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Quantum Chemical Studies of Mechanisms and Stereoselectivities of Organocatalytic Reactions
KTH, Skolan för bioteknologi (BIO), Teoretisk kemi. (Theoretical Chemistry)
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH , 2009. , s. viii, 72
Serie
Trita-BIO-Report, ISSN 1654-2312 ; 2009:27
Nationell ämneskategori
Teoretisk kemi Organisk kemi
Identifikatorer
URN: urn:nbn:se:kth:diva-11616ISBN: 978-91-7415-498-6 (tryckt)OAI: oai:DiVA.org:kth-11616DiVA, id: diva2:278360
Disputation
2009-12-18, Svedbergsalen, FD5, Roslagstullsbacken 21, AlbaNova, Stockholm, 14:00 (Engelska)
Opponent
Handledare
Anmärkning
QC 20100719Tillgänglig från: 2009-12-04 Skapad: 2009-11-25 Senast uppdaterad: 2022-06-25Bibliografiskt granskad
Delarbeten
1. Density Functional Theory Study of the Stereoselectivity in Small Peptide-Catalyzed Intermolecular Aldol Reactions
Öppna denna publikation i ny flik eller fönster >>Density Functional Theory Study of the Stereoselectivity in Small Peptide-Catalyzed Intermolecular Aldol Reactions
2008 (Engelska)Ingår i: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 19, s. 1617-1621Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
asymmetric-synthesis, enantioselective aldol, versatile catalysts, transition-states, amino-acids, proline, aldehydes, water, organocatalysis, mechanism
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
urn:nbn:se:kth:diva-8240 (URN)10.1016/j.tetasy.2008.06.014 (DOI)000258433400016 ()2-s2.0-48949114919 (Scopus ID)
Anmärkning
QC 20100716Tillgänglig från: 2008-04-22 Skapad: 2008-04-22 Senast uppdaterad: 2022-06-26Bibliografiskt granskad
2. Enantioselective Organocatalytic Hydrophosphination of α,β-Unsaturated Aldehydes
Öppna denna publikation i ny flik eller fönster >>Enantioselective Organocatalytic Hydrophosphination of α,β-Unsaturated Aldehydes
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2007 (Engelska)Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 46, nr 24, s. 4507-4510Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Aldehydes, Asymmetric synthesis, Conjugate addition, Organocatalysis, Phosphanes
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
urn:nbn:se:kth:diva-8241 (URN)10.1002/anie.200700916 (DOI)000247500600018 ()17492816 (PubMedID)2-s2.0-34250780536 (Scopus ID)
Anmärkning
QC 20100716Tillgänglig från: 2008-04-22 Skapad: 2008-04-22 Senast uppdaterad: 2022-06-26Bibliografiskt granskad
3. Organocatalytic Asymmetric Addition of Phosphorus Nucleophiles to α,β-Unsaturated Aldehydes: Mechanism and Scope
Öppna denna publikation i ny flik eller fönster >>Organocatalytic Asymmetric Addition of Phosphorus Nucleophiles to α,β-Unsaturated Aldehydes: Mechanism and Scope
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(Engelska)Artikel i tidskrift (Övrigt vetenskapligt) Submitted
Nationell ämneskategori
Kemiteknik
Identifikatorer
urn:nbn:se:kth:diva-8242 (URN)
Anmärkning
QS 20120327Tillgänglig från: 2008-04-22 Skapad: 2008-04-22 Senast uppdaterad: 2022-06-26Bibliografiskt granskad
4. Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry reaction: Mechanism and Enantioselectivity
Öppna denna publikation i ny flik eller fönster >>Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry reaction: Mechanism and Enantioselectivity
2007 (Engelska)Ingår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, nr 17-18, s. 2537-2548Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
cinchona alkaloids, density functional theory, enantioselectivity, nitroaldol reaction, organocatalysis
Nationell ämneskategori
Kemiteknik
Identifikatorer
urn:nbn:se:kth:diva-8243 (URN)10.1002/adsc.200700367 (DOI)000251737500003 ()2-s2.0-37349098707 (Scopus ID)
Anmärkning
QC 20100719Tillgänglig från: 2008-04-22 Skapad: 2008-04-22 Senast uppdaterad: 2022-06-26Bibliografiskt granskad
5. Phosphoric Acid Catalyzed Enantioselective Transfer Hydrogenationof Imines: A Density Functional Theory Study of Reaction Mechanismand the Origins of Enantioselectivity
Öppna denna publikation i ny flik eller fönster >>Phosphoric Acid Catalyzed Enantioselective Transfer Hydrogenationof Imines: A Density Functional Theory Study of Reaction Mechanismand the Origins of Enantioselectivity
2008 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 14, s. 8562-8571Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Weinheim: Wiley-VCH Verlag GmbH&Co. KGaA, 2008
Nyckelord
ensity functional calculations; hydrogenation; imines; organocatalysis; pyridines
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:kth:diva-11611 (URN)10.1002/chem.200800890 (DOI)000260035900018 ()18683177 (PubMedID)2-s2.0-53849122697 (Scopus ID)
Anmärkning
QC 20100719Tillgänglig från: 2009-11-25 Skapad: 2009-11-25 Senast uppdaterad: 2022-06-25Bibliografiskt granskad
6. Origin of Enantioselectivity in the Organocatalytic Reductive Amination of α-Branched Aldehydes
Öppna denna publikation i ny flik eller fönster >>Origin of Enantioselectivity in the Organocatalytic Reductive Amination of α-Branched Aldehydes
2009 (Engelska)Ingår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 351, nr 4, s. 525-529Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Weinheim: Wiley-VCH Verlag GmbH&Co. KGaA, 2009
Nyckelord
density functional theory; dynamic kinetic resolution; Hantzsch esters; organocatalysis; reduction
Nationell ämneskategori
Teoretisk kemi Organisk kemi
Identifikatorer
urn:nbn:se:kth:diva-11612 (URN)10.1002/adsc.200800613 (DOI)000264831500003 ()2-s2.0-62549085227 (Scopus ID)
Anmärkning
QC 20100719Tillgänglig från: 2009-11-25 Skapad: 2009-11-25 Senast uppdaterad: 2022-06-25Bibliografiskt granskad
7. Theoretical Mechanistic Study of the TBD-Catalyzed Intramolecular Aldol Reaction of Ketoaldehydes
Öppna denna publikation i ny flik eller fönster >>Theoretical Mechanistic Study of the TBD-Catalyzed Intramolecular Aldol Reaction of Ketoaldehydes
Visa övriga...
2010 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, nr 14, s. 4728-4736Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
RING-OPENING POLYMERIZATION, DENSITY-FUNCTIONAL THEORY, ASYMMETRIC ORGANOCATALYSIS, CYCLIC ESTERS, ENANTIOSELECTIVE ORGANOCATALYSIS, PROLINE, WATER, GUANIDINE, ACETALDEHYDE, ALDEHYDES
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:kth:diva-11613 (URN)10.1021/jo100488g (DOI)000279569500007 ()20545376 (PubMedID)2-s2.0-77954554809 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet
Anmärkning
Uppdaterad från manuskift 20100719 QC 20100719Tillgänglig från: 2009-11-25 Skapad: 2009-11-25 Senast uppdaterad: 2022-06-25Bibliografiskt granskad
8. Structure and reactivity relationship studies for guanidine-organocatalyzed direct intramolecular aldolization of ketoaldehydes
Öppna denna publikation i ny flik eller fönster >>Structure and reactivity relationship studies for guanidine-organocatalyzed direct intramolecular aldolization of ketoaldehydes
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(Engelska)Manuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
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.

Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:kth:diva-11615 (URN)
Anmärkning
QC 20100719Tillgänglig från: 2009-11-25 Skapad: 2009-11-25 Senast uppdaterad: 2022-06-25Bibliografiskt granskad

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