1. Macrocyclic Ligands: Functional Host Guest Systems. Post Graduate Lecture Course January 2000 Lecture 1

2. 1. Introduction DefinitionsDefinitions –What is a macrocycle? “A macrocycle is a large ring molecule, normally having 12 or more atoms in the ring and normally containing heteroatoms capable of binding substrates” Small Rings (3-6), Mesocycles (7-11), Macrocycles (  12)

3. Macrocyclic LigandsMacrocyclic Ligands Usually stretch the definition to include: Ring sizes  9 At least 3 donor atoms

4. Why Macrocycles?Why Macrocycles? Biological Systems for: Photosynthesis Oxygen transport Redox reactions Ion transport

5. 2. Natural Macrocycles 2.1 Cyclic Antibiotics 2 types: Neutral Macrocycles Acyclic Monobasic Acids

6. Enniatin BEnniatin B 18-membered ring Depsipeptide alternating  -amino acid and  - hydroxy acid residues ValinomycinValinomycin 36-membered ring Also Depsipeptide

7. NonactinNonactin 32-membered ring Macrotetrolide - Alternating ester and ether groups All complex K + selectively vs other alkali metal ions. Consider some of their X-ray structures….

17. Biological Action Transport of ions through biological membranes (e.g. cell walls)Transport of ions through biological membranes (e.g. cell walls) Construction: Lipids/proteins Thickness:ca 70Å Function:selective transport Substances capable of transporting ions across such membranes are IONOPHORES

18. Porphyrins and Related Systems By far the most common biological macrocyclesBy far the most common biological macrocycles three main ring types:three main ring types: Porphyrin Chlorin Corrin

19. Vitamin B 12 Coenzyme

20. Naturally Occurring Organometallic!Naturally Occurring Organometallic! Cobalt(III) with R -.Cobalt(III) with R -. Reduction to Co(II) and Co(I) ?Reduction to Co(II) and Co(I) ? R =

21. Chlorophyll Initiates Photo- synthesisInitiates Photo- synthesis Absorbs in redAbsorbs in red Oxidation of H 2 O to O 2Oxidation of H 2 O to O 2 Glucose formation from CO 2 and H 2 OGlucose formation from CO 2 and H 2 O

22. Haem Proteins Two functions: - O 2 transport and storage - Electron Transfer Contain Fe porphyrin complexes Examples: - Haemoglobin - Myoglobin - Cytochrome P 450

26. 3. Synthetic Macrocycles 3.1 History Baeyer, 1886 - First Reported Macrocycle Chem. Ber. 1886, 19, 2184

27. Metal Phthalocyanines, first reported 1928 The only well known synthetic macrocycle pre-1960

28. Cyclam (Cyclic Amine) Alphen, Recl. Trav. Chim, 1937, 56, 343.Cyclam (Cyclic Amine) Alphen, Recl. Trav. Chim, 1937, 56, 343. Dibenzoaza-crowns Krässig and Greber, Makromol. Chem., 1953, 11, 231.Dibenzoaza-crowns Krässig and Greber, Makromol. Chem., 1953, 11, 231. Other Pre-1960 Macrocycles

29. 3.2 Nomenclature 1,4,7-trithiacyclononane: trithia-9-crown-3; 9aneS 31,4,7-trithiacyclononane: trithia-9-crown-3; 9aneS 3 1,4,8,11-tetraazacyclotetradecane: tetraaza-14- crown-4; 14aneN 4.1,4,8,11-tetraazacyclotetradecane: tetraaza-14- crown-4; 14aneN 4. 4,13-diaza-1,7,10,16-oxacyclooctadecane: diaza-18- crown-6; 18aneN 2 O 4.4,13-diaza-1,7,10,16-oxacyclooctadecane: diaza-18- crown-6; 18aneN 2 O 4.

30. 3.4 Synthesis: General Methodology Formation of One Bond:Formation of One Bond: Linear compound with a reactive group on each end.

31. Examples This “head to tail” method is sometimes known as the snake reaction!This “head to tail” method is sometimes known as the snake reaction!

32. Formation of two Bonds:Formation of two Bonds: 1 + 1 Cyclisation Most Commonly Used Method of Macrocycle Preparation

33. ExamplesExamples