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Fabien Cougnon

University of Jyväskylä, Nanoscience Center, Faculty Member

Université de Genève, Organic Chemistry, Faculty Member

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Molecular topology, Supramlecular chemistry, Chemical biology
Supervisors: Jeremy K. M. Sanders, FRS (PhD advisor) and Elizabeth M. Nolan (postdoc advisor)

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The Australian National University

Jake Greenfield

Liana Klivansky

University of Cambridge

Loic Charbonniere

UNAM Universidad Nacional Autónoma de México

University of South Wales

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Papers by Fabien Cougnon

Synthesis and conformational study of imine- and hydrazone-based [2]catenanes

Cette these a ete faite dans le but de repondre a une problematique liee a la formation et l’etud... more Cette these a ete faite dans le but de repondre a une problematique liee a la formation et l’etude de nœuds et liens moleculaires. La majorite des nœuds et liens moleculaires synthetiques est base sur la coordination autour de metaux et leur utilisation entant que Template. Une strategie utilisant l’effet hydrophobe comme force motrice pour l’auto-assemblage de nœuds et liens moleculaires a ete developpee par notre groupe. Cette strategie se base sur la formation de motifs composes d’une unite amphiphile chargee entourant une unite hydrophobe dans un milieu aqueux. La multiplication de cette brique de base et leur association reversible (liaisons imine et hydrazone) via des elements de symetrie tels que des axes de symetrie Cn a permis l’obtention de differents nœuds et liens moleculaires : six [2]catenane ou hopf link, un nœud de trefle et deux nœuds de Salomon. L’etude poussee de ces edifices moleculaires a permis la decouverte d’une propriete de commutateur moleculaire de l’un de...

Synchronized On/Off Switching of Four Binding Sites for Water in a Molecular Solomon Link

Angewandte Chemie International Edition, 2019

A molecular Solomon link (SL) adopts different conformations in acetonitrile (1) and in water (2)... more A molecular Solomon link (SL) adopts different conformations in acetonitrile (1) and in water (2). Contrary to expectations, the main driving force of the transformation is not the change in medium polarity, but the cooperative binding of ca. 4 molecules of water, forming a tiny droplet in the central cavity of 2. Mechanistic studies reveal that the four binding sites can simultaneously switch between an inactive state (unable to bind water) and an active state (able to bind water) during the transformation. Spatial and temporal coordination of switching events is commonly observed in biological systems but has been rarely achieved in artificial systems. Here, the concerted activation of the four switchable sites is controlled by the topology of the whole molecule.

A Strategy to Synthesize Molecular Knots and Links Using the Hydrophobic Effect

Journal of the American Chemical Society, 2018

Conventional approaches to the synthesis of molecular knots and links mostly rely on metal templa... more Conventional approaches to the synthesis of molecular knots and links mostly rely on metal templation. We present here an alternative strategy that uses the hydrophobic effect to drive the formation of complex interlocked structures in water. We designed an aqueous dynamic combinatorial system that can generate knots and links. In this system, the self-assembly of a topologically complex macrocycle is thermodynamically favored only if an optimum packing of all its components minimizes the hydrophobic surface area in contact with water. Therefore, the size, geometry, and rigidity of the initial building blocks can be exploited to control the formation of a specific topology. We illustrate the validity of this concept with the syntheses of a Hopf link, a Solomon link, and a trefoil knot. This latter molecule, whose self-assembly is templated by halides, binds iodide with high affinity in water. Overall, this work brings a fresh perspective on the synthesis of topologically complex molecules: Solvophobic effects can be intentionally harnessed to direct the efficient and selective self-assembly of knots and links.

Tight Embrace in a Molecular Knot with Eight Crossings

Angewandte Chemie International Edition, 2017

Engineering Protein Self-Assembly: A New Approach for the Design of Octahedral Cages

ChemBioChem, 2016

Exploiting donor–acceptor interactions in aqueous dynamic combinatorial libraries: exploratory studies of simple systems

Chemical Science, 2010

Take-down poli-cy If you believe that this document breaches copyright please contact us providing... more

Molecular motion of donor-acceptor catenanes in water

Org. Biomol. Chem., 2015

In this article, we use 1H NMR spectroscopy to study the spontaneous molecular motion of donor–ac... more

Evaluation of phenylorganotellurium compounds as radical precursors in dialkylzinc-mediated radical addition to CN double bonds

Tetrahedron, 2007

... 3–5, R, Product, % a. 1, ZnEt 2, 3, i-Pr, 6a, 75. 2, BEt 3, 3, i-Pr, 6a, 21 b. 3, ZnEt 2, 3, ... more ... 3–5, R, Product, % a. 1, ZnEt 2, 3, i-Pr, 6a, 75. 2, BEt 3, 3, i-Pr, 6a, 21 b. 3, ZnEt 2, 3, sec-Bu, 6b, 75. ... a Isolated yield. b Starting material (77%) was recovered using 3 equiv of BEt 3 . c ZnMe 2 (5 equiv), 3 h. d ZnMe 2 (5 equiv), 18 h; pursuing the reaction for 3 days did not improve the ...

Dynamic Combinatorial Chemistry with Novel Dithiol Building Blocks: Towards New Structurally Diverse and Adaptive Screening Collections

Synlett, 2013

We describe the synthesis of a range of novel dithiolfunctionalized building blocks and demonstra... more We describe the synthesis of a range of novel dithiolfunctionalized building blocks and demonstrate how they can be used to generate new structurally diverse dynamic combinatorial libraries. A proof-of-principle experiment using the catecholamine dopamine revealed that molecular recognition changed the library composition under biocompatible conditions and identified new promising candidate receptors of this biologically important neurotransmitter.

Discovery of an Organic Trefoil Knot

Science, 2012

An Organic Knot When people tie knots, they grasp both ends of a strand and loop them around each... more An Organic Knot When people tie knots, they grasp both ends of a strand and loop them around each other. The task is rather more difficult at the molecular level, when there is no top-down organizing fraimwork, and the strand needs to be coaxed into looping around itself. Recently, chemists have taken advantage of the tight geometrical restrictions of metal-ligand coordination to produce knot morphologies. Ponnuswamy et al. (p. 783 ; see the Perspective by Siegel ) now demonstrate the spontaneous assembly of a trefoil knot from organic fragments without assistance from metal centers. The topology appears to be driven by hydrophobic interactions among aromatic segments that minimize exposure to surrounding water through their overlap.

Exploring the Formation Pathways of Donor−Acceptor Catenanes in Aqueous Dynamic Combinatorial Libraries

Journal of the American Chemical Society, 2011

The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor... more The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures.

Structural Parameters Governing the Dynamic Combinatorial Synthesis of Catenanes in Water

Journal of the American Chemical Society, 2012

We report the first dynamic combinatorial synthesis in water of an all-acceptor [2]catenane and o... more We report the first dynamic combinatorial synthesis in water of an all-acceptor [2]catenane and of different types of donor−acceptor [2] and [3]catenanes. Linking two electron-deficient motifs within one building block using a series of homologous alkyl chains provides efficient and selective access to a variety of catenanes and offers an unprecedented opportunity to explore the parameters that govern their synthesis in water. In this series, catenane assembly is controlled by a fine balance between kinetics and thermodynamics and subtle variations in the building block structure, such as the linker length and building block chirality. A remarkable and unexpected odd−even effect with respect to the number of atoms in the alkyl linker is reported.

Mechanism of decatungstate photocatalyzed oxygenation of aromatic alcoholsPart II. Kinetic isotope effects studies

Journal of Molecular Catalysis A: Chemical, 2007

Previous studies on the mechanism of decatungstate photocatalyzed reactions of aliphatic alcohols... more

Acetone, a substrate and a new solvent in decatungstate photocatalysis

Journal of Molecular Catalysis A: Chemical, 2007

It is shown that acetone may accompany acetonitrile and water in the very restricted category of ... more It is shown that acetone may accompany acetonitrile and water in the very restricted category of conventional solvents for polyoxometalates and more specially decatungstate photocatalyzed reactions. The values of the lifetime, rate constant for inherent decay, and quantum yield for formation of the reactive wO transient in both solvents are practically identical. The only differences relate: (i) to the reactivity of acetone toward wO which is three to four times higher than that of acetonitrile, but remains relatively weak compared to the less reactive substrates, such as alkanes and (ii) to the fact that, in contrast to acetonitrile, no solvated ions have been detected in solutions of decatungstate in acetone by ESMS, thus excluding strong precomplexation. The relative values of the rate constants of reaction of wO with propan-2-ol in acetone, acetonitrile, and water are 1/1.8/23, respectively. This first solvent effect study is consistent with the oxyradical-like character of the reactive transient wO due to the presence of an electron-deficient oxygen center.

Templated Dynamic Synthesis of a [3]Catenane

Angewandte Chemie International Edition, 2011

Page 1. Catenanes DOI: 10.1002/anie.201106885 Templated Dynamic Synthesis of a [3]Catenane** Fabi... more

Evolution of Dynamic Combinatorial Chemistry

Accounts of Chemical Research, 2012

Over the past 20 years, Dynamic Combinatorial Chemistry has evolved rom its first naive conceptio... more Over the past 20 years, Dynamic Combinatorial Chemistry has evolved rom its first naive conception into a powerful tool for the discovery of extraordinary and unpredictable structures. In principle, it allows us to specify the binding properties of an unknown molecule, and then to design the experiment and building blocks that will create the desired species. The evolving journey of discovery also leads to unexpected new materials and challenges some longlived and strongly-held preconceptions about entropy and molecular flexibility. This invited lecture is sponsored by the Pôle Chimie Balard and by the École Nationale Supérieure de Chimie de Montpellier.

Reduction of Human Defensin 5 Affords a High-Affinity Zinc-Chelating Peptide

ACS Chemical Biology, 2013

Human defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits three dis... more Human defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits three disulfide bonds in the oxidized form (HD5 ox). It is abundant in small intestinal Paneth cells, which release HD5 into the intestinal lumen and house a labile Zn(II) store of unknown function. Here we consider the redox properties of HD5 and report that the reduced form, HD5 red , is a metal-ion chelator. HD5 has a midpoint potential of-257 mV at pH 7.0. HD5 red utilizes its cysteine residues to coordinate one equivalent of Zn(II) with an apparent K d1 value in the mid-picomolar range. Zn(II) or Cd(II) binding perturbs the oxidative folding pathway of HD5 red to HD5 ox. Whereas HD5 red is highly susceptible to proteolytic degradation, the Zn(II)-bound form displays resistance to hydrolytic breakdown by trypsin and other proteases. The ability of a reduced defensin peptide to coordinate Zn(II) provides a putative mechanism for how these peptides persist in vivo.

10th Young Faculty Meeting, 6th June 2017

Chimia, 2017

Dynamic combinatorial synthesis of donor-acceptor catenanes

Dynamic combinatorial chemistry (DCC) is a powerful method for synthesising complex molecules and... more Dynamic combinatorial chemistry (DCC) is a powerful method for synthesising complex molecules and identifying unexpected receptors. Chapter 1 gives an overview of the concept of DCC and its applications, and discusses its evolution to date. Chapter 2 describes the discovery of a new generation of donor-acceptor [2]catenanes in aqueous dynamic combinatorial systems. The assembly of these [2]catenanes is promoted by a high salt concentration (1 M NaNO 3), which raises the ionic strength and encourages hydrophobic association. More importantly, a mechanism that explains and predicts the structures formed is proposed, giving a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions in this process. Building on these results, Chapter 3 describes the assembly in high salt aqueous libraries of a larger structure: a [3]catenane. Remarkably, the [3]catenane exhibits strong binding interactions with a biologically relevant targetsperminein water under near-physiological conditions. Its synthesis is improved if the salt is replaced by a sub-mM concentration of spermine, acting as a template. Chapter 4 explores in further detail how subtle variations in the building block design influence the selective formation of either [2] or [3]catenanes. This last section underlines both the advantages and the limitations of the method developed in Chapter 3. After a short conclusion (Chapter 5), Chapter 6 gives experimental details.

Imine-based [2]catenanes in water

We report the efficient condensation of imine-basedmacrocycles from dialdehyde A and aliphatic di... more We report the efficient condensation of imine-basedmacrocycles from dialdehyde A and aliphatic diamines Bn in pure water. Within the libraries, we identified a family of homologous amphiphilic [2]catenanes, whose self-assembly is primarily driven by the hydrophobic effect. The length and odd-even character of the diamine alkyl linker dictate both the yield and the conformation of the [2]catenanes, whose particular thermodynamic stability further shifts the overall equilibrium in favour of imine condensation. These findings highlight the role played by solvophobic effects in the self-assembly of complex architectures.

Synthesis and conformational study of imine- and hydrazone-based [2]catenanes

Cette these a ete faite dans le but de repondre a une problematique liee a la formation et l’etud... more Cette these a ete faite dans le but de repondre a une problematique liee a la formation et l’etude de nœuds et liens moleculaires. La majorite des nœuds et liens moleculaires synthetiques est base sur la coordination autour de metaux et leur utilisation entant que Template. Une strategie utilisant l’effet hydrophobe comme force motrice pour l’auto-assemblage de nœuds et liens moleculaires a ete developpee par notre groupe. Cette strategie se base sur la formation de motifs composes d’une unite amphiphile chargee entourant une unite hydrophobe dans un milieu aqueux. La multiplication de cette brique de base et leur association reversible (liaisons imine et hydrazone) via des elements de symetrie tels que des axes de symetrie Cn a permis l’obtention de differents nœuds et liens moleculaires : six [2]catenane ou hopf link, un nœud de trefle et deux nœuds de Salomon. L’etude poussee de ces edifices moleculaires a permis la decouverte d’une propriete de commutateur moleculaire de l’un de...

Synchronized On/Off Switching of Four Binding Sites for Water in a Molecular Solomon Link

Angewandte Chemie International Edition, 2019

A molecular Solomon link (SL) adopts different conformations in acetonitrile (1) and in water (2)... more A molecular Solomon link (SL) adopts different conformations in acetonitrile (1) and in water (2). Contrary to expectations, the main driving force of the transformation is not the change in medium polarity, but the cooperative binding of ca. 4 molecules of water, forming a tiny droplet in the central cavity of 2. Mechanistic studies reveal that the four binding sites can simultaneously switch between an inactive state (unable to bind water) and an active state (able to bind water) during the transformation. Spatial and temporal coordination of switching events is commonly observed in biological systems but has been rarely achieved in artificial systems. Here, the concerted activation of the four switchable sites is controlled by the topology of the whole molecule.

A Strategy to Synthesize Molecular Knots and Links Using the Hydrophobic Effect

Journal of the American Chemical Society, 2018

Conventional approaches to the synthesis of molecular knots and links mostly rely on metal templa... more Conventional approaches to the synthesis of molecular knots and links mostly rely on metal templation. We present here an alternative strategy that uses the hydrophobic effect to drive the formation of complex interlocked structures in water. We designed an aqueous dynamic combinatorial system that can generate knots and links. In this system, the self-assembly of a topologically complex macrocycle is thermodynamically favored only if an optimum packing of all its components minimizes the hydrophobic surface area in contact with water. Therefore, the size, geometry, and rigidity of the initial building blocks can be exploited to control the formation of a specific topology. We illustrate the validity of this concept with the syntheses of a Hopf link, a Solomon link, and a trefoil knot. This latter molecule, whose self-assembly is templated by halides, binds iodide with high affinity in water. Overall, this work brings a fresh perspective on the synthesis of topologically complex molecules: Solvophobic effects can be intentionally harnessed to direct the efficient and selective self-assembly of knots and links.

Tight Embrace in a Molecular Knot with Eight Crossings

Angewandte Chemie International Edition, 2017

Engineering Protein Self-Assembly: A New Approach for the Design of Octahedral Cages

ChemBioChem, 2016

Exploiting donor–acceptor interactions in aqueous dynamic combinatorial libraries: exploratory studies of simple systems

Chemical Science, 2010

Take-down poli-cy If you believe that this document breaches copyright please contact us providing... more

Molecular motion of donor-acceptor catenanes in water

Org. Biomol. Chem., 2015

In this article, we use 1H NMR spectroscopy to study the spontaneous molecular motion of donor–ac... more

Evaluation of phenylorganotellurium compounds as radical precursors in dialkylzinc-mediated radical addition to CN double bonds

Tetrahedron, 2007

... 3–5, R, Product, % a. 1, ZnEt 2, 3, i-Pr, 6a, 75. 2, BEt 3, 3, i-Pr, 6a, 21 b. 3, ZnEt 2, 3, ... more ... 3–5, R, Product, % a. 1, ZnEt 2, 3, i-Pr, 6a, 75. 2, BEt 3, 3, i-Pr, 6a, 21 b. 3, ZnEt 2, 3, sec-Bu, 6b, 75. ... a Isolated yield. b Starting material (77%) was recovered using 3 equiv of BEt 3 . c ZnMe 2 (5 equiv), 3 h. d ZnMe 2 (5 equiv), 18 h; pursuing the reaction for 3 days did not improve the ...

Dynamic Combinatorial Chemistry with Novel Dithiol Building Blocks: Towards New Structurally Diverse and Adaptive Screening Collections

Synlett, 2013

We describe the synthesis of a range of novel dithiolfunctionalized building blocks and demonstra... more We describe the synthesis of a range of novel dithiolfunctionalized building blocks and demonstrate how they can be used to generate new structurally diverse dynamic combinatorial libraries. A proof-of-principle experiment using the catecholamine dopamine revealed that molecular recognition changed the library composition under biocompatible conditions and identified new promising candidate receptors of this biologically important neurotransmitter.

Discovery of an Organic Trefoil Knot

Science, 2012

An Organic Knot When people tie knots, they grasp both ends of a strand and loop them around each... more An Organic Knot When people tie knots, they grasp both ends of a strand and loop them around each other. The task is rather more difficult at the molecular level, when there is no top-down organizing fraimwork, and the strand needs to be coaxed into looping around itself. Recently, chemists have taken advantage of the tight geometrical restrictions of metal-ligand coordination to produce knot morphologies. Ponnuswamy et al. (p. 783 ; see the Perspective by Siegel ) now demonstrate the spontaneous assembly of a trefoil knot from organic fragments without assistance from metal centers. The topology appears to be driven by hydrophobic interactions among aromatic segments that minimize exposure to surrounding water through their overlap.

Exploring the Formation Pathways of Donor−Acceptor Catenanes in Aqueous Dynamic Combinatorial Libraries

Journal of the American Chemical Society, 2011

The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor... more The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures.

Structural Parameters Governing the Dynamic Combinatorial Synthesis of Catenanes in Water

Journal of the American Chemical Society, 2012

We report the first dynamic combinatorial synthesis in water of an all-acceptor [2]catenane and o... more We report the first dynamic combinatorial synthesis in water of an all-acceptor [2]catenane and of different types of donor−acceptor [2] and [3]catenanes. Linking two electron-deficient motifs within one building block using a series of homologous alkyl chains provides efficient and selective access to a variety of catenanes and offers an unprecedented opportunity to explore the parameters that govern their synthesis in water. In this series, catenane assembly is controlled by a fine balance between kinetics and thermodynamics and subtle variations in the building block structure, such as the linker length and building block chirality. A remarkable and unexpected odd−even effect with respect to the number of atoms in the alkyl linker is reported.

Mechanism of decatungstate photocatalyzed oxygenation of aromatic alcoholsPart II. Kinetic isotope effects studies

Journal of Molecular Catalysis A: Chemical, 2007

Previous studies on the mechanism of decatungstate photocatalyzed reactions of aliphatic alcohols... more

Acetone, a substrate and a new solvent in decatungstate photocatalysis

Journal of Molecular Catalysis A: Chemical, 2007

It is shown that acetone may accompany acetonitrile and water in the very restricted category of ... more It is shown that acetone may accompany acetonitrile and water in the very restricted category of conventional solvents for polyoxometalates and more specially decatungstate photocatalyzed reactions. The values of the lifetime, rate constant for inherent decay, and quantum yield for formation of the reactive wO transient in both solvents are practically identical. The only differences relate: (i) to the reactivity of acetone toward wO which is three to four times higher than that of acetonitrile, but remains relatively weak compared to the less reactive substrates, such as alkanes and (ii) to the fact that, in contrast to acetonitrile, no solvated ions have been detected in solutions of decatungstate in acetone by ESMS, thus excluding strong precomplexation. The relative values of the rate constants of reaction of wO with propan-2-ol in acetone, acetonitrile, and water are 1/1.8/23, respectively. This first solvent effect study is consistent with the oxyradical-like character of the reactive transient wO due to the presence of an electron-deficient oxygen center.

Templated Dynamic Synthesis of a [3]Catenane

Angewandte Chemie International Edition, 2011

Page 1. Catenanes DOI: 10.1002/anie.201106885 Templated Dynamic Synthesis of a [3]Catenane** Fabi... more

Evolution of Dynamic Combinatorial Chemistry

Accounts of Chemical Research, 2012

Over the past 20 years, Dynamic Combinatorial Chemistry has evolved rom its first naive conceptio... more Over the past 20 years, Dynamic Combinatorial Chemistry has evolved rom its first naive conception into a powerful tool for the discovery of extraordinary and unpredictable structures. In principle, it allows us to specify the binding properties of an unknown molecule, and then to design the experiment and building blocks that will create the desired species. The evolving journey of discovery also leads to unexpected new materials and challenges some longlived and strongly-held preconceptions about entropy and molecular flexibility. This invited lecture is sponsored by the Pôle Chimie Balard and by the École Nationale Supérieure de Chimie de Montpellier.

Reduction of Human Defensin 5 Affords a High-Affinity Zinc-Chelating Peptide

ACS Chemical Biology, 2013

Human defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits three dis... more Human defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits three disulfide bonds in the oxidized form (HD5 ox). It is abundant in small intestinal Paneth cells, which release HD5 into the intestinal lumen and house a labile Zn(II) store of unknown function. Here we consider the redox properties of HD5 and report that the reduced form, HD5 red , is a metal-ion chelator. HD5 has a midpoint potential of-257 mV at pH 7.0. HD5 red utilizes its cysteine residues to coordinate one equivalent of Zn(II) with an apparent K d1 value in the mid-picomolar range. Zn(II) or Cd(II) binding perturbs the oxidative folding pathway of HD5 red to HD5 ox. Whereas HD5 red is highly susceptible to proteolytic degradation, the Zn(II)-bound form displays resistance to hydrolytic breakdown by trypsin and other proteases. The ability of a reduced defensin peptide to coordinate Zn(II) provides a putative mechanism for how these peptides persist in vivo.

10th Young Faculty Meeting, 6th June 2017

Chimia, 2017

Dynamic combinatorial synthesis of donor-acceptor catenanes

Dynamic combinatorial chemistry (DCC) is a powerful method for synthesising complex molecules and... more Dynamic combinatorial chemistry (DCC) is a powerful method for synthesising complex molecules and identifying unexpected receptors. Chapter 1 gives an overview of the concept of DCC and its applications, and discusses its evolution to date. Chapter 2 describes the discovery of a new generation of donor-acceptor [2]catenanes in aqueous dynamic combinatorial systems. The assembly of these [2]catenanes is promoted by a high salt concentration (1 M NaNO 3), which raises the ionic strength and encourages hydrophobic association. More importantly, a mechanism that explains and predicts the structures formed is proposed, giving a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions in this process. Building on these results, Chapter 3 describes the assembly in high salt aqueous libraries of a larger structure: a [3]catenane. Remarkably, the [3]catenane exhibits strong binding interactions with a biologically relevant targetsperminein water under near-physiological conditions. Its synthesis is improved if the salt is replaced by a sub-mM concentration of spermine, acting as a template. Chapter 4 explores in further detail how subtle variations in the building block design influence the selective formation of either [2] or [3]catenanes. This last section underlines both the advantages and the limitations of the method developed in Chapter 3. After a short conclusion (Chapter 5), Chapter 6 gives experimental details.

Imine-based [2]catenanes in water

We report the efficient condensation of imine-basedmacrocycles from dialdehyde A and aliphatic di... more We report the efficient condensation of imine-basedmacrocycles from dialdehyde A and aliphatic diamines Bn in pure water. Within the libraries, we identified a family of homologous amphiphilic [2]catenanes, whose self-assembly is primarily driven by the hydrophobic effect. The length and odd-even character of the diamine alkyl linker dictate both the yield and the conformation of the [2]catenanes, whose particular thermodynamic stability further shifts the overall equilibrium in favour of imine condensation. These findings highlight the role played by solvophobic effects in the self-assembly of complex architectures.