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Selective transfer hydrogenations: Catalyst development and mechanistic investigations
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

By generating a library of amino acid-based ligands, pseudo-dipeptides, and combining them with transition metals, we have created selective and efficient ruthenium and rhodium catalysts for the asymmetric transfer hydrogenation of ketones. The ruthenium-catalyzed reaction was studied in detail, and we found that alkali metals play a crucial role for the reactivity and selectivity of the reaction. Furthermore, we have performed kinetic studies on the catalytic system, and the experimental data does neither support the established inner-sphere nor the classical outer-sphere mechanism. Hence, a novel mechanism for the ruthenium-pseudo-dipeptide-catalyzed transfer hydrogenation is proposed. In this unprecedented outer-sphere mechanism, a hydride and an alkali metal ion are transferred from the donor to the ruthenium complex in the rate determining step.

In addition, the pseudo-dipeptide ligands were employed in the rhodium-catalyzed transfer hydrogenation of aryl alkyl ketones to yield the corresponding alcohols in high yields and excellent enantioselectivities (up to 98% ee). The study revealed that the alkali metals, so important in the ruthenium analogue of the reaction, do not improve the enantioselectivity of the reaction. Deuterium labeling experiments showed that the reaction follows the mono hydridic route.

Furthermore, a novel method for efficient catalyst screening has been developed. We have demonstrated that ligand synthesis, catalyst formation, and enantioselective catalysis can be performed using an in situ one-pot procedure. The efficacy of the concept was demonstrated in the enantioselective reduction of ketones. In addition to the simplification of the catalyst formation, this approach resulted in improvement of the product ee.

Finally, the development of a reduction protocol for the transfer hydrogenation of ketones to alcohols without the involvement of transition metal catalysts is described. Using microwave irradiation, a range of ketones was efficiently reduced in high yields using catalytic amounts of lithium 2-propoxide in 2-propanol.

Place, publisher, year, edition, pages
Stockholm: Institutionen för organisk kemi , 2008. , 68 p.
Keyword [en]
asymmetric catalysis, transfer hydrogenation, transition metal, amino acids, amino alcohols
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-8300ISBN: 978-91-7155-768-1 (print)OAI: oai:DiVA.org:su-8300DiVA: diva2:200026
Public defence
2008-12-05, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-11-13 Created: 2008-11-13Bibliographically approved
List of papers
1. Ruthenium-Catalyzed Enantioselective Reduction of Electron-Rich Aryl Alkyl Ketones
Open this publication in new window or tab >>Ruthenium-Catalyzed Enantioselective Reduction of Electron-Rich Aryl Alkyl Ketones
2006 In: Advanced Synthesis and Catalysis, ISSN 1615-4150, Vol. 348, no 10-11, 1277-1282 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25589 (URN)
Note
Part of urn:nbn:se:su:diva-8300Available from: 2008-11-13 Created: 2008-11-13Bibliographically approved
2. The Importance of Alkali Cations in the [{RuCl2(p-cymene)}2]-Pseudo-dipeptide-Catalyzed Enantioselective Transfer Hydrogenation of Ketones
Open this publication in new window or tab >>The Importance of Alkali Cations in the [{RuCl2(p-cymene)}2]-Pseudo-dipeptide-Catalyzed Enantioselective Transfer Hydrogenation of Ketones
Show others...
2006 In: Chemistry - A European Journal, ISSN 0947-6539, Vol. 12, no 12, 3218-3225 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25590 (URN)
Note
Part of urn:nbn:se:su:diva-8300Available from: 2008-11-13 Created: 2008-11-13Bibliographically approved
3. Mechanistic Investigation on the Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Pseudo-Dipeptides Ruthenium complexes
Open this publication in new window or tab >>Mechanistic Investigation on the Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Pseudo-Dipeptides Ruthenium complexes
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 23, 5709-5718 p.Article in journal (Refereed) Published
Abstract [en]

Lithium-powered: A kinetic investigation into the asymmetric transfer hydrogenation of non-activated aryl alkyl ketones, catalyzed by N-Boc-protected -amino acid hydroxyamide ruthenium–arene complexes, has revealed that the reactions proceed through an unprecedented bimetallic outer-sphere mechanism. Under optimized conditions, these catalysts provide access to secondary alcohols in high yields and with excellent enantioselectivities (>99 % ee).

The combination of N-Boc-protected -amino acid hydroxyamides (pseudo-dipeptides) and [{Ru(p-cymene)Cl2}2] resulted in the formation of superior catalysts for the asymmetric transfer hydrogenation (ATH) of non-activated aryl alkyl ketones in propan-2-ol. The overall kinetics of the ATH of acetophenone to form 1-phenylethanol in the presence of ruthenium pseudo-dipeptide catalysts were studied, and the individual rate constants for the processes were determined. Addition of lithium chloride to the reaction mixtures had a strong influence on the rates and selectivities of the processes. Kinetic isotope effects (KIEs) for the reduction were determined and the results clearly show that the hydride transfer is rate-determining, whereas no KIEs were detected for the proton transfer. From these observations a novel bimetallic outer-sphere-type mechanism for these ATH process is proposed, in which the bifunctional catalysts mediate the transfer of a hydride and an alkali metal ion between the hydrogen donor and the substrate. Furthermore, the use of a mixture of propan-2-ol and THF (1:1) proved to enhance the rates of the ATH reactions. A series of aryl alkyl ketones were reduced under these conditions in the presence of 0.5 mol % of catalyst, and the corresponding secondary alcohols were formed in high yields and with excellent enantioselectivities (>99 % ee) in short reaction times.

Place, publisher, year, edition, pages
John Wiley & Sons, 2009
Keyword
amino acids;asymmetric catalysis;kinetics;reaction mechanisms;ruthenium;transfer hydrogenation
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-25591 (URN)10.1002/chem.200802496 (DOI)000267037800013 ()
Note
Part of urn:nbn:se:su:diva-8300Available from: 2008-11-13 Created: 2008-11-13 Last updated: 2017-12-13Bibliographically approved
4. Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Alkyl Ketones Employing Ligands Derived from Amino Acids
Open this publication in new window or tab >>Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Alkyl Ketones Employing Ligands Derived from Amino Acids
2007 In: Advanced Synthesis and Catalysis, ISSN 1615-4150, Vol. 349, no 17-18, 2556-2562 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25592 (URN)000251737500005 ()
Note
Part of urn:nbn:se:su:diva-8300Available from: 2008-11-13 Created: 2008-11-13Bibliographically approved
5. In situ formation of ligand and catalyst- application in ruthenium-catalyzed enantioselective reduction of ketones
Open this publication in new window or tab >>In situ formation of ligand and catalyst- application in ruthenium-catalyzed enantioselective reduction of ketones
2005 In: Chemical communications, ISSN 1359-7345, no 32, 4039-4041 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25593 (URN)
Note
Part of urn:nbn:se:su:diva-8300Available from: 2008-11-13 Created: 2008-11-13Bibliographically approved
6. A Simple and Efficient Catalytic Method for the Reduction of Ketones
Open this publication in new window or tab >>A Simple and Efficient Catalytic Method for the Reduction of Ketones
2007 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, no 10, 1609-1613 p.Article in journal (Refereed) Published
Abstract [en]

A range of ketones was efficiently reduced in the presence of catalytic amounts of lithium isopropoxide in 2-propanol under microwave heating, with alcohol products being formed in yields up to 99 %.

Keyword
alkali metals, hydrogen transfer, ketones, microwave heating, reduction
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-25594 (URN)10.1002/adsc.200700091 (DOI)000248365300009 ()
Available from: 2008-11-13 Created: 2008-11-13 Last updated: 2017-12-13Bibliographically approved

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