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Theoretical Mechanistic Study of the TBD-Catalyzed Intramolecular Aldol Reaction of Ketoaldehydes
KTH, School of Biotechnology (BIO), Theoretical Chemistry. (Theoretical Chemistry)
(Laboratory of Functional ChemoSystem)
(Laboratory of Functional ChemoSystem)
(Laboratory of Functional ChemoSystem)
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2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 14, 4728-4736 p.Article in journal (Refereed) Published
Abstract [en]

The intramolecular aldol reaction of acyclic ketoaldehydes catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is investigated using density functional theory calculations. Compared to the aldol reaction catalyzed by proline, the use of TBD provides a unique and unusual complete switch of product selectivity. Three mechanistic pathways are proposed and evaluated. In the favored mechanism TBD catalyzes the reaction through proton transfer in two steps, enolization and C-C bond formation. The computationally predicted stereochemical outcome of the reaction is in agreement with experimental findings. Additionally, these studies provide new insights into the activation mode of bifunctional guanidine catalysts in aldol reactions.

Place, publisher, year, edition, pages
2010. Vol. 75, no 14, 4728-4736 p.
Keyword [en]
National Category
Organic Chemistry
URN: urn:nbn:se:kth:diva-11613DOI: 10.1021/jo100488gISI: 000279569500007ScopusID: 2-s2.0-77954554809OAI: diva2:278332
Swedish Research Council
Uppdaterad från manuskift 20100719 QC 20100719Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2011-02-02Bibliographically approved
In thesis
1. Quantum Chemical Studies of Mechanisms and Stereoselectivities of Organocatalytic Reactions
Open this publication in new window or tab >>Quantum Chemical Studies of Mechanisms and Stereoselectivities of Organocatalytic Reactions
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As the field of organocatalysis is growing, it is becoming more important to understand the specific modes of action of these new organic catalysts. Quantum chemistry, in particular density functional theory, has proven very powerful in exploring reaction mechanisms as well as selectivities in organocatalytic reactions, and is the tool used in this thesis. Different reaction mechanisms of several organocatalytic reactions have been examined, and we have been able to exclude various reaction pathways based on the calculated reaction barriers. The origins of stereoselection in a number of reactions have been rationalized. The computational method has generally reproduced the experimental stereoselectivities satisfactorily.

The amino acid-catalyzed aldol reaction has previously been established to go through an enamine intermediate. In the first study of this thesis the understanding of this kind of reactions has been expanded to the dipeptide-catalyzed aldol reaction. The factors governing the enantioselection have been studied, showing how the chirality of the amino acids controls the conformation of the transition state, thereby determining the configuration of the product.

In the cinchona thiourea-catalyzed Henry reaction two reaction modes regarding substrate binding to the two sites of the catalyst have been investigated, showing the optimal arrangement for this reaction. This enabled the rationalization of the observed stereoselectivity.

The hydrophosphination of α,β-unsaturated aldehydes was studied. The bulky substituent of the chiral prolinol-derived catalyst was shown to effectively shield one face of the reactive iminium intermediate, thereby inducing the stereoselectivity.

The transfer hydrogenation of imines using Hantzsch esters as hydride source and axially chiral phosphoric acid catalyst has also been explored. A reaction mode where both the Hantzsch ester and the protonated imine are hydrogen bonded to the phosphoric acid is demonstrated to be the preferred mode of action. The different arrangements leading to the two enantiomers of the product are evaluated for several cases, including the hydride transfer step in the reductive amination of α-branched aldehydes via dynamic kinetic resolution.

Finally, the intramolecular aldol reaction of ketoaldehydes catalyzed by guanidinebased triazabicyclodecene (TBD) has been studied. Different mechanistic proposals have been assessed computationally, showing that the favoured reaction pathway is catalyzed by proton shuttling. The ability of a range of guanidines to catalyze this reaction has been investigated. The calculated reaction barriers reproduced the experimental reactivities quite well.

Place, publisher, year, edition, pages
Stockholm: KTH, 2009. viii, 72 p.
Trita-BIO-Report, ISSN 1654-2312 ; 2009:27
National Category
Theoretical Chemistry Organic Chemistry
urn:nbn:se:kth:diva-11616 (URN)978-91-7415-498-6 (ISBN)
Public defence
2009-12-18, Svedbergsalen, FD5, Roslagstullsbacken 21, AlbaNova, Stockholm, 14:00 (English)
QC 20100719Available from: 2009-12-04 Created: 2009-11-25 Last updated: 2011-11-23Bibliographically approved

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