A Practical Guide to Supramolecular Chemistry is an introductory manual of practical experiments for chemists with little or no prior experience of supramolecular chemistry. Syntheses are clearly presented to facilitate the preparation of acyclic and macrocyclic compounds frequently encountered in supramolecular chemistry using straightforward experimental procedures.

Many of the compounds can be used to illustrate classic supramolecular phenomena, for which clear directions are given, or may be developed further as part of the reader’s own research. The book also describes techniques commonly used in the analysis of supramolecular behaviour, including computational methods, with many detailed examples.

An invaluable reference for students and researchers in the field embarking on supramolecular chemistry projects and looking for a ‘tried and tested’ route into the chemistry of key compounds.

An introductory guide to practical syntheses focusing on supramolecular chemistry.

Fully referenced introductions explain the historical and contemporary importance of each compound

Supplementary website including 3D molecular structures, FAQ’s about syntheses and suggestions for further experiments

Dr Peter J. Cragg, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK

A Practical Guide to Supramolecular Chemistry

By Peter Cragg

John Wiley & Sons

Copyright © 2005 John Wiley & Sons, Ltd
All right reserved.
ISBN: 978-0-470-86654-2

Chapter One

Linear Components for Supramolecular Networks

1.1 Flexible Components

The origins of supramolecular chemistry are intimately linked to Pedersen’s pioneering work on crown ethers. His fortuitous discovery of dibenzo crown-6 in 1967 occurred when he was attempting to prepare a flexible phenol-terminated polyether which was expected to bind to the vanadyl ion and thus support its catalytic activity. Although the importance of the new class of cyclic polyethers was recognized across the globe, researchers were also alerted to Pedersen’s original goal: the potential for acyclic polyethers to act as metal=binding ligands. Starting points for many of the experiments were the widely available polyethylene glycols that could be modified readily. Foremost among those preparing functionalized polyethers were Vgtle and Weber who coined the term ‘podands’ for their compounds.

Polyethers are well known for their abilities to wrap around metal ions, particularly those in groups 1 and 2 and the lanthanides (Figure 1.1), but the introduction of coordinating termini in concert with variable lengths of the polyether tether gave greater specificity to the ligands. More recently, polyethers have been used to prepare coordination networks through the incorporation of transition metals. The inherent flexibility of the ether link coupled to the preferred geometry of certain metals gives rise to some very interesting nanoscale complexes, many of which have a helical motif.

Two methods to prepare polyether-based podands are described here. The first is a direct modification of polyethylene glycols and comes originally from the work of Piepers and Kellogg, later modified by Hosseini. A simple reaction between hexaethylene glycol and isonicotinyl chloride, as shown in Figure 1.2, results in the formation of podand 1 in good yield. When treated with silver salts its bifunctional nature becomes apparent: while the polyether wraps around the metal ion, the donor groups of the isonicotinyl termini coordinate axially to give a self-assembling linear polymer as illustrated in the computational simulation of the X-ray structure (Figure 1.3). As shown by later work by the Hosseini group, many variations of the synthesis can be envisaged. This method gives a yield that is in close agreement with the published 86 per cent.

The second method can be used to synthesize Vgtle-type podands in two high-yielding steps from polyethylene glycol ditosylates. The ditosylate derivatives, which are also precursors of cyclic crown ethers, azacrown ethers and lariat ethers, can be prepared with pyridine as the base. However, they are synthesized more effectively in higher yields using aqueous sodium hydroxide and tetrahydrofuran (Figure 1.4). These conditions also remove the necessity to work with large amounts of an unpleasant solvent. Furthermore it avoids problems inherent in the removal of excess pyridine from the reaction. Once the ditosylates have been prepared they can be treated with simple metal salts such as sodium 8-hydroxyquinolinate, as shown in Figure 1.5, to introduce useful termini. Although the products have high conformationalmobility, the termini converge on alkalimetals while the oxygen donors in the polyether backbone wrap around the metals as shown in crystal structures of related compounds and illustrated in Figure 1.6.

Tosyl derivatives are widely used in polyether chemistry as the tosylate anion makes a good leaving group. Diiodopolyethers are often encountered too; however, iodide is no better as a leaving group under the conditions used in the examples given here. Tosylate derivatives have three clear advantages. First, they are often crystalline (though unfortunately not in the case of tetraethylene glycol ditosylate) and can therefore be obtained in high purity. Second, they add significantly to the mass of the parent compound (a mole of triethylene glycol weighs 150 g, its ditosylate derivative, 458 g) making transfer more accurate in the laboratory. Finally, the tosylate salts form as insoluble precipitates upon reaction with the alkali metal salts of alcohols and phenols in non-aqueous solvents. As a result, simple filtration followed by solvent removal is often all that is necessary to isolate the functi onalized polyether.

Syntheses of ditosylates 2 and 3 are representative of the procedures required to make crystalline and non-crystalline polyether derivatives: continuation to bis(quinoline) 4 is typical of the method used to prepare a range of symmetrically substituted polyethers with aromatic termini.

Preparation of an isonicotinyl podand

1,19-Bis(isonicotinyloxy)-4,7,10,13,16-pentaoxaheptadecane (1)

Reagents Equipment

Hexaethylene glycol 2-Necked round-bottomed flask (250mL) Triethylamine [FLAMMABLE] Pressure equalized dropping funnel Isonicotinyl chloride hydrochloride Reflux condenser Tetrahydrofuran (THF) [FLAMMABLE] Heating/stirring mantle and stirrer bar Diethyl ether [FLAMMABLE] Inert atmosphere line Distilled water Glassware for filtration and work up Hexane [FLAMMABLE] Dichloromethane [TOXIC] Magnesium sulphate

Note: Wherever possible all steps of this synthesis should be carried out in a fume hood.

In a 250 mL two-necked round-bottomed flask, stir finely powdered isonicotinyl chloride hydrochloride (3.56 g, 20 mmol) in dry THF (50 mL) under an inert atmosphere and add triethylamine (7.0 mL, 5.0 g, 50 mmol). Immediately the cream hydrochloride salt dissolves and a white precipitate of triethylamine hydrochloride forms. After 30 min add hexaethylene glycol (2.5 mL, 2.82 g, 10 mmol) in dry THF (30 mL) dropwise from a pressure-equalized dropping funnel. Once all the hexaethylene glycol solution has been added stir for a further 30 min then heat to reflux for 1 h. Allow the mixture to cool to room temperature and stir for a further 48 h. Filter the mixture and remove the THF under reduced pressure. (Place the precipitate in a fume hood as it may appear to smoke due to residual HCl. It should be dissolved in distilled water and neutralized with base prior to disposal.) Add distilled water (50 mL) to the residue and wash with hexane to remove any unreacted hexaethylene glycol. If the THF was dried with sodium hydride in mineral oil this process will also remove the oil. Extract the aqueous solution with dichloromethane (50 mL then twice with 25 mL). Dry the organic phase over anhydrous magnesium sulphate (ca. 1 g), filter and remove the solvent under reduced pressure to give the product, 1,19-bis(isonicotinyloxy)-4,7,10,13, 16-pentaoxaheptadecane (1), as an orange oil.

Yield: 3.8 g (80%); IR ([upsilon], [cm.sup.-1]): 3440, 3035, 2875, 1955, 1730, 1410, 1285, 1120, 760, 710, 680; [sup.1]H NMR ([delta], ppm; CD[Cl.sub.3]) 8.8, 7.9 (dd, 8 H, ArH), 4.5 (t, 4 H, C[H.sub.2]OC(O)Ar), 3.85 (t, 4 H, C[H.sub.2]C[H.sub.2]OC(O)Ar), 3.75-3.6 (m, 16 H, OC[H.sub.2]C[H.sub.2]O).

Preparation of polyethylene glycol ditosylates

Triethyleneglycol ditosylate (2)

Reagents Equipment

Triethylene glycol 2-Necked round-bottomed flask (2 L) Sodium hydroxide [CORROSIVE] Pressure equalized addition funnel p-Toluenesulphonyl chloride Thermometer (-10 to 100 C) [CORROSIVE] Magnetic stirrer and stirrer bar Tetrahydrofuran (THF) [FLAMMABLE] Ice bath Distilled water Glassware for recrystallization Ethanol [FLAMMABLE]

Note: Work in a fume hood wherever possible, particularly when handling p-toluenesulphonyl chloride and when recrystallizing the product.

Prepare a solution of sodium hydroxide (40 g, 1 mol) in distilled water (200 mL) and cool to room temperature. Place the solution in a 2 L two-necked round-bottomed flask fitted with a thermometer and add a solution of triethylene glycol (56.5 g, 50 mL, 0.35 mol) in THF (200 mL) while stirring. Put the flask in an ice bath and cool to 0 C. Place a solution of p-toluenesulphonyl chloride (145 g, 0.76 mol) in THF (200 mL) in a pressure-equalized addition funnel and add dropwise to the stirred glycol solution over 3 h or so. Carefully monitor the temperature of the solution and keep below 5 C throughout the addition. Once the addition of the p-toluenesulphonyl chloride solution is complete continue to stir the solution for a further 1 h below 5 C. Pour onto a mixture of ice and water (250 g/250 mL) and continue to stir. After all the ice has melted filter the product, which forms as a white powder. Although the crude ditosylate could be used directly it is worthwhile recrystallizing from a minimum quantity of hot ethanol (ca. 2 mL per g). Note that the ditosylate will only dissolve when the ethanol is boiling, whereupon it becomes extremely soluble. Filter the boiling solution as quickly as possible to remove any insoluble matter, cool to room temperature, filter again to isolate the precipitate and dry thoroughly to remove residual ethanol. The product, triethylene glycol ditosyate (2), is obtained as a colourless microcrystalline solid or white powder.

Yield: 100 + g (60%); m.p.: 77-79 C; IR ([upsilon], [cm.sup.-1]): 3060, 2940, 1460, 1375, 1350, 1300, 1175, 1100; [sup.1]H NMR ([delta], ppm; CD[Cl.sub.3]) 8.8, 7.3 (dd, 8 H, ArH), 4.2 (m, 4 H, C[H.sub.2]OS[O.sub.2]), 3.7 (m, 4 H, C[H.sub.2]C[H.sub.2]OS[O.sub.2]), 3.9-3.8 (m, 8 H, OC[H.sub.2]C[H.sub.2]O), 2.4 (s, 6 H, ArC[H.sub.3]).

Tetraethyleneglycol ditosylate (3)

Reagents Equipment

Tetraethylene glycol Two-necked round-bottomed flask (2 L) Sodium hydroxide [CORROSIVE] Pressure equalized addition funnel p-Toluenesulphonyl chloride Thermometer (-10 to 100C) [CORROSIVE] Magnetic stirrer and stirrer bar Tetrahydrofuran (THF) [FLAMMABLE] Ice bath Distilled water Glassware for recrystallization Dichloromethane [TOXIC] Rotary evaporator Calcium sulphate

Note: Work in a fume hood wherever possible, particularly when handling p-toluenesulphonyl chloride.

Prepare a solution of sodium hydroxide (40 g, 1 mol) in distilled water (200 mL) and cool to room temperature. Place the solution in a 2 L two-necked round-bottomed flask fitted with a thermometer and add a solution of tetraethylene glycol (68 g, 60 mL, 0.35 mol) in THF (200 mL) while stirring. Put the flask in an ice bath and cool to 0 C. Place a solution of p-toluenesulphonyl chloride (145 g, 0.76 mol) in THF (200 mL) in a pressure-equalized addition funnel and add dropwise to the stirred glycol solution over 3 h or so. Carefully monitor the temperature of the solution and keep below 5 C throughout. Once the addition of the p-toluenesulphonyl chloride solution is complete, continue to stir the solution for a further 1 h at below 5 C. Pour onto a mixture of ice and water (250 g/250 mL) and continue to stir. When all the ice has melted, remove most of the THF by rotary evaporation and extract the product into dichloromethane (3 100 mL). Dry the dichloromethane extract over calcium chloride, filter and remove the solvent by rotary evaporation. The product, tetraethylene glycol ditosylate (3), is obtained as a colourless oil.

Yield: ~160 g (95+%); IR ([upsilon], [cm.sup.-1]): 3060, 2930, 1460, 1375, 1350, 1300, 1175, 1120; [sup.1]H NMR ([delta], ppm; CD[Cl.sub.3]) 8.8, 7.3 (dd, 8 H, ArH), 4.2 (m, 4 H, C[H.sub.2]OS[O.sub.2]), 3.7 (m, 4 H, C[H.sub.2]C[H.sub.2]OS[O.sub.2]), 3.9-3.8 (m, 12 H, OC[H.sub.2]C[H.sub.2]O), 2.4 (s, 6 H, ArC[H.sub.3]).

Preparation of a quinoline podand

1,9-Bis(8-quinolinyloxy)-3,6-dioxanonane (4)

Reagents Equipment

Triethylene glycol ditosylate (2) 2-Necked round-bottomed flask (250mL) 8-Hydroxyquinoline Heating/stirring mantle and stirrer bar Sodium hydride (50% oil suspension) Pressure equalized addition funnel [CORROSIVE; REACTS VIOLENTLY Inert atmosphere line WITH WATER] Rotary evaporator Tetrahydrofuran (THF) [FLAMMABLE] Glassware for column chromatography Distilled water Dichloromethane [TOXIC] Anhydrous sodium sulphate Acetone [FLAMMABLE] Silica (for chromatography)

Note: Work in a fume hood wherever possible and exercise due caution when handling sodium hydride.

Under an inert atmosphere, prepare a suspension of sodium hydride (0.96 g, 20 mmol [50 per cent in mineral oil]) in dry THF (50 mL) in a 250 mL two-necked round-bottomed flask fitted with a reflux condenser and pressure equalized addition funnel. Stir for 30 min under an inert atmosphere. Slowly add a solution of 8-hydroxyquinoline (2.90 g, 20 mmol) in dry THF (50 mL) to this through the addition funnel. Make up a solution of triethylene glycol ditosylate, 2, (4.60 g, 10 mmol) in dry THF (50 mL), ensuring that no solids remain (filter if necessary) or the addition funnel may become blocked. Once the effervescence subsides following the formation of the sodium 8-hydroxyquinolinate salt, add the ditosylate solution and reflux for 24 h. After 24 h, allow the solution to cool to room temperature, filter off the precipitated sodium tosylate and remove the THF by rotary evaporation. Dissolve the residue in dichloromethane (30 mL) and wash with distilled water (3 30 mL). Dry the organic phase over anhydrous sodium sulphate, filter and remove dichloromethane by rotary evaporation to give the crude product, 1,9-bis(8-quinolinyloxy)-3,6-dioxanonane (4) as a pale brown oil. Further purification may be afforded by column chromatography (silica, elute with acetone/dichloromethane).

Yield: 2.0 g (50%); IR ([upsilon], [cm.sup.-1]): 3060, 2950, 1600, 1460, 1375, 1175, 1125; [sup.1]H NMR ([delta], ppm; CD[Cl.sub.3]) 8.9 (dd, 2 H, ArH), 8.1 (dd, 2 H, ArH), 7.4 (m, 6 H, ArH), 7.1 (d, 2 H, ArH), 4.4 (t, 4 H, OC[H.sub.2]C[H.sub.2]OAr), 4.1 (m, 4 H, OC[H.sub.2]C[H.sub.2]OAr), 3.8 (s, 4 H, OC[H.sub.2]C[H.sub.2]O).

1.2 Rigid Components from Schiff Bases

While the flexibility of polyethers may be advantageous in many instances, it is often necessary to have a greater degree of preorganization in the ligands in order to entice guests, usually transition metals, into complex formation. Examples of this type include sexipyridine ligands used by Constable for metal complexation within a double helix and Sauvage’s copper-assisted formation of molecular trefoil knots from ligands derived from 1,10-phenanthroline.

Hannon’s group has prepared a range of rigid Schiff base ligands based on inexpensive starting materials. The synthesis of these compounds is based on the addition of an aldehyde to a diamine (a method long used by coordination chemists to prepare ligands such as salens) with convergent binding sites, as shown in Figure 1.7. Coordination to transition metals results in highly coloured triple helical complexes containing two metal centres as can be seen in a simulation of Hannon’s [Ni.sub.2][L.sub.3] complex, where L = bis(4-(2-pyridylmethyliminephenyl)methane) (Figure 1.8). Here, the diamine has divergent functionality leading to an extended ligand with an enforced twist.

(Continues…)

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