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: [email protected]
Héctor Carneros
Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   Email: [email protected]
Anna M Costa
Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   Email: [email protected]
Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   Email: [email protected]
› Author Affiliations
The 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).
Further Information

Publication History

Received: 10 July 2017

Accepted after revision: 23 August 2017

Publication Date:
04 October 2017 (online)

Dedicated to Pere Mir, in memoriam


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

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  • 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.
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    • Also see:
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      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
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      For an outstanding study of Pro-catalyzed aldol reactions of acetone, see:
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    • For pioneering works, see:
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    • 28c Notz W. List B. J. Am. Chem. Soc. 2000; 122: 7386
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    • 28f Nyberg AI. Usano A. Pihko PM. Synlett 2004; 1891

    • For some very recent papers focused on acetone reactions, see:
    • 28g Ref. 8e.
    • 28h Niessing S. Czekelius C. Janiak C. Catal. Commun. 2017; 95: 12
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      For aldol reactions of 4-methylcyclohexanone with desymmetrization, see refs cited in:
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    • 29e Triandafillidi I. Bisticha A. Voutyritsa E. Galiatsatou G. Kokotos CG. Tetrahedron 2015; 71: 932
    • 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.
    • 31a Pyrrolidine-sulfonamide, nitro-Michael: Wang J. Li H. Lou B. Zu L. Guo H. Wang W. Chem. Eur. J. 2006; 12: 4321
    • 31b 5-(Pyrrolidin-2-yl)tetrazole: Arnó M. Zaragozá RJ. Domingo LR. Tetrahedron: Asymmetry 2007; 18: 157
    • 31c Pro-NHSO2Ar, Mannich: Veverková E. Strasserová J. Sebesta R. Toma S. Tetrahedron: Asymmetry 2010; 21: 58
    • 31d 4-OH-pyrrolidine derivatives, Mannich anti-selective: Gómez-Bengoa E. Maestro M. Mielgo A. Otazo I. Palomo C. Velilla I. Chem. Eur. J. 2010; 16: 5333
    • 31e Pyrrolidine-ureas, nitro-Michael: Cao X.-Y. Zheng J.-C. Li Y.-X. Shu Z.-C. Sun X.-L. Wang B.-Q. Tang Y. Tetrahedron 2010; 66: 9703
    • 31f 2-CHPh2 and 2-CPh2OMe, MVK: Patil MP. Sharma AK. Sunoj RB. J. Org. Chem. 2010; 75: 7310
    • 31g Thiaproline: Parasuk W. Parasuk V. Comput. Theor. Chem. 2011; 964: 133
    • 31h Mannich, thiaproline: Parasuk W. Parasuk V. Asian J. Org. Chem. 2013; 2: 85
    • 31i 4-OH-prolinamides, nitro-Michael: Watts J. Luu L. McKee V. Carey E. Kelleher F. Adv. Synth. Catal. 2012; 354: 1035
    • 31j Mannich, 2-(pyrrolidin-1-ylmethyl)pyrrolidine: ref. 26g.
    • 31k Pro dipeptides vs. Pro tripeptides, aldol: Szöllösi G. Csámpai A. Somlai C. Fekete M. Bartók M. J. Mol. Catal. A: Chem. 2014; 382: 86
    • 31l Pyrrolidinyl-oxazolecarboxamides: Kamal A. Sathish M. Srinivasulu V. Chetna J. Shekar KC. Nekkanti S. Tangella Y. Shankaraiah N. Org. Biomol. Chem. 2014; 12: 8008
    • 31m Pro-hydrazide, explicit water: Chakrabarty K. Ghosh A. Basak A. Das GK. Comput. Theor. Chem. 2015; 1062: 11
    • 31n For a review, see: ref. 26a.

      For studies on the nucleophilicity of enamines, see:
    • 32a Kempf B. Hampel N. Ofial AR. Mayr H. Chem. Eur. J. 2003; 9: 2209
    • 32b Ref. 4e.