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Doctoral Thesis

Stockholm 2020

Secondary Interactions in Symmetric Double Bond

Formation Catalysed by Molecular Ruthenium

Complexes

Oleksandr Kravchenko

Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av doktorsexamen i kemi onsdagen den 14:e oktober kl 13.00 i Kollegiesalen, KTH, Brinellvägen 8, Stockholm. Avhandlingen försvaras på engelska. Opponent är Prof. Roger Alberto, University of Zurich.

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ISBN 978-91-7873-638-6

TRITA-CBH-FOU-2020:42

© Oleksandr Kravchenko, 2020

Printed by: Universitetsservice US AB, Sweden 2020

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Oleksandr Kravchenko, 2020: “Secondary Interactions in Symmetric Double Bond Formation Catalysed by Molecular Ruthenium Complexes”, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH – Royal Institute of Technology, SE-100 44 Stockholm, Sweden.

Abstract Chemistry has a tremendous impact on everyone’s life, although society does not always realize its power and ubiquity. In recent years, improved economy and sustainability of chemical processes has become a worldwide priority. Since its discovery, catalysis has been leveraged in industry to decrease energy demands in chemical reactions and reduce their cost. This thesis focuses on two catalytic transformations and various aspects of catalyst design that improve the catalytic efficiency and applicability.

The first chapter contains an introduction of important concepts in catalysis and an overview of weak interactions, often used when designing catalysts. As symmetry plays a big role in chemistry in general and especially in the reactions discussed in this thesis, a brief overview of some symmetry aspects in molecules and reactions is provided.

The second chapter addresses applications of olefin metathesis in dynamic chemistry. The catalysts for establishing equilibria in simple dynamic systems under mild conditions are analysed from a structure-activity relationship perspective. An ability to perform self- and cross-metathesis of functionalized substrates in water is evaluated and used to improve selectivity.

The following chapters focus on water oxidation catalysis, which is an essential part of solar fuel generation and the development of sustainable energy solutions. Therefore, the third chapter focuses on the electronic effects in functionalized catalysts. The influence of substituents and backbone modifications on the properties of the catalysts is discussed. The fourth chapter introduces novel design of axial and equatorial ligands in state-of-the-art water oxidation catalysts for improvements in catalytic activity and stability.

The research presented in this thesis demonstrates the influence of weak intra- and intermolecular interactions on catalysis and the strategies of using these interactions in transition metal complexes to improve catalytic properties.

Keywords: homogeneous catalysis, transition metal catalysis, ruthenium catalyst, olefin metathesis, dynamic covalent chemistry, water oxidation, solar fuels, Ru-bda, secondary interactions, hydrophobic interactions, π-π stacking.

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Sammanfattning på svenska Kemi har en enorm påverkan på allas liv även om samhället inte inser dess kraft och allmänna utbredning. Under de senaste åren har ekonomi och hållbarhet i kemiska processer blivit en världsomfattande prioritering. Ända sedan dess upptäckt har katalys utnyttjats i industrin för att minska energibehovet i kemiska reaktioner. Den här avhandlingen behandlar två katalytiska transformationer och olika aspekter av katalysatordesign som förbättrar den katalytiska effektiviteten och användbarheten.

Det första kapitlet innehåller en introduktion av viktiga begrepp inom katalys och en översikt över svaga interaktioner som ofta används i katalysatordesign. Eftersom symmetri spelar en stor roll i kemi i allmänhet och särskilt i de reaktioner som diskuteras i den här avhandlingen ges också en kort översikt av vissa symmetriaspekter i molekyler och reaktioner.

Det andra kapitlet behandlar tillämpningar av olefinmetatesen i dynamisk kemi. Katalysatorerna för etablering av jämvikt i enkla dynamiska system under milda förhållanden analyseras i en struktur-aktivitetsförhållande studie. Förmågan att utföra själv- och korsmetates av mycket funktionaliserade substrat i vatten utvärderas och används för att öka selektivitet.

Följande kapitel fokuserar på vattenoxidationskatalys som är en väsentlig del för produktionen av solbränsle och utvecklingen av hållbar energi. Det tredje kapitlet fokuserar på de elektroniska effekterna i funktionaliserade katalysatorer. Påverkan av substituenter och andra modifikationer på katalysatorernas egenskaper diskuteras. Det fjärde kapitlet introducerar ny design av axiella och ekvatoriella ligander i toppmoderna vattenoxidations-katalysatorer och betydande förbättringar av katalytisk aktivitet och stabilitet.

Forskningen som presenteras i den här avhandlingen demonstrerar påverkan av svaga intra- och intermolekylära interaktioner på katalys och sätten att använda dessa interaktioner i övergångsmetallkomplex för att förbättra katalytiska egenskaper.

Nyckelord: homogen katalys, övergångsmetallkatalys, rutheniumkatalysator, olefinmetates, dynamisk kovalent kemi, vattenoxidation, solbränslen, Ru-bda, sekundära interaktioner, hydrofoba interaktioner, π-π stapling.

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Abbreviations Ac acetyl bda [2,2'-bipyridine]-6,6'-dicarboxylate biqa [1,1'-biisoquinoline]-3,3'-dicarboxylate Bnd benzylidenyl bpa [2,2'-bipyrazine]-6,6'-dicarboxylate Brisq 6-bromoisoquinoline Bu n-butyl CAAC cyclic (alkyl)(amino)carbene CM cross-metathesis Cy cyclohexyl DFT density functional theory dmbda 4,4'-dimethoxy-[2,2'-bipyridine]-6,6'-dicarboxylate DMF N,N-dimethylformamide DMSO dimethylsulfoxide DNA deoxyribonucleic acid dnbda 4,4'-dinitro-[2,2'-bipyridine]-6,6'-dicarboxylate Et ethyl HMDS hexamethyldisilazide HOMO highest occupied molecular orbital I2M inter/intramolecular coupling of two metal-oxo units Ind 3-phenylindenylidenyl iPr isopropyl Ipy 4-iodopyridine iso-biqa [3,3'-biisoquinoline]-1,1'-dicarboxylate Me methyl MS mass spectrometry NHC N-heterocyclic carbene NHE normal hydrogen electrode NMR nuclear magnetic resonance pda 1,10-phenanthroline-2,9-dicarboxylate PEG pentaethylene glycol Ph phenyl pic 4-picoline pKa negative logarithm of acid dissociation constant ppa 6-(6-carboxylatopyridin-2-yl)pyrazine-2-carboxylate RCM ring-closing metathesis SM self-metathesis Tf trifluoromethanesulfonate TFE 2,2,2-trifluoroethanol TOF turnover frequency TON turnover number WNA water nucleophilic attack

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List of Publications

This thesis is based on the following papers, referred to in the text by their Roman numerals I–VI:

I. Stable CAAC-based Ruthenium Complexes for Dynamic Olefin Metathesis Under Mild Conditions Kravchenko, O., Timmer, B.J.J., Biedermann, M., Inge, A.K. and Ramström, O. Submitted

II. Selective Cross-Metathesis of Highly Chelating Substrates in Aqueous Media Timmer, B.J.J., Kravchenko, O. and Ramström, O. ChemistrySelect 2020, 5, 7254–7257

III. Modulation of the First and Second Coordination Sphere Effects by Backbone Substitution in Ru(bda)L2 Water Oxidation Catalysts Kravchenko, O., Timmer, B.J.J., Liu, T., Karalius, A., Zhang, B. and Sun, L. Manuscript in preparation

IV. Electronic Influence of the 2,2'-Bipyridine-6,6'-dicarboxylate Ligand in Ru-based Type Water Oxidation Catalysts Timmer, B.J.J., Kravchenko, O., Zhang, B., Liu, T. and Sun, L. Submitted

V. Improving the Stability of Ru-bda Molecular Water Oxidation Catalysts via π-System Extension of Backbone Ligand Kravchenko, O., Timmer, B.J.J., Liu, T., Zhang, B. and Sun, L. Submitted

VI. Off-set Interactions for Low Concentration Water Splitting Catalysis with Ru(bda)L2 Timmer, B.J.J., Kravchenko, O., Liu, T., Zhang, B. and Sun, L. Submitted

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Papers not included in this thesis:

I. Effects of Molecular Modifications for Water Splitting Enhancement of BiVO4 Grądzka-Kurzaj, I., Meng, Q., Timmer, B.J.J., Kravchenko, O., Zhang, B., Gierszewski, M. and Ziółek, M. Int. J. Hydrog. Energy 2020, 45, 15129–15141

II. Switching O–O Bond Formation Mechanism between WNA and I2M Pathways by Modifying the Ru-bda Backbone Ligands of Water-Oxidation Catalysts Zhang, B.*, Zhan, S.*, Liu, T., Wang, L., Inge, A.K., Duan, L., Timmer, B.J.J., Kravchenko, O., Li, F., Ahlquist, M.S.G. and Sun, L. J. Energy Chem. 2021, 54, 815–821

III. Formation and Out-of-Equilibrium, High/Low State Switching of a Nitroaldol Dynamer in Neutral Aqueous Media Karalius, A., Zhang, Y., Kravchenko, O., Elofsson, U., Szabó, Z., Yan, M. and Ramström, O. Angew. Chem. Int. Ed. 2020, 59, 3434–3438

IV. A Robotics-Inspired Screening Algorithm for Molecular Caging Prediction Kravchenko, O.*, Varava, A.*, Pokorny, F.T., Devaurs, D., Kavraki, L.E. and Kragic, D. J. Chem. Inf. Model. 2020, 60, 1302–1316

V. Bio-Inspired Water Oxidation Catalysts Zhang, B., Kravchenko, O. and Sun, L. In: Comprehensive Coordination Chemistry III, Elsevier, 2021 Accepted

VI. Recent Progress in Nonprecious Water Oxidation Catalysts for Acidic OER Yang, H., Liu, T., Kravchenko, O., Meng, Q., Li, F. and Sun, L. Submitted

VII. Isolated Pseudo Seven-Coordinate RuIII-bda Water Oxidation Catalyst with a “Ready-To-Go” Aqua Ligand Liu, T., Shen, N., Wang, L., Timmer, B.J.J., Li, G., Zhou, S., Ahlquist, M.S.G., Zhang, B., Kravchenko, O., Xu, B. and Sun, L. Submitted

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VIII. 2D MnOx Composite Catalysts Inspired by Natural OEC for Efficient Catalytic Water Oxidation Fan, L.*, Zhang, B.*, Zhang, F., Timmer, B.J.J., Kravchenko, O., Pan, J. and Sun, L. Submitted

IX. Configurational and Constitutional Dynamics of Enamine Molecular Switches Ren, Y., Kravchenko, O. and Ramström, O. Submitted

X. Stimuli-Responsive Enaminitrile Molecular Switches as Tunable AIEgens Covering the Chromaticity Space and Acting as Vapor Sensors Ren, Y., Kravchenko, O., Xie, S., Svensson Grape, E., Inge, A.K., Yan, M. and Ramström, O. To be submitted

XI. Rapidly Exchanging, Double-Dynamic, Catalyst-Free Nitroaldol-Hemiacetal Systems for Metal-Responsive Reversible Polymerization Karalius, A., Kravchenko, O., Elofsson, U., Szabó, Z., Yan, M. and Ramström, O. To be submitted

XII. Control Over Emergent π-π Interactions in Double-Dynamic Coordination Complexes Through a Nature-Inspired Coordination-Triggered System Karalius, A., Svensson Grape, E., Inge, K., Kravchenko, O., Szabó, Z., Yan, M. and Ramström, O. To be submitted

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Table of Contents

Abstract .................................................................................................. III Sammanfattning på svenska ................................................................. IV Abbreviations .......................................................................................... V List of Publications ................................................................................. VI Table of Contents ................................................................................... IX 1.  Introduction .................................................................................. 1 

1.1  Catalysis ............................................................................................. 2 1.1.1  Organometallic catalysis ..........................................................................3 

1.2  Secondary interactions ....................................................................... 4 1.2.1  Hydrogen bonds .......................................................................................5 1.2.2  Van der Waals forces ...............................................................................5 1.2.3  Pi-interactions ...........................................................................................6 1.2.4  Hydrophobic effects ..................................................................................7 

1.3  Symmetry in catalysis ......................................................................... 7 1.3.1  Symmetry in ligands .................................................................................7 1.3.2  Symmetry in reactions ..............................................................................8 

1.4  Aim of this thesis................................................................................. 9 2.  Applications of C-C Bond Formation via Olefin Metathesis in Dynamic Chemistry .............................................................................. 10 

2.1  Olefin metathesis .............................................................................. 10 2.1.1  Olefin metathesis catalysts .....................................................................10 2.1.2  Dynamic olefin metathesis .....................................................................11 2.1.3  Olefin metathesis in protic solvents ........................................................12 

2.2  Dynamic olefin metathesis in mild conditions ................................... 12 2.2.1  Catalyst synthesis ..................................................................................13 2.2.2  Reactivity in ring-closing metathesis ......................................................16 2.2.3  Dynamic systems equilibration ...............................................................17 2.2.4  Functional group tolerance .....................................................................19 

2.3  Cross-metathesis of functionalized substrates ................................. 21 2.3.1  Reactivity in self-metathesis ...................................................................21 2.3.2  Selective cross-metathesis .....................................................................22 

2.4  Conclusions ...................................................................................... 24 3.  Electronic Effects in the Backbone Ligands of Ru-based Water Oxidation Catalysts ............................................................................... 25 

3.1  Water oxidation ................................................................................. 25 3.1.1  Ru-bda catalysts .....................................................................................26 3.1.2  Substitution effects in water oxidation catalysts .....................................28 

3.2  Functionalization of bda-based ligands ............................................. 29 

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3.2.1  Ligand synthesis .....................................................................................30 3.2.2  Functionalized catalysts .........................................................................32 3.2.3  Electrochemical and catalytic properties ................................................33 

3.3  Electronic vs. supramolecular effects of the catalyst backbone ........ 35 3.3.1  Ligand design and synthesis ..................................................................35 3.3.2  Electrochemical properties .....................................................................36 3.3.3  Water oxidation activity...........................................................................38 

3.4  Conclusions ...................................................................................... 39 4.  Efficient O-O Bond Formation via Enhanced Catalytic Stability and Activity ........................................................................................... 40 

4.1  Improving catalyst stability via backbone π-extension ...................... 40 4.1.1  Implications of π-system modifications ..................................................40 4.1.2  Ligand design and synthesis ..................................................................41 4.1.3  Catalytic performance ............................................................................42 4.1.4  Catalyst stability......................................................................................44 

4.2  Enhancement of radical coupling ...................................................... 46 4.2.1  Ligand design .........................................................................................46 4.2.2  Catalytic performance ............................................................................48 4.2.3  Substituent effects ..................................................................................50 

4.3  Conclusions ...................................................................................... 52 5.  Concluding remarks ................................................................... 53 Acknowledgements .............................................................................. 55 Appendix ............................................................................................... 58 References ........................................................................................... 59 

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1. Introduction

“Chemistry without catalysis would be a sword without a handle, a light without brilliance, a bell without sound.”

Alwin Mittasch (1869–1953)

Chemical reactions have a larger occurrence in our everyday lives than it is commonly perceived. The notion of chemical reaction rate is intuitively defined as a measure of how fast the reaction progresses. Common examples may include burning (fast), cooking (medium), rusting (slow). The most essential chemical reactions, however, occur in human bodies. Rates of biological reactions are extremely important, as thousands of reactions are interconnected and thus should work in a concerted fashion.

Large-scale reactions occur in industry, where fuels, materials, fertilizers, and drugs are synthesized. Many of these reactions are naturally slow, and therefore require catalysts to proceed at reasonable rates. Typically, reaction rate decreases exponentially with the increase in the amount of energy required for the reaction to occur. Catalysts effectively reduce this energy, therefore making an exponential impact on the rates. This makes catalyst design essential, as even small changes can lead to a drastic acceleration of the catalysed reaction.

The use of transition metals in catalysis was, to some extent, inspired by the discovery of metalloenzymes in nature. Noble metals, such as Ru, Rh, Pd, albeit inert in bulk, were found to exhibit unique reactivity at the nanoscale, allowing their use in catalysis. In recent years, some of the mechanisms and concepts, developed in noble-metal catalysis, have been adopted to earth-abundant metals, such as Fe, Co, Ni. In light of these successes, detailed mechanistic investigations of known noble metal-catalysed processes are extremely important for transferring acquired knowledge to other metals. Despite recent developments in base metal catalysis, there are many examples of reactions that are much more efficiently catalysed by complexes based on noble metals.

Catalysis is one of important chemical tools for sustainable development, as it reduces costs of valuable materials and offers alternative pathways to inefficient and wasteful industrial processes. The achievement of many sustainability goals, such as the ones outlined by United Nations,1 can therefore benefit from the discovery of new catalysts. The works presented in this thesis do not only address the development of various ruthenium catalysts, but also contribute to the development of sustainable energy in the form of solar fuels.

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1.1 Catalysis

Development of catalysis has made a tremendous impact on chemistry. The concept of a sub-equimolar additive able to accelerate reactions, while remaining unchanged, was an attractive topic since the early days of chemistry.2 Small amounts of a material, required for catalysis, led to the unconscious use of catalysis long before it was discovered – a phenomenon, still occurring in modern chemistry.3, 4 Low loadings also made catalysis particularly useful in industrial applications, where it significantly reduced costs and enabled the access to large amounts of products.5

Generally, catalysts decrease the activation energy (𝐸 ) of a chemical reaction by offering an alternative reaction pathway, where the catalyst is involved in the reaction intermediates but released upon reaction completion (Figure 1).

Figure 1. Schematic energy profiles for non-catalysed and catalysed reactions.

Reaction rate can be linked to the activation energy via various expressions, such as Eyring or Arrhenius equations.6-8 All such equations provide an exponential relationship between the rate constant and activation energy:

𝑘 𝐴𝑒 (1)

According to equation (1), temperature is another parameter that can affect the reaction rate. Indeed, higher temperatures are commonly used to speed up reactions. For large scale reactions, however, high temperatures imply a large energy demand, which significantly affects the production costs and sometimes poses additional technological constraints (e.g. if the required temperature is higher than the solvent boiling temperature). For example, to achieve a 1000-fold acceleration of a very slow room temperature reaction with 𝐸 = 30 kcal/mol, the reaction temperature needs to be raised up to 72 °C. On the

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other hand, the same acceleration can be achieved at room temperature if activation energy is lowered by only 4.1 kcal/mol, which can be done by using a catalyst.

There are many non-specific catalysts that are effective for a variety of reactions. These include, for example, Lewis acids, which are used in Diels-Alder, Friedel-Crafts, Mukaiyama aldol, and many other reactions. Although such catalysts enable numerous useful transformations, they rely on certain common features of reacting molecules and can therefore not be utilized in more complex reactions. The opposite phenomenon can be illustrated with enzymes, each of which has evolved in nature to catalyse a single reaction with predetermined substrates. Such catalysts are quite complex, but their ultimate efficiency is a source of inspiration for the development of active and more robust catalysts.

1.1.1 Organometallic catalysis

Most of the catalytic reactions mentioned above rely on the presence of various functional groups near the reaction centres, allowing modulation of electron density distribution to an extent, enough to trigger a reaction. However, some reactants naturally do not bear such functional groups. For example, an aryl-aryl coupling reaction forms a bond between two aromatic rings, which cannot have any functional groups close to the forming bond. Such reactions thus require alternative approaches.

In many cases the catalytic pathway involves intermediates that resemble starting materials or other related compounds that are known for their reactivity. With the discovery and development of organometallic compounds, it was realized that certain fragments of organic molecules, which can form stable compounds with metals, are good candidates for such intermediates. In the above example of the aryl-aryl coupling, an intuitive scheme of reaction between two aryl fragments (in the form of radicals or ions) was not feasible due to the high energy of individual fragments. Conveniently, existence of stable aryl-metal complexes allows to lower this energy and thus create an alternative catalytic pathway.9

Thousands of organometallic catalysts have been developed in recent years, and many of them have found use in industrial applications (Scheme 1). The high cost of noble metal-based catalysts is often compensated by high turnover numbers (TONs), making them commercially viable.10

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Scheme 1. Examples of transition metal catalysts widely applied in industry.

The uniqueness of transition metals as catalysts is primarily determined by their electronic structure. The presence of numerous d-electrons allows for relatively low-energetic shuffling between oxidation states, which is important in redox catalysis, as well as in some key transformations, such as oxidative addition and reductive elimination. Moreover, the proximity of (n+1)s and nd energy levels increases flexibility in oxidation state changes. The latter effect is more pronounced in the fifth period, where Ru, Rh, and Pd are located.11 The primary reason for the tendency of d-elements to form organometallic compounds is the ability to create covalent bonds with carbon, especially π-bonds. Large variation in the shape and symmetry of the d-orbitals contributes to the flexibility in bonding with various organic molecules. Another important feature of late transition metals is the presence of both empty and filled d-orbitals in various oxidation states, which enables both electron donation from the ligands and π backdonation from the metal.12 The exact reasons for the higher activity of certain noble metals in the respective types of reactions are often not understood, as they originate from a complex interplay of relativistic effects and changes in atomic energy levels upon bonding.

1.2 Secondary interactions

The covalent bond is the major type of bonding in organic compounds, as well as the strongest (formally, ionic bonds are stronger, but they are unidirectional and strongly affected by solvation). Covalent bond energies lie in the range of 50–200 kcal/mol and therefore ensure stable structure of molecules. As these bonds and constituting atoms are essentially clouds of high electron density, extending to more than 1 Å from the nuclei, they can interact with each other in other ways. Such interactions are much weaker than covalent bonds and are often called secondary interactions due to their marginal strength. Crucially, they do not directly affect molecular connectivity but can tweak three-dimensional alignment of molecules and provide a beneficial gain of 1–5 kcal/mol in the energy of transition states, which is much sought after in catalysis.13

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In this section a short overview of secondary interactions, often utilized in catalysis, is presented. Ionic bonding, including ion-π interactions,14-16 is not covered separately as it can be considered as an extreme case of other electronic interactions.

1.2.1 Hydrogen bonds

One of the most well-studied and important secondary interactions is hydrogen bonding. Many unique properties of liquid water, cellulose, and DNA are attributed to the hydrogen bonds (Figure 2).17, 18 In polymers, regular arrangement of monomeric units, capable of hydrogen bonding, often favours formation of well-defined three-dimensional structures due to the additive force of numerous weak interactions, like in nucleic acids.19 Being a medium-range interaction of primarily electrostatic nature, hydrogen bonding is typically the strongest non-covalent interaction, with bond energies in the range of 1–10 kcal/mol.13, 20

Figure 2. Examples of supramolecular implications of hydrogen bonding: (a) double helix of DNA, (b) Grotthuss mechanism of proton transport.

Hydrogen bonding has been heavily utilized in organic synthesis and catalysis. Its applications include product selectivity,21 Brønsted acid-like activation,22 and transition state stabilisation,23 to name a few. This interaction becomes particularly important in the catalysis of biologically relevant substrates, which often have functional groups with hydrogen bond donors and acceptors.

1.2.2 Van der Waals forces

Weak intermolecular forces, operating at short distances, have been known since the middle of the 19th century as they resulted in macroscopic effects.24 It has been early understood that these forces have an electronic nature, similar to electrostatic interactions between dipoles. The current view on van der Waals forces combines all interactions between multipoles – both permanent and

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induced.25 Such forces provide only weak attraction – 0.1–1 kcal/mol – but can become pronounced in collective interactions.13, 26 Although van der Waals forces are not commonly used in catalyst design, they are often responsible for particular effects, such as chemical affinity or π-interactions.27, 28

1.2.3 Pi-interactions

Aromatic systems are known to interact with each other, resulting in various effects, such as π-π stacking in crystals and nucleic acids (Figure 3a-b).29 Although stacking is the most common example, it does not reflect the origins of the interaction and therefore the term “π-stacking” is considered misleading.30, 31 The primary driving force for the interaction between aromatic systems is the formation of a quadrupole with negative charges above and below the aromatic ring (Figure 3c). Such configuration favours off-centre face-to-face and “unintuitive” T-shaped interactions. The commonly occurring face-centred stacking is only possible, when one of the quadrupoles is inverted, usually due to the presence of a strong electron-withdrawing substituent.32 Therefore, π-π interactions, especially in small molecules, are determined by the substituents and their electronic properties rather than by intrinsic attraction between aromatic systems.33, 34

Figure 3. Pronounced π-π interactions between (a) base pairs in DNA, (b) host crystal and guest benzene molecules.35 (c) Schematic interactions between

multipoles; benzene (left) and hexafluorobenzene (right) represent molecules with the opposite quadrupole moments.

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Apart from the extensive use of π-π interactions in catalyst immobilization on surfaces,36 they have also been directly employed in catalyst design to steer substrate selectivity,37 product selectivity,38 and bimolecular coupling of catalytic intermediates.39 The energy of π-π attractions typically varies within 0.5–3 kcal/mol, but can reach 10 kcal/mol in long aromatic systems, such as carbon nanotubes.40

1.2.4 Hydrophobic effects

Unlike other secondary interactions, hydrophobicity is a cumulative effect, rather than a direct interaction between particles. Despite being specific to aqueous solutions, it is well studied due to its importance in biological processes.41 Since water is an abundant green solvent, development of numerous organic reactions includes adapting them to aqueous conditions, where hydrophobic effects become very important, especially if the substrates have limited solubility.42 Hydrophobicity is ubiquitous due to the nature of organic compounds, and therefore it has been utilized in many areas of catalysis.43-46

1.3 Symmetry in catalysis

Another factor that can play an important role in catalysis is symmetry, which is a central concept in many areas of chemistry.47 In many cases it emerges from the symmetry of various functions, such as electronic wavefunctions and overlap integrals, that attain non-zero values only in the case of identical symmetry. This section briefly discusses some aspects of symmetry related to transition metal catalysis.

1.3.1 Symmetry in ligands

Symmetry in molecules is usually considered to be a stabilising factor. Qualitatively it can be perceived as the absence of gradients that lead to an uneven distribution of electron density. Differences in the latter potentially result in the lack or excess of electron density on some atoms, which seeks to be resolved via chemical reactions.48 Symmetry in the structure of metal complexes is typically determined by the alignment of d-orbitals, which often results in tetrahedral or octahedral arrangement of the ligands. To enable catalytic properties, a metal complex usually bears different ligands, which reduces the overall symmetry. In many cases certain symmetry elements, such as rotation axis or plane of symmetry, are nevertheless preserved, facilitating characterization by some physicochemical techniques.49

Intuitively, symmetry in many transition metal complexes can be explained not only by the intrinsic symmetry of d-orbitals, but also by the presence of energetically favourable bonds or interactions, which are multiplicated to as

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much extent as possible to lower the overall energy of the complex. This concept is best illustrated by the presence of a long-range order in crystal structures: the most favourable alignment of a molecule with its periodic images is multiplicated in all directions, as any change will lead to undesirable interactions, increasing the energy. Although there are many exceptions to the benefits of symmetric ligands, these considerations are essential in transition metal catalysis.50, 51

1.3.2 Symmetry in reactions

Similarly to a collective electron movement, which requires the presence of a potential difference, chemical reactions occur when there is a difference in the thermodynamic potential. The concept of potential gradients can also be applied to certain processes that occur due to the difference in some property. For example, many classes of organic reactions are driven by the difference in local partial charges on reactants’ atoms or occupation of frontier molecular orbitals.52 This often implies different nature of reactants, such as “electrophile and nucleophile” or “diene and dienophile”. Although some of these reactions can yield symmetric molecules, certain symmetric bonds cannot be easily formed by the reactants of different nature. For example, a heterolytic retrosynthetic approach to biaryls yields two aryl ions, which is, although possible to realize in the reactants, challenging from the mechanistic and practical perspective53 (Figure 4a). Another prominent example is the formation of dioxygen in water oxidation, which can be accomplished via coupling of two identical radicals without the need to create species with opposite charges on oxygen (Figure 4b). In the aforementioned examples of symmetric bonds, a homolytic retrosynthetic approach appears to be more feasible, as it would not require two drastically different reactants and uncommon unstable intermediates. It is anticipated that transition metal catalysis in part realizes this idea. Indeed, despite Suzuki reaction engages two synthons with opposite charges, the bond formation step is essentially a coupling of two identical moieties, attached to the metal (Figure 4d).

A similar phenomenon occurs in intermolecular O-O coupling, catalysed by Ru complexes.54 It is worth noting that symmetric double bonds are more challenging in this regard, as their corresponding neutral synthons have two unpaired electrons, which is more demanding for the metal catalyst. An elegant approach to this problem has been demonstrated in the olefin metathesis, where sacrificial terminal methylene group and the exchange mechanism allowed accommodation of only one carbene on the metal centre at once (Figure 4c).55 Although only several such catalytic reactions have been discovered, they are often indispensable and therefore well-developed.

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Figure 4. Reactant, intermediate and product symmetry in various catalytic bond formation reactions.

1.4 Aim of this thesis

This thesis focuses on the ruthenium-catalysed formation of symmetric double bonds, namely C=C bond in alkenes and O=O bond in dioxygen. The main objective of the thesis is to provide valuable insights on how the secondary interactions in the first and second coordination spheres can affect the catalysis and its application potential. The second chapter discusses the performance of novel olefin metathesis catalysts under challenging conditions. Herein, dynamic chemistry applications, where slow equilibration of highly functionalized substrates poses high demands on the catalyst stability, are discussed. The third chapter investigates the electronic effects on ruthenium redox catalysts for O-O bond formation. Herein, the functionalization of the bipyridine scaffold is performed, and the influence of modifications on reactivity and potential applications is assessed. The fourth chapter is devoted to the development of highly efficient water oxidation catalysts, acting via an intermolecular radical coupling mechanism. Various π-effects are leveraged to improve the activity and stability of the catalysts, enhancing the potential for future applications.

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2. Applications of C-C Bond Formation via Olefin Metathesis in Dynamic Chemistry

(Papers I–II)

The first scientific chapter discusses the most prominent C-C double bond formation reaction – olefin metathesis. The symmetry of this bond and of both reactants and products makes it a valuable tool in the dynamic chemistry framework. The chapter focuses on the state-of-the-art catalysts for olefin metathesis and their potential use in dynamic systems with challenging environment.

2.1 Olefin metathesis

Originally discovered as an industrial method for conversion of propylene to ethylene and butene and polymerization over inorganic catalysts,56-58 olefin metathesis became an ubiquitous reaction in organic chemistry,59 primarily due to the mechanism discovery by Chauvin55 and development of organometallic catalysts by Schrock60, 61 and Grubbs.62, 63 Recognized with a Nobel prize, olefin metathesis became an invaluable reaction in industry64 and research.65

2.1.1 Olefin metathesis catalysts

Virtually impossible at reasonable temperatures, olefin metathesis reactions can be realized with the help of catalysts. With the discovery of well-defined molecular catalysts (Figure 5), olefin metathesis became available for advanced organic synthesis.66, 67 Schrock catalysts are known to be the most active, albeit at the cost of air and moisture tolerance. This limitation, along with good shelf stability of Ru complexes and easily customizable N-heterocyclic carbenes (NHCs) in Grubbs catalysts, led to the wider use of the latter in practice.

Figure 5. Schrock (S), first- and second-generation Grubbs (GI, GII) and Hoveyda-Grubbs (HGI, HGII) catalysts are representative examples of olefin metathesis

catalysts.

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Large variety of NHCs, which are commonly used in transition metal catalysis, allowed for development of olefin metathesis catalysts, exhibiting various types of stereoselectivity,68 responsiveness,69 and solubility.70 Recent advancements also include the use of novel types of NHCs, such as cyclic (alkyl)(amino)carbenes (CAACs), which offer higher stability and extension of a substrate scope.71, 72

2.1.2 Dynamic olefin metathesis

Chemical bonds which are easily formed and broken down constitute a toolbox of dynamic chemistry. Lability of the bonds ensures efficient dynamics of the system and fast equilibration. This property often comes with the insufficient stability of reaction products, leading to problems with separation and isolation of individual molecules.73 The C-C double bond has a particularly high bond energy (147 kcal/mol),74 which makes it a unique example of a strong dynamic covalent bond. Olefin metathesis not only allows to form stable products, but also is orthogonal to other reactions.75

Uniqueness of a C-C double bond was leveraged in many applications in dynamic covalent chemistry, including drug discovery,76 adaptive materials,77 supramolecular structures,75 and self-healing polymers.78 Since olefin metathesis is often considered as a perfect tool for late-stage functionalization of bioactive compounds and one of the best methods to form macrocycles in functionalized molecules,79 it is an important tool for chemical biology.80 In one of the early applications, the ability to create a mixture of cross-metathesis products was used by Poulsen in the pre-screening of enzyme inhibitors without isolation of individual products.76 A prominent example of the dynamic systemic resolution of a dynamic library of alkenes was reported by Hartwig, where an equilibrated mixture of olefins was exposed to an enzyme, which selectively processed one of them in the irreversible epoxidation reaction, shifting the equilibrium (Figure 6).81 Such resolution led to a 2.6-fold increase in the yield of epoxidized cross-metathesis product, if compared with a maximum theoretical yield in a 2-step procedure.

With more applications of olefin metathesis in dynamic chemistry being reported, the focus in this field moves to more biologically relevant conditions, such as aqueous media and highly functionalized substrates.82, 83

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Figure 6. Formation of a dynamic library of olefins and its resolution with a P450 BM3 metalloenzyme selector, resulting in an amplification of one of the alkenes.

Yields are specified for 25 mM loadings of the fatty acid in various conditions.

2.1.3 Olefin metathesis in protic solvents

Early olefin metathesis catalysts suffered from low solubility and instability in protic solvents, rendering aqueous metathesis impossible. Introduction of an NHC in GII vastly improved catalyst stability and allowed for easier functionalization of the complexes, which provided water-soluble catalysts.84, 85 However, even small degree of decomposition can cause significant disturbance to the reaction progress. Various paths of decomposition of Ru-based olefin metathesis catalysts, including the most stable HGII, have been identified in non-aqueous mixtures.86 The presence of protic solvents, such as alcohols and water, is known to facilitate decomposition, resulting in the formation of hydrides.87 The latter are very active in the isomerization of alkenes and therefore constitute a serious concern in olefin metathesis.88 Recently, this problem has been addressed by suppressing the formed hydrides89 and designing catalysts with unfavourable hydride formation.71, 90

2.2 Dynamic olefin metathesis in mild conditions

Applications in dynamic chemistry impose certain constraints on reaction conditions. For example, performing a dynamic kinetic resolution of a mixture of alkenes with a biological selection pressure (such as receptor or enzyme) requires mild temperature and the presence of various additives.81 Common Ru-based olefin metathesis catalysts are either active at high temperatures (over 100 °C) and demonstrate high stability, or active at lower temperatures (5–40 °C) but unstable.91, 92 These properties, despite affording high TONs,71 usually do not match the demands of dynamic chemistry, where both low temperature and long catalyst lifetimes are required. As many other organometallic compounds, Ru-based olefin metathesis catalysts suffer from

13

decomposition and inhibition by nucleophilic species.86, 87, 93, 94 While in the early days of aqueous olefin metathesis solvent was the primary source of decomposition, stability problems have been solved, primarily by introducing protecting groups, such as in Hoveyda-Grubbs catalysts.95, 96

Development of CAAC-based Ru complexes became a breakthrough in olefin metathesis catalysis.97 Enhanced stability of methylidene species,71 low tendency to form hydrides,90 and expansion of the substrate scope72 made CAAC-based catalysts promising candidates for dynamic chemistry, where catalyst stability is a key to successful system equilibration.

2.2.1 Catalyst synthesis

To probe the activity of state-of-the-art CAAC-based catalysts in the equilibration of dynamic systems, a series of Ru complexes was synthesized. A conventional approach to Hoveyda-Grubbs 2nd generation catalysts (HGII) is based on commercially available Grubbs 1st generation precursors (GI) and two sequential ligand exchange reactions (Scheme 2).

Scheme 2. Synthetic approaches towards Hoveyda-Grubbs 2nd generation catalysts (HGII), starting from Grubbs 1st generation catalysts (GI).

Since potential catalysts in aqueous dynamic olefin metathesis would likely bear water-soluble groups on a Hoveyda-type ligand, pathway B was pursued due to easier preparation and purification procedures (Scheme 3).70 Extensive optimization of conditions proved the formation of CAAC-based GII impossible; however, in the case of the more reactive benzylidene-substituted GI-Bnd (R = benzylidenyl, Bnd) and excessive amount of the CAAC precursor, distinct signals emerged in the 1H NMR and MS spectra, indicating formation of a bis-CAAC complex (Figure 7).

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Scheme 3. Reaction of GI with an in situ formed CAAC.

Figure 7. Evidence for the formation of a bis-CAAC complex: (a) 1H NMR spectrum of the crude reaction mixture, CDCl3; (b) mass spectrum of the crude reaction

mixture and a simulated spectrum for [M-Cl]+ = 741.3.

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Reaction conditions were optimized to maximize the yield of the bis-CAAC complex; however, it lacked stability with R = Bnd. To overcome this issue, a GII precursor with a less labile 3-phenylindenylidenyl (Ind) ligand was used, affording a stable bis-CAAC adduct (Scheme 3).

Comprehensive work on the discovery and catalytic activity of bis-CAAC complexes was then published by Gawin et al.,98 prompting us to explore synthetic applications of these complexes. The authors proposed a mechanism of catalyst initiation that involved dissociation of one of the CAAC ligands, supporting the hypothesis by preparing a CAAC-based HGII catalyst from a bis-CAAC complex.98 Later Gawin et al. reported preparation of CAAC-based HGII catalysts from a triphenylphosphine analogue of GI-Ind via a two-step reaction without isolation of bis-CAAC intermediate.72 As the only advantage of this procedure was avoiding intermediate isolation and purification, while sacrificing total yields, we developed a more conservative approach (Scheme 4).

Scheme 4. Synthetic pathways towards CAAC-based catalysts C1 (pathway A) and C2-C4 (pathway B).

For this study four CAAC-based Hoveyda-Grubbs 2nd generation catalysts (C1–C4) with varying substituents on the CAAC were selected. Previous studies by Grubbs71, 99 and Skowerski72 have established structure-activity relationships for CAAC-based catalysts; however, these works did not include variability in the structures of both the catalysts and the substrates.

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2.2.2 Reactivity in ring-closing metathesis

First, the catalytic activity in benchmark ring-closing metathesis (RCM) reactions was explored. A standard selection of dialkenyl malonates S1–S3 was used to model formation of di-, tri-, and tetrasubstituted olefins (Table 1).100

Table 1. Ring-closing metathesis of dialkenyl malonates, catalysed by complexes C1–C4.a

Entry Substrate T (°C) Reaction timeb (h) and maximum conversion

C1 C2 C3 C4

1

22 372 95%

3.1 95%

2.5 95%

1.5 95%

2 40 28

95% < 0.25 98%

< 0.25 98%

< 0.25 98%

3

40 172 95%

0.5 95%

0.5 96%

0.5 93%

4 60 30

95% ― ― ―

5

40 0% 0% 0% 0%

6 80 0% 400 5%

480 22%

70 6%

a Reactions were performed using 1 mol% of catalyst at the stated temperature in an NMR tube until conversion stopped increasing or reached 95%. Initial substrate concentration was 0.1 M in C6D6. R = COOEt. Conversions were determined by 1H NMR spectroscopy. b Time required to reach maximum conversion.

Both S1 and S2 were successfully transformed into products within 30 min by C2–C4 at 40 °C (Table 1, entries 2–3). In contrast, S3 was inactive in RCM at temperatures up to 80 °C (Table 1, entries 5–6), suggesting that the presence of a terminal alkene is crucial for the reactivity at lower temperatures. The reaction of a primary Ru alkylidene with disubstituted olefins is not slow (Table 1, entry 3), and big difference between reactions of S2 and S3 indicates that formation of secondary Ru alkylidenes is highly disfavoured. Formation of tetrasubstituted olefins, however, proved possible, despite early studies suggested the opposite.99

Relative reactivity of all four catalysts was demonstrated by RCM of S1 (Table 1, entry 1). In the series of C2–C4 reaction times decreased with the decrease of steric bulk of the biggest substituent on the CAAC aryl ring. Interestingly, in all cases C1 was consistently more than 100 times less reactive, albeit stable for many days and able to complete cyclization of S1 and S2. Although the high stability of C1 was expected due to steric protection of the reactive site, its low reactivity compared with C2, also bearing isopropyl groups, was surprising. Since these bulky groups should not directly influence neither the approach of incoming olefin nor the stability of small and flexible allyl-

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derived Ru alkylidene, the effect could be explained by the catalyst initiation mechanism, originally proposed by Grubbs.99 The striking difference in case of C1 and C2 possibly appeared due to the presence of a small substituent (methyl) on the CAAC aryl ring, which allowed a sterically less demanding initiation mode (Figure 8).

Figure 8. Suggested conformations of C2 initiation, including rotations towards more substituted (disfavoured, left) and less substituted (favoured, right) sides of

CAAC aryl ring.

2.2.3 Dynamic systems equilibration

Cross-metathesis (CM) of two terminal alkenes produces an internal alkene and ethylene. This is considered a benefit in organic synthesis, as gaseous ethylene can be easily removed from the solution, driving the reaction forward. On the other hand, high pressures can allow the reverse reaction – ethenolysis. Due to the increased stability of alkylidene species, CAAC-based complexes are naturally good at catalysing both the forward and backward reactions. This feature was utilized in the following experiments of establishing a dynamic equilibrium.

First, the simplest system, containing one terminal alkene, was studied. While allyloxy compounds (allyl alcohol and allyl acetate) seemingly led to the decomposition of the catalyst before reaching equilibrium, non-coordinating allyl benzene (S4) formed an equilibrium with its homodimer and ethylene. Catalysts C1 and C4 appeared to be on the opposite sides of the activity spectrum: C1 reached 50% conversion only after 600 h, and C4 decomposed within first 10 h, reaching only 35% conversion (Figure 9a). The independence of equilibrium position on the catalyst loading was confirmed by varying catalyst concentration (Figure 9b). C2 was determined as the most stable catalyst capable of reaching equilibrium and therefore was used in the following experiments.

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Figure 9. Self-metathesis of allyl benzene (S4), catalysed by (a) C1-C4 at 1 mol% loading; (b) C2 at 1-5 mol% loading. Reactions were performed in a sealed NMR

tube. Conversions were determined by 1H NMR spectroscopy and are given for the combined cis- and trans-isomers.

To rule out the presence of kinetic sinks in the formation of less reactive trans-isomers, we explored equilibration of cis- and trans-1,4-diacetoxy-2-butene (S5) in a dual entry point analysis.73 Despite showing slower kinetics, trans-S5 reached the same equilibrium point as cis-S5 (Figure 10).

Figure 10. Isomerization of cis- and trans-S5 via self-metathesis, catalysed by C2.

Reactions were performed in an NMR tube. Conversions were determined by 1H NMR spectroscopy.

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Finally, a more complex dynamic system was created, starting from a 1:1 mixture of S4 and S5. Distribution of products stopped changing after 60 h with signals of catalyst still visible in the 1H NMR spectrum, suggesting reaching the equilibrium (Figure 11). To demonstrate responsiveness of the system, the formed equilibrium was disturbed by adding another equivalent of S5. The product distribution started changing rapidly, eventually stopping at 71% conversion to the cross-metathesis product. The same composition of the mixture was also achieved by starting from a 1:2 mixture of S4 and S5, confirming equilibration and formation of a fully responsive dynamic system at room temperature and only 1 mol% catalyst loading (Figure 11).

Figure 11. Formation of a dynamic system by cross-metathesis, catalysed by C2. Reactions were performed in a sealed NMR tube. Conversions to the major CM

product trans-3-(acetoxymethyl)allylbenzene were determined by 1H NMR spectroscopy.

2.2.4 Functional group tolerance

With the confirmed ability of C2 to establish a dynamic equilibrium, the applicability of the CAAC-based catalyst was further explored. As dynamic chemistry is of particular interest in drug development,76, 79, 101, 102 catalysts for dynamic olefin metathesis should be compatible with the functional groups, present in the substrates or selectors. Many nucleophilic groups pose a significant threat to the catalyst stability and therefore can potentially inhibit

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catalysis, if present on the substrates.86, 87, 93 The influence of various functional groups on the catalytic activity of CAAC-based catalysts was modelled in a robustness screen.103 An RCM reaction of S1, catalysed by C2, was taken as a model example. Basic aliphatic amines were found to retard the reaction almost completely, with only noticeable conversion reached in 3 days in the presence of triethylamine (Table 2). Imidazole also inhibited the catalyst, presumably by coordinating to the Ru centre and replacing the isopropoxy group. Surprisingly, only propylamine led to the complete disappearance of the alkylidene proton signals from the 1H NMR spectrum, while other additives presumably formed stable inactive adducts.

Table 2. Ring-closing metathesis of S1, catalysed by C2 in the presence of nucleophilic additives.a

Additive

Conversion (%) Catalyst alive (2 h) 2 h 3 d

― 87 100 ✓ n-propylamine 0 0 ✘ diethylamine 0 < 1 ✓ triethylamine < 1 4 ✓ morpholine 0 0 ✓ imidazole 0 0 ✓

a Reactions were performed in an NMR tube with 1 equivalent of additive. Conversions were determined by 1H NMR spectroscopy. Remaining catalyst was identified by the most downfield signal in 1H NMR spectrum.

Less nucleophilic additives, primarily of heteroaromatic nature, have mostly shown significant conversions after 2 h and full conversions after 3 d, prompting us to compare their effects in a slower self-metathesis reaction (Table 3). Electron-rich heterocycles did not have an inhibiting effect on the catalysis, while mono- and unsubstituted anilines significantly slowed down the reaction, presumably by offering more labile protons and leading to the loss of chlorides and formation of strong ionic bonds with the metal centre.93 Another electron-deficient heterocycle of strongly coordinating nature – pyridine – initially inhibited catalysis, likely forming marginally active adducts. Overall, these results complement previous studies on decomposition of other NHC-based Hoveyda-Grubbs 2nd generation catalysts, which were performed with low loadings of additives, thus not reflecting the effect of functional groups being present in the substrate to the full extent. 93

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Table 3. Self-metathesis of S4, catalysed by C2 in the presence of weakly nucleophilic additives.a

Additive

Conversion (%) Catalyst alive (2 h) 2 h 16 h

― 23 45 ✓ N,N-dimethylaniline 19 40 ✓

N-methylaniline 2 19 ✓ aniline 1 8 ✓ furan 18 42 ✓

thiophene 22 44 ✓ pyrrole 13 40 ✓

N-methylpyrrole 19 41 ✓ pyridine 0 2 ✓b

a Reactions were performed in an NMR tube with 1 equivalent of additive. Conversions were determined by 1H NMR spectroscopy. Remaining catalyst was identified by the most downfield signal in 1H NMR spectrum. b Catalyst signal shifted; solution colour changed from green to orange.

2.3 Cross-metathesis of functionalized substrates

As mentioned above, many biologically relevant substrates for olefin metathesis have great metal coordination properties due to the abundance of electronegative heteroatoms. When a coordinating group is located in proximity to the alkene within the same molecule, it can chelate the formed Ru-alkylidene species, blocking the available coordination site for incoming olefins, thus temporarily or permanently deactivating one catalytic centre.104, 105 This effect implies slower catalysis with the same rates of catalyst decomposition, especially pronounced in aqueous media.

Challenges of substrate chelation and aqueous instability were separately addressed in numerous works by Davis,82, 104, 106, 107 Hoye,108 Grela,70, 109-112 and Grubbs.85, 95 However, attempts to utilize chelating substrates in aqueous olefin metathesis were not practical, suffering from either high catalyst loadings or narrow substrate scope, limited to allyl alcohols, allyl chalcogenides and ammonium salts.70, 113, 114 Recently, successful olefin metathesis of unprotected carbohydrates in water was reported,89 enabling us to study the aqueous olefin metathesis of various functionalized substrates in more detail.

2.3.1 Reactivity in self-metathesis

Alkenyl pentaethylene glycols (PEGs) were selected as model substrates for this study. These molecules possess high degree of flexibility and present 6 coordinating groups each, which makes them capable of demonstrating various

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coordination modes. Using the water-soluble catalyst from the work by Timmer et al.,89 we performed self-metathesis of allyl pentaethylene glycol (allyl-PEG, Table 4, entry 1), which yielded only 6% conversion after 5 h. Marginal extension of the chain length between the terminal alkene and PEG produced the same results (butenyl-PEG, Table 4, entry 2), suggesting formation of inactive chelates.

Table 4. Self-metathesis of allyl alcohol, terminal alkene substituted PEGs and diglycine, performed in water.a

a Reactions were performed using 5 mol% of catalyst at 35 °C for the stated duration. Initial substrate concentration was 0.1 M in D2O containing 2.5 vol% CD3COOD. Conversions were determined by 1H NMR spectroscopy and are given for the combined cis- and trans-isomers.

Further increase in the alkenyl linker length resulted in slight improvement of conversions up to 20% (pentenyl-PEG, Table 4, entry 3) and 28% (hexenyl-PEG, Table 4, entry 4). These results are in good agreement with the self-metathesis of corresponding alkenyl glycosides, which followed a similar trend.89

An alkenyl substituted dipeptide was subsequently used to assess the effect of amide bonds on self-metathesis (hexenyl-Gly-Gly, Table 4, entry 5). As expected from stronger nucleophiles, this amide-containing substrate significantly degenerated catalysis, affording less than 10% conversion. The efficiency of the catalyst in self-metathesis of less functionalized substrates was confirmed with a control experiment, where allyl alcohol was successfully converted into butene-1,4-diol (Table 4, entry 6).

2.3.2 Selective cross-metathesis

The observed low reactivity of highly functionalized substrates is the other extreme of allylic effects in olefin metathesis. In a similar way to the use of

Entry Substrate Conversion (%)

15 min 60 min 300 min

1

1 5 6

2

3 5 5

3

15 19 20

4

22 26 28

5

4 9 9

6 58 74 82

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chalcogen activation in driving the selectivity of CM and RCM, deactivation of catalysis with strongly coordinating molecules can be utilized in a complementary fashion. To demonstrate this, allyl alcohol was subjected to cross-metathesis with the previously studied functionalized substrates (Table 5).

Table 5. Cross-metathesis of alkene substituted PEGs and diglycine with equimolar amounts of allyl alcohol.a

a Reactions were performed using 2.5 mol% of catalyst (based on total alkene content) at 35 °C for the stated duration. Initial substrate concentration was 0.1 M in D2O containing 2.5 vol% CD3COOD and an equimolar amount of allyl alcohol. Conversions were determined by 1H NMR spectroscopy and are given for the combined cis- and trans-isomers. b Exact values of conversion could not be determined due to overlapping signals in the 1H NMR spectrum.

The overall reactivity of the substrates in cross-metathesis follows the trend of activity in self-metathesis. Interestingly, allyl-PEG was still only marginally active in CM (Table 5, entry 1), indicating that lack of reactivity is not only caused by chelating itself, but also by the intrinsically lower activity of allyl ethers in metathesis, compared with allyl alcohols.104, 115 Other alkenes showed higher conversions (Table 5, entries 2-5), suggesting the ability to react with alkylidene species, formed by allyl alcohol. In these cases, despite the high reactivity of allyl alcohol in the SM, the amount of butene-1,4-diol was significantly lower than expected from self-metathesis. The selectivity in these CM reactions thus arise from the behaviour of functionalized alkenes as type II or type III olefins, which is not typical for non-branched terminal olefins.116

To further exploit the selectivity of these cross-metathesis reactions, two modifications of the conditions were explored. In the first modification, the reaction temperature was lowered to room temperature. Although a decrease in the temperature was expected to slow down all reactions, the reduction of self-metathesis rate was crucial to the cross-metathesis, which resulted in 50% conversion for hexenyl-PEG (Table 6, entry 1) and 33% conversion for hexenyl-Gly-Gly (Table 6, entry 2). The improvement in conversion compared with 35 °C conditions (Table 5, entry 4) was more effective for hexenyl-PEG, particularly active in self-metathesis, thus confirming the feasibility of our approach.

Entry Substrate Conversion (%)

15 min 60 min 300 min

1 allyl-PEG < 10b < 10b < 10b

2 butenyl-PEG 13 20 21

3 pentenyl-PEG 31 42 43

4 hexenyl-PEG 40 43 43

5 hexenyl-Gly-Gly 19 27 28

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Table 6. Cross-metathesis of hexenyl-PEG and hexenyl-Gly-Gly with allyl alcohol under different conditions.a

a Reactions were performed using 2.5 mol% of catalyst (based on total alkene content) at the given temperature for the stated duration. Total initial alkene concentration was 0.2 M in D2O containing 2.5 vol% CD3COOD. Conversions were determined by 1H NMR spectroscopy and are given for the combined cis- and trans-isomers. 

Another modification, aiming to increase cross-metathesis selectivity, included the change in the ratio between reactants. The concentration of the slow-reacting substrates was reduced from 0.1 M to 0.05 M, and the concentration of allyl alcohol was increased to 0.15 M to keep the total alkene content constant in respect to the amount of catalyst. Increased active-to-passive alkene ratio was expected to reduce the amount of deactivated catalyst, replacing it with active Ru-alkylidene species formed by allyl alcohol. Indeed, this modification resulted in higher conversions for both hexenyl-PEG (62%, Table 6, entry 3) and hexenyl-Gly-Gly (41%, Table 6, entry 4). These results demonstrate that highly coordinating olefins can be successfully employed in cross-metathesis with particularly active alkenes at physiologically relevant temperatures in water.

2.4 Conclusions

This chapter has shown the potential of state-of-the-art catalysts for olefin metathesis in dynamic chemistry applications, with focus on biologically relevant conditions. The reactivity of CAAC-based catalysts at mild temperatures revealed the selectivity towards Type I olefins, which are perfect candidates for dynamic libraries.75, 116 The excellent performance of CAAC-based catalysts in ethenolysis allowed for the formation of responsive dynamic systems from terminal alkenes and their cross-metathesis products. Weakly nucleophilic additives showed little effect on the catalytic activity, while aliphatic amines and electron-deficient heterocycles appeared to be strong inhibitors. These results can be further used to create more stable catalysts, taking advantage of hemilabile adduct formation.117

Entry Temperature Substrates Conversion (%)

15 min 60 min 300 min

1 22 °C hexenyl-PEG (0.1 M) allyl alcohol (0.1 M)

41 49 50

2 22 °C hexenyl-Gly-Gly (0.1 M)

allyl alcohol (0.1 M) 18 27 33

3 35 °C hexenyl-PEG (0.05 M) allyl alcohol (0.15 M)

39 58 62

4 35 °C hexenyl-Gly-Gly (0.05 M)

allyl alcohol (0.15 M) 31 38 41

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3. Electronic Effects in the Backbone

Ligands of Ru-based Water Oxidation Catalysts

(Papers III–IV)

The second scientific chapter discusses the importance of various ligand properties in the catalytic formation of O-O double bonds. Unlike carbon-carbon double bonds, which are ubiquitous in chemistry, the oxygen-oxygen double bond appears only in oxygen allotropes. Dioxygen is an abundant molecule, therefore its generation is not essential per se. However, it becomes a bottleneck reaction in certain coupled processes, such as hydrogen evolution or carbon dioxide reduction via electrolysis of water. The properties of the ligands have been shown to play a crucial role in water oxidation, catalysed by molecular ruthenium complexes, and this chapter studies the influence of electronic effects on the catalyst properties and performance.

3.1 Water oxidation

Despite being a very old method, electrolysis has not had a widespread synthetic use until recent years, when the benefits of electricity as a green and renewable source of energy have been recognized to the full extent.118-120 Electrolysis provides a convenient way of “reversing” the redox reactions by using electrical energy to drive an endergonic reaction in the opposite direction. Such a process offers a sustainable approach towards the fuel-based energy generation paradigm (Figure 12a).121, 122 In this regard, water and carbon dioxide are perfect reactants, as they are eventual products of the fuel combustion processes, cheap and abundant.

Figure 12. (a) Schematic diagram of conventional energy generation. (b) Summary of energy conversion processes, highlighting the sustainability of solar fuels. aSome solar fuels can contain oxygen, but for simplicity formulated as CnHm. bThese include useful forms of energy: electricity, mechanical work, energy of chemical bonds, etc.

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Cathodic half-reactions of water electrolysis proceed quite smoothly, partly due to the presence of readily reducible protons in water and high reactivity of the atomic hydrogen.123, 124 These reactions provide the fuels, and therefore are being actively developed from a catalytic perspective.125-127 In contrast, anodic half-reactions provide the oxidant. Most fuel oxidations on Earth occur with oxygen as electron acceptor; water electrolysis conveniently generates oxygen in the anodic reaction, effectively maintaining the chemical balance in the overall solar energy conversion scheme (Figure 12b).

As water is the only substrate in the anodic oxidation to oxygen, this half-reaction is commonly referred to as “water oxidation”. The challenge of this process is, however, not only in the oxidation of water itself, but rather in forming an O-O double bond. Formation of dioxygen requires two water molecules, meaning that 4 electrons need to be removed to form one oxygen molecule. Consecutive electron removals are generally increasingly more demanding in energy; however, the simultaneous removal of 4 protons facilitates this process due to the proton-coupled electron transfers.128, 129 Nevertheless, O-O bond formation is still a major challenge in water oxidation and is recognized as the rate-determining step of this process, as well as the bottleneck of the entire water splitting.130, 131 Many efforts are thus devoted to the development of catalysts that can facilitate formation of the O-O bond.132, 133

3.1.1 Ru-bda catalysts

Retrosynthetic approaches towards oxygen-oxygen bond can provide an intuition behind the existing mechanisms. A heterolytic approach affords two synthons: “O–” and “O+” (Figure 13). The first one is quite common, and it can correspond to a hydroxide ion or even water molecule itself, as oxygen bears a partial negative charge. The positively charged oxygen is, however, not common, but in such species it can be mimicked via binding to some positively charged moiety, which cannot be attacked by “O–” directly. Conveniently, this construction can be realized with coordinatively saturated metal oxo species (Figure 13). This mechanism is known as water nucleophilic attack (WNA). It is worth noting that in this case the terminal oxygen does not bear a positive charge, which would be kinetically favourable, but instead a positive charge on the metal provides a thermodynamic driving force for this process by accepting electron density released from the nucleophilic attack.

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Figure 13. Retrosynthetic approach to O-O bond formation, and two primary mechanisms operating in metal-catalysed water oxidation.

Alternatively, homolytic splitting of the O-O bond affords two oxyl radicals. Theoretically, such a reaction could be realized with just hydroxyl radicals, but O-O bonds in peroxides are not strong, and therefore such reactions are thermodynamically less favourable.134 Interestingly, this approach can also be pursued with metal oxo catalysts of radical character135 (Figure 13). These catalysts represent an elegant concept of symmetric bond formation via bimolecular coupling of identical fragments.136 Such a mechanism is commonly abbreviated as I2M (inter- or intramolecular coupling of two metal oxo units).

Figure 14. Ru-bda structure and the featured I2M mechanism.

Ru-bda (bda = [2,2'-bipyridine]-6,6'-dicarboxylate) complexes are the main representatives of the catalysts operating via an I2M mechanism (Figure 14).137 Notably, these catalysts are capable of chemically-driven water oxidation, where oxidative force is provided by a sacrificial oxidant rather than

28

electrochemically. This feature allows to study catalytic mechanisms in more detail and to control formation of inorganic catalytic species, which tend to compromise pure reactivity of molecular electrocatalysts.138, 139 A bimolecular mechanism implies quadratic dependence of reaction rate on the catalyst concentration, meaning that very high specific activity (turnover frequency, TOF) can be attained at high concentrations of the catalyst. This consideration has been exploited in various supramolecular strategies, aimed at increasing the local concentration while keeping the overall amount of catalyst low.140, 141 Nevertheless, a significant effort has been put on studying the radical coupling step and understanding which interactions and properties of the catalysts are important for realization of the bimolecular mechanism.142-145

3.1.2 Substitution effects in water oxidation catalysts

Introducing substituents on the ligands is a common way of tuning properties of transition metal catalysts.146-150 Such modifications are usually preceded by the elucidation of structure-activity relationship, which is often performed by screening substituents with varying properties, e.g., Hammett constant, steric bulk, and solvophobicity. Such studies have been performed for many types of water oxidation catalysts. It is commonly believed that electron-donating ligands are the most suitable for redox catalysts operating at high oxidation states, as they tend to stabilize the latter.151-153 However, this influence has proven to be highly dependent on the molecular structure of the catalysts and the function of the ligand in the rate-determining step.154-156 For example, electron-donating substituents on the axial ligands of Ru-bda catalysts have been shown to enhance stability by raising the highest occupied molecular orbital (HOMO) energy and therefore strengthening the metal-ligand bond.136 On the other hand, the electronic effects of the axial ligands on the activity seem to be limited. Instead, the catalytic activity in bimolecular coupling can be amplified by intermolecular van der Waals interactions between the axial ligands.145

Figure 15. Reported modifications of the bda ligand.

29

While axial ligands in Ru-bda catalysts can bring a several orders of magnitude enhancement in both stability and activity,157 they only amplify the mechanisms that are already present in the parent Ru(bda)(pic)2 (pic = 4-picoline) catalyst.158 In contrast, modification of the bda ligand is crucial for the understanding of its essential properties and ground factors that can be potentially improved. A few examples of bda functionalization addressing this question have been reported (Figure 15). Studies by Duan and Concepcion revealed effects exerted by carboxylic groups and their analogues.159-161 Effects of rigidity and planarity have been investigated by Sun and Richmond.162, 163 Influence of the substituents on the bipyridine core has been studied by Liu, Concepcion, Würthner, and Sun.156, 164-166. Nevertheless, exact implications of introduction of substituents with different electronic and hydrophobic properties are not understood in full detail.

3.2 Functionalization of bda-based ligands

Catalyst functionalization is typically required for the tuning of catalytic properties or adding functions on the catalyst, such as putting it on a solid support, enabling bioconjugation, constructing tandem catalytic systems, or establishing a stimuli-responsive behaviour. First iterations of new types of transition metal catalysts often bear non-functionalized ligands, which simplifies initial synthetic approaches. Further development of the catalysts, especially the one based on substituent screening, requires robust synthetic methods, which can tolerate various functional groups without significantly affecting the yields, as more substituted starting materials tend to be more expensive. This task can prove challenging, as the originally developed synthetic path does not always take into account the possible influence of substituents. An example can be taken from Section 2.2.1, where the introduction of smaller ortho-substituents on the aryl ring of a carbene ligand required an alternative synthetic approach, as the carbene decomposition rate appeared higher than the dissociation rate of phosphine ligand, rendering synthesis impossible.

Substitutions in positions 3 and 3' of the bipyridyl backbone in bda, albeit being readily accessible via oxidation of phenanthroline derivatives, such as neocuproine, are not particularly useful, as they might compromise planarity and flexibility of the ligand.166 Similarly, substitution in positions 5 and 5' might lead to undesirable interactions with carboxylic groups and can only weakly affect the first coordination sphere. In contrast, para-positions in respect to the nitrogen atoms are not sterically demanding and have bigger influence on the ligand coordination properties.

30

3.2.1 Ligand synthesis

Bda-based ligands readily form complexes with Ru due to the presence of 4 coordinating groups and certain flexibility of carboxylic groups, which can rotate out of plane to decrease the denticity. Rather than the attachment of the ligands to Ru, the ligand preparation itself is more likely to be a bottleneck in the overall synthesis of the complex. The bipyridine core is typically either formed by cross-coupling reactions (Scheme 5, pathway A) or present in the starting material (Scheme 5, pathway B). In the cases when the following steps are challenging, the bipyridine scaffold can be assembled from non-heterocyclic starting materials.163, 167 Pathway A allows the formation of asymmetric ligands, which provides a significant variability of the products,165 but in some cases coupling reactions can yield mixtures of homo- and heterocoupled products, which can be challenging to separate. In contrast, pathway B is only practical when the corresponding starting bipyridine is easily accessible. Both approaches share two primary challenges: functionalization in the position 4 and methyl group oxidation. Para-substituted and, in particular, 2,4,6-trisubstituted pyridines are less common, therefore starting materials for 4,4'-disubstituted bda are expensive. Strong electron-withdrawing or electron-donating groups can significantly influence the reactivity of pyridines in cross-coupling reactions; therefore, pathway B appears to be a more promising strategy, especially for large-scale applications.

Scheme 5. Common synthetic approaches to bda-based ligands.

Scheme 6. Proposed approach towards 4,4'-disubstituted 6,6'-dimethyl-2,2'-bipyridines.

31

The synthetic approach was based on the synthesis of 4,4'-dimethoxy-6,6'-dimethyl-2,2'-bipyridine.168 As the para-functionalization of electron-deficient pyridine can generally be achieved via N-oxide activation, the bda precursor (6,6'-dimethyl-2,2'-bipyridine), was first converted into a N,N'-dioxide (Scheme 6). It is worth noting that with the use of a stoichiometric peroxoacid, bipyridines can be transformed into mono-N-oxides, which due to the drastic difference in reactivity between a pyridine and its N-oxide can be used in the formation of asymmetric derivatives. The N-oxide was nitrated to afford pure dinitro product, which was used as a scaffold for further transformations. Deprotection of N-oxide with PBr3 afforded 6,6'-dimethyl-4,4'-dinitro-2,2'-bipyridine, where -NO2 can be converted into various -NRR' and -NR3

+ groups (Scheme 6). Nitrated N-oxides are noticeably reactive towards nucleophiles, which allows introduction of various electron-donating groups in the para-position to nitrogen.168 For example, simple treatment with methanol in the presence of base and subsequent deprotection provided 4,4'-dimethoxy-6,6'-dimethyl-2,2'-bipyridine in 77% yield over two steps. This approach allows installation of both electron-rich and electron-deficient functional groups, using inexpensive chemicals and straightforward purification methods without column chromatography.

The proposed synthetic scheme requires a reliable and mild method for methyl group oxidation, as CrVI oxidations are harsh and can lead to decomposition. This step has been proven challenging for electron-rich bipyridine analogues, often requiring either alternative oxidation methods169 or a complete change of the synthetic approach.163 Numerous attempts to oxidize 4,4'-dimethoxy-6,6'-dimethyl-2,2'-bipyridine with K2Cr2O7, CrO3, or KMnO4 in the temperature range of 0–100 °C led to the decomposition of bipyridine with concomitant formation of a monooxidized product. A two-step selective procedure, inspired by the pda (pda = 1,10-phenanthroline-2,9-dicarboxylate) synthesis,169 was therefore developed for this purpose (Scheme 7). Notably, this protocol was successfully applied to both nitro- and methoxy-substituted ligands, indicating high tolerance to bipyridine rings with varying electron density. Interestingly, the methoxy-substituted substrate could be efficiently oxidized at lower temperatures in dioxane-water mixtures, while the nitro-substituted substrate underwent substitution of the nitro groups with water, therefore requiring low water content and higher temperatures.

Scheme 7. Selective methyl group oxidation on bipyridines.

32

3.2.2 Functionalized catalysts

As previous studies mostly focused on electron-withdrawing substituents on the bda backbone,164-166 and recent reports show that electron-donating substituents in the trans-position to the metal oxo can enhance the catalytic activity, three catalysts were selected for the comparative study (Figure 16): Ru-bda, Ru-dmbda (dmbda = 4,4'-dimethoxy-[2,2'-bipyridine]-6,6'-dicarboxylate), and Ru-dnbda (dnbda = 4,4'-dinitro-[2,2'-bipyridine]-6,6'-dicarboxylate).

Figure 16. Catalysts bearing backbone substituents with different electronic effects.

A common two-step procedure39 was not successful for the Ru-dnbda synthesis, as dnbda was more prone towards forming a Ru(HL)2-type complex even in substoichiometric solutions,169 prompting us to explore a milder approach, starting from dichloro(para-cymene)ruthenium(II) dimer, which resulted in a clean formation of Ru-dnbda. Both two-step procedures applied to dmbda resulted in the formation of complex mixtures; therefore, Ru(dmbda)(DMSO)2 was first isolated. The excess of axial ligand is sometimes used to ensure full exchange of DMSO (or other precursor ligand) with the desired ligand and increase the yield of the final product. Although this strategy was successful for Ru-bda and Ru-dnbda, when Ru(dmbda)(DMSO)2 reacted with 5 equivalents of 4-picoline in methanol, a clean mixture of two products formed. The two products were identified as Ru-dmbda and Ru(dmbda)(pic)3, and both complexes could be separated by column chromatography (Figure 17). The loss of the equatorial picoline ligand for Ru(dmbda)(pic)3 was observed upon heating in vacuum and, to a lesser degree, in methanol solution, which was accelerated by the presence of acid and small amount of water.

33

Figure 17. (a) 1H NMR spectrum of the crude mixture in CD3OD with the addition of ascorbic acid to suppress aerobic oxidation; dmbda signals can be easily distinguished by their lower coupling constant. (b) Proposed structure of

Ru(dmbda)(pic)3. Reduction of symmetry is reflected by the appearance of 4 distinct 1H NMR signals from dmbda. The horizontal plane of symmetry is retained, as

suggested by identical signals from axial picolines.

In contrast to the similar trisubstituted species, reported for pyrazole complexes of bda as kinetic products, Ru-dmbda can react with pyridine in methanol to form a mixture of two compounds, indicating thermodynamic preference for Ru(dmbda)(pic)3. This feature of dmbda points to a strong trans-effect in Ru-bda complexes, which ultimately leads to the decoordination of a stronger σ-donor (carboxylate) in the presence of electron-donating group in the para-position to trans-located nitrogen. Substitution of the pyridines in bda can therefore be considered as an alternative strategy towards formation of a dangling carboxylate, as compared to the excessive coordination in terpyridine dicarboxylates.170

3.2.3 Electrochemical and catalytic properties

The influence of different substituents on the redox properties of the complexes was probed electrochemically. Ru-dmbda exhibits a similar cathodic shift of ca. 100 mV for both RuIII/II and RuIV/III redox couples, compared with Ru-bda (Figure 18). This effect is observed in other substituted Ru-bda analogues; however, the shifts are typically much lower for higher oxidation states,164, 165 indicating that the electron-donating groups might have larger impact on the RuIV state. On the other hand, the effects exerted by the nitro groups in Ru-dnbda appear stronger, as the RuIII/II redox couple shifts anodically by 359 mV. These differences are also reflected in the behaviour of the three complexes in the air. Ru-bda is known for being slowly oxidized in air, and methoxy groups in Ru-dmbda enhance this effect, therefore oxidation occurs instantly. In contrast, Ru-dnbda is stable in the solution in air for several days.

34

Figure 18. (a) Cyclic and (b) differential pulse voltammograms of Ru-dnbda, Ru-bda, and Ru-dmbda in pH 1 HNO3/TFE 4:1 (v/v) at 500 μM, and blank electrolyte

response.

All three catalysts were also evaluated in chemical water oxidation at pH 1. Ru-bda and Ru-dnbda exhibit a second order kinetics in the concentration range of 25–200 μM (Figure 19a–b), suggesting that the introduction of strong electron-withdrawing groups does not diminish the bimolecular coupling process, i.e., the radical properties and geometry of metal oxo are retained. Moreover, the I2M step is approximately 1.5 times faster for Ru-dnbda. In stark contrast, Ru-dmbda follows first-order kinetics, independent on CeIV concentration, indicating WNA as the rate-limiting step. Such difference might arise from the decomposition processes caused by facilitated oxidation; however, the stability of Ru-dmbda in acidic solutions can be confirmed by repeated voltammetric cycling over 0.2–1.7 V (Figure 19c). As the TOF values of Ru-dmbda are close to the corresponding values of Ru-bda and Ru-dnbda in the WNA regime, only the I2M mechanism is affected. DFT-calculated spin density on oxygen is identical for all three catalysts, indicating that the I2M mechanism in Ru-dmbda is compromised due to intermolecular effects, such as π-stacking, exerted by a more electron-rich backbone.

Figure 19. (a) Dependence of initial TOF on catalyst concentration; 0.365 M CeIV, pH 1 HNO3. (b) Logarithmic plots of reaction rate versus concentration, indicating

first-order and second-order kinetics. (c) Consecutive cyclic voltammetry scans (25) of pH 1 HNO3/TFE 4:1 (v/v) solution of Ru-dmbda at 500 μM.

35

3.3 Electronic vs. supramolecular effects of the catalyst backbone

As was shown in the previous section and previously discussed in the literature,165, 166 the overall efficiency of the catalysts operating via a bimolecular mechanism is an interplay between electronic, hydrophobic, and steric influence of the substituents. To separate these effects, we have designed pyrazine-based backbone ligands, where an electronegative nitrogen atom was incorporated in the bda rings, effectively acting as an electron-deficient group without affecting the steric properties of the ligand. The pyrazine nitrogen can also be used to extend the functionality of the backbone ligands by forming supramolecular coordination compounds with other metals.

3.3.1 Ligand design and synthesis

The strategy of tuning the electronic properties of a ligand by modification with substituents has its own advantages and drawbacks. On one hand, established synthetic procedures can be easily applied to the substituted analogues, especially if the ligand synthesis can be performed in mild conditions, or substituents are indifferent towards the ligand assembly reactions. On the other hand, introduction of the substituents might have other implications, such as steric hindrance or changes in the solvation processes. The structural similarity of pyridine and other azines allows to effectively introduce an electron-withdrawing group while keeping the structure intact. To maximize the electronic effects on the nitrogen atoms coordinating to Ru, pyrazine was selected as the core structure in the backbone ligand (Figure 20a). According to the DFT calculations of the key [RuV=O]+ species, the geometry of the reactive intermediate is not expected to change, suggesting that potential differences in reactivity would reflect the true influence of the electronic effects (Figure 20b).

Figure 20. (a) Design of pyrazine-based ligands ppa and bpa; (b) overlaid geometries of catalytic intermediate [RuV=O]+ with bda and bpa.

36

Unlike bda precursors (dimethylbipyridines), substituted arylpyrazines are less common and therefore usually not available from commercial suppliers. The most convenient strategy in this case is the aryl-aryl coupling. Symmetric bpa ([2,2'-bipyrazine]-6,6'-dicarboxylate) ligand was synthesized via a Negishi coupling with in situ formation of the organozinc compound (Scheme 8). Similarly, an asymmetric ppa (6-(6-carboxylatopyridin-2-yl)pyrazine-2-carboxylate) was formed via a Stille coupling. The high tolerance of non-functionalized electron-deficient pyridine and pyrazine rings was employed in a SeO2/pyridine benzylic oxidation, while standard approaches, such as CrO3/H2SO4 oxidation, proved unsuccessful. Like dnbda (Section 3.2.2), ppa and bpa exhibited a different behaviour in the conventional synthesis, starting from Ru(DMSO)4Cl2. Both ligands were therefore attached to Ru in milder conditions, using [Ru(p-cymene)Cl2]2 as a precursor and excess of 4-picoline as a base, affording Ru-ppa and Ru-bpa (Scheme 8).

Scheme 8. Synthesis of pyrazine-based ligands and corresponding Ru complexes.

3.3.2 Electrochemical properties

Basic electrochemical properties of the new complexes were probed with cyclic and differential pulse voltammetry and compared with Ru-bda. Each of the complexes shows a typical electrochemical response in 0–1.7 V vs. NHE potential range (Figure 21). The first oxidation wave, attributed to the RuIII/II redox couple, is significantly shifted towards higher potentials for Ru-ppa and Ru-bpa, in accordance with the number of additional nitrogen atoms in the bda

37

backbone (214 mV shift for Ru-ppa and 404 mV shift for Ru-bpa). This phenomenon clearly indicates the importance of the electronics of the backbone ligand on the RuIII/II oxidation. This process has only minor influence on the catalytic performance, as the catalytic cycle of bda-based catalysts primarily involves the RuIII state. On the other hand, many water oxidation catalysts operate via mechanisms involving RuII species,171 therefore strong electronic effects on the RuIII/II oxidation can be leveraged in other pyridine-based catalysts. In addition, high oxidation potential implies higher resistance to the aerobic autoxidation of RuII precatalysts and therefore might offer a longer shelf life.172

Figure 21. (a) Cyclic and (b) differential pulse voltammograms of Ru-bda, Ru-ppa, and Ru-bpa in pH 1 HNO3/TFE 4:1 (v/v) at 500 μM, and blank electrolyte response.

Further oxidations, RuIV/III and RuV/IV, are less affected by incorporation of the extra nitrogen atoms in the ligand, conveniently keeping the overpotential for water oxidation low (Figure 21). This phenomenon has been observed in Ru-bda analogues with various substituents both on the axial154, 173 and the equatorial164, 165 ligands, as well as Ru-dnbda (Section 3.2.3). The higher oxidation potentials are typically governed by the energetics of proton-coupled electron transfers, which are primarily determined by the internal base, such as the bda carboxylate.174

Figure 22. Pourbaix diagrams of (a) Ru-bda, (b) Ru-ppa, (c) Ru-bpa in Britton-Robinson buffer with 20 vol% TFE. Estimated positions of RuIV/III oxidation peaks are

depicted with thick dashed lines.

38

To assess the electronic effects of the backbone and establish dominant species at different pH values, the corresponding Pourbaix diagrams of Ru-bda, Ru-ppa, and Ru-bpa were constructed (Figure 22). Despite the obvious presence of the RuIV/III redox couples, these potentials could not be unambiguously extracted from differential pulse voltammograms of the new catalysts due to overlaps with other oxidation waves, both RuIII/II and RuV/IV oxidations were identified for all catalysts. It is worth to note that the introduction of nitrogen in the bda backbone significantly affected the acidity of ruthenium-aquo complex [RuIII-OH2]+. The pKa value of metal aquo complex gradually decreased from ca. 6 in Ru-bda to ca. 4 in Ru-ppa and ca. 3 in Ru-bpa. This feature can be utilized in the catalysts with weaker internal bases, where protons of bound aquo ligands need to be more acidic for the internal proton transfer to occur efficiently. Finally, the observed increase of the RuIII/II oxidation potential with the RuV/IV oxidation being almost unaffected results in unique features, such as very small potential window covering all oxidation states, reaching 250 mV for Ru-bpa.

3.3.3 Water oxidation activity

As only minor influence of the electronics of backbone ligand on the active RuV species was established, the modified complexes were evaluated in chemical water oxidation. At concentrations lower than 200 μM, reproducibility of the results was compromised by the competing decomposition of Ru-ppa and Ru-bpa, so the concentration range of 200–600 μM was explored. All three catalysts were found to follow an I2M mechanism with the bimolecular step being rate-limiting at concentrations lower than 400 μM and close values of TOF, indicating that the catalytic properties were not significantly affected by the incorporation of pyrazines in the backbone ligand (Figure 23a). In the interval of 200–400 μM, asymmetric Ru-ppa catalyst exhibited the highest catalytic activity – a phenomenon, previously observed in trifluoromethyl-substituted bda catalysts and attributed to the changes in polarity.165 Such an effect can arise from the de-symmetrisation of the dipole moment of RuV species and more favourable interactions in the bimolecular coupling step. Other properties of the key metal oxo species are almost identical for all three catalysts (Figure 23b). On the other hand, Ru-ppa switches to a first-order oxidation-limited regime already at 400 μM, while for Ru-bpa the bimolecular step remains rate-limiting up to 500 μM, affording higher maximum TOF values. This indicates that the rate of the oxidation steps is not affected significantly upon introduction of the second pyrazine, while acceleration of the bimolecular step by the asymmetric catalyst is more pronounced. Overall, the catalytic activities of Ru-ppa and Ru-bpa are close to that of Ru-bda, suggesting that the observed differences in other substituted catalysts with electron-

39

withdrawing groups might result from other effects, such as excessive hydrophobicity.164, 165

Figure 23. (a) Dependence of initial TOF on catalyst concentration; 0.365 M CeIV, pH 1 HNO3/TFE 19:1 (v/v). (b) Properties of catalytic intermediate [RuV=O]+,

calculated with DFT.

3.4 Conclusions

This chapter has discussed several ways of backbone ligand functionalization in the Ru-bda family of water oxidation catalysts. Efficient synthetic approaches have been proposed, allowing both manipulation of the electronic properties of bda ligand and creating a functionality on the backbone ligand for the conjugation with other molecules or surfaces. The influence of electronic effects on the properties and activity of functionalized catalysts has been evaluated. More electron-deficient backbone ligands were found to not affect the catalytic activity significantly, indicating that the steric and hydrophobic effects of the backbone substituents might play an important role in water oxidation catalysis.

40

4. Efficient O-O Bond Formation via

Enhanced Catalytic Stability and Activity

(Papers V–VI)

The third scientific chapter discusses the latest developments in molecular water oxidation catalysis, aimed at improving stability and activity. Significant progress in this field in recent years resulted in the discovery of particularly active and stable Ru-based catalysts. The ultimate goal of water oxidation catalysis development is to gradually transfer to inexpensive and abundant transition metals, using the knowledge acquired for ruthenium catalysts. Ru-bda water oxidation catalysts constitute a convenient platform that allows to study the structure-activity relationships in detail and to elucidate which parameters of the ligand design are important for the activity and long-term stability. This chapter introduces various changes to the ligands, which result in more efficient catalysts and understanding of the mechanisms behind the improvements.

4.1 Improving catalyst stability via backbone π-extension

With pyridine being a common structural block in many transition metal complexes, extension to larger aromatic systems is a common approach in increasing electron delocalization and intermolecular stacking. In Ru-bda water oxidation catalysts, the positive influence of both of these properties has been leveraged in isoquinoline-based complexes. In fact, π-extension of the axial ligand became a breakthrough modification, as it dramatically improved both stability (higher TON) and activity (higher TOF).39, 136

4.1.1 Implications of π-system modifications

Several attempts to apply the π-extension strategy to the Ru-bda catalyst backbone have been made.162, 163 While π-π stacking of the backbone ligands is not particularly useful in the catalysis, it can be utilized in the non-covalent functionalization on flat conductive surfaces, such as carbon electrode materials. On the other hand, a larger conjugated system implies larger charge buffering capabilities and therefore potentially higher stability at high oxidation states.

The first design of a slightly extended π-system included replacing bipyridine with phenanthroline to afford the pda ligand.162 Although the increased structural rigidity was expected to improve stability by eliminating the possibility of single picolinate decoordination, it instead revealed that certain

41

flexibility of the backbone is required to attain seven-coordinated configuration in the higher oxidation states. A more direct approach was taken by Scherrer et al., where the pyridine rings were replaced with isoquinoline blocks in biqa (biqa = [1,1'-biisoquinoline]-3,3'-dicarboxylate) ligand.163 A binaphthyl-like design of the backbone ligand, however, resulted in a similar structural rigidity to the pda-based catalyst. Moreover, the non-planarity of biqa ligand obscured all potentially beneficial electronic effects and resulted in diminished stability and activity. It is worth noting that the mentioned modifications altered the geometry of the backbone ligand severely and therefore prevented the catalysts from reacting via I2M mechanism, characteristic for Ru-bda catalysts.166

4.1.2 Ligand design and synthesis

To preserve both the flexibility and planarity of bda ligand, an alternative isoquinoline-based ligand iso-biqa (iso-biqa = [1,1'-biisoquinoline]-3,3'-dicarboxylate) was designed (Figure 24a). According to the DFT calculations, the geometry of the ruthenium complex Ru(iso-biqa)(pic)2 (Ru-iso-biqa) is similar to Ru(bda)(pic)2 (Ru-bda), with a planar arrangement (∠N-C-C-N = 0.5°) in the RuII state and a slight twist in the RuV state (∠N-C-C-N = 10.8°), indicating flexible response to the seven-coordination (Figure 24b).

Figure 24. (a) Design of iso-biqa ligand and comparison with biqa. (b) Geometries of RuII and [RuV=O]+ species of Ru-iso-biqa predicted by DFT calculations.

A common approach to the bda backbone – synthesis of the dimethyl derivative, followed by methyl group oxidation – was adopted to the iso-biqa synthesis (Scheme 9). Commercially available 1,3-dichloroisoquinoline was methylated

42

with high regioselectivity,175 and the product was subjected to a Negishi coupling with in situ formation of the organozinc reagent. A similar strategy was reported by Scherrer et al. for biqa ligand; however, the conventional procedures for methyl group oxidation failed, prompting the authors to form carboxylates at the early stages of synthesis and assemble the isoquinoline ring in 3 steps.163 Direct CrO3 and KMnO4 oxidations also proved unsuccessful in the case of 3,3'-dimethyl-1,1'-biisoquinoline, therefore a milder or more selective oxidation protocol was required. An aldehyde route, developed for the oxidation-sensitive bipyridine substrates (Section 3.2.1), was successfully applied to biisoquinolines. Notably, allylic SeO2 oxidation proceeded much faster in this case, allowing use of conventional heating. Overall, the proposed synthetic approach is economically viable, provided recyclability of formed Ag, and can be potentially applied to other substituted isoquinolines. A conventional two-step approach from Ru(DMSO)4Cl2 provided Ru-iso-biqa in a good yield, completing the synthesis.

Scheme 9. (a) Reported unsuccessful approach to H2biqa by Scherrer et al.163 (b) Synthesis of H2iso-biqa.

4.1.3 Catalytic performance

The large aromatic backbone of Ru-iso-biqa significantly reduced its aqueous solubility, similarly to biqa derivatives, making it possible to perform homogeneous water oxidation only in mixtures with high TFE content (33% was selected as it has proven to be suitable for Ru-biqa complexes).163 To account for the potential influence of the large amount of co-solvent, the performance of Ru-bda was also evaluated in 33% TFE mixtures. Second-order dependence of the initial oxygen evolution rate on the catalyst concentration in the range of 50–500 μM revealed that Ru-bda follows the I2M mechanism with only marginally lower TOFs compared to the ones reported for lower co-solvent contents (Figure 25a).39, 145 The stability of the catalyst was seemingly not affected, as maximum TON of 1300 was reached at 70 μM.

43

Figure 25. Dependence of initial TOF on catalyst concentration: (a) Ru-bda, (b) Ru-iso-biqa; 0.365 M CeIV, pH 1 HNO3/TFE 2:1 (v/v).

Since the significant influence of higher TFE content on the catalyst activity and stability was ruled out, Ru-iso-biqa was evaluated in CeIV-driven water oxidation within a wide range of concentrations. The dependence of reaction rate on Ru-iso-biqa concentration revealed the presence of two kinetic regimes: first-order (5–20 and 200–400 μM) and second-order (25–200 μM) – previously reported for other water oxidation catalysts (Figure 25b).144, 165 At low concentrations, a standard WNA mechanism is prevalent, while at high concentrations bimolecular O-O bond formation becomes too fast, therefore one of the oxidation steps becomes rate-limited. Compared with Ru-bda, Ru-iso-biqa exhibits lower range of concentrations where the I2M mechanism dominates. This property is a result of an interplay of various effects, such as slower oxidation steps and lower bimolecular coupling rates. In order to understand the origin of these effects, the catalytic behaviour was studied in more detail.

Figure 26. (a) Cyclic and (b) differential pulse voltammograms of Ru-iso-biqa in pH 1 HNO3/TFE 2:1 (v/v) at 300 μM, and blank electrolyte response.

44

Figure 27. Pourbaix diagram of Ru-iso-biqa in Britton-Robinson buffer with 50 vol% TFE.

The behaviour of Ru-iso-biqa upon oxidation was studied in electrochemical experiments. The cyclic voltammogram shows two reversible redox waves, typically attributed to the RuIII/II and RuIV/III electron transfers, not leading to a catalytic turnover (Figure 26). A small RuV/IV oxidation wave is followed by a sharp current increase, indicating water oxidation catalysis with low overpotential, characteristic for Ru-bda derivatives. To elucidate the nature of species in various oxidation states along the catalytic cycle, a Pourbaix diagram of Ru-iso-biqa was constructed from individual differential pulse voltammograms at different pH values (Figure 27). The overall shape of the diagram is consistent with other water oxidation catalysts active at low pH, where the metal aquo complex is transformed into a high-valent metal oxo via two proton-coupled electron transfers. The similarities with the diagram of Ru-bda (Figure 22a) suggest that the observed difference in the oxidation-limited regime can be associated with the higher reorganisation energy in Ru-iso-biqa. The latter might be a consequence of the presence of the larger conjugated structure, all parts of which are directly influenced by the changes in the metal oxidation state.

4.1.4 Catalyst stability

The slower bimolecular coupling step can originate from the low stability of metal oxo species in the RuV state, which is one of the main reasons why rigid and non-planar backbone ligands form only WNA-active catalysts.162, 163, 166 This possibility was assessed by lowering the concentration of Ru-iso-biqa until the catalyst was not being able to consume all CeIV. The resulting maximum TON reached 3700 (at 25 μM), which is 3 times higher than the maximum TON of Ru-bda (1300), indicating significantly higher stability of the Ru-iso-biqa

45

intermediates. The radical coupling in this case should not be compromised by monomolecular decomposition processes, implying that the interaction between radicals itself is affected by the backbone ligand. Careful analysis of metal oxo species suggests a high level of similarity in the geometric and electronic structure of the reactive centre between bda and iso-biqa catalysts (Figure 28). In particular, high spin density (0.70) on the oxygen atom should lead to a barrierless coupling upon collision.142 The formation of a prereactive dimer is known to be affected by axial ligands,143 which are identical in Ru-bda and Ru-iso-biqa. Therefore, a sluggish collision rate, caused by the hydrophobicity of the iso-biqa backbone and potential formation of non-productive back-to-back dimers, enhanced by π-π interactions, is one possible reason for the lower coupling rate of Ru-iso-biqa.

Figure 28. DFT-predicted structures and spin density isosurfaces of [RuV=O]+ intermediates of Ru-bda (left) and Ru-iso-biqa (right).

Higher stability of Ru-iso-biqa can in general be attributed to the delocalisation of electron density over a larger π-system, as was envisioned by the design of iso-biqa. Exact decomposition pathways of water oxidation catalysts in acidic media are not known in full detail, however, one of the theories consists of acid-assisted displacement of an axial ligand with water as the primary reason for decomposition.136 Although this approach has been successfully applied in the rational design of more stable catalysts by adjusting the HOMO levels of the axial ligands, it does not provide similar strategies for the equatorial ligands. The effect of the backbone ligand was therefore assessed by comparing the Gibbs free energies of the ligand exchange reaction with water in Ru-bda and Ru-iso-biqa. The difference of only 0.7 kcal/mol was found, with Ru-iso-biqa being less prone towards the loss of picoline ligand. Nevertheless, such small difference corresponds to ca. 3-fold difference in the reaction rate, which can be linked to a 3-fold difference in the reactive species lifetimes and, consequently, the maximum TONs. Designing a 4-iodopyridine (Ipy) ligated complex Ru(iso-biqa)(Ipy)2, inspired by the most stable pyridine-derived bda complex, afforded

46

a catalyst with maximum TON of 19900, which completes full conversion of CeIV at concentrations lower than 5 μM.

Isoquinoline-based catalysts are predicted to have a positive Gibbs free energy of the ligand exchange with water, suggesting that other decomposition pathways operate in these cases.136 Another known catalyst degradation process – formation of a trimer – is unlikely to occur at low pH and at low concentrations in which maximum TONs are measured.172 For the biqa ligand, the instability caused by the rigidity and non-planarity of the complex backbone suppressed the differences in the axial ligands, affording similar TOF and TON values for 4-picoline and 6-bromoisoquinoline (Brisq) catalysts.163 It was therefore investigated if the observed stability gains in iso-biqa catalysts would apply in isoquinoline complexes. Similar to picoline complexes, Ru(iso-biqa)(Brisq)2 demonstrated higher stability (TONmax = 12200) than its bda analogue (TONmax = 7400) and biqa analogue (TONmax = 80). Notably, Ru(iso-biqa)(Brisq)2 was found to outperform Ru(bda)(Brisq)2 in water oxidation in I2M regime (194 s–1 vs. 73 s–1), suggesting that the larger axial ligand prevents non-productive interactions of the hydrophobic parts of the catalyst.

4.2 Enhancement of radical coupling

Bimolecular catalysis is a rare and unique phenomenon that has been leveraged in the catalytic O-O bond formation. A second-order dependence of reaction rate on the catalyst concentration allows to reach very high catalytic reaction rates, up to the point where other steps become rate-limiting and not dependent only on the catalyst.165 One of the most important parameters of a catalyst, turnover frequency, grows linearly with the catalyst concentration in the case of bimolecular catalysts. While in practice homogeneous water oxidation catalysis does not allow to reach oxidant concentrations high enough to exploit this feature to the full extent, theoretically such catalysts would provide an effective and cost-efficient solution to water oxidation in the presence of a sustained oxidation pressure. Although high catalyst concentrations required for reaching the maximum TOF values might seem impractical, supramolecular approaches can utilize the benefits of bimolecular catalysis by creating environments with high local concentration of the catalysts.140, 176 A deeper understanding of how the bimolecular catalysis can be designed to outperform monomolecular mechanisms is therefore an important research direction, which can pave the way for applications of this phenomenon in other catalytic processes.

4.2.1 Ligand design

The defining role of axial ligands in the bimolecular coupling of water oxidation catalysts was proposed in 2012 by Duan et al., when isoquinoline ligands were

47

found to dramatically improve the efficiency of the catalysts.39 A computational study by Fan et al. found no significant correlation between low activation energy of the coupling step and catalytic activity, suggesting that O-O bond formation should be barrierless and independent on the interaction between axial ligands in the transition state.142 Inclusion of the explicit solvation in computational models revealed the concomitant π-π stacking upon formation of the O-O bond,177 which was later ruled out as a factor stabilising the transition state and was considered as a significant contributor to the binding energy, leading to the higher diffusion rate and faster formation of the prereactive dimer.143

Figure 29. (a) Geometry of the O-O bond formation product with an offset along the z-axis. (b) Asymmetric stacking between axial ligands and an offset along the x-axis.

(c) Design of meta-substituted complexes.

Certain correlation with the π-π interaction energies was at the same time elucidated in a thorough experimental and computational screening by Xie et al.145 Surprisingly, no stacking was observed for pyridine complexes, which are believed to benefit only from van der Waals interactions of substituents, when functionalized with halogens. To understand the reasons behind efficient coupling of unsubstituted pyridine and picoline complexes, meta-substituted complexes were designed. The geometry of the prereactive dimer is known to have a certain offset in the axial direction due to the interaction of spins, primarily localized on the p-orbitals of the oxygen atoms (Figure 29a). This leads to an arrangement of axial ligands of two molecules, in which ligands are not facing each other directly, but rather displaced along the

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z-axis. Such placement is optimal for the two-ring ligands, where the electron-deficient ring of one ligand is located over the electron-rich ring of another ligand (Figure 29b).145 The π-π stacking in isoquinoline-based complexes is not symmetric due to the low symmetry of the isoquinoline ligand itself, which leads to an offset along the x-axis. The design of meta-substituted complexes was therefore based on the suggestion that these two offsets can be exploited in the efficient interaction between axial ligands, if the substituent on pyridine is placed in meta-position (Figure 29c).

4.2.2 Catalytic performance

The change in the substituent position from para to meta has a small impact on the electronic properties of the axial ligand, particularly insignificant in the case of weakly electron-donating methyl group. The electrochemical response of mMe (Ru(bda)L2, L = meta-picoline), compared with pMe (Ru(bda)L2, L = para-picoline = pic), shows a minor decrease in the axial ligand donating properties, as RuIII/II redox couple only shifts by several millivolts (Figure 30a). In contrast to the electrochemical results, mMe is significantly more efficient in water oxidation, compared with pMe, at 100 μM, where a bimolecular mechanism prevails, indicating faster radical coupling (Figure 30b).

Figure 30. (a) Cyclic voltammograms of pMe and mMe in pH 1 HNO3/TFE 4:1 (v/v) solution, 500 μM. (b) Oxygen evolution, catalysed by pMe and mMe; 0.365 CeIV solution in pH 1 HNO3/TFE 19:1 (v/v), 100 μM catalyst. Reaction progress was

monitored by sensing the pressure in a sealed reaction vessel.

To rationalize the acceleration of radical coupling, a DFT analysis of the coupling products was performed. While the peroxo-dimers themselves do not reflect the process of radical coupling, the arrangement of the axial ligands in the coupling product is similar to the one in the transition state and prereactive dimer.145 Moreover, peroxo-dimers are more reliable for the comparison between mMe and pMe, as transition state geometry might be influenced by the

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axial ligands to a higher extent, resulting in the different O-O bond lengths and less comparable geometric parameters.

Figure 31. (a) Schematic representation of various configurations of peroxo-dimers. (b) Alignment of two catalytic units in the equatorial plane, extracted from DFT-

optimized geometries. (c) Alignment of axial ligands in the corresponding configurations of peroxo-dimer. aTotal peroxo-dimer energy, relative to mMe-A.

bComplexation energy between a pair of isolated axial ligands (average of 2 pairs).

Unlike para-substituted pyridines, rings with meta-substituents are not symmetric, therefore 4 possibilities for the configuration of a π-complex between two rings exist. All 4 configurations (denoted A, B, C, D) of the mMe peroxo-dimer have been analysed along with a single configuration of pMe (Figure 31a). Three configurations – pMe, mMe-C, and mMe-D – have very similar geometries, with the Ru-bda units oriented at over 40° in respect to each other (Figure 31b). This arrangement brings two axial ligands closer to each other; however, the π-π stacking is not apparent, as pyridine rings are not parallel to each other (Figure 31c). Due to the symmetry of the singly occupied molecular orbital, which has a significant pz-character, the interaction between two radicals is not significantly affected by the rotation around the z-axis, suggesting that the interaction between the axial ligands can be a major contributor to the driving force of such rotation. Interestingly, mMe-A and mMe-B have a small Ru-O-O-Ru dihedral angle, while the axial ligands align parallel to each other in a π-π stacking fashion (Figure 31b–c). Accordingly, mMe-A and mMe-B are ca. 4 kcal/mol lower in energy, compared with mMe-C

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and mMe-D, and therefore must be dominant encounters in the radical coupling (Figure 31a). To confirm that the energy difference originates primarily from the positive interaction between the axial ligands, the complexation energy of picolines in the computed geometries was extracted. Although this interaction was found to be favourable in all cases, mMe-A and mMe-B show an additional 1–1.5 kcal/mol per pair gain in ligand interaction, seemingly due to the beneficial alignment of π-systems (Figure 31c). In both of these configurations, a substituent C-C bond is located over the centre of another pyridine ring, while the distances between ring centroids are only marginally different. This result highlights the importance of considering π-π stacking in the context of interaction of a π-system with a substituent on another ring, rather than some specific interaction between π-electron clouds (see Section 1.2.3). A slightly more “closed” form in mMe-B can also lead to a more favourable hydrophobic interaction due to the smaller solvent-accessible surface area (370 Å2 in mMe-B, 385 Å2 in pMe, measured for a pair of isolated ligands, average of two pairs).

4.2.3 Substituent effects

Since the origins of improved activity were rationalized by structural considerations, a screening of various substituents was additionally performed to further elucidate the structure-activity relationship. Catalysts with different substituents in meta-position of the pyridine ring were evaluated in CeIV-driven water oxidation by measuring the initial turnover frequency TOFinit. Certain substituents, such as -OH, -NH2, and -NMe2, diminished water oxidation reactivity, which can be explained by their redox non-innocence, reflected in additional peaks in the voltammograms. Overall, the performance trends were in agreement with those observed for para-substituted catalysts, with halogen substituents being the most effective (Figure 32).145, 154, 155 In all cases where the substituents have also been evaluated in para-analogues, the activity of corresponding meta-substituted catalysts was superior. In the case of 3-chloropyridine and 3-bromopyridine, more than 3-fold improvement in the TOFinit was observed, compared with the corresponding 4-substituted analogues. This allows the use of complexes with more soluble and cheaper 3-halopyridines (mCl: 207 s–1, mBr: 331 s–1) to reach the efficiency of the most active 4-iodopyridine-based catalyst (pI: 334 s–1). These results are not only of high importance for water oxidation catalysts, but also for any type of catalysis involving non-covalent π-interactions.

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Figure 32. Structure and activity of various meta-substituted catalysts. Conditions:

0.365 M CeIV, 100 μM catalyst, pH 1 HNO3/TFE 19:1 (v/v). aRapid catalyst decomposition was observed, and full conversion of CeIV was not reached.

As only half of the dimer configurations seem to contribute to the improved performance, a better arrangement of substituents would present the favourable substituent-π interactions in all of configurations. This can be achieved by increasing the symmetry – in this case via introduction of the same substituent in another meta-position (mBr-mBr, Figure 33a). Surprisingly, even lower TOFinit was observed for mBr-mBr (226 s–1) compared with mBr (331 s–1), which can be explained by the loss of asymmetry, leading to the less favourable interaction of symmetric quadrupoles. As noted in Section 3.3.3, the interaction of asymmetric catalytic intermediates can be stronger, suggesting that asymmetric bromopyridines might follow this trend. By moving the second bromine atom to a para-position, the C2v symmetry can be reduced back to C1h, and Br-π interactions in mBr can be complemented by the beneficial van der Waals interactions between the para-bromine substituents, already present in pBr. Indeed, mBr-pBr catalyst (Figure 33b) outperforms mBr-mBr, mBr, and pBr (TOFinit = 449 s–1). The difference in reactivity is also reflected in the concentration at which the oxidation steps become rate-limiting instead of the O-O bond formation step: 25 μM for mBr-mBr and 15 μM for mBr-pBr. Finally, the I2M mechanism, provided by fast radical coupling, prevails over the WNA mechanism for concentrations as low as 1 μM for mBr-pBr, affording a high TOFinit of 31 s–1 at such low concentration.

Figure 33. Structure and interactions between axial ligands in (a) mBr-mBr and

(b) mBr-pBr.

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4.3 Conclusions

This chapter has summarised the approaches towards more active and stable water oxidation catalysts via rational ligand design. Gentle modifications of the backbone ligand retain the unique features of a bipyridyl ligand with carboxylic groups, while adding extra functionality and amplifying the catalyst stability. A deeper understanding of the intermolecular interactions in the radical coupling resulted in the redesign of axial ligands, leading to the dramatic enhancement of the catalytic activity. The knowledge acquired in these studies can be utilized in the development of other catalysts and, potentially, the applications of bimolecular catalysis in other reactions.

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5. Concluding remarks

This thesis presents the work on two reactions, which result in the formation of symmetric double bonds – olefin metathesis and formation of dioxygen from water. These reactions require catalysis to proceed with reasonable rates, and active development in the last several decades has provided advanced catalysts, eventually allowing to use mentioned reactions in the daily academic research and industry. The economic impact of olefin metathesis is tremendous, as it enabled cheap production of high-value polymers and late-stage modification of complex molecules, such as drugs and supramolecular assemblies. Molecular water oxidation is yet to unleash its full economic potential in the coming decade of renewable energy, as the efficient cooperation of homogeneous and heterogeneous catalysis takes shape. The symmetry of these double bond forming reactions provided the field of catalysts with new mechanisms, significantly expanding the list of “design tips” for future molecular catalysts. The primary goal of this thesis has therefore been to investigate the implications of the fine structure of catalysts on their properties and reactivity, and to answer how certain catalytic processes can be enforced by utilizing weak interactions.

The first chapter introduced important concepts of catalysis and, in particular, the origins and benefits of organometallic catalysis. A small overview of weak interactions on the molecular level that can result in significant effects, such as drastic acceleration of reaction rates, has been given. Some approaches towards utilizing the symmetry of reactions in the design of catalysts have been presented.

The second chapter investigates the potential of olefin metathesis in challenging applications, such as creating dynamic libraries of biologically relevant substrates in protic media. Alkene metathesis has found many applications in dynamic chemistry; however, the limitations in catalyst stability prevent it from being used efficiently. The use of CAAC-based catalysts has been proposed for the creation of dynamic mixtures of alkenes. Several catalysts have been evaluated in this process, resulting in the catalyst capable of establishing equilibrium in simple dynamic systems at room temperature. A water-soluble ruthenium alkylidene catalyst was evaluated in the metathesis of substrates presenting numerous functional groups. The ability of functionalized substrates to create chelates with the catalyst was utilized to induce the selective formation of cross-metathesis products, which is a particularly important pathway in the dynamic alkene scrambling process.

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The third chapter addresses modifications of the backbone ligand of Ru-bda water oxidation catalysts, associated with the changes in electronic properties of the complex. A simple and cost-efficient approach to the synthesis of bda derivatives was proposed and used to prepare a series of complexes with varying electronic effects. An electron-rich complex was found to impair bimolecular coupling without significant effect on the properties of metal oxo, suggesting the influence on supramolecular interactions. The possible impact of the hydrophobic, supramolecular, and other specific effects of the backbone substituents was mitigated by designing pyrazine-based analogues of bda and corresponding ruthenium complexes. While the introduction of electron-withdrawing units in the backbone positively affected the shelf stability of the catalysts, no evidence for the impact on catalytic performance was found. These findings provide new strategies for the enforcement or prevention of the intermolecular interactions of backbone ligands and utilising them as the base for modifications, including immobilization on materials.

In the fourth chapter, further improvements of the Ru-bda water oxidation catalysts are discussed. A novel backbone ligand iso-biqa, designed to stabilize the catalytic species and provide a non-covalent functionalization framework, was used to prepare new water oxidation catalysts. The formed complexes exhibited higher stability than their bda-based analogues and certain indications of the hydrophobicity of the backbone, offering a potential of being used in electrolytic devices. The bimolecular radical coupling, which is yet to be leveraged in electrochemical water oxidation, was investigated in detail by varying a substitution pattern of the axial ligands, partially responsible for the intermolecular interactions. Proposed factors for the efficient ligand interaction were successfully applied in the design of new ligands, which provided the catalysts with significantly improved activity. Replacement of one hydrogen atom with bromide atom resulted in nearly 15-fold enhancement in activity, with 3-fold difference between different position of substitution, demonstrating the importance of weak non-covalent interactions in catalysis.

In summary, works included in this thesis have demonstrated how weak intra- and intermolecular interactions can influence catalysis and presented approaches of how the detailed information about these interactions can be employed in the catalyst design or reaction selectivity. Although concrete effects and trends discovered for the catalysts in this thesis cannot always be transferred onto other catalytic reactions, they can be used and developed further in future catalysts.

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Acknowledgements Although acknowledgements in a PhD thesis are supposed to detail who contributed to the thesis and in which way, de facto they serve as “the only fun part” of the thesis, so they had better be entertaining and sincere. I list the acknowledgements in an arbitrary order, but, if you like riddles, try to figure out why the order is such.

My biggest gratitude goes to Licheng, because without him this thesis would not have happened at all. I could say that I was lucky, but it was the actual person who accepted me as a student when I needed it most. Licheng has not only become my supervisor, but also provided all the means and support that were necessary to continue and do a top-level research, and for that I cannot thank enough. All the things: from learning about the new field to the ability to write this thesis and settle in Sweden – could not happen without Licheng, and I was really blessed to become a part of his group. The entire group was particularly friendly and helpful, so all the practical knowledge I have about electrochemistry, material science, and solar fuels is their merit, for which I am extremely grateful. In particular, I thank Brian, Biaobiao, Qijun, and Xia for their help and wise advices.

I thank my parents and family for forcing me to study in the early years, when I did not want to, and providing support and tools to do so. Additionally, I would like to thank for their support during the times I decided to switch from subjects that I am really good at to chemistry. Whether this was the right decision or not, it was my own decision, and I value this.

“Cooking is at once child's play and adult joy. And cooking done with care is an act of love.” Craig Claiborne.

I would like to (and I did and will ever keep doing so) thank my wife Anastasia and her mom for supporting me throughout the last years, which includes but not limited to: helping me to move to Sweden and look for a position, accepting me working late and during the weekends, taking a large share of housekeeping duties despite being at least as busy PhD student as I was, and in general ensuring that I live a happy pet life. Thanks to her, I was blessed to believe that tasty food comes from the fridge, already prepared, and there is nothing more to it. Now that I know it is not true, her efforts look miraculous.

I am incredibly thankful to Olof, my supervisor, who offered me a temporary position, where I upgraded my lab skills, and a PhD position, which was not just a possibility to perform research, but also a good salary and a contract for 4 years. The moment I called Olof to ask for a position and heard him laughing hard about it, I knew it would be an unforgettable experience, and it indeed was.

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I thank Olof not only for giving me a PhD position, but also for being kind and very friendly. I cannot imagine a less stressful working environment, and although it seems I am more productive under stress, it was a truly happy time.

“If any of you need anything at all... too bad, deal with your problems yourselves like adults.” Ron Swanson

Although she might never read it, I thank Lena for all the administrational help with my employment, Migrationsverket, and numerous other things. Accordingly, I am grateful to Migrationsverket for providing me with necessary documents in time, so that my work has never been interrupted. My work would have been much harder without the help from Ulla with the falling apart infrastructure, for which I thank her. Also, I would like to express my gratitude to Inger for managing my doctoral program, helping with the defense preparation, and making sure my studies go as they should.

Most of these contributions made sure I had enough opportunities to perform well, but the rest of the work was up to me. Therefore the biggest “real achievement” award of this acknowledgements list and an enormous gratitude goes to Brian, who has not only been my mentor during the first years, but also became my biggest collaborator and a significant contributor to this thesis! If not for Brian, I would have definitely had a harder time working on ruthenium catalysts, and I was really lucky to have him working with me. Among all other things that resulted in papers and manuscripts, especially papers II, IV, and VI, I thank Brian for proof-reading (a large part of) my thesis. If you notice some nonsense in my thesis, it is surely the part that he did not read, so have a fun time figuring out which sections he corrected!

Speaking of people who really know what they are talking about, I thank Fredrik for sharing his knowledge and being a voice of reason in the scientific discussions. I am also thankful to other members of our group for taking critical views on my work. Based on your feedback, I gradually learned how to present dull results in a good way, and this thesis is the best illustration for this skill!

“Nobody should have to go to work thinking, oh this is the place that I might die today. That's what a hospital is for.” Michael Scott

I thank Peter for bearing so little resemblance to the bosses and division heads in the East. Among other things that indirectly yielded this work, Peter has created a safe, democratic, and friendly environment at work, and is a primary reason for the division not being in ruins, as much as we all increase its entropy.

I am very thankful to Christina for her support and kindness. Although we have not worked together a lot, the things she does are the ones that really matter.

I would like to thank Yansong, Antanas, and Yanmiao specifically for inviting me to collaborate with them. Whenever I look back at my PhD years and try to

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recall where I wasted so much time, I quickly realize – that’s where! Just kidding, everyone knows I watch cat videos too much, but I regret nothing.

I would like to thank Mingdi for her kind support and plenty of knowledge, shared during the short time we worked together.

I am especially grateful to Pamina, Allan, Augustin, and Maurice, for helping me with the work and testing my supervision skills, which should be better now!

Although not all courses had some influence on this thesis, I would like to pick those that were extremely important. I therefore thank Jan-Erling and Per – for my deeper understanding of organic chemistry, Michael and Jesper – for nearly all my knowledge of quantum chemistry and calculations, Zoltan – for explaining the ins and outs of how NMR works, Nicklas and Kalman – for the solid background in organometallics, and Istvan – for showing how NMR really works and being an ultimately perfect lecturer.

“Calling the cis/trans isomerization of 9 a "dynamic covalent system" is quite a stretch, but let's move on.” Reviewer 1

As much as I wanted, I cannot forget to mention and thank sincerely my very first reviewer for writing a review which almost destroyed my desire to publish, but also became a hilarious collection of quotes that sometimes still light up my day. Calling it “hilarious” is quite a stretch, but let's move on.

I would like to particularly thank Markus for all his wisdom and an invaluable help with reviewing my thesis. I hope it was not too bad and at least entertaining!

Getting to this point would not be possible without Alexandra, and I am very thankful for her help with documents at any time – incredibly professional!

Finally, I am grateful to my financing sources that payed my salary and allowed me to buy chemicals and spend time doing research instead of purifying solvents and washing 2 mL vials (NMR tubes I still had to wash though). One should imagine the level of their support, judging from the fact I am still not entirely sure which my financing sources are. I would also like to thank the Aulin-Erdtman foundation, and Pia and Christina for everything they do to keep it up.

P.S. Many acknowledgements also include all the fun time, friends, and activities. I do not really understand why – if not all the fun time I have spent during the last 5 years, my thesis would have been twice as thick. Do they say negative contribution is also a contribution? It’s quite a stretch…

They say I look like a person who has some evil plan, and all I do has a hidden reason. In reality, most of the time I am trying to remember how to say something in English. I have a really bad memory. So, if I forgot to acknowledge you for something, it is not the plan, it is stupidity.

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Appendix

The following is a description of my contributions to Papers I–VI: Paper I: I formulated the research problem, supervised Master student Maurice Biedermann, designed and performed a major part of the experimental work, and wrote the manuscript. Paper II: I contributed to the formulation of the research problem and scientific discussions as well as performed minor experimental work. Paper III: I formulated the research problem, designed and performed the experimental work, and wrote the manuscript. Paper IV: I contributed to the scientific discussions, performed computational experiments, and wrote part of the manuscript. Paper V: I formulated the research problem, designed and performed the experimental work and theoretical calculations, and wrote the manuscript. Paper VI: I contributed to the formulation of the research problem and scientific discussion, performed computational experiments and minor laboratory work, and wrote part of the manuscript.

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