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Catalysis in Dynamic Systems: Control within Molecular Reaction Networks
KTH, School of Chemical Science and Engineering (CHE), Chemistry. (Olof Ramström)ORCID iD: 0000-0001-5298-4310
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Life as we know it is based on complex networks of biochemical reactions that constantly interact within large dynamic systems. The field of systems chemistry uses chemical models to study how reaction networks – and thereby life – function on a molecular level. This thesis focuses on different aspects of catalysis in dynamic systems of interconnected reversible reactions. Using the reversible imine bond as the primary tool, such dynamic systems have both been used for catalyst screening and to achieve emergent systemic behavior.

First, constitutional dynamic chemistry was used to discover catalysts within large mixtures. A method based on dynamic deconvolution was used to identify a bifunctional organocatalyst for the Morita-Baylis-Hillman (MBH) reaction from a mixture of 16 candidates. A second method involved amplification of an organometallic intermediate from a dynamic system and was used to discover directing group/metal combinations for C-H functionalization of aldehydes.

Subsequently, the consequences of integrating the catalyst itself into a dynamic system were investigated. Here, dynamic covalent catalysts formed reaction networks with programmable systemic properties. Using the MBH reaction and dynamic imine exchange, catalysts capable of self-resolution, feedback regulation and error-correction were constructed.

Finally, selective catalyst systems for activation of new reversible covalent behavior for imines were developed. H-bond catalysis was used to facilitate imine exchange under mild conditions, and transamination was introduced as a dynamic covalent linkage that could change the directionality of the imine bond.

The research in this thesis should both be applicable for catalyst discovery within synthetic organic chemistry, for understanding connectivity in chemical and biological systems as well as for studies of the origin of life on earth and the evolution of simple molecules into advanced systems with emergent functionality.

Place, publisher, year, edition, pages
Stockholm: Kungliga Tekniska högskolan, 2017. , p. 90
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2017:7
Keywords [en]
systems chemistry, dynamic covalent chemistry, catalyst screening, reaction networks, organocatalysis, imine exchange, combinatorial chemistry, dynamic systemic resolution, feedback, error-correction, Morita-Baylis-Hillman reaction, C-H activation, H-bond catalysis, transamination
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-199708ISBN: 978-91-7729-255-5 (print)OAI: oai:DiVA.org:kth-199708DiVA, id: diva2:1065355
Public defence
2017-02-17, F3, Lindstedtsvägen 26, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20170216

Available from: 2017-01-16 Created: 2017-01-15 Last updated: 2017-01-27Bibliographically approved
List of papers
1. Dynamic Covalent Organocatalysts Discovered from Catalytic Systems through Rapid Deconvolution Screening
Open this publication in new window or tab >>Dynamic Covalent Organocatalysts Discovered from Catalytic Systems through Rapid Deconvolution Screening
2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 36, p. 12735-12740Article in journal (Refereed) Published
Abstract [en]

The first example of a bifunctional organocatalyst assembled through dynamic covalent chemistry (DCC) is described. The catalyst is based on reversible imine chemistry and can catalyze the Morita-Baylis-Hillman (MBH) reaction of enones with aldehydes or N-tosyl imines. Furthermore, these dynamic catalysts were shown to be optimizable through a systemic screening approach, in which large mixtures of catalyst structures were generated, and the optimal catalyst could be directly identified by using dynamic deconvolution. This strategy allowed one-pot synthesis and in situ evaluation of several potential catalysts without the need to separate, characterize, and purify each individual structure. The systems were furthermore shown to catalyze and re-equilibrate their own formation through a previously unknown thiourea-catalyzed transimination process.

Keywords
catalyst screening, dynamic covalent chemistry, organocatalysis, Schiff bases, transimination
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-173763 (URN)10.1002/chem.201502088 (DOI)000360312100026 ()26174068 (PubMedID)2-s2.0-84940178757 (Scopus ID)
Funder
Swedish Research Council
Note

QC 20150922

Available from: 2015-09-22 Created: 2015-09-18 Last updated: 2017-12-01Bibliographically approved
2. Resolving a Reactive Organometallic Intermediate from Dynamic Directing Group Systems by Selective C-H Activation
Open this publication in new window or tab >>Resolving a Reactive Organometallic Intermediate from Dynamic Directing Group Systems by Selective C-H Activation
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Catalyst discovery from systems of potential precursors is a challenging endeavor. Herein, a new strategy applying dynamic chemistry to the identification of catalyst precursors from C-H activation of imines is proposed and evaluated. Using hydroacylation of imines as a model reaction, the selection of an organometallic reactive intermediate from a dynamic imine system, involving many potential directing group/metal entities, is demonstrated. The identity of the amplified reaction intermediate with the best directing group could be resolved in situ via ESI-MS, and coupling of the procedure to an iterative deconvolution protocol generated a system with high screening efficiency.

Keywords
Dynamic chemistry, C-H activation, Catalysis, Directing group, Systems chemistry
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-199715 (URN)
Funder
EU, FP7, Seventh Framework Programme, 289033Swedish Research Council
Note

QC 20170116

Available from: 2017-01-16 Created: 2017-01-16 Last updated: 2017-08-07Bibliographically approved
3. Kinetic Self-Sorting of Dynamic Covalent Catalysts with Systemic Feedback Regulation
Open this publication in new window or tab >>Kinetic Self-Sorting of Dynamic Covalent Catalysts with Systemic Feedback Regulation
2016 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 25, p. 7836-7839Article in journal (Refereed) Published
Abstract [en]

Constructing small molecule systems that mimic the functionality exhibited in biological reaction networks is a key objective of systems chemistry. Herein, we report the development of a dynamic catalytic system where the catalyst activity is modulated through a dynamic covalent bond. By connecting a thermodynamically controlled rearrangement process to resolution under kinetic control, the catalyst system underwent kinetic self sorting, resulting in amplification of a more reactive catalyst while establishing a catalytic feedback mechanism. The dynamic catalyst system furthermore responded to catalytic events by self-perturbation to regulate its own activity, which in the case of upregulation gave rise to systemic autocatalytic behavior.

Place, publisher, year, edition, pages
American Chemical Society, 2016
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-190675 (URN)10.1021/jacs.6b04250 (DOI)000378984300009 ()27304874 (PubMedID)2-s2.0-84976597278 (Scopus ID)
Note

QC 20160816

Available from: 2016-08-16 Created: 2016-08-12 Last updated: 2017-11-28Bibliographically approved
4. Programmed Error-Correction within Dynamic Catalyst Systems for the Morita-Baylis-Hillman reaction
Open this publication in new window or tab >>Programmed Error-Correction within Dynamic Catalyst Systems for the Morita-Baylis-Hillman reaction
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The understanding of complex reaction networks of small molecules with emergent systemic functionality is integral to both systems chemistry and origin-of-life studies. In this work, a dynamic catalytic system of nucleophilic catalysts for the Morita-Baylis-Hillman (MBH) reaction is demonstrated, exhibiting self-resolution behavior along with thermodynamically driven error-correction. A class of readily reversible MBH adducts from substrates with internal H-transfer capabilities is furthermore presented, displaying rate accelerations of retro-MBH reactions up to 10 000 times. The retro-MBH reaction was used as a design element in a self-resolving dynamic catalytic system, yielding a transient product that was eventually transformed into a more stable thermodynamic product. This study demonstrates efficient self-sorting of complex small molecular catalytic systems.

Keywords
Dynamic Chemistry, Systems Chemistry, Morita-Baylis-Hillman reaction, Error-Correction, Catalysis
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-199716 (URN)
Funder
Swedish Research Council
Note

QC 20170116

Available from: 2017-01-16 Created: 2017-01-16 Last updated: 2017-01-16Bibliographically approved
5. Biomimetic Hydrogen Bonding Catalysis of Imine Exchange for Rapid Equilibration of Dynamic Systems
Open this publication in new window or tab >>Biomimetic Hydrogen Bonding Catalysis of Imine Exchange for Rapid Equilibration of Dynamic Systems
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The reversibility of imine bonds has been exploited to great effect in the field of dynamic covalent chemistry, for example in the preparation of dynamic systems for a wide variety of applications. However, acid catalysis is commonly needed for efficient equilibration of imine mixtures. Herein, it is demonstrated that hydrogen bond donors, such as thioureas and squaramides, can catalyze the equilibration of dynamic imine systems under unprecedentedly mild conditions. Catalysis occurs in a range of solvents and in the presence of many sensitive additives, showing moderate to good rate accelerations for both imine metathesis and transimination with amines, hydrazines and hydroxylamines. Furthermore, the catalyst proved simple to immobilize, introducing both reusability and extended control of the equilibration process.

Keywords
Dynamic Chemistry, Imine Exchange, Hydrogen Bonding Catalysis, Dynamic Systems, Solid-Supported Catalyst
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-199717 (URN)
Funder
Swedish Research Council
Note

QC 20170116

Available from: 2017-01-16 Created: 2017-01-16 Last updated: 2017-01-16Bibliographically approved
6. Trans-Symmetric Dynamic Covalent Systems: Connected Transamination and Transimination Reactions
Open this publication in new window or tab >>Trans-Symmetric Dynamic Covalent Systems: Connected Transamination and Transimination Reactions
2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 27, p. 9776-9783Article in journal (Refereed) Published
Abstract [en]

The development of chemical transaminations as a new type of dynamic covalent reaction is described. The key 1,3-proton shift is under complete catalytic control and can be conducted orthogonally to, or simultaneous with, transimination in the presence of an amine to rapidly yield two-dimensional dynamic systems with a high degree of complexity evolution. The transamination-transimination systems are proven to be fully reversible, stable over several days, compatible with a range of functional groups, and highly tunable. Kinetic studies show transamination to be the rate-limiting reaction in the network. Furthermore, it was discovered that readily available quinuclidine is a highly potent catalyst for aldimine transaminations. This study demonstrates how connected dynamic reactions give rise to significantly larger systems than the unconnected counterparts, and shows how reversible isomerizations can be utilized as an effective diversity-generating element.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-171289 (URN)10.1002/chem.201500520 (DOI)000357027300027 ()26044061 (PubMedID)2-s2.0-84934980702 (Scopus ID)
Note

QC 20150728

Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved

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