Computer-Aided Insight into the Relative Stability of Enamines

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


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• 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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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-workers^22c,d and references cited therein, ref. 5b and refs therein, and ref. 2d and references cited therein. Also see the following highlight:
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For [2+4]-cycloadducts, see ref. 22c and:
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For related computational studies, see:
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For reviews, see:
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Also see:
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• 26m Nitro-Michael, role of PhCOOH: Shi H. Huang X. Liu G. Yu K. Xu C. Li W. Zeng B. Tang Y. Int. J. Quant. Chem. 2013; 113: 1339
• 26n COO^– vs. COOH: Hubin PO. Jacquemin D. Leherte L. Vercauteren DP. Chem. Phys. 2014; 434: 30

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:
• 28a Martinez A. Zumbansen K. Dohring A. van Gemmeren M. List B. Synlett 2014; 25: 932

For pioneering works, see:
• 28b List B. Lerner RA. Barbas CF. J. Am. Chem. Soc. 2000; 122: 2395
• 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
• 28i Porcar R. Burguete MI. Lozano P. Garcia-Verdugo E. Luis SV. ACS Sustainable Chem. Eng. 2016; 4: 6062
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For aldol reactions of 4-methylcyclohexanone with desymmetrization, see refs cited in:
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• 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.