Macrocyclic Ligands: Functional Host Guest Systems.

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Macrocyclic Ligands Functional Host Guest
Systems.

• Post Graduate Lecture Course
• February 2000
• Lecture 3

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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

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Cyclisation vs Polymerisation

• Competing Processes
• Linear Polymerisation favoured by solvent free
  reactions
• 11 and 22 cyclisation are slow favoured by low
  temperatures and high dilution (lt10-3 M). Ziegler
  et al., Liebigs Ann. Chem., 1933, 504, 95.
• Polycyclisation (33, 44 etc) generally
  difficult to obtain high yields

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Synthetic Solutions

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

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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)

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Examples

• Curtis Synthesis
• Curtis, J. Chem. Soc., 1960, 4409.

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• Busch, J. Amer. Chem. Soc., 1964, 86, 3651.
• Inorg. Synth., 1975, 16, 220.

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Metal mediated cyclo-oligomerisation

• Norman, J. Am. Chem. Soc., 1982, 104, 4700
• Edwards, J.Chem. Soc. Dalton Trans., 1999, 1024

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Metal-Mediated Schiff Base Condensation

• Example of thermodynamic template effect.
• Busch, 1966, J. Am. Chem. Soc.,1966, 88, 3170.

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Schiff Base Ligands Other Substrates

• Reaction usually involves an ?,?-diamine and a
  diketone or dialdehyde.
• Some dialdehydes and diketones...

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Schiff Base Ligands Other Substrates

• Some typical diamines
• Some Schiff base macrocycles

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High Dilution Synthesis

• Relatively uncommon
• Generally more difficult experimentally
• Yields often lower
• Less product selective
• Hence separation of products necessary
• So why use it at all...

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• Some substrates not amenable to template methods
• Sometimes metal template ion cannot be removed
  from macrocycle
• Sometimes it just works well!

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High Dilution Apparatus
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Examples of high dilution syntheses

• Lehn, Tetrahedron, 1973, 29, 1629
• At 0?C - slower reaction but higher yield (Babb,
  J. Heterocyclic Chem., 1986,23,609)
• Can speed up reaction by activating the acid
  chloride.

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• Here the thiazolidine increases the activity of
  the carbonyl function, increasing reaction rate
  significantly.

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Note that many apparently high dilution syntheses
are in fact template reactions.

• For example
• The alkali metal ion acts as template for the
  cyclisation

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• Changing alkali metal ion alters the yield..
• Solvent Template ion
• Li Na K Cs
• MeCN 6 44 27 15
• dioxane - 16 24 -
• glyme - 8 24 15
• MeOH - - lt5 -