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Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry reaction: Mechanism and Enantioselectivity
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
Van't Hoff Institute of Molecular Sciences, University of Amsterdam.
Van't Hoff Institute of Molecular Sciences, University of Amsterdam.
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
2007 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, no 17-18, 2537-2548 p.Article in journal (Refereed) Published
Abstract [en]

We report a density functional theory investigation of the enantioselective Cinchona thiourea-catalyzed Henry reaction of aromatic aldehydes with nitromethane. We show that two pathways (differing in the binding modes of the reactants to the catalyst) are possible for the formation of the C-C bond, and that they have comparable reaction barriers. The enantioselectivity is investigated, and our results are in agreement with the experimentally observed solvent dependence of the reaction.

Place, publisher, year, edition, pages
2007. Vol. 349, no 17-18, 2537-2548 p.
Keyword [en]
cinchona alkaloids, density functional theory, enantioselectivity, nitroaldol reaction, organocatalysis
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-8243DOI: 10.1002/adsc.200700367ISI: 000251737500003Scopus ID: 2-s2.0-37349098707OAI: oai:DiVA.org:kth-8243DiVA: diva2:13512
Note
QC 20100719Available from: 2008-04-22 Created: 2008-04-22 Last updated: 2010-11-11Bibliographically approved
In thesis
1. Quantum Chemical Studies of Enantioselective Organocatalytic Reactions
Open this publication in new window or tab >>Quantum Chemical Studies of Enantioselective Organocatalytic Reactions
2008 (English)Licentiate thesis, comprehensive summary (Other scientific)
Abstract [en]

Density Functional Theory is used in order to shed light on the reaction mechanisms and the origins of stereoselectivity in enantioselective organocatalytic reactions. The reactions investigated are the dipeptide-catalyzed aldol reaction, the cinchona thiourea-catalyzed nitroaldol reaction and the prolinol derivative-catalyzed hydrophosphination reaction. We can justify the stereoselectivity in the reactions from the energies arising from different interactions in the transition states. The major contributions to the energy differences are found to be hydrogen bond-type attractions and steric repulsions. This knowledge will be useful in the design of improved catalysts as well as general understanding of the basis of selection in other reactions.

Place, publisher, year, edition, pages
Stockholm: KTH, 2008. vii, 30 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2008:6
Keyword
DFT, enantioselective, asymmetric, organocatalysis
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-4701 (URN)978-91-7178-934-1 (ISBN)
Presentation
2008-04-29, FB52, Albanova, Roslagstullsbacken 21, Stockholm, 10:15
Supervisors
Note
QC 20101111Available from: 2008-04-22 Created: 2008-04-22 Last updated: 2010-11-11Bibliographically approved
2. 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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