Chemical Papers

, Volume 69, Issue 9, pp 1244–1252 | Cite as

Formation of a vanillic Mannich base — theoretical study

  • Vladimir P. PetrovićEmail author
  • Dušica Simijonović
  • Zorica D. Petrović
  • Svetlana Marković
Original Paper


One-pot anti-Mannich reaction of vanillin, aniline and cyclohexanone was successfully catalyzed by ionic liquid triethanolammonium chloroacetate, at room temperature. Yield of the obtained Mannich base was very good and excellent diastereoselectivity was achieved. Mechanism of the reaction was investigated using the density functional theory. The reaction started with a nucleophilic attack of aniline nitrogen at the carbonyl group of vanillin. The intermediate α-amino alcohol formed in this way was further subjected to protonation by the triethanolammonium ion yielding the imminium ion. Theoretically, the obtained imminium ion and the enol form of cyclohexanone can build the protonated Mannich base via the anti and syn pathways. The chloroacetic anion spontaneously abstracts the proton yielding the final product of the reaction anti 2-[1-(N-phenylamino)-1-(4-hydroxy-3-methoxyphenyl)]methylcyclohexanone (MB-H). The syn pathway requires lower activation energy but the anti pathway yields a thermodynamically more stable product, which implies that the examined Mannich reaction is thermodynamically controlled.


catalysis ionic liquid anti-diastereoselectivity reaction mechanism M052X functional 


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  1. Abbott, A. P., Capper, G., Davies, D. L., Rasheed, R. K., & Tambyrajah, V. (2002). Quaternary ammonium zinc- or tin-containing ionic liquids: Water insensitive, recyclable catalysts for Diels-Alder reactions. Green Chemistry, 4, 24–26. DOI:  10.1039/b108431c.CrossRefGoogle Scholar
  2. Aggarwal, A., Lancaster, N. L., Sethi, A. R., & Welton, T. (2002). The role of hydrogen bonding in controlling the selectivity of Diels-Alder reactions in room temperature ionic liquids. Green Chemistry, 4, 517–520. DOI:  10.1039/b206472c.CrossRefGoogle Scholar
  3. Akiyama, T., Takaya, J., & Kagoshima, H. (2001). A highly stereo-divergent Mannich-type reaction catalyzed by Brønsted acid in aqueous media. Tetrahedron Letters, 42, 4025–4028. DOI:  10.1016/s0040-4039(01)00648-7.CrossRefGoogle Scholar
  4. Arend, M., Westermann, B., & Risch, N. (1998). Modern variants of the Mannich reaction. Angewandte Chemie International Edition, 37, 1044–1070. DOI:  10.1002/(sici)1521-3773(19980504)37:8<1044∷aid-anie1044>;2-e.CrossRefGoogle Scholar
  5. Azuma, T., Kobayashi, Y., Sakata, K., Sasamori, T., Tokitoh, N., & Takemoto, Y. (2014). Synthesis and characterization of binary-complex models of ureas and 1,3-dicarbonyl compounds: Deeper insights into reaction mechanisms using snap-shot structural analysis. The Journal of Organic Chemistry, 79, 1805–1817. DOI:  10.1021/jo4028775.CrossRefGoogle Scholar
  6. Barone, V., & Cossi, M. (1998). Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. Journal of Physical Chemistry A, 102, 1995–2001. DOI:  10.1021/jp9716997.CrossRefGoogle Scholar
  7. Chang, Q., Zhou, J., & Gan, L. H. (2012). Theoretical study on the mechanisms of proline-catalyzed Mannich reaction between acetaldehyde and N-Boc imines. Journal of Physical Organic Chemistry, 25, 667–673. DOI:  10.1002/poc.2898.CrossRefGoogle Scholar
  8. Chiappe, C., & Pieraccini, D. (2005). Ionic liquids: Solvent properties and organic reactivity. Journal of Physical Organic Chemistry, 18, 275–297. DOI:  10.1002/poc.863.CrossRefGoogle Scholar
  9. Cole, A. C., Jensen, J. L., Ntai, I., Tran, K. L. T., Weaver, K. J., Forbes, D. C., & Davis, J. H. (2002). Novel Brønsted acidic ionic liquids and their use as dual solvent — catalysts. Journal of the American Chemical Society, 124, 5962–5963. DOI:  10.1021/ja026290w.CrossRefGoogle Scholar
  10. Córdova, A. (2004). The direct catalytic asymmetric Mannich reaction. Accounts of Chemical Research, 37, 102–112. DOI:  10.1021/ar030231l.CrossRefGoogle Scholar
  11. Cossi, M., Rega, N., Scalmani, G., & Barone, V. (2003). Energies, structures and electronic properties of molecules in solution with the C-PCM solvation model. Journal of Computational Chemistry, 24, 669–681. DOI:  10.1002/jcc.10189.CrossRefGoogle Scholar
  12. Cota, I., Gonzalez-Olmos, R., Iglesias, M., & Medina, F. (2007). New short aliphatic chain ionic liquids: Synthesis, physical properties and catalytic activity in aldol condensations. The Journal of Physical Chemistry B, 111, 12468–12477. DOI:  10.1021/jp073963u.CrossRefGoogle Scholar
  13. Dong, F., Jun, L., Zhou, X. L., & Liu, Z. L. (2007). Mannich reaction in water using acidic ionic liquid as recoverable and reusable catalyst. Catalysis Letters, 116, 76–80. DOI:  10.1007/s10562-007-9095-8.CrossRefGoogle Scholar
  14. Fang, D., Gong, K., Zhang, D. Z., & Liu, Z. L. (2009). One-pot, three-component Mannich-type reaction catalyzed by functionalized ionic liquid. Monatshefte für Chemie — Chemical Monthly, 140, 1325–1329. DOI:  10.1007/s00706-009-0182-y.CrossRefGoogle Scholar
  15. Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G. A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H. P., Izmaylov, A. F., Bloino, J., Zheng, G., Sonnenberg, J. L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J. A., Jr., Peralta, J. E., Ogliaro, F., Bearpark, M., Heyd, J. J., Brothers, E., Kudin, K. N., Staroverov, V. N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J. C., Iyengar, S. S., Tomasi, J., Cossi, M., Rega, N., Millam, J. M., Klene, M., Knox, J. E., Cross, J. B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Martin, R. L., Morokuma, K., Zakrzewski, V. G., Voth, G. A., Salvador, P., Dannenberg, J. J., Dapprich, S., Daniels, A. D., Farkas, O., Foresman, J. B., Ortiz, J. V., Cioslowski, J., & Fox, D. J. (2009). Gaussian 09 [computer software]. Wellingford, CT, USA: Gaussian Inc. Wallingford CT.Google Scholar
  16. Fu, A. P., Li, H. L., Si, H. Z., Yuan, S. P., & Duan, Y. B. (2008). Theoretical studies of stereoselectivities in the direct syn- and anti-Mannich reactions catalyzed by different amino acids. Tetrahedron: Asymmetry, 19, 2285–2292. DOI:  10.1016/j.tetasy.2008.09.023.CrossRefGoogle Scholar
  17. Gong, K., Fang, D., Wang, H. L., & Liu, Z. L. (2007). Basic functionalized ionic liquid catalyzed one-pot Mannich-type reaction: Three component synthesis of β-amino carbonyl compounds. Monatshefte für Chemie — Chemical Monthly, 138, 1195–1198. DOI:  10.1007/s00706-007-0767-2.CrossRefGoogle Scholar
  18. Huddleston, J. G., Visser, A. E., Reichert, W. M., Willauer, H. D., Broker, G. A., & Rogers, R. D. (2001). Characterization and comparison of hydrophilic and hydrophobic room temperature ionic liquids incorporating the imidazolium cation. Green Chemistry, 3, 156–164. DOI:  10.1039/b103275p.CrossRefGoogle Scholar
  19. Ibrahem, I., Zou, W. B., Casas, J., Sundén, H., & Córdova, A. (2006). Direct organocatalytic enantioselective α-aminomethylation of ketones. Tetrahedron, 62, 357–364. DOI:  10.1016/j.tet.2005.08.113.CrossRefGoogle Scholar
  20. Iglesias, M., Gonzalez-Olmos, R., Cota, I., & Medina, F. (2010). Brønsted ionic liquids: Study of physico-chemical properties and catalytic activity in aldol condensations. Chemical Engineering Journal, 162, 802–808. DOI:  10.1016/j.cej.2010.06.008.CrossRefGoogle Scholar
  21. Janey, J. M., Hsiao, Y., & Armstrong, J. D. (2006). Proline-catalyzed, asymmetric Mannich reactions in the synthesis of a DPP-IV inhibitor. The Journal of Organic Chemistry, 71, 390–392. DOI:  10.1021/jo0519458.CrossRefGoogle Scholar
  22. Kantam, M. L., Rajasekhar, C. V., Gopikrishna, G., Rajender Reddy, K., & Choudary, B. M. (2006). Proline catalyzed two-component, three-component and self-asymmetric Mannich reactions promoted by ultrasonic conditions. Tetrahedron Letters, 47, 5965–5967. DOI:  10.1016/j.tetlet.2006.06.042.CrossRefGoogle Scholar
  23. Keskin, S., Kayrak-Talay, D., Akman, U., & Hortaçsu, Ö. (2007). A review of ionic liquids towards supercritical fluid applications. The Journal of Supercritical Fluids, 43, 150–180. DOI:  10.1016/j.supflu.2007.05.013.CrossRefGoogle Scholar
  24. Kumar, A., & Pawar, S. S. (2004). Converting exo-selective Diels-Alder reaction to endo-selective in chloroloaluminate ionic liquids. The Journal of Organic Chemistry, 69, 1419–1420. DOI:  10.1021/jo035038j.CrossRefGoogle Scholar
  25. List, B., Pojarliev, P., Biller, W. T., & Martin, H. J. (2002). The proline-catalyzed direct asymmetric three-component Mannich reaction: Scope, optimization and application to the highly enantioselective synthesis of 1,2-amino alcohols. Journal of the American Chemical Society, 124, 827–833. DOI:  10.1021/ja0174231.CrossRefGoogle Scholar
  26. Liu, B. Y., Xu, D. Q., Dong, J. F., Yang, H. L., Zhao, D. S., Luo, S. P., & Xu, Z. Y. (2007). Highly efficient AILs/l-proline synergistic catalyzed three-component asymmetric Mannich reaction. Synthetic Communications, 37, 3003–3010. DOI:  10.1080/00397910601163976.CrossRefGoogle Scholar
  27. Loh, T. P., Liung, S. B. K. W., Tan, K. L., & Wei, L. L. (2000). Three component synthesis of β-amino carbonyl compounds using indium trichloride-catalyzed one-pot Mannich-type reaction in water. Tetrahedron, 56, 3227–3237. DOI:  10.1016/s0040-4020(00)00221-0.CrossRefGoogle Scholar
  28. Loh, T. P., & Chen, S. L. (2002). InCl3-Catalyzed three-component asymmetric Mannich-type reaction in methanol. Organic Letters, 4, 3647–3650. DOI:  10.1021/ol0265968.CrossRefGoogle Scholar
  29. Manabe, K., Mori, Y., Kobayashi, S. (2001). Three-component carbon-carbon bond-forming reactions catalyzed by a Brønsted acid — surfactant-combined catalyst in water. Tetrahedron, 57, 2537–2544. DOI:  10.1016/s0040-4020(01)00081-3.CrossRefGoogle Scholar
  30. Mukhopadhyay, C., Datta, A., & Butcher, R. J. (2009). Highly efficient one-pot, three-component Mannich reaction catalysed by boric acid and glycerol in water with major “syn” diastereoselectivity. Tetrahedron Letters, 50, 4246–4250. DOI:  10.1016/j.tetlet.2009.04.135.CrossRefGoogle Scholar
  31. Parasuk, W., & Parasuk, V. (2008). Theoretical investigations on the stereoselectivity of the proline catalyzed Mannich reaction in DMSO. The Journal of Organic Chemistry, 73, 9388–9392. DOI:  10.1021/jo801872w.CrossRefGoogle Scholar
  32. Petrović Z. D., Simijonović, D., Petrović, V. P., & Marković, S. (2010). Diethanolamine and N,N-diethylethanolamine ionic liquids as precatalyst-precursors and reaction media in green Heck reaction protocol. Journal of Molecular Catalysis A, 327, 45–50. DOI:  10.1016/j.molcata.2010.05.010.CrossRefGoogle Scholar
  33. Petrović Z. D., Marković, S., Petrović, V. P., & Simijonović, D. (2012). Triethanolammonium acetate as a multifunctional ionic liquid in the palladium-catalyzed green Heck reaction. Journal of Molecular Modeling, 18, 433–440. DOI:  10.1007/s00894-011-1052-1.CrossRefGoogle Scholar
  34. Petrović V. P., Simijonović, D., Živanović, M. N., Košarić, J. V., Petrović, Z. D., Marković, S., & Marković, S. D. (2014). Vanillic Mannich bases: Synthesis and screening of biological activity. Mechanistic insight into the reaction with 4-chloroaniline. RSC Advances, 4, 24635–24644. DOI:  10.1039/c4ra03909b.CrossRefGoogle Scholar
  35. Phukan, P., Kataki, D., & Chakraborty, P. (2006). Direct synthesis of Cbz-protected β-amino ketones by iodine-catalyzed three-component condensation of aldehydes, ketones and benzyl carbamate. Tetrahedron Letters, 47, 5523–5525. DOI:  10.1016/j.tetlet.2006.05.136.CrossRefGoogle Scholar
  36. Sahoo, S., Joseph, T., & Halligudi, S. B. (2006). Mannich reaction in Brønsted acidic ionic liquid: A facile synthesis of β-amino carbonyl compounds. Journal of Molecular Catalysis A, 244, 179–182. DOI:  10.1016/j.molcata.2005.09.012.CrossRefGoogle Scholar
  37. Shariati, A., & Peters, C. J. (2005). High-pressure phase equilibria of systems with ionic liquids. The Journal of Supercritical Fluids, 34, 171–176. DOI:  10.1016/j.supflu.2004.11.011.CrossRefGoogle Scholar
  38. Shariati, A., Gutkowski, K., & Peters, C. J. (2005). Comparison of the phase behavior of some selected binary systems with ionic liquids. AIChE Journal, 51, 1532–1540. DOI:  10.1002/aic.10384.CrossRefGoogle Scholar
  39. Simijonović, D., Petrović, Z. D., & Petrović, V. P. (2013). Some physico-chemical properties of ethanolamine ionic liquids: Behavior in different solvents. Journal of Molecular Liquids, 179, 98–103. DOI:  10.1016/j.molliq.2012.12.020.CrossRefGoogle Scholar
  40. Singh, R., Sharma, M., Mamgain, R., & Rawat, D. S. (2008). Ionic liquids: A versatile medium for palladium-catalyzed reactions. Journal of the Brazilian Chemical Society, 19, 357–379. DOI:  10.1590/s0103-50532008000300002.CrossRefGoogle Scholar
  41. Touré, B. B., & Hall, D. G. (2009). Natural product synthesis using multicomponent reaction strategies. Chemical Reviews, 109, 4439–4486. DOI:  10.1021/cr800296p.CrossRefGoogle Scholar
  42. Wang, L. M., Han, J. W., Sheng, J., Tian, H., & Fan, Z. Z. (2005). Rare earth perfluorooctanoate [RE(PFO)3] catalyzed one-pot Mannich reaction: Three component synthesis of β-amino carbonyl compounds. Catalysis Communications, 6, 201–204. DOI:  10.1016/j.catcom.2004.12.009.CrossRefGoogle Scholar
  43. Xiao, Y., & Malhotra, S. V. (2005). Friedel-Crafts alkylation reactions in pyridinium-based ionic liquids. Journal of Molecular Catalysis A, 230, 129–133. DOI:  10.1016/j.molcata.2004.12.015.CrossRefGoogle Scholar
  44. Yalalov, D. A., Tsogoeva, S. B., Shubina, T. E., Martynova, I. M., & Clark, T. (2008). Evidence for an enol mechanism in a highly enantioselective Mannich-type reaction catalyzed by primary amine-thiourea. Angewandte Chemie International Edition, 47, 6624–6628. DOI:  10.1002/anie.200800849.CrossRefGoogle Scholar
  45. Yang, Y. Y., Shou, W. G., & Wang, Y. G. (2006). Synthesis of β-amino carbonyl compounds via a Zn(OTf)2-catalyzed cascade reaction of anilines with aromatic aldehydes and carbonyl compounds. Tetrahedron, 62, 10079–10086. DOI:  10.1016/j.tet.2006.08.063.CrossRefGoogle Scholar
  46. Yang, J. W., Stadler, M., & List, B. (2007). Proline-catalyzed Mannich reaction of aldehydes with N-Boc-imines. Angewandte Chemie International Edition, 46, 609–611. DOI:  10.1002/anie.200603188.CrossRefGoogle Scholar
  47. Yi, W. B., & Cai, C. (2006). Mannich-type reactions of aromatic aldehydes, anilines and methyl ketones in fluorous biphase systems created by rare earth(III) perfluorooctane sulfonates catalysts in fluorous media. Journal of Fluorine Chemistry, 127, 1515–1521. DOI:  10.1016/j.jfluchem.2006.07.009.CrossRefGoogle Scholar
  48. Yin, D. H., Li, C. Y., Tao, L., Yu, N. G., Hu, S., & Yin, D. L. (2006). Synthesis of diphenylmethane derivatives in Lewis acidic ionic liquids. Journal of Molecular Catalysis A, 245, 260–265. DOI:  10.1016/j.molcata.2005.10.010.CrossRefGoogle Scholar
  49. Yue, C. B., Yi, T. F., Zhu, C. B., & Liu, G. (2009). Mannich reaction catalyzed by a novel catalyst under solvent-free conditions. Journal of Industrial and Engineering Chemistry, 15, 653–656. DOI:  10.1016/j.jiec.2009.09.038.CrossRefGoogle Scholar
  50. Zhao, G. Z., Jiang, T., Gao, H. X., Han, B. X., Huang, J., & Sun, D. H. (2004). Mannich reaction using acidic ionic liquids as catalysts and solvents. Green Chemistry, 6, 75–77. DOI:  10.1039/b309700p.CrossRefGoogle Scholar
  51. Zhao, H., Xia, S. Q., & Ma, P. S. (2005). Use of ionic liquids as ‘green’ solvents for extractions. Journal of Chemical Technology & Biotechnology, 80, 1089–1096. DOI:  10.1002/jctb.1333.CrossRefGoogle Scholar
  52. Zhao, Y., Schultz, N. E., & Truhlar, D. G. (2006). Design of density functionals by combining the method of constraint satisfaction with parametrization for thermochemistry, thermochemical kinetics and noncovalent interactions. Journal of Chemical Theory and Computation, 2, 364–382. DOI:  10.1021/ct0502763.CrossRefGoogle Scholar
  53. Zhou, X., Liu, B., Luo, F., Zhang, W., & Song, H. (2011). Novel Brønsted-acidic ionic liquids based on benzothiazolium cations as catalysts for esterification reactions. Journal of the Serbian Chemical Society, 76, 1607–1615. DOI:  10.2298/jsc110102144z.CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2015

Authors and Affiliations

  • Vladimir P. Petrović
    • 1
    Email author
  • Dušica Simijonović
    • 1
  • Zorica D. Petrović
    • 1
  • Svetlana Marković
    • 1
  1. 1.Faculty of ScienceUniversity of KragujevacKragujevacSerbia

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