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Secondary Amine Catalysis:

What is your actual catalyst? TMS cleavage rates of diarylprolinol silyl ethers studied by in situ NMR

Haindl, M. H.; Schmid, M. B.; Zeitler, K. & Gschwind, R. M. 

RSC Advances, Royal Society of Chemistry, 2012, 2, 5941-5943



Diarylprolinol silyl ethers are excellent and broadly applicable organocatalysts for various enamine and iminium-type synthetic transformations. However, their undesired degradation to the corresponding diarylprolinols and the subsequent formation of oxazolidines during reaction with aldehydes may significantly affect their catalytic performance. Therefore, in situ NMR was used to examine the TMS cleavage rate of diarylprolinol silyl ethers as a function of solvent properties, acidic/basic additives and the presence of water. Highly polar solvents with strong hydrogen bond acceptor properties and especially moderate acidic additives with pKa (DMSO) values around 10 accelerate the deprotection significantly, whereas basic and highly acidic additives are not detrimental. Additional mechanistic studies reveal that the substitution reaction takes places at the silicon atom. 

Stabilization of Proline Enamine Carboxylates by Amine Bases

Schmid, M. B.; Zeitler, K. & Gschwind, R. M.

Chemistry - A European Journal, 2012, 18, 3362-3370


As part of our ongoing studies to provide an experimental basis for the improved understanding of organocatalytic reaction mechanisms we present a study on the influence of amine bases on enamine intermediate stabilization in proline catalysis. The (partial) deprotonation of the proline acid function is displayed by characteristic shifts of certain proton resonances and is also manifested by an increase of the amount of enamine intermediate upon reaching a critical pKaH. Strong bases, such as 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), allow for outstanding enamine stabilization in various solvents and, hence, permit the detection of enamine species that have been inaccessible until now (illustrated by the observation of minor amounts of Z enamines). The in situ NMR detection of a prolinate–DBUH+ ion pair supports the well-documented reversal of enantioselectivity of proline-catalyzed aminations in the presence of amine bases by disabling the bifunctional activity and switching to a “simple” stereocontrol effect (as known from the Jørgensen/Hayashi-type diarylprolinol ethers). In addition, the possibility of attractive ionic interactions between both the iminium ion and prolinate enamines available in the presence of strong amine bases suggests promotion of the Mannich pathway in aldol reactions to mainly form condensation products. 

Formation and Stability of Prolinol and Prolinol Ether Enamines by NMR: Delicate Selectivity and Reactivity Balances and Parasitic Equilibria

Schmid, M. B.; Zeitler, K. & Gschwind, R. M.

Journal of the American Chemical Society, ACS Publications, 2011, 133, 7065-7074 


Enamine key intermediates in organocatalysis, derived from aldehydes and prolinol or Jørgensen−Hayashi-type prolinol ether catalysts, were generated in different solvents and investigated by NMR spectroscopy. Depending on the catalyst structure, trends for their formation and amounts are elucidated. For prolinol catalysts, the first enamine detection in situ is presented and the rapid cyclization of the enamine to the oxazolidine (“parasitic equilibrium”) is monitored. In the case of diphenylprolinol, this equilibrium is fully shifted to the endo-oxazolidine (“dead end”) by the two geminal phenyl rings, most probably because of the Thorpe−Ingold effect. With bulkier and electron-withdrawing aryl rings, however, the enamine is stabilized relative to the oxazolidine, allowing for the parallel detection of the enamine and the oxazolidine. In the case of prolinol ethers, the enamine amounts decrease with increasing sizes of the aryl meta-substituents and the O-protecting group. In addition, for small aldehyde alkyl chains, Z-configured enamines are observed for the first time in solution. Prolinol silyl ether enamines are evidenced to undergo slow desilylation and subsequent rapid oxazolidine formation in DMSO. For unfortunate combinations of aldehydes, catalysts, solvents, and additives, the enamine formation is drastically decelerated but can be screened for by a rapid and facile NMR approach. Altogether, especially by clarifying the delicate balances of catalyst selectivity and reactivity, our NMR spectroscopic findings can be expected to substantially aid synthetically working organic chemists in the optimization of organocatalytic reaction conditions and of prolinol (ether) substitution patterns for enamine catalysis.


NMR Investigations on the Proline-Catalyzed Aldehyde Self-Condensation: Mannich Mechanism, Dienamine Detection, and Erosion of the Aldol Addition Selectivity

Schmid, M. B.; Zeitler, K. & Gschwind, R. M.

The Journal of Organic Chemistry, ACS Publications, 2011, 76, 3005-3015


The proline-catalyzed self-condensation of aliphatic aldehydes in DMSO with varying amounts of catalyst was studied by in situ NMR spectroscopy. The reaction profiles and intermediates observed as well as deuteration studies reveal that the proline-catalyzed aldol addition and condensation are competing, but not consecutive, reaction pathways. In addition, the rate-determining step of the condensation is suggested to be the C−C bond formation. Our findings indicate the involvement of two catalyst molecules in the C−C bond formation of the aldol condensation, presumably by the activation of both the aldol acceptor and donor in a Mannich-type pathway. This mechanism is shown to be operative also in the oligomerization of acetaldehyde with high proline amounts, for which the first in situ detection of a proline-derived dienamine was accomplished. In addition, the diastereoselectivity of the aldol addition is evidenced to be time-dependent since it is undermined by the retro-aldolization and the competing irreversible aldol condensation; here NMR reaction profiles can be used as a tool for reaction optimization.


Distinct conformational preferences of prolinol and prolinol ether enamines in solution revealed by NMR

Schmid, M. B.; Zeitler, K. & Gschwind, R. M.

Chemical Sciene, The Royal Society of Chemistry, 2011, 2, 1793-1803


Enamines, which are key intermediates in organocatalysis derived from aldehydes and prolinol or Jørgensen–Hayashi-type prolinol ether catalysts, were investigated conformationally in different solvents by means of NMR spectroscopy, in order to provide an experimental basis for a better understanding of the origin of stereoselection. For all of the enamines studied, surprisingly strong conformational preferences were observed. The enamines of the diarylprolinol (ether) catalysts were found to exclusively exist in the s-trans conformation due to the bulkiness of the pyrrolidine α-substituent. For prolinol enamines, however, a partial population of the s-cis conformation in solution was also evidenced for the first time. In addition, for all of the enamines studied, the pyrrolidine ring was found to adopt the down conformation. Concerning the exocyclic C–C bond, the sc-exo conformation, stabilized by CH/π interactions, is exclusively observed in the case of diarylprolinol ether enamines. In contrast, diarylprolinol enamines adopt the sc-endo conformation, allowing for an OHN hydrogen bond and a CH/π interaction. A rapid screening approach for the different conformational enamine features is presented and this was applied to show their generality for various catalysts, aldehydes and solvents. Thus, by unexpectedly revealing the pronounced conformational preferences of prolinol and prolinol ether enamines in solution, our study provides the first experimental basis for discussing the previously controversial issues of s-cis/s-trans and sc-endo/sc-exo conformations. Moreover, our findings are in striking agreement with the experimental results from synthetic organic chemistry. They are therefore expected to also have a significant impact on future theoretical calculations and synthetic optimization of asymmetric prolinol (ether) enamine catalysis.

The Elusive Enamine Intermediate in Proline-Catalyzed Aldol Reactions: NMR Detection, Formation Pathway, and Stabilization Trends

Schmid, M. B.; Zeitler, K. & Gschwind, R. M.

Angewandte Chemie International Edition, Wiley VCH-Verlag, 2010, 49, 4997-5003


Angewandte Chemie, Wiley  VCH-Verlag, 2010, 122, 5117-5123 

Web-EditionThe missing link: The elusive enamine intermediate of nucleophilic proline catalysis was detected and stereochemically characterized by NMR analysis of the aldehyde self-aldolization reaction in dipolar aprotic solvents. NMR exchange spectroscopy (EXSY) was used to observe direct enamine formation from oxazolidinones. Additionally, the stabilization of the intermediate by the appropriate choice of solvent and substitution pattern on the aldehyde is presented.




Brønsted Acid Catalysis

Brønsted Acid Catalysis: Hydrogen Bonding versus Ion Pairing in Imine Activation

Fleischmann, M.; Drettwan, D.; Sugiono, E.; Rueping, M. & Gschwind, R. M.

Angewandte Chemie International Edition, Wiley VCH-Verlag, 2011, 50, 6364-6369


Web-EditionBehind the scenes: NMR spectroscopy was used to distinguish hydrogen bonding and ion pairing in the activation of imines by a phosphate catalyst (see structures). Hydrogen-bond strength and the amount of the hydrogen-bonded species present are decisive for the catalytic reaction and can be manipulated by introducing substituents with different electronic properties. This insight should guide the development of more efficient catalytic systems.




  1. Fakultät für Chemie und Pharmazie
  2. Institut für Organische Chemie

Arbeitskreis Prof. Gschwind

Prof. Dr.
Ruth M. Gschwind


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