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Structure and reactivity relationship studies for guanidine-organocatalyzed direct intramolecular aldolization of ketoaldehydes
(Laboratory of Functional ChemoSystem)
KTH, School of Biotechnology (BIO), Theoretical Chemistry. (Theoretical Chemistry)
(Laboratory of Functional ChemoSystem)
(Laboratory of Functional ChemoSystem)
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(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

Structure-reactivity studies are performed to explore the reaction mechanism of guanidine-catalyzed intramolecular aldol reaction of ketoaldehydes. A large number of guanidines and guanidine-like catalysts were synthesized and their properties were determined. Kinetic profiles and pKa values of the catalysts were measured and correlated to reaction barriers calculated using density functional theory. The calculations show that the structural rigidity determines the pKa of the guanidines. Although the basicity is a very important factor in the catalyst, it is not sufficient to account for the full catalytic power. The availability of two reaction sites aligned for proton shuttling in the transition states is also an essential feature that helps us rationalize the reactivity pattern observed.

National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-11615OAI: oai:DiVA.org:kth-11615DiVA: diva2:278333
Note
QC 20100719Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2010-07-19Bibliographically 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.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2009:27
National Category
Theoretical Chemistry Organic Chemistry
Identifiers
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)
Opponent
Supervisors
Note
QC 20100719Available from: 2009-12-04 Created: 2009-11-25 Last updated: 2011-11-23Bibliographically approved

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