Abstract
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.
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References
Sweeney JB (2002) Aziridines: epoxides’ ugly cousins? Chem Soc Rev 31:247–258
Zwanenburg B, Holte PT (2001) The synthetic potential of three-membered ring aza-heterocycles. Top Curr Chem 216:93–124
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 41:5925–5933
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 24:2370–2374
Noll DM, Mason TM, Miller PS (2006) Formation and repair of interstrand cross-links in DNA. Chem Rev 106:277–301
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 1126:1–6
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 31:1–7
Lugiņina J, Turks M (2016) Non-activated aziridines as building blocks for the synthesis of aza-heterocycles. Chem Heterocycl Compd 52:773–775
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 73:5993–5999
Watson ID, Yu L, Yudin K (2006) Advances in nitrogen transfer reactions involving aziridines. Acc Chem Res 39:194–206
Paz MM, Kumar GS, Glover M, Waring MJ, Tomasz M (2004) Mitomycin dimers: polyfunctional cross-linkers of DNA. J Med Chem 47:3308–3319
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 133:81–89
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):226–232
Torabifard H, Fattahi A (2013) DFT study on thiotepa and tepa interactions with their DNA receptor. Struct Chem 24:1–11
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 14:263–272
Lwowsky W (1967) Nitrenes and the decomposition of carbonylazides. Angew Chem Int Ed Engl 6:897–1012
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 68:6407–6410
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 14:1554–1556
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 54:1948–1951
Li Z, Conser KR, Jacobsen EN (1993) Asymmetric alkene aziridination with readily available chiral diimine-based catalysts. J Am Chem Soc 115:5326. 1
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 95:37–44
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 1010:11–18
Hu XE (2004) Nucleophilic ring opening of aziridines. Tetrahedron 60:2701–2743
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 19:924–927
Bornholdt J, Felding J, Clausen RP, Kristensen JL (2010) Ring opening of pymisyl-protected aziridines with organocuprates. Chem Eur J 16:12474–12480
Ottesen LK, Jaroszewski JW, Franzyk H (2010) Ring opening of a resin-bound chiral aziridine with phenol nucleophiles. J Org Chem 75:4983–4991
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 74:7958–7961
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 75:137–151
Isobe T, Oriyama T (2016) Ring-opening reaction of aziridines with amines under the influence of dimethyl sulfoxide. Tetrahedron Lett 57:2849–2852
Zhang YQ, Vogelsang E, Qu ZW, Grimme S, Gansauer A (2017) Titanocene-catalyzed radical opening of N-acylated aziridines. Angew Chem Int Ed 56:12654–12657
Metro TX, Duthion B, Pardo DG, Cossy J (2010) Rearrangement of β-amino alcohols via aziridiniums: a review. Chem Soc Rev 39:89–102
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 16:796–806
Lu Y (2014) Nitric oxide-releasing chitosan oligosaccharides as antibacterial agents. Biomaterials 35:1716–1724
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 37:785–789
Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652
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 132:154104–154113
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., Wallingford
Fukui K (1981) The path of chemical reactions - the IRC approach. Acc Chem Res 14:363–368
Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3094
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:753–754
Padwa A, Battisti A (1971) Isolation and chemistry of the invertomers of N-chlorobenzoylphenylaziridine. J Org Chem 36:230–231
Krueger P, Jan J (1970) Conformational equilibria in some cyclic imines: NH and CH. Stretching vibrations and the axial lone pair. Can J Chem 48:3236–3248
Boggs GR, Gerig JT (1969) Nitrogen inversion in N-benzoylaziridines. J Org Chem 34:1484–1486
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 92:4050–4056
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 75:4530–4541
Pearson WH, Lian BW, Bergmeier SC (1996) Aziridines and azirines monocyclic. In: Padwa A (ed) Comprehensive heterocyclic chemistry II. Pergamon, Oxford, p 1
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 28:1953–1958
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 27:17–23
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 904:21–27
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 41:643–665
Dwivedi SK, Ghandi S, Rastogi N, Singh VK (2007) Lewis acid catalyzed ring opening of azetidines with alcohols and thiols. Tetrahedron Lett 48:5375–5377
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 6:4499–4501
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 70:9411–9416
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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.
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Cherni, E., Essalah, K., Besbes, N. et al. Theoretical investigation of the regioselective ring opening of 2-methylaziridine. Lewis acid effect. J Mol Model 24, 309 (2018). https://doi.org/10.1007/s00894-018-3833-2
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DOI: https://doi.org/10.1007/s00894-018-3833-2