Chapter 1

• A macrocycle is a cyclic compound containing 9 or more atoms in the ring, including at least 3 donor atoms (heteroatoms) such as N, O, S, P, Se, Te.
• Macrocyclic ligands often have a central cavity for bonding to a guest ion, although some, like 9-membered ring tridentates, are too small so bind facially.
• Common macrocycles include Crown ether, aza-macrocycle, aza-crown, H2porphyrin and Schiff base, containing one or more imine functional groups, R2C=N-R’, where R’ ≠ H.
• Nomenclature for macrocycles is abbreviated for convenience, with the ring size given in square brackets, and if the backbone is saturated, “ane” is normally used. Heteroatoms given alphabetically
• Anion receptors are larger and have a more diffuse charge, usually requiring much larger binding cavities.
• The ability to bind, sense and extract specific anions is of interest for environmental reasons and also because over 75% of enzyme cofactors are anionic, while DNA and RNA are poly-anions.
• In amine functions in aza macrocycles and oxa-aza macrocycles may be readily quaternized to create ammonium derivatives.
• The cavity of these macrocycles acts as a host for anions which bind through H-bonding interactions and electrostatic interactions, which are typically much weaker (~10% bond strength) than cation-ligand bonding interactions.
• An ionic bonding - Potentially important for removal of TcO4- from nuclear fuel reprocessing and the removal of H2PO4- and NO3- from rivers.
• Anion receptors may also be modified to act as sensors for specific anions.
• Heteroatoms are cited in alphabetical order with a subscript denoting the number of each type.
• Simple substituents are cited before the ring size using standard abbreviations such as Me, Et, Bn, Ph.
• Macrocyclic ligands may be designed (‘tuned’) to incorporate particular features or to offer a specific donor set or electronic/steric environment at a metal ion.
• The parameters which are commonly varied in macrocyclic ligands include ring size, donor atom type(s), denticity, degree/type of functionalisation of the donor atoms, and degree of unsaturation/conjugation of the C-backbone.
• The unusually high thermodynamic stability of complexes and their resistance to dissociation lead to applications in catalysis, biological models and biomimicry, magnetic resonance imaging, tumour imaging and therapy by radiolabelling, selective metal binding and extraction, and small molecule binding and catalysis.
• Macrocycles can impose unusual coordination geometries and/or create vacant coordination sites on metal ions, potentially leading to small molecule activation.
• Macrocyclic ligands occur in nature, such as cytochrome c, and are also used in biomimicry to mimic some of the spectroscopic, chemical, physical and/or structural properties of metalloenzymes.
• Complexes of expanded porphyrins and simple pendant arm aza-macrocycles are widely used for applications in magnetic resonance imaging.
• Gd III, with 7 unpaired electrons (f 7), has a high paramagnetism and a coordinated H2O ligand, making it widely used in MRI agents.
• The paramagnetism of Gd III causes the H2O resonance to broaden in the NMR spectrum and its chemical shift is very different from free H2O.
• Gd-enhanced tissues or fluids appear very bright by MRI in a body scanner, allowing these tissues/organs to be imaged.
• The high 'relaxivity' of the protons in the water molecules in the primary and secondary coordination spheres is due to their interaction with paramagnetic Gd(III).
• The majority of applications of macrocyclic complexes are connected with the macrocyclic effect.
• 99m Tc, 111 In, 64 Cu are bound within a macrocyclic ligand, linked to a monoclonal antibody which binds selectively to tumour associated antigens.
• External detection of γ or β + emission leads to the location of the tumour.
• The macrocyclic complex must form the complex rapidly in aqueous solution under mild conditions (t 1/2 ).
• Non-invasive imaging methods such as Positron Emission Tomography (PET) are increasingly of interest with radioisotopes like 68 Ga, 18 F.
• β-emitting radionucleotides such as 90 Y can be coordinated to a macrocyclic ligand and used for targeting a dose of radiation at the tumour cells in radiotherapy.
• A ligand proposed for binding to radioactive nuclide 90 Y for use in radiotherapy is Triazacyclononane-phosphinic acid chelators (TRAP).
• Macrocyclic Complexes for Positron Emission Tomography (PET) Imaging can be formed with Al/Ga 3+ triaza-macrocyclic systems, with rapid uptake of 18 F in water, minimal purification required. Radiolabelling and stability dependent on M and macrocyclic chelate pendant groups.
• In some cases, macrocyclic ligands can be designed to specifically complex certain metal ions, leading to applications in hydrometallurgical processes and extraction of metals from low grade ores.
• Crown ethers and lariat crown ethers are used for selective binding of alkali metal ions.
• The majority of macrocyclic ligands coordinate cations which are much smaller than anions and electropositive.
• The macrocyclic effect is the high thermodynamic stability and resistance to dissociation
• Small molecule activation is using the macrocyclic ligand to block coordination sites of a metal, forming a fragment resistant to decomposition and allowing uptake of substrates at other coordination sites.
• Macrocycles can bind, modify and transport small molecules and act as electron transfer
• a lariat crown ether is a crown ether with one or more side arms on the carbon backbone
• crown ether

  
• aza-macrocycle

  
• aza-crown