Ab initio quantum chemical and ReaxFF-based study of the intramolecular iminium–enamine conversion in a proline-catalyzed reaction

  • Pierre O. HubinEmail author
  • Denis Jacquemin
  • Laurence Leherte
  • Jean-Marie André
  • Adri C. T. van Duin
  • Daniel P. VercauterenEmail author
Regular Article
Part of the following topical collections:
  1. Theoretical and Computational Chemistry in Belgium Collection


Among all strategies used by organic chemists to control the stereoselectivity of reactions, organocatalysis, which consists in using the chirality of a small organic molecule, is an increasingly popular method. The proline-catalyzed aldol reaction was one of the first reported cases that demonstrated the power of organocatalysis in the field of asymmetric synthesis. Previous theoretical contributions focused on the reaction mechanism using quantum mechanics (QM) methods. We here present a theoretical study about one specific step of the proline-catalyzed aldol reaction, namely, the conversion of the iminium intermediate into the corresponding enamine. It consists of an intramolecular rearrangement that involves the transfer of a hydrogen atom. First, we investigate this transfer using modern QM models, that is, density functional theory calculations with the M06-2X functional. On the basis of these QM results, we then assess the performance of a reactive force field, ReaxFF, used in combination with molecular dynamics simulations in order to provide a complementary light on this reaction.


ReaxFF Force field development Molecular dynamics simulation Organocatalysis Reaction pathway Proline catalysis Enamine Iminium Solvent effects DFT M06-2X 



The authors acknowledge the support of the F.R.S.-FRFC (convention no. 2.4.617.07.F), and the “Facultés Universitaires Notre-Dame de la Paix” (FUNDP) for the use of the Interuniversity Scientific Computing Facility (ISCF) Center. They are also thankful to Prof. S. Lanners (FUNDP) for fruitful discussions. DJ indebted to the Régions des Pays de Loire (recrutement sur poste stratégique) and to the ERC StG program (Grant: Marches–278845) for financial support.

Supplementary material

214_2012_1261_MOESM1_ESM.pdf (728 kb)
Supplementary material 1 (PDF 727 kb)


  1. 1.
    MacMillan DWC (2008) Nature 455:304–308CrossRefGoogle Scholar
  2. 2.
    Dalko PI, Moisan L (2004) Angew Chem Int Ed 43:5138–5175CrossRefGoogle Scholar
  3. 3.
    Geary LM, Hultin PG (2009) Tetrahedron Asymmetry 20:131–173CrossRefGoogle Scholar
  4. 4.
    List B, Lerner RA, Barbas CF III (2000) J Am Chem Soc 122:2395–2396CrossRefGoogle Scholar
  5. 5.
    Doyle AG, Jacobsen EN (2007) Chem Rev 107:5713–5743CrossRefGoogle Scholar
  6. 6.
    Ouellet SG, Tuttle JB, MacMillan DWC (2005) J Am Chem Soc 127:32–33CrossRefGoogle Scholar
  7. 7.
    Reisman SE, Doyle AG, Jacobsen EN (2008) J Am Chem Soc 130:7198–7199CrossRefGoogle Scholar
  8. 8.
    Yang HY, Hong JB, MacMillan DWC (2007) J Am Chem Soc 129:7004–7005CrossRefGoogle Scholar
  9. 9.
    Bahmanyar S, Houk KN (2001) J Am Chem Soc 123:11273–11283CrossRefGoogle Scholar
  10. 10.
    Bahmanyar S, Houk KN (2001) J Am Chem Soc 123:12911–12912CrossRefGoogle Scholar
  11. 11.
    Bahmanyar S, Houk KN, Martin HJ, List B (2003) J Am Chem Soc 125:2475–2479CrossRefGoogle Scholar
  12. 12.
    Allemann C, Gordillo R, Clemente FR, Cheong PH-Y, Houk KN (2004) Acc Chem Res 37:558–569CrossRefGoogle Scholar
  13. 13.
    Clemente FR, Houk KN (2005) J Am Chem Soc 127:11294–11302CrossRefGoogle Scholar
  14. 14.
    Allemann C, Um JM, Houk KN (2010) J Mol Catal A 324:31–38CrossRefGoogle Scholar
  15. 15.
    Sharma AK, Sunoj RB (2010) Angew Chem Int Ed 49:6373–6377CrossRefGoogle Scholar
  16. 16.
    Klussmann M, Iwamura H, Mathew SP, Wells DH Jr, Pandya U, Armstrong A, Blackmond DG (2006) Nature 441:621–623CrossRefGoogle Scholar
  17. 17.
    Seebach D, Beck AK, Badine DM, Limbach M, Eschenmoser A, Treasurywala AM, Hobi R (2007) Helv Chim Acta 90:425–471CrossRefGoogle Scholar
  18. 18.
    Kanzian T, Lakhdar S, Mayr H (2010) Angew Chem Int Ed 49:9526–9529CrossRefGoogle Scholar
  19. 19.
    van Duin ACT, Dasgupta S, Lorant F, Goddard WA III (2001) J Phys Chem A 105:9396–9409CrossRefGoogle Scholar
  20. 20.
    Chenoweth K, Cheung S, van Duin ACT, Goddard WA III, Kober EM (2005) J Am Chem Soc 127:7192–7202CrossRefGoogle Scholar
  21. 21.
    Chenoweth K, van Duin ACT, Goddard WA III (2008) J Phys Chem A 112:1040–1053CrossRefGoogle Scholar
  22. 22.
    Zhang L, Zybin SV, van Duin ACT, Dasgupta S, Goddard WA III, Kober EM (2009) J Phys Chem B 113:10619–10640Google Scholar
  23. 23.
    Rahaman O, van Duin ACT, Goddard WA III, Doren DJ (2011) J Phys Chem B 115:249–261CrossRefGoogle Scholar
  24. 24.
    Raghavachari K, Trucks GW, Pople JA, Head-Gordon M (1989) Chem Phys Lett 157:479–483CrossRefGoogle Scholar
  25. 25.
    Gaussian 09, Revision B01, Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery, Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ, Gaussian, Inc, Wallingford CT, 2010Google Scholar
  26. 26.
    Becke AD (1993) J Chem Phys 98:1372–1377CrossRefGoogle Scholar
  27. 27.
    Boese AD, Martin JML (2004) J Chem Phys 121:3405–3416CrossRefGoogle Scholar
  28. 28.
    Chai JD, Head-Gordon M (2008) Phys Chem Chem Phys 10:6615–6620CrossRefGoogle Scholar
  29. 29.
    Zhao Y, Truhlar DG (2008) Theor Chem Acc 120:215–241CrossRefGoogle Scholar
  30. 30.
    Møller C, Plesset MS (1934) Phys Rev 46:618–622CrossRefGoogle Scholar
  31. 31.
    Tomasi J, Mennucci B, Cammi R (2005) Chem Rev 105:2099–3093CrossRefGoogle Scholar
  32. 32.
    Plimpton SJ (1995) J Comp Phys 117:1–19CrossRefGoogle Scholar
  33. 33.
    van Duin ACT, Baas JMA, van de Graaf B (1994) J Chem Soc, Faraday Trans 90:2881–2895CrossRefGoogle Scholar
  34. 34.
    Halgren TA (1996) J Comp Chem 17:490–519CrossRefGoogle Scholar
  35. 35.
    Ponder J (2011) Tinker 5.1.09, program available on: Last consulted on 2 December 2011
  36. 36.
    Shinoda W, DeVane R, Klein ML (2007) Mol Sim 33:27–36CrossRefGoogle Scholar
  37. 37.
    Izrailev S, Stepaniants S, Isralewitz B, Kosztin D, Lu H, Molnar F, Wriggers W, Schulten K (1998) Computational molecular dynamics: challenges, methods, ideas. In: Deuflhard P, Hermans J, Leimkuhler B, Mark AE, Reich S, Skeel RD (eds) Lecture notes in computational science and engineering, vol 4. Springer, Berlin, pp 39–65Google Scholar
  38. 38.
    Wodrich MD, Corminboeuf C, Schleyer PVR (2006) Org Lett 8:3631–3634CrossRefGoogle Scholar
  39. 39.
    Burns LA, Vazquez-Mayagoitia A, Sumpter BG, Sherrill CD (2011) J Chem Phys 134:84107–84114CrossRefGoogle Scholar
  40. 40.
    Pihko PM, Laurikainen KM, Usano A, Nyberg AI, Kaavi JA (2006) Tetrahedron 62:317–328CrossRefGoogle Scholar
  41. 41.
    Rankin KN, Gauld JW, Boyd RJ (2002) J Phys Chem A 106:5155–5159CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Pierre O. Hubin
    • 1
    Email author
  • Denis Jacquemin
    • 2
  • Laurence Leherte
    • 1
  • Jean-Marie André
    • 3
  • Adri C. T. van Duin
    • 4
  • Daniel P. Vercauteren
    • 1
    Email author
  1. 1.Laboratoire de Physico-Chimie InformatiqueUniversity of NamurNamurBelgium
  2. 2.CESIAM UMR CNRS 6230, Université de NantesNantes 3France
  3. 3.University of Namur, Académie Royale de BelgiqueNamurBelgium
  4. 4.Department of Mechanical and Nuclear EngineeringPennsylvania State UniversityUniversity ParkUSA

Personalised recommendations