AR (2017) The mechanism of the reaction between an aziridine and carbon dioxide with no added catalyst. J Phys Org Chem 31:1–7Google Scholar
  8. 8.
    Lugiņina J, Turks M (2016) Non-activated aziridines as building blocks for the synthesis of aza-heterocycles. Chem Heterocycl Compd 52:773–775CrossRefGoogle Scholar
  9. 9.
    Jung JH, Kim S, Eum H, Lee WK, Ha HJ (2017) N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile. Tetrahedron 73:5993–5999CrossRefGoogle Scholar
  10. 10.
    Watson ID, Yu L, Yudin K (2006) Advances in nitrogen transfer reactions involving aziridines. Acc Chem Res 39:194–206CrossRefGoogle Scholar
  11. 11.
    Paz MM, Kumar GS, Glover M, Waring MJ, Tomasz M (2004) Mitomycin dimers: polyfunctional cross-linkers of DNA. J Med Chem 47:3308–3319CrossRefGoogle Scholar
  12. 12.
    Bruzaca EES, Lopes IC, Silva EHC, Carvalho PAV, Tanaka AA (2017) Electrochemical oxidation of the antitumor antibiotic mitomycin C and in situ evaluation of its interaction with DNA using a DNA-electrochemical biosensor. Microchem J 133:81–89CrossRefGoogle Scholar
  13. 13.
    Bosschieter J, Nieuwenhuijzen JA, Van Ginkel T, Vis AN, Witte B, Newling D, Beckers GMA, Moorselaar RJAV (2017) Value of an immediate Intravesical instillation of mitomycin C in patients with non–muscle-invasive bladder cancer: a prospective multicentre randomised study in 2243 patients. Eur Urol 73(2):226–232CrossRefGoogle Scholar
  14. 14.
    Torabifard H, Fattahi A (2013) DFT study on thiotepa and tepa interactions with their DNA receptor. Struct Chem 24:1–11CrossRefGoogle Scholar
  15. 15.
    Peng YC, Kuo HS, Tsai HD, Yang YP, Lin YL (2006) The lethal effect of bis-type azridinylnaphthoquinone derivative on oral cancer cells (OEC-M1) associated with anti-apoptotic protein bcl-2. Bioorg Med Chem 14:263–272CrossRefGoogle Scholar
  16. 16.
    Lwowsky W (1967) Nitrenes and the decomposition of carbonylazides. Angew Chem Int Ed Engl 6:897–1012CrossRefGoogle Scholar
  17. 17.
    Concellón JM, Riego E (2003) Ring opening of nonactivated 2-(1-Aminoalkyl) aziridines: unusual regio- and stereoselective C-2 and C-3 cleavage. J Org Chem 68:6407–6410CrossRefGoogle Scholar
  18. 18.
    D’hooghe M, Van Speybroeck V, Waroquier M, De Kimpe N (2006) Regio- and stereospecific ring opening of 1,1-dialkyl-2-(aryloxymethyl)aziridinium salts by bromide. Chem Commun 14:1554–1556CrossRefGoogle Scholar
  19. 19.
    Yu WL, Chen JQ, Wei YL, Wang ZY, Xu PF (2018) Alkene functionalization for the stereospecific synthesis of substituted aziridines by visible-light photoredox catalysis. Chem Commun 54:1948–1951CrossRefGoogle Scholar
  20. 20.
    Li Z, Conser KR, Jacobsen EN (1993) Asymmetric alkene aziridination with readily available chiral diimine-based catalysts. J Am Chem Soc 115:5326. 1CrossRefGoogle Scholar
  21. 21.
    Missaoui D, Rahmouni A, Bensaid O, Besbes N (2017) Conformational-dependent reaction mechanism: case of acid hydrolysis of N-benzoyl-9-azabicyclo[6.1.0]non-4-ene. Can J Chem 95:37–44CrossRefGoogle Scholar
  22. 22.
    Berger G (2013) Using conceptual density functional theory to rationalize regioselectivity: a case study on the nucleophilic ring-opening of activated aziridines. Comput Theor Chem 1010:11–18CrossRefGoogle Scholar
  23. 23.
    Hu XE (2004) Nucleophilic ring opening of aziridines. Tetrahedron 60:2701–2743CrossRefGoogle Scholar
  24. 24.
    Huang YY, Lv ZC, Yang X, Wang ZL, Zou XX, Zhao ZN, Chen F (2017) Nucleophilic ring opening of aziridines with amines under catalyst- and solvent-free conditions. Green Chem 19:924–927CrossRefGoogle Scholar
  25. 25.
    Bornholdt J, Felding J, Clausen RP, Kristensen JL (2010) Ring opening of pymisyl-protected aziridines with organocuprates. Chem Eur J 16:12474–12480CrossRefGoogle Scholar
  26. 26.
    Ottesen LK, Jaroszewski JW, Franzyk H (2010) Ring opening of a resin-bound chiral aziridine with phenol nucleophiles. J Org Chem 75:4983–4991CrossRefGoogle Scholar
  27. 27.
    Sureshkumar D, Ganesh V, Vidyarini RS, Chandrasekaran S (2009) Direct synthesis of functionalized unsymmetrical β-Sulfonamido disulfides by tetrathiomolybdate mediated aziridine ring-opening reactions. J Org Chem 74:7958–7961CrossRefGoogle Scholar
  28. 28.
    Ghorai MK, Kumar A, Tiwari DP (2010) BF3·OEt2-mediated highly regioselective SN2-type ring-opening of N-activated aziridines and N-activated azetidines by tetraalkylammonium halides. J Org Chem 75:137–151CrossRefGoogle Scholar
  29. 29.
    Isobe T, Oriyama T (2016) Ring-opening reaction of aziridines with amines under the influence of dimethyl sulfoxide. Tetrahedron Lett 57:2849–2852CrossRefGoogle Scholar
  30. 30.
    Zhang YQ, Vogelsang E, Qu ZW, Grimme S, Gansauer A (2017) Titanocene-catalyzed radical opening of N-acylated aziridines. Angew Chem Int Ed 56:12654–12657CrossRefGoogle Scholar
  31. 31.
    Metro TX, Duthion B, Pardo DG, Cossy J (2010) Rearrangement of β-amino alcohols via aziridiniums: a review. Chem Soc Rev 39:89–102CrossRefGoogle Scholar
  32. 32.
    Boydas EB, Tanriver G, D’hooghe M, Ha HJ, Van Speybroeckd V, Catak S (2018) Theoretical insight into the regioselective ring-expansions of bicyclic aziridinium ions. Org Biomol Chem 16:796–806CrossRefGoogle Scholar
  33. 33.
    Lu Y (2014) Nitric oxide-releasing chitosan oligosaccharides as antibacterial agents. Biomaterials 35:1716–1724CrossRefGoogle Scholar
  34. 34.
    Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789CrossRefGoogle Scholar
  35. 35.
    Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652CrossRefGoogle Scholar
  36. 36.
    Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J Chem Phys 132:154104–154113CrossRefGoogle Scholar
  37. 37.
    Gaussian 09, Revision A.02, Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich A, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA 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, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2016) Gaussian Inc., WallingfordGoogle Scholar
  38. 38.
    Fukui K (1981) The path of chemical reactions - the IRC approach. Acc Chem Res 14:363–368CrossRefGoogle Scholar
  39. 39.
    Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3094CrossRefGoogle Scholar
  40. 40.
    Stamm H, Assithianakis P, Weiss R, Bentz G, Buchholz B (1984) Electron attachment to N-benzoylaziridines followed by C–N homolysis of the aziridine ring. J Chem Soc Chem Commun:753–754Google Scholar
  41. 41.
    Padwa A, Battisti A (1971) Isolation and chemistry of the invertomers of N-chlorobenzoylphenylaziridine. J Org Chem 36:230–231CrossRefGoogle Scholar
  42. 42.
    Krueger P, Jan J (1970) Conformational equilibria in some cyclic imines: NH and CH. Stretching vibrations and the axial lone pair. Can J Chem 48:3236–3248CrossRefGoogle Scholar
  43. 43.
    Boggs GR, Gerig JT (1969) Nitrogen inversion in N-benzoylaziridines. J Org Chem 34:1484–1486CrossRefGoogle Scholar
  44. 44.
    Andose JD, Lehn JM, Mislow K, Wagner J (1970) Effect of substituents on the rate of pyramidal inversion of 1-aryl-2,2-dimethylaziridines. J Am Chem Soc 92:4050–4056CrossRefGoogle Scholar
  45. 45.
    Catak S, Dhooghe M, Verstraelen T, Hemelsoet K, Nieuwenhove AV, Ha HJ, Waoquier M, De Kimpe N, Van Speybroeck V (2010) Opposite regiospecific ring opening of 2-(cyanomethyl)aziridines by hydrogen bromide and benzyl bromide: experimental study and theoretical rationalization. J Og Chem 75:4530–4541CrossRefGoogle Scholar
  46. 46.
    Pearson WH, Lian BW, Bergmeier SC (1996) Aziridines and azirines monocyclic. In: Padwa A (ed) Comprehensive heterocyclic chemistry II. Pergamon, Oxford, p 1Google Scholar
  47. 47.
    Bourkhis M, Ayadi S, Abderrahim R (2017) Thermodynamic and orbital studies of the reactivity of amidine with phosphoryl chloride and thionyl chloride. J Struct Chem 28:1953–1958CrossRefGoogle Scholar
  48. 48.
    Bucholz B, Stamm H (1986) Reactions with aziridines, XXXII[1]. Mechanistic aspects in nucleophilic opening of three-membered rings. Alcoholyses of activated aziridines. Israel J Chem 27:17–23CrossRefGoogle Scholar
  49. 49.
    Méndez PS, Cachau RE, Seoane G, Ventura ON (2009) Regioselective epoxide ring-opening using boron trifluoride diethyl etherate: DFT study of an alternative mechanism to explain the formation of syn-fluorohydrins. J Mol Struct THEOCHEM 904:21–27CrossRefGoogle Scholar
  50. 50.
    Stanković S, D’hooghe M, Catak S, Eum H, Waroquier M, Van Speybroeck V, De Kimpe N, Ha J (2012) Regioselectivity in the ring opening of non-activated aziridines. Chem Soc Rev 41:643–665CrossRefGoogle Scholar
  51. 51.
    Dwivedi SK, Ghandi S, Rastogi N, Singh VK (2007) Lewis acid catalyzed ring opening of azetidines with alcohols and thiols. Tetrahedron Lett 48:5375–5377CrossRefGoogle Scholar
  52. 52.
    Concellon JM, Riego E, Suarez JR, Garcia-Granda S, Rosario Diaz M (2004) Synthesis of enantiopure imidazoline through a Ritter reaction of 2-(1-Aminoalkyl)-aziridine with nitriles. Org Lett 6:4499–4501CrossRefGoogle Scholar
  53. 53.
    Concellon JM, Bernad PL, Suárez JR, Granda S, Rosario Díaz M (2005) Selective ring-opening of nonactivated amino aziridines by thiols and unusual nucleophilic substitution of a dibenzylamino group. J Org Chem 70:9411–9416CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Emna Cherni
    • 1
    • 2
    Email author
  • Khaled Essalah
    • 3
  • Néji Besbes
    • 4
  • Manef Abderrabba
    • 2
  • Sameh Ayadi
    • 2
    • 5
  1. 1.Université de Tunis El Manar, Faculté des Sciences de TunisTunisTunisie
  2. 2.Université de Carthage, LR11ES22, Laboratoire Matériaux Molécules et Applications (LMMA), IPEST, BP51La MarsaTunisie
  3. 3.Université de Tunis El Manar, Unité de Recherche en Sciences Fondamentales et Didactiques- Equipe de chimie théorique et réactivité, (UR14ES10) IPEI El ManarTunisTunisie
  4. 4.Laboratoire Matériaux Composites et Minéraux Argileux - Groupe de Chimie Organique Verte et Appliquée (LMCMA), Centre National de Recherches en Sciences des Matériaux, Technopole Borj CédriaSolimanTunisie
  5. 5.Institut National des Sciences et Technologies de la Mer (INSTM), Laboratoire Milieu Marin, Centre la GouletteLa GouletteTunisie

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