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Synthesis 2017; 49(24): 5285-5306
DOI: 10.1055/s-0036-1590909
short review
© Georg Thieme Verlag Stuttgart · New York

Computer-Aided Insight into the Relative Stability of Enamines

Alejandro Castro-Alvarez
Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   eMail: jvilarrasa@ub.edu
,
Héctor Carneros
Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   eMail: jvilarrasa@ub.edu
,
Anna M Costa
Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   eMail: jvilarrasa@ub.edu
,
Jaume Vilarrasa  *
Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   eMail: jvilarrasa@ub.edu
› InstitutsangabenThe authors acknowledge the Spanish Government for financial support (CTQ2015-71506R, FEDER). A.C.A. is grateful to Fundació Privada Cellex de Barcelona for a fellowship. H.C. has a studentship of the Spanish Government (CTQ2012-39230, FEDER).
Weitere Informationen

Publikationsverlauf

Received: 10. Juli 2017

Accepted after revision: 23. August 2017

Publikationsdatum:
04. Oktober 2017 (online)

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Dedicated to Pere Mir, in memoriam

Abstract

Venerable aldol, Michael, and Mannich reactions have undergone a renaissance in the past fifteen years, as a consequence of the development of direct organocatalytic versions, mediated by chiral amines. Chiral enamines are key intermediates in these reactions. This review focuses on the formation of enamines from secondary amines and their relative thermodynamic stability, as well as on the reverse reactions (hydrolysis). Experimental results and predictions based on MO calculations are reviewed to show which enamine forms may predominate in the reaction medium and to compare several secondary amines as organocatalysts.

1 Introduction

2 Relative Stability of Enamines as Determined Experimentally

3 Pyrrolidine Enamines

4 Enamines of the Jørgensen–Hayashi Catalyst

5 Proline Enamines

6 Free Enthalpies and Polar Solvent Effects

7 Comparison of Organocatalysts

8 Summary and Outlook

9 Appendix

Key words

organocatalysis - enamine formation - enamine hydrolysis - DFT and MP2 calculations - pyrrolidine enamines - Jørgensen–Hayashi catalyst - proline enamines - catalyst comparison
 

  • References

    • 3a Bahmanyar S. Houk KN. Martin HJ. List B. J. Am. Chem. Soc. 2003; 125: 2475 ; [among 24 reasonable TSs for the Pro-catalyzed aldol reactions, 8 of those involving H bonding were investigated at the B3LYP/6-31G level]
      CrossrefPubMedSuche in Google Scholar

      • For revisions of the Houk–List TS model for aldol reactions, see:
    • 3b Armstrong A. Boto RA. Dingwall P. Contreras-Garcia J. Harvey MJ. Mason NJ. Rzepa HS. Chem. Sci. 2014; 5: 2057
      CrossrefSuche in Google Scholar
    • 3c Bakr BW. Sherrill CD. Phys. Chem. Chem. Phys. 2016; 18: 10297
      CrossrefPubMedSuche in Google Scholar
  • 6 Sánchez D. Carneros H. Castro-Alvarez A. Llácer E. Planas F. Vilarrasa J. Tetrahedron Lett. 2016; 57: 5254 ; and refs cited therein
    CrossrefSuche in Google Scholar

      • For entries on the theme, see:
    • 11a Beeson TD. Mastracchio A. Hong J.-B. Ashton K. MacMillan DW. C. Science 2007; 582
      PubMed
    • 11b Um JM. Gutierrez O. Schoenebeck F. Houk KN. MacMillan DW. C. J. Am. Chem. Soc. 2010; 132: 6001
      CrossrefPubMedSuche in Google Scholar

      • α-Allylation of cyclohexanone(s) via SOMO catalysis required the modification of the standard catalysts, to lower steric hindrance at C2, in order to favor the formation of the starting enamines:
    • 11c Mastracchio A. Warkentin AA. Walji AM. MacMillan DW. C. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 20648
      CrossrefPubMedSuche in Google Scholar

      • Also see:
    • 11d Tisovsky P. Meciarova M. Sebesta R. Org. Biomol. Chem. 2014; 12: 9446
      CrossrefPubMedSuche in Google Scholar

      Previous QCC of enamines of pyrrolidine:
    • 13a Enamines + 1,2,3-triazines: Prieto P. Cossío FP. Carrillo JR. de la Hoz A. Díaz-Ortiz A. Moreno A. J. Chem. Soc., Perkin Trans. 2 2002; 1257
    • 13b Nitroso aldol: Akakura M. Kawasaki M. Yamamoto H. Eur. J. Org. Chem. 2008; 4245
    • 13c [3+2]-Cycloadditions: Lopez SA. Munk ME. Houk KN. J. Org. Chem. 2013; 78: 1576
      CrossrefPubMedSuche in Google Scholar
    • 13d E/Z Alkoxy-enamines: Mukaiyama T. Uchimaru T. Hayashi Y. Bull. Chem. Soc. Jpn. 2016; 89: 455
      CrossrefSuche in Google Scholar
    • 14a 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. Gaussian 09 package (Revision D.01, 2013), Gaussian 09. Revision D.01. Gaussian, Inc; Wallingford: 2013. www.gaussian.co
      Suche in Google Scholar
    • 14b Becke AD. J. Chem. Phys. 1993; 98: 5648
      CrossrefSuche in Google Scholar
    • 14c Stephens PJ. Devlin FJ. Chabalowski CF. Frisch MJ. J. Phys. Chem. 1994; 98: 11623
      CrossrefSuche in Google Scholar
    • 14d Møller C. Plesset MS. Phys. Rev. 1934; 46: 618
      CrossrefSuche in Google Scholar
    • 14e Head-Gordon M. Pople JA. Frisch MJ. Chem. Phys. Lett. 1988; 153: 503
      CrossrefSuche in Google Scholar
    • 14f Zhao Y. Truhlar DG. Theor. Chem. Acc. 2008; 120: 215
      CrossrefSuche in Google Scholar
    • 14g Zhao Y. Truhlar DG. Acc. Chem. Res. 2008; 41: 157
      CrossrefPubMedSuche in Google Scholar
    • 14h Marenich AV. Cramer CJ. Truhlar DG. J. Phys. Chem. B 2009; 113: 6378
      CrossrefPubMedSuche in Google Scholar
    • 14i ORCA 3.0.2, The ORCA program system, Wiley Interdiscip. Rev.: Neese F. Comput. Mol. Sci. 2012; 2: 73
      CrossrefSuche in Google Scholar
  • 17 We carried out additional experiments that confirm the relative position of 2-methylpropanal (isobutyraldehyde) and 2-methylcyclohexanone (2MC) in Figure 2 and the Appendix. For example, when a solution of the pyrrolidine–cyclohexanone enamine was prepared from its components in the presence of 3 Å molecular sieves and CaH2, and 100 mol% of 3-methylbutanal was added, we observed by 1H NMR that in DMSO-d 6 the peaks at δ = 4.10 (enamine proton, t, J = 3.9 Hz) and 2.92 (4 H α to the N atom) started to disappear and signals at δ = 5.57 (new enamine proton) and 2.85 (4 H α to the N atom) appeared, and the equilibrium was reached in less than 1 h (K eq ≈ 28); three days later the ratios between carbonyl compounds and their enamines were maintained. A similar result was observed in CD3CN. In contrast, when we added commercially available 2MC to the pyrrolidine–cyclohexanone enamine, in DMSO-d 6, only a slight decrease of the peaks of the cyclohexanone enamine was observed whereas the peaks of the 2MC enamine were hardly observable; however, by adding 10 equiv of 2MC the exchange was clearly seen; an approximate value of K eq (0.03) was determined.
  • 18 A trace of water or of pyrrolidine may catalyze these exchange reactions. For example, a trace of water hydrolyzes a small amount of pyrrolidine–cyclohexanone enamine and the resulting pyrrolidine reacts with carbonyl A leading to the production of water, which repeats the cycle. Eventually, equilibrium is reached. Similarly, a trace of pyrrolidine remaining in the vial, by reacting with carbonyl compound A gives some enamine A plus some water, which continues the exchange process, as above. Although other exchange mechanisms might be operative, they have not yet been demonstrated.
  • 19 For malonaldehyde (propanedial) the calculated total energies of the main conformer are –267.13926 [B3LYP/6-31G(d)], –266.35922 [MP2/6-31G(d)//B3LYP/6-31G(d)], and –266.51761 a.u. [MP2/6-311+G(d,p)//B3LYP/6-31G(d)]. For its enol with an intramolecular hydrogen bond, (Z)-3-hydroxypropenal, the values are –267.14885, –266.36273, and –266.52384 a.u., respectively (that is, a few kcal/mol lower at every level). Thus, ΔE r in Figure 2 would be –15.6 instead of –17.8 (still the ‘best’ carbonyl compound in Figure 2); this is the only case of our series in which an enol form is more stable than the lowest-energy carbonyl form, in the gas phase.
  • 21 Seebach D. Groselj U. Badine DM. Schweizer WB. Beck AK. Helv. Chim. Acta 2008; 91: 1999
    CrossrefSuche in Google Scholar
    • 23a Franzen J. Marigo MD. Fielenbach D. Wabnitz TC. Jørgensen KA. J. Am. Chem. Soc. 2005; 127: 18296
      CrossrefPubMedSuche in Google Scholar
    • 23b Bertelsen S. Marigo M. Brandes S. Dinér P. Jørgensen KA. J. Am. Chem. Soc. 2006; 128: 12973
      CrossrefPubMedSuche in Google Scholar
    • 23c Dinér P. Kjærsgaard A. Lie MA. Jørgensen KA. Chem. Eur. J. 2008; 14: 122
      CrossrefPubMedSuche in Google Scholar
    • 23d Zhao J.-Q. Gan L.-H. Eur. J. Org. Chem. 2009; 2661
    • 23e Ref. 22a.
    • 23f Hutka M. Polácková V. Marák J. Kaniansky D. Sebesta R. Toma S. Eur. J. Org. Chem. 2010; 6430
    • 23g Ref. 5b [conformational population, M06-2X/6-311+G(2df,2p)//B3LYP/6-31G, phenylethanal].
    • 23h Ref. 5c (enamines, dienamines, trienamines, and cross-trienamines of the J–H catalyst).

      • For DFT calculations of nitro-Michael reactions, which are a hot topic nowadays due to the relevance of cyclobutane intermediates, see the extensive review of Seebach and co-workers22c,d and references cited therein, ref. 5b and refs therein, and ref. 2d and references cited therein. Also see the following highlight:
    • 23i Moberg C. Angew. Chem. Int. Ed. 2013; 52: 2160
      CrossrefPubMedSuche in Google Scholar

      • For [2+4]-cycloadducts, see ref. 22c and:
    • 23j Sahoo G. Rahaman H. Madarász A. Pápai I. Melarto M. Valkonen A. Pihko PM. Angew. Chem. Int. Ed. 2012; 51: 13144
      CrossrefPubMedSuche in Google Scholar

      • For related computational studies, see:
    • 23k Sun H. Zhang D. Zhang C. Liu C. Chirality 2010; 22: 813
      CrossrefPubMedSuche in Google Scholar
    • 23l Gan L.-H. Zhou J. Guo X. J. Theor. Comput. Chem. 2013; 12: 1350004/1
      Suche in Google Scholar

      For classical studies on the structure of carboxylic acids (and the corresponding calculations of the s-cis/s-trans forms, formerly so-called syn/anti), see references cited in:
    • 25a Allinger NL. Zhu ZQ. S. Chen K. J. Am. Chem. Soc. 1992; 114: 6120
      CrossrefSuche in Google Scholar
    • 25b Wiberg KB. Ochterski J. Streitwieser A. J. Am. Chem. Soc. 1996; 118: 8291
      CrossrefSuche in Google Scholar
    • 25c Dimerization energy: Colominas C. Teixidó J. Cemeli J. Luque FJ. Orozco M. J. Phys. Chem. B 1998; 102: 2269
      CrossrefSuche in Google Scholar
    • 25d Da Silva CO. Da Silva EC. Nascimento MA. C. J. Phys. Chem. A 1999; 103: 11194
      CrossrefSuche in Google Scholar

      For aldol reactions of 4-(2-oxopropyl)- and 4-(3-oxopropyl)cyclohexanone derivatives, where the reaction selectively occurs at the cyclohexanone ring, see:
    • 27a Nugent TC. Spiteller P. Hussain I. Hussein HA. E. D. Najafian FT. Adv. Synth. Catal. 2016; 358: 3706
      CrossrefSuche in Google Scholar
    • 27b Nugent TC. Najafian FT. Hussein HA. E. D. Hussain I. Chem. Eur. J. 2016; 22: 14342
      CrossrefPubMedSuche in Google Scholar
    • 30a With the J–H catalyst, the related values, in kcal/mol, are as follows: propanedial, ΔE –19.7, ΔG ѳ –18.6, ΔG ѳ(DMSO) –20.5, ΔG ѳ(H2O) –22.1; PhCH2CHO, ΔE –10.3, ΔG ѳ –10.4, ΔG ѳ(DMSO) –12.8, ΔG ѳ(H2O) –12.7; Me2CHCH2CHO, ΔE –5.0, ΔG ѳ –5.6, ΔG ѳ(DMSO) –7.3, ΔG ѳ(H2O) –6.6; Me3CCOMe, enamine ap, ΔE 6.3, ΔG ѳ 7.4, ΔG ѳ(DMSO) 7.5, ΔG ѳ(H2O) 7.6; Me3CCOMe, sc-exo, ΔE 10.3, ΔG ѳ 11.4, ΔG ѳ(DMSO) 10.5, ΔG ѳ (H2O) 9.9.
    • 30b With Pro, the values are as follows: propanedial, CO2H s-cis, ΔE –11.5, ΔG ѳ –13.4, ΔG ѳ(DMSO) –13.0, ΔG ѳ(H2O) –15.6; propanedial, s-trans, ΔE –8.7, ΔG ѳ –10.4, ΔG ѳ(DMSO) –12.6, ΔG ѳ(H2O) –14.3; PhCH2CHO, s-cis, ΔE –5.5, ΔG ѳ –6.7, ΔG ѳ(DMSO) –6.4, ΔG ѳ(H2O) –7.6; Me2CHCH2CHO, s-trans, ΔE –1.8, ΔG ѳ –2.9, ΔG ѳ(DMSO) –4.4, ΔG ѳ(H2O) –4.0; EtCHO, s-trans, ΔE –1.1, ΔG ѳ –1.6, ΔG ѳ(DMSO) –2.7, ΔG ѳ(H2O) –2.5; Me3CCOMe, s-cis, ΔE 9.4, ΔG ѳ 10.6, ΔG ѳ(DMSO) 12.3, ΔG ѳ(H2O) 11.2.