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Quantum Chemical Studies of Mechanisms and Stereoselectivities of Organocatalytic Reactions
KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512). (Theoretical Chemistry)
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: urn:nbn:se:kth:diva-11616ISBN: 978-91-7415-498-6 (print)OAI: oai:DiVA.org:kth-11616DiVA: diva2:278360
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
List of papers
1. Density Functional Theory Study of the Stereoselectivity in Small Peptide-Catalyzed Intermolecular Aldol Reactions
Open this publication in new window or tab >>Density Functional Theory Study of the Stereoselectivity in Small Peptide-Catalyzed Intermolecular Aldol Reactions
2008 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 19, 1617-1621 p.Article in journal (Refereed) Published
Abstract [en]

The origins of the stereoselection of the dipeptide-catalyzed intermolecular aldol reaction are explored by means of hybrid density functional theory. Transition states were located for the (S)-ala-(S)-ala-catalyzed aldol reaction with cyclohexanone as the donor and benzaldehyde as the acceptor. The calculations reproduce the experimental trends very satisfactorily. It is demonstrated that the main Source of stereoselectivity is the interaction of the N-terminal amino acid side chain of the dipeptide with the cyclohexene ring.

Keyword
asymmetric-synthesis, enantioselective aldol, versatile catalysts, transition-states, amino-acids, proline, aldehydes, water, organocatalysis, mechanism
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:kth:diva-8240 (URN)10.1016/j.tetasy.2008.06.014 (DOI)000258433400016 ()2-s2.0-48949114919 (Scopus ID)
Note
QC 20100716Available from: 2008-04-22 Created: 2008-04-22 Last updated: 2010-11-11Bibliographically approved
2. Enantioselective Organocatalytic Hydrophosphination of α,β-Unsaturated Aldehydes
Open this publication in new window or tab >>Enantioselective Organocatalytic Hydrophosphination of α,β-Unsaturated Aldehydes
Show others...
2007 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 46, no 24, 4507-4510 p.Article in journal (Refereed) Published
Abstract [en]

Keeping it simple: Optically active phosphine derivatives can be obtained in high yields and in up to 99% ee by using simple chiral amines to catalyze the hydrophosphination of α,β-unsaturated aldehydes (see scheme, green sphere = chiral group). The synthetic utility of this highly chemo- and enantioselective transformation was exemplified by the one-pot asymmetric synthesis of β-phosphine oxide acids.

Keyword
Aldehydes, Asymmetric synthesis, Conjugate addition, Organocatalysis, Phosphanes
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:kth:diva-8241 (URN)10.1002/anie.200700916 (DOI)000247500600018 ()2-s2.0-34250780536 (Scopus ID)
Note
QC 20100716Available from: 2008-04-22 Created: 2008-04-22 Last updated: 2010-11-11Bibliographically approved
3. Organocatalytic Asymmetric Addition of Phosphorus Nucleophiles to α,β-Unsaturated Aldehydes: Mechanism and Scope
Open this publication in new window or tab >>Organocatalytic Asymmetric Addition of Phosphorus Nucleophiles to α,β-Unsaturated Aldehydes: Mechanism and Scope
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(English)Article in journal (Other academic) Submitted
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8242 (URN)
Note
QS 20120327Available from: 2008-04-22 Created: 2008-04-22 Last updated: 2012-03-27Bibliographically approved
4. Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry reaction: Mechanism and Enantioselectivity
Open this publication in new window or tab >>Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry reaction: Mechanism and Enantioselectivity
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.

Keyword
cinchona alkaloids, density functional theory, enantioselectivity, nitroaldol reaction, organocatalysis
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-8243 (URN)10.1002/adsc.200700367 (DOI)000251737500003 ()2-s2.0-37349098707 (Scopus ID)
Note
QC 20100719Available from: 2008-04-22 Created: 2008-04-22 Last updated: 2010-11-11Bibliographically approved
5. Phosphoric Acid Catalyzed Enantioselective Transfer Hydrogenationof Imines: A Density Functional Theory Study of Reaction Mechanismand the Origins of Enantioselectivity
Open this publication in new window or tab >>Phosphoric Acid Catalyzed Enantioselective Transfer Hydrogenationof Imines: A Density Functional Theory Study of Reaction Mechanismand the Origins of Enantioselectivity
2008 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 14, 8562-8571 p.Article in journal (Refereed) Published
Abstract [en]

The phosphoric acid catalyzedreaction of 1,4-dihydropyridineswith N-arylimines has been investigatedby using density functional theory.We first considered the reaction of acetophenonePMP-imine (PMP=p-methoxyphenyl)with the dimethylHantzsch ester catalyzed by diphenylphosphate. Our study showed that, inagreement with what has previouslybeen postulated for other reactions, diphenylphosphate acts as a Lewis base/Brønsted acid bifunctional catalyst inthis transformation, simultaneously activatingboth reaction partners. The calculationsalso showed that the hydridetransfer transition states for the E andZ isomers of the iminium ion havecomparable energies. This observationturned out to be crucial to the understandingof the enantioselectivity of theprocess. Our results indicate that whenusing a chiral 3,3’-disubstituted biarylphosphoric acid, hydride transfer to theRe face of the (Z)-iminium is energeticallymore favorable and is responsiblefor the enantioselectivity, whereas thecorresponding transition states for nucleophilicattack on the two faces ofthe (E)-iminium are virtually degenerate.Moreover, model calculations predictthe reversal in enantioselectivityobserved in the hydrogenation of 2-arylquinolines,which during the catalyticcycle are converted into (E)-iminiumions that lack the flexibility of thosederived from acyclic N-arylimines. Inthis respect, the conformational rigidityof the dihydroquinolinium cation imposesan unfavorable binding geometryon the transition state for hydridetransfer on the Re face and is thereforeresponsible for the high enantioselectivity.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH&Co. KGaA, 2008
Keyword
ensity functional calculations; hydrogenation; imines; organocatalysis; pyridines
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-11611 (URN)10.1002/chem.200800890 (DOI)000260035900018 ()2-s2.0-53849122697 (Scopus ID)
Note
QC 20100719Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2017-12-12Bibliographically approved
6. Origin of Enantioselectivity in the Organocatalytic Reductive Amination of α-Branched Aldehydes
Open this publication in new window or tab >>Origin of Enantioselectivity in the Organocatalytic Reductive Amination of α-Branched Aldehydes
2009 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 351, no 4, 525-529 p.Article in journal (Refereed) Published
Abstract [en]

The reason for enantioselectivity in thereductive amination of α-branched aldehydes wasinvestigated. The relative energies of all the diastereomeric transition states for hydride transfer of a suitable computational model were calculated at the B3LYP/6-311+(2d,2p) level of theory. Our calculations successfully reproduce and rationalize the experimentally observed stereochemical outcome of the reaction.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH&Co. KGaA, 2009
Keyword
density functional theory; dynamic kinetic resolution; Hantzsch esters; organocatalysis; reduction
National Category
Theoretical Chemistry Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-11612 (URN)10.1002/adsc.200800613 (DOI)000264831500003 ()2-s2.0-62549085227 (Scopus ID)
Note
QC 20100719Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2017-12-12Bibliographically approved
7. Theoretical Mechanistic Study of the TBD-Catalyzed Intramolecular Aldol Reaction of Ketoaldehydes
Open this publication in new window or tab >>Theoretical Mechanistic Study of the TBD-Catalyzed Intramolecular Aldol Reaction of Ketoaldehydes
Show others...
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.

Keyword
RING-OPENING POLYMERIZATION, DENSITY-FUNCTIONAL THEORY, ASYMMETRIC ORGANOCATALYSIS, CYCLIC ESTERS, ENANTIOSELECTIVE ORGANOCATALYSIS, PROLINE, WATER, GUANIDINE, ACETALDEHYDE, ALDEHYDES
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-11613 (URN)10.1021/jo100488g (DOI)000279569500007 ()2-s2.0-77954554809 (Scopus ID)
Funder
Swedish Research Council
Note
Uppdaterad från manuskift 20100719 QC 20100719Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2017-12-12Bibliographically approved
8. Structure and reactivity relationship studies for guanidine-organocatalyzed direct intramolecular aldolization of ketoaldehydes
Open this publication in new window or tab >>Structure and reactivity relationship studies for guanidine-organocatalyzed direct intramolecular aldolization of ketoaldehydes
Show others...
(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:nbn:se:kth:diva-11615 (URN)
Note
QC 20100719Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2010-07-19Bibliographically approved

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