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DOI: 10.1055/s-0036-1590909
Computer-Aided Insight into the Relative Stability of Enamines
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).Publikationsverlauf
Received: 10. Juli 2017
Accepted after revision: 23. August 2017
Publikationsdatum:
04. Oktober 2017 (online)
![](https://www.thieme-connect.de/media/synthesis/201724/lookinside/thumbnails/ss-2017-z0449-sr_10-1055_s-0036-1590909-1.jpg)
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
-
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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.
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For historical reviews, see:
Also see:
For a non-exhaustive list of recent reviews of organocatalytic reactions involving enamine chemistry, see:
For the combined use of aminocatalysis and transition-metal catalysis (which will not be dealt with here), see refs cited in:
For the J–H catalyst, see:
For revisions of the Houk–List TS model for aldol reactions, see:
When the carboxyl group is in its anionic form or under basic catalysis (with the carboxyl group in its standard s-cis arrangement), anchimeric assistance is plausible, with an attack of the electrophile from the rear face of the s-cis conformer1d and formation of the corresponding bicyclic exo-oxazolidinone, the more stable of the two possible oxazolidinones formed from aldehydes. For pros and cons of this model and for other models, see:
For pioneering works on organocatalytic Mannich reactions, see:
For entries on the theme, see:
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:
Also see:
Previous QCC of enamines of pyrrolidine:
For excellent reviews of dienamines and trienamines (generally of 2-substituted pyrrolidines, mainly derivatives of the J–H catalyst), see:
For NMR studies (in agreement with the calculations reported here), see:
For calculations of N-(cyclohexadienyl)ethenyl-substituted pyrrolidines, see:
For an excellent summary of the so-called Z/E dilemma and its experimental and QCC-based explanation, see:
For X-ray crystal structures of imidazolidinone-derived enamines, see:
For X-ray crystal structures of 2-Tr and 2-SiPh3-pyrrolidine enamines, see:
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:
For [2+4]-cycloadducts, see ref. 22c and:
For related computational studies, see:
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:
For reviews, see:
Also see:
For aldol reactions of 4-(2-oxopropyl)- and 4-(3-oxopropyl)cyclohexanone derivatives, where the reaction selectively occurs at the cyclohexanone ring, see:
For an outstanding study of Pro-catalyzed aldol reactions of acetone, see:
For pioneering works, see:
For some very recent papers focused on acetone reactions, see:
For aldol reactions of 4-methylcyclohexanone with desymmetrization, see refs cited in: