Handout IRTG-4, May Lectures overview. Lecture Content

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1 andout IRTG-4, May Jan Reedijk. eiden Institute of Chemistry Bifunctionality in ligands and coordination compounds: application in design of new materials, catalysts and drugs. Slide copies (selection), stored as pdf; allowed for private use only. From Structural Biomimetics to Functional Catalysts 1 IRTG: Spring 2009, Münster Jan Reedijk eiden Institute of Chemistry, Gorlaeus laboratories, eiden University, The etherlands. 2 ectures overview ecture Content 1a. Introduction igands (general) 1b. Introduction Bifunctionality 2. Introduction Metal-DA binding and anticancer drugs, followed by: Bifunctionality in M-DA binding 3. Bifunctionality in Molecular Materials 4. Bifunctionality omogeneous Catalysis Conclusions and utlook 3 Introduction group and biomimetics Introduction proteins Biomimetic xidations with compounds ther metals and other oxidations: Paint Drying alternatives Concluding remarks 4 Why interest in Biomimetics? 1. Better Understanding a) speculative (protein structure unknown) b) corroborative (when structures are available for proteins) 2. Application in mind a) Metal transport (in vivo; waste water) b) Metal catalysis Approach: 1. Design and synthesis 2. Structure and characterisation 3. Tests in applications (functionality) 5 Molecular roles of metal ions in living systems Also often called "biocoordination chemistry" 1. Understanding the role of metal ions in living systems (toxic and beneficial). 2. Application of knowledge of effects of metal ions (and compounds) in living systems. 6 1

2 Definition Bioinorganic Chemistry: A branch of science dealing with the study of the role and effect of metal ions and metal compounds in "living" systems. Characteristics Proteins: Many contain metals or need metals Enzymes: ver 40% has a metal at the active site; at least another 25% require a metal ion for activation and operation 7 8 Definitions and descriptions: Catalysis: The process in which a specific reaction occurs for a certain (selectively chosen) (group of) compound(s), according to a mechanism in which a unique site is involved. This site can be used repetitively. (bio-)catalyst: A compound (a system) that allows a certain specific reaction to take place repetitively, selectively, and efficiently. 9 Role of metal (ion) in catalysis a) as a ewis acid (acceptor) b) as a Π base (donor) c) as a redox source ACTIS F META ARE EITER: Stabilisation of a reactive intermediate Activation of an inert substrate As a template for bringing together reactants in the optimal geometry 10 Important reactions in biology with small molecules 1. Photosynthesis 2 ---> 2 2. Cytochrome oxidase > 2 3. itrogenase > Superoxide dismutase > Catalase > Methane monooxygenase C > C 3 All these enzymes use metal-ions; often more than one metal ion! Fast and specific biocatalytic reactions Catalase (Fe containing heme) [2x10 6 /sec] Superoxide Dismutase ( containing) [2x10 9 /sec]

3 For a difficult Job ature uses Metal Ions!! For a VERY difficult Job, ature uses CUSTERS of metal Ions! Metalloproteins, enzymes, mimics Selection of short examples: Zn, Fe,Mn Major example: Copper proteins Transport: electron and dioxygen Catalysis with and Mn biomimetics The Bioinorganic Chemistry of Alcohol Intake of Et: appy Zn in Alcohol dehydrogenase Formation of Acetaldehyde: angover Mo in Aldehyde xidase Formation of Acetic Acid: The Recovery Stage Functions of Metals in Biology Transport functions: electrons, dioxygen, metals Chaperones and DA binders, such as Zinc fingers (structure organisers) Charge compensation for anions Catalysis (6 enzyme classes) Metals & applications in Biology What is special in Metals? Structure organiser (Ca; Zn; Zn finger) Catalyst (Mn, Co, Fe, Zn,, Mo, V) Drug (Au, Pt, Bi, i, Ag) Diagnostic (signal from metal: Tc, Gd) Analytical reagent (probe; s, Pt) Transporter of electrons (, Fe) Transporter of ligands, like dioxygen Geometry preferences (xidation-state dependent; size dependent) 2. Binding strengths (weak, strong) 3. Binding kinetics (fast, slow) 4. Binding preferences for ligands (SAB) 5. Reactivity patterns a) Redox properties b) Photoreactivity and charge transfer c) Coordination changes (catalysis) d) Powerful template possibilities 6. Cluster formation possibilities 18 3

4 Reactivity and ligand exchange reactions Metalloproteins and metalloenzymes Kinetics versus Thermodynamics Kinetics and Thermodynamics are influenced by: a) metal ion (intrinsic property) b) ligand (strength, covalency, steric bulk) c) (macro-)chelate effect d) solvent assistance Mechanistic discriminations (associative, Proteins: Transport, storage (metals, electrons) myoglobin, azurin, cytochromes, ferritin Enzymes: Catalytic reactions P-450, ascorbate oxidase, catalase Co-enzyme: Agent that actives an enzyme Apo-enzyme: Enzyme without a metal (usually inactive) Pro-enzym: Inactive enzyme, lacking the activator Synzyme: Biomimetic product micking the enzyme (structure, activity) dissociative, intermediate mechanisms) Biomimetic Copper Chemistry Copper proteins (introduction) Why biomimetics studied? Reactions with dioxygen species Example of stable dioxygen adducts with dinuclear sites and catalytic oxidation reactions Applications in xidations 21 Copper Protein Examples Spectroscopic Classification Type 1: Blue; unusual EPR Type 2: ormal spectroscopy Type 3: Dinuclear; EPR silent Type A: Dinuclear Blue (purple) Type B: Mixed Fe- Type Z: Tetranuclear Type 4: Mixtures of types 1,2,3,A 22 Common features in redox proteins All ions have at least an imidazole ligand (from istidine). Many have 2 or 3 imidazole ligands In SD has 4 imidazole ligands emocyanin Active site: type 3 ote: on-redox proteins have imidazole ligands (Thioneines)

5 Cytochrome oxidase Process of dioxygen binding + Karlin Kitajima 25 Tolman 26 Dinuclear copper protein containing the type-3 site: hemocyanin is Synthetic peroxido dicopper(ii) complexes using macrocyclic ligands is is I I is is is is is is II II is is - distance: ~ 3.6 Å in oxy-hemocyanin 2 coordination mode: side-on μ-η 2 :η 2 EPR silent UV/Vis: 345 nm (ε=20000) 570 nm (ε=1000) Raman: ν(-) = 750 cm -1 MePy22Pz + 2 eq (I) + 2 is 27 Johan Bol, PhD Thesis 28 Synthesis of the peroxido complex 1/ Under argon, at RT, in C 2 Cl 2 : [ I 2 (MePy22Pz)] [ II 2 (MePy22Pz) 2 ]2+ purple solution 15 min green solution Synthesis of the peroxido complex 2/ At -30 C, and after evaporation of the solvent: [ I 2 (MePy22Pz)] [ II 2 (MePy22Pz) 2 ]2+ purple powder stable at room temperature

6 Dinuclear structure for a dicopper peroxide-bridged system Decomposition of the purple peroxido complex 1/2 2 II II 2 II II 2 2 μ-peroxido μ-oxido 31 Applicable in catalysis??? 32 verall scheme oxidations Ascorbate oxidase ascorbate 2 dehydroascorbate Quercetinase C + depsid Galactose xidase 2 R R emocyanin dioxygen transport 2 2 Copper-containing proteins Tyrosinase 2-2 Amine oxidases 2 R 2 R Dopamine β- mono-oxygenase alkeen oxidatie alkenes Most important oxidation reactions studied (eiden): 2 2, 2 phenols fenoloxidaties 2 2, 2 * * n 'Blue' copper proteins e - e - itrite reductase 2 - Cytochrome c oxidase reductase Superoxide dismutase catechols catecholoxidaties 2, C C 34 xidation reactions Reaction Process 1. xidative phenol coupling (dehydrogenation) * polymerisation (desired) * dimerisation (not desired) 2. Epoxidations (with Mn) Best catalysed by: Paint drying (oxidations) 35 (PPE) 36 m Dinuclear (II) complex and a base (DMP) Unwanted: (DPQ) n 6

7 Why research on the oxidative coupling of DMP? xidative coupling of DMP (2,6-dimethylphenol) produces a high-performance thermoplast. It can provide a better understanding in type III copper proteins used in dioxygen metabolism. 37 Findings in xidative Coupling (II) complexes of ligands with -donor atoms are best catalysts. Basicity of the ligand increases activity. Bulkiness of the ligand increases activity. Dualistic character of water: some needed; too much water poisons the catalyst. Standard ligand -methylimidazole (miz). Preferred solvent: acetonitrile. 38 Major recent mechanistic findings (Aubel, Boldron, Gamez) 1. Dinuclear catalytic species most likely: second order kinetics in ; first order in for preformed dinuclear species 2. Two-electron transfer reactions and phenoxonium species most likely. 3. Reoxidation with dioxygen is rate limiting 39 Polymerization of 2,6-dimethylphenol Meim DMP -Catalyst + 2 Mea Toluene/Water Biphasic System n PPE igand Base C Atm. % 2 Conv. Min. T R 0 M w 30 Meim , Meim , Meim , Meim , Meim 2 25 Air ,400 4 Meim 2 25 Air ,800 4 Meim , R P R1 Mechanism R R1 + + R1 + utlook Phenol Coupling igands: More dinucleating ligands Solvents: Mixtures; biphasic; water role Reoxidation mechanism from (I) Chain growth and rearrangements ther metal ions: Fe, Mn ther alcoholic substrates R2 R2 R

8 The transition-metal chemistry of alkyd paints. Watching paint dry Substitutes for cobalt complexes in driers for alkyd paints 1. Mechanistic studies, with commercial (uodex) and synthetic systems 2. Search for other metals and reagents utline What is in a can of paint? What is alkyd paint The problem Model system and analysis A possible solution Pigments 45% Additives 4% Solvent 16% Binder 32% inseed inolenic acid Binder: alkyd resin Polyester of: Polyol (glycerol) Phthalic acid Fatty acid inoleic acid Sunflower 47 Fatty acids leic acid inoleic acid Ricinoleic acid inolenic acid 48 8

9 Initiation: Radical Generation Via oxygen activation: Co Co 3+ Co 3+ + R Co 3+ + R Via direct hydrogen abstraction Co 3+ + R Co R Free radical chain autoxidation Initiation R R + Propagation R + 2 R R + R R + R R + M n+1 R + M n+ + + R + M n+ R + M n Termination 2 R RR R R + R= Initiator - Binder: chemical drying. (R ) + 2 (R ) + RR, RR and RR RR Dry paint film Catalyst (R ) (R) 51 (R ) Additives Drying catalyst Cobalt octoate (primary drier) Ca, Zr, Sr (secondary driers) Anti-skinning agent Methyl ethyl ketoxime (MEK) Anti-foaming agents Emulsifying agents Suspected carcinogenic The problem! 52 Coatings Project Aim Understand role of methyl ethyl ketonoxim (Meko) as antiskin agent Find suitable model paint system Measure initiation (FTIR) Measure propagation (Size exclusion chromatography, SEC) Replacement of Co as active drying species by environmentally more acceptable Mn complexes

10 Used model compounds for the alkyd resin 1,4-hexadiene R 1 R 2 1,4-cyclohexadiene ow do we watch paint dry? t = 0 h t = 3 h Infrared Spectroscopy ethyl linoleate 70% (E) CEt 0.2 ethyl linoleate ,2 1 0,8 0,6 0,4 0,2 Consumption of substrate (E) induction R R n(100[e]t/[e]0] time time (min) slope, rate ln([e]) 4,6 4,5 4,4 4,3 4,2 4,1 Proces shows First order kinetics ln([e]) inear (ln([e])) S. Warzeska et al., Prog.rg.Coat. 2002, 44, time (min) 58 RI-signal (V) Second T: Formation of the E oligomers: SEC ligomers Trimers Dimers E E 2h 4h 6h 24h 48h 2.5 cm Tests in alkyd paints Film thickness: 60 μm 70 cm elution volume (ml) 59 Start End 60 10

11 drier Example Uralac AD 152 WS-40 from DSM Co-Ca-Sr Mn-Ca-Zr Mn-bipy drying by hand on glass 60 µm s.d 1.45 > t.d > 6.00 drying time Braive recorder, 76 µm at 23 C and 50% relative humidity stage a stage b stage c Isolated from catalyst: Structure of Mn 4 2 (bpy) 2 (2-ethylhexanoate) 6 Mixed valence! 2 Mn 2+ 2 Mn ethylhexanoate 2 bipyridine 2 2- Mn(acac) R. van Gorkum et al. EP A1, Activity of the Mn cluster in Mn 4 2 (bpy) 2 (2-ethylhexanoate) 6 Most active systems Mn UDEX Mn eq bpy Mn + 1 eq bpy Mn42-cluster Mn(acac) 3 as such: good results BUT: even better when bpy is added to the solution of Mn(acac) 3 Substituted acac ligands and co-ligands (chelating donor ligands): further improvements R. van Gorkum, E. Bouwman and J. Reedijk. (2004). Drier for alkyd based coating; Pat. Appl EP A1 (The etherlands) Results: FT-IR plots of (new) driers 5 [Mn II (acac) 2 (bpy)] structure 4.5 (n([e]t/[e]0)*100) Mn bpy Mn nuodex Co nuodex [Mn(acac)3] [Mn(acac)3] + 1 eq bpy Mn(acac) 3 Time (min) R. van Gorkum et al., Inorg.Chem. 2004, 43, R. van Gorkum et al., submitted for publication Trigonal prismatic coordination geometry 66 11

12 Bipyridine facilitates the reduction of Mn(III) to Mn(II) This enhances the initiation... [Mn III (acac) 3 ] + E- The magic of bipyridine: + bpy [Mn II (acac) 2 (bpy)] + E + acac and also the peroxide decomposition [Mn III (acac) 3 ] + R [Mn II (acac) 2 (bpy)] + R + acac + bpy [Mn II (acac) 2 (bpy)] + R [Mn III (acac) 3 ] + R bpy + acac 67 X-ray structure of [Co(acetaldoxime) 4 Br 2 ] Co-Br = 2.65 Å Co- = 2.15 Å ---Br = 3.1 Å - Intramolecular hydrogen bonding Several related complexes made with other oximes 68 Conclusions Mn catalysts Conclusions Co replacers Mn compounds offer a good alternative to Cobalt drying catalysts; good prototype: [Mn(acac) 3 ] Tripodal, tetradentate ligands have been used successfully in Mn paint-drying catalysts With these ligands Mn is much more active than Fe and even better than the best so far: [Mn(acac) 3 ] A rate difference is observed when peroxides are present initially compared to clean model systems The rate is influenced by the pk a of the ligands The differences in induction time cannot be fully understood at the moment 69 Mn-uodex + bipyridine 2 equivalents bpy bound to Mn-uodex in situ best activity (FTIR): Mn-uodex + 2 equiv. bipy active species?: Mn 4 2 (bpy) 2 (2-ethylhexanoate) 6 Co-uodex + bipyridine 1 equivalent bipy is bound to Co-uodex in situ adding bpy has a negative influence on the performance of Co-uodex (FTIR) 70 Fundamental Chemist: It is a pity that this reaction does not run; fortunately, I do know why! Applied Chemist: It is a pity that we do not know why this catalyst works; however, it runs with a good yield. Concluding Remarks and utlook igands are TE tool for all coordination chemist whether making materials or catalysts or drugs. Fine tuning applications of coordination compounds, requires always also DESIG & FIETUIG of the ligands