Macrocyclic Ligands: Functional Host Guest Systems.

1. Macrocyclic Ligands: Functional Host Guest Systems. Post Graduate Lecture Course January 2000 Lecture 2

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

3. Metal Phthalocyanines, first reported 1907 The only well known synthetic macrocycle pre-1960

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

5. 3.2 Nomenclature • 1,4,7-trithiacyclononane: trithia-9-crown-3; 9aneS3 • 1,4,8,11-tetraazacyclotetradecane: tetraaza-14- crown-4; 14aneN4. • 4,13-diaza-1,7,10,16-oxacyclooctadecane: diaza-18-crown-6; 18aneN2O4.

6. 3.4 Synthesis: General Methodology • Formation of One Bond: Linear compound with a reactive group on each end.

7. Examples Kuo, J.Chem. Soc., Chem.Commun., 1978, 504 • This “head to tail” method is sometimes known as the snake reaction!

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

9. Examples Dietrich, Lehn & Sauvage, Tetrahedron, 1973, 29, 1629 Müller et al., Monatsch. Chem., 1952, 83, 386.

10. 2 : 1 Cyclisations Unusual, but one example: Mechanism is not known definitively...

11. …but is thought to proceed by the mechanism below:

12. 2 : 2 Cyclisations • Can also produce 1:1 and higher (3:3, 4:4) cyclisation products • Concentration Dependent

13. Rigid difunctional molecules tend to favour 2 : 2 Cyclisation, for example: Pederson, J. Amer. Chem. Soc., 1967, 89, 2495

14. “Higher” Cyclisations • Generally seen as by-products from 2:2 reactions • Yields decrease as ring size increases • One exception:

15. Oligomerisation Reactions

16. Synthesis: Ring Closure • This is the key step • Chemistry generally simple but product selectivity often poor • Thermodynamically large rings are stable • Kinetics favour 5-membered rings - macrocycles are not favourable

17. Cyclisation vs Polymerisation • Competing Processes • Linear Polymerisation favoured by solvent free reactions • 1:1 and 2:2 cyclisation are slow; favoured by low temperatures and high dilution (<10-3 M). Ziegler et al., Liebigs Ann. Chem., 1933, 504, 95. • Polycyclisation (3:3, 4:4 etc) generally difficult to obtain high yields

18. Synthetic Solutions • Two methodologies have been adopted to overcome ring closure difficulties • High Dilution Synthesis • Template-Mediated Synthesis

19. Template-Mediated Cyclisation • Use of a metal (usually) ion • interacts with heteroatoms of reactants Two possible roles: • Pre-arrangement of functional groups so that orientation favours cyclisation (Kinetic Template Effect) • Extracting Cyclic product from reaction mixture, thus altering equilibrium position (Thermodynamic Template Effect)

20. Examples • Curtis Synthesis: Curtis, J. Chem. Soc., 1960, 4409.

21. Busch, J. Amer. Chem. Soc., 1964, 86, 3651. Inorg. Synth., 1975, 15,