Philip Clements

Tailoring Polymeric Hydrogels through Cyclodextrin Host―Guest Complexation

A close correllation between molecular-level interactions and macroscopic characteristics of polymer networks exists. The characteristics of the polymeric hydrogels assembled from β-cyclodextrin (β-CD) and adamantyl (AD) substituted poly(acrylate)s can be tailored through selective host-guest complexation between β-CD and AD substituents and their tethers. Dominantly, steric effects and competitive intra- and intermolecular host-guest complexation are found to control poly(acrylate) isomeric inter-strand linkage in polymer network formation. This understanding of the factors involved in polymeric hydrogel formation points the way towards the construction of increasingly sophisticated biocompatible materials.

Diazacoronand linked β-cyclodextrin dimer complexes of Brilliant Yellow tetraanion and their sodium(I) analogues

Complexation of the Brilliant Yellow tetraanion, 3(4-), by two new diazacoronand linked beta-cyclodextrin (beta CD) dimers 4,13-bis(2-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl- and 4,13-bis(8-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl)-4,13- diaza-1,7,10-trioxacyclopentadecane, 1 and 2, respectively, has been studied in aqueous solution. UV-visible spectrophotometric studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NEt4ClO4) yielded complexation constants for the complexes 1 x 3(4-) and 2 x 3(4-), K1 = (1.08 +/- 0.01) x 10(5) and (6.21 +/- 0.08) x 10(3) dm3 mol-1, respectively. Similar studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NaClO4) yielded K3 = (4.63 +/- 0.09) x 10(5) and (3.38 +/- 0.05) x 10(4) dm3 mol-1 for the complexation of 3(4-) by Na+ x 1 and Na+ x 2 to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-), respectively. Potentiometric studies of the complexation of Na+ by 1 and 2 by the diazacoronand component of the linkers to give Na+ x 1 and Na+ x 2 yielded K2 = (2.00 +/- 0.05) x 10(3) and (1.8 +/- 0.05) x 10(3) dm3 mol-1, respectively, at 298.2 K and I = 0.10 mol dm-3(NEt4ClO4). For complexation of Na+ by 1 x 3(4-) and 2 x 3(4-) to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-) K2K3/K1 = K4 = 8.6 x 10(2) and 9.8 x 10(3) dm3 mol-1, respectively. The pKaS of 1H4(4+) are 7.63 +/- 0.01, 6.84 +/- 0.02, 5.51 +/- 0.04 and 4.98 +/- 0.03, and those of 2H4(4+) are 8.67 +/- 0.02, 8.11 +/- 0.02, 6.06 +/- 0.02 and 5.14 +/- 0.05. The larger magnitude of K1 for 1 by comparison with K1 for 2 is attributed to the octamethylene linkers of 2 competing with 3(4-) for occupancy of the annuli of the beta CD entities while the competitive ability of the dimethylene linkers of 1 is less. A similar argument applies to the relative magnitudes of K3 for Na+ x 1 and Na+ x 2. Increased electrostatic attraction probably accounts for K3 > K1 for Na+ x 1 x 3(4-) and 1 x 3(4-) and for Na+ x 2 x 3(4-) and 2 x 3(4-). The lesser magnitudes of K2 and K4 for Na+ x 1 and Na+ x 1 x 3(4-) compared with those for Na+ x 2 and Na+ x 2 x 3(4-) are attributed to the octamethylene linkers of 2 producing a more hydrophobic environment for the diazacoronand than that produced by the dimethylene linkers of 1. 1H NMR spectroscopic studies and the syntheses of 1 and 2 are described.

Pre-organisation or a hydrogen bonding mismatch: silver(I) diamide ligand coordination polymers versus discrete metallo-macrocyclic assemblies

The investigation of novel motifs to selectively complex anions is an area of considerable importance due to the significant environmental, biological and medicinal roles of anions. The synthesis of discrete metallo-macrocyclic compounds or coordination polymers displaying anion-binding pockets can generate specific anion receptors from relatively simple components. Here, we examine the self-assembly of a series of flexible diamide compounds L1–L5 with silver(I) metal salts. A new diamide ligand, 2,6-[N,N′-bis(di-(pyridin-2-yl)methyl)pyridine]-2,6-dicarboxamide (L5), with two chelating di-2-pyridylmethyl donor groups, was also prepared. Compounds L1–L3, lacking the pre-organising effect of a central 2,6-pyridine dicarboxamide core, form 1D coordination polymers {[Ag(L1)(CH3CN)](PF6)} n (6), {[Ag(L2)](NO3)·(H2O)]} n (7) and {[AgNO3(L3)]·(CH3OH)]} n (9) which in turn form 2D and 3D hydrogen-bonded networks through orthogonal hydrogen bonding. In one instance, L2 gives rise to a dinuclear metallo-macrocycle in the solid state, [Ag2(CF3CO2)2(L2)2][Ag2(μ2-CF3CO2)2(L2)2] (8). Both diamide ligands L4 and L5 form dinuclear metallo-macrocycles, [Ag2(NO2)2(L4)2] (10) and [Ag2(L5)2](NO3)2·2CH3OH·2H2O (11), in solution and in the solid state. Where possible, all compounds were investigated in solution and their solid-state structures were determined using X-ray crystallography. This enabled the effect of competing supramolecular synthons, covalent M–L bonding and hydrogen bonding, to be examined by comparing the solution and solid-state behaviour of each metal–ligand combination.

Host-Guest Complexation of Aromatic Carboxylic Acids and their Conjugate Bases by β-Cyclodextrins Monosubstituted at C 6 by Linear and Cyclic Alkyl Triamines in Aqueous Solution

A pH titrimetric study of the complexation of the guests benzoic acid, 4-methylbenzoic acid and (R)- and (S)-2-phenylpropanoic acids and their conjugate bases by the host 6A-[2-(2-aminoethylamino)ethylamino]-, 6A-[3-(3-aminopropylamino)propylamino]-, 6A-(1,4,7-triazacyclononan-1-yl)-, and 6A-(1,5,9-triazacyclododecan-1-yl)-6A-deoxy-β-cyclodextrins (βCDdien, βCDdipn, βCDtacn and βCDtacdo, respectively) is reported. Over the pH range 3.0–11.0, 49 host–guest complexes were detected. Their stability constants (K) range from 220±50 dm3 mol–1 for the βCDdienH22+ ·benzoate– complex to 48000±11000 dm3 mol–1 for the βCDdipnH22+·(S)-2-phenylpropanoic acid complex at 298.2 K and I = 0.10 mol dm–3 (NaClO4). The latter K value is among the highest reported for a complex of a simple carboxylic acid with a substituted β-cyclodextrin. The charge, hydrophobicity and stereochemistry of both host and guest appear to be significant factors in the variation of host–guest complex stability. 1H ROESY n.m.r. studies of some of the complexes formed are also reported.

Dimerisation and complexation of 6-(4′-t-butylphenylamino)naphthalene-2-sulphonate by β-cyclodextrin and linked β-cyclodextrin dimers

This study shows that stereochemical factors largely determine the extent to which 6-(4′-t-butylphenylamino)-naphthalene-2-sulphonate, BNS− and its dimer, (BNS− )2, are complexed by β-cyclodextrin, βCD, and a range of linked βCD dimers. Fluorescence and 1H NMR studies, respectively, show that BNS− and (BNS− )2 form host–guest complexes with βCD of the stoichiometry βCD.BNS− (10− 4 K 1 = 4.67 dm3 mol− 1) and βCD.BNS2 2 − (10− 2 K 2′ = 2.31 dm3 mol− 1), where the complexation constant K 1 = [βCD.BNS− ]/([βCD][BNS− ]) and K 2′ = [βCD. (BNS− )2]/([βCD.BNS− ][BNS− ]) in aqueous phosphate buffer at pH 7.0, I = 0.10 mol dm3 at 298.2 K. (The dimerisation of BNS− is characterised by 10− 2 K d = 2.65 dm3 mol− 1.) For N,N-bis((2AS,3AS)-3A-deoxy-3A-β-cyclodextrin)succinamide, 33βCD2su, N-((2AS,3AS)-3A-deoxy-3A-β-cyclodextrin)-N′-(6A-deoxy-6A-β-cyclodextrin)urea, 36βCD2su, N,N-bis(6A-deoxy-6A-β-cyclodextrin)succinamide, 66βCD2su, N-((2AS,3AS)-3A-deoxy-3A-β-cyclodextrin)-N′-(6A-deoxy-6A-β-cyclodextrin)urea, 36βCD2ur, and N,N-bis(6A-deoxy-6A-β-cyclodextrin)urea, 66βCD2ur, the analogous 10− 4 K 1 = 11.0, 101, 330, 29.6 and 435 dm3 mol− 1 and 10− 2 K 2′ = 2.56, 2.31, 2.59, 1.82 and 1.72 dm3 mol− 1, respectively. A similar variation occurs in K 1 derived by UV–vis methods. The factors causing the variations in K 1 and K 2 are discussed in conjunction with 1H ROESY NMR and molecular modelling studies.

Diazacoronand-Linked α- and β-Cyclodextrin Dimer Complexes of the Brilliant Yellow Tetraanion

Complexation of the Brilliant Yellow tetraanion, 14–, by the new coronand-linked α- and β-cyclodextrin (αCD and βCD) dimers 4,13-bis(6 A-deoxy-α-cyclodextrin-6 A-ylamidomethyl)-4,13-diaza-1,7,10-trioxacyclodecapentane and 4,13-bis(6 A-deoxy-β-cyclodextrin-6 A-ylamidomethyl)-4,13-diaza-1,7,10-trioxacyclodecapentane, 2 and 3, respectively, has been studied in aqueous solution. The complexation constants for 2 · 14– and 3 · 14– are K1 = (3.20 ± 0.05) × 105 and (2.76 ± 0.09) × 104 dm3 mol–1, respectively, at 298.2 K, pH 10.0, and I 0.10 mol dm–3 (NEt4ClO4). The pK a values of 2 · H22+ are 6.57 ± 0.04 and 5.88 ± 0.05, and of 3 · H22+ are 6.70 ± 0.03 and 6.08 ± 0.02. Complexation of the alkaline earth metal ions by 2 is characterized by complexation constants (2.73 ± 0.51) × 102, (1.52 ± 0.36) × 105, (1.49 ± 0.03) × 105, and (4.28 ± 0.07) × 104 dm3 mol–1 for Mg2+, Ca2+, Sr2+, and Ba2+, respectively. These data are compared with those reported for analogous coronand-linked βCD dimer complexes to establish the hierarchy of the factors determining the stability of such complexes.

Supramolecular Chemistry of Pyronines B and Y, β-Cyclodextrin and Linked β-Cyclodextrin Dimers

The complexation of cationic pyronine B (PB+) and pyronine Y (PY+) by β-cyclodextrin (βCD) and two linked βCD dimers, N,N′-bis((2AS,3AS)-3A-deoxy-β-cyclodextrin-3A-yl)succinamide, 33βCD2suc, and N,N′-bis(6A-deoxy-β-cyclodextrin-6A-yl)succinamide, 66βCD2suc, in aqueous solution has been studied by UV-vis, fluorescence, and 1H NMR spectroscopy. The complexation constants for the 1:1 complexes: βCD.PB+, 33βCD2suc.PB+, 66βCD2suc.PB+, and the analogous PY+ complexes are reported as are the dimerization constants for PB+ and PY+. The modes of complexation, dimerization, and fluorescence quenching are discussed.

Square pegs in round holes. Preparation and intramolecular complexation of cubyl substituted β-cyclodextrins† and of an adamantane analogue

The reaction of either 1-methoxycarbonyl-4-(4-nitrophenoxycarbonyl)cubane or its dimethyl analogue, 2,3-dimethyl-1-methoxycarbonyl-4-(4-nitrophenoxycarbonyl)cubane, with the primary amine of 6A-(6-aminohexyl)amino-6A-deoxy-β-cyclodextrin produces the first cubyl substituted β-cyclodextrins, 6A-deoxy-6A-{6-[N-(4-methoxycarbonylcuban-1-ylcarbonyl)amino]hexylamino}-β-cyclodextrin and its dimethyl analogue, respectively, and 4-nitrophenolate. The reaction of 1,4-bis(4-nitrophenoxycarbonyl)cubane with 6A-(6-aminohexyl)amino-6A-deoxy-β-cyclodextrin produces the dimer 1,4-bis{6-[N-(6A-deoxy-β-cyclodextrin-6A-yl)amino]hexylaminocarbonyl}cubane. 1H NMR ROESY studies are consistent with the cubyl moiety of each of the above three cubyl-substituted β-cyclodextrins complexing in the β-cyclodextrin annuli in D2O. The reaction of 1-(4-nitrophenoxycarbonyl)adamantane with β-cyclodextrin produces 6A-{6-[N-(1-adamantylcarbonyl)amino]hexylamino}-6A-deoxy-β-cyclodextrin which shows a strong intramolecular complexation of its adamantyl moiety. Adamantane-1-carboxylate forms intermolecular complexes with the above three cubyl-substituted β-cyclodextrins in D2O solution and excludes the cubyl moiety from the β-cyclodextrin annulus. However, this does not occur for 6A-{6-[N-(1-adamantylcarbonyl)amino]hexylamino}-6A-deoxy-β-cyclodextrin where intramolecular complexation appears to be sufficiently strong to prevent intermolecular complexation of adamantane-1-carboxylate.

β-Cyclodextrin- and adamantyl-substituted poly(acrylate) self-assembling aqueous networks designed for controlled complexation and release of small molecules

Three aqueous self-assembling poly(acrylate) networks have been designed to gain insight into the factors controlling the complexation and release of small molecules within them. These networks are formed between 8.8% 6A-(2-aminoethyl)amino-6A-deoxy-6A-β-cyclodextrin, β-CDen, randomly substituted poly(acrylate), PAAβ-CDen, and one of the 3.3% 1-(2-aminoethyl)amidoadamantyl, ADen, 3.0% 1-(6-aminohexyl)amidoadamantyl, ADhn, or 2.9% 1-(12-aminododecyl)amidoadamantyl, ADddn, randomly substituted poly(acrylate)s, PAAADen, PAAADhn and PAAADddn, respectively, such that the ratio of β-CDen to adamantyl substituents is ca. 3:1. The variation of the characteristics of the complexation of the dyes methyl red, methyl orange and ethyl orange in these three networks and by β-cyclodextrin, β-CD, and PAAβ-CDen alone provides insight into the factors affecting dye complexation. The rates of release of the dyes through a dialysis membrane from the three aqueous networks show a high dependence on host–guest complexation between the β-CDen substituents and the dyes as well as the structure and the viscosity of the network as shown by ITC, 1H NMR and UV–vis spectroscopy, and rheological studies. Such networks potentially form a basis for the design of controlled drug release systems.

Complexation by α- and β-cyclodextrin C(6) linked homo- and hetero-dimers of Brilliant Yellow tetraanion: a study of host-guest size relationships

Complexation by α- and β-cyclodextrin (αCD and βCD) homo- and heterodimers linked at C(6) by a urea linker (N,N′-bis(6A-deoxy-α-cyclodextrin-6A-yl)urea, N-(6A-deoxy-α-cyclodextrin-6A-yl)-N′-(6A-deoxy-β-cyclodextrin-6A-yl)urea and N,N′-bis(6A-deoxy-β-cyclodextrin-6A-yl)urea 1–3) of the tetraanion of the dye Brilliant Yellow (4) has been studied. In aqueous solution at 298.2 K, pH 10.0 (borate) and I = 0.10 mol dm−3 (NaClO4) the spectrophotometrically determined complexation constants K = (1.40 ± 0.08) × 104, (9.05 ± 0.16) × 104 and (3.92 ± 0.06) × 104 dm3 mol−1, for the complexes 1···4, 2··4 and 3··4, respectively, that compare with K = (1.05 ± 0.08) × 104 and (2.20 ± 0.05) × 103 dm3 mol−1 for the αCD·4 and βCD·4 complexes, respectively. Thus, the complexation of 4 in 1···4 shows little cooperativity consistent with the annulus of each αCD component of 1 being too small to pass over the phenylsulfonate component of 4. It is probable that two complexes are formed when 2 complexes 4: one in which 4 is complexed by the αCD component alone and which has a similar stability to 1···4 and a second complex where 4 is complexed by both the αCD and βCD components of 2 to form a complex 8.6 and 41 times more stable than αCD·4 and βCD·4, respectively. The cooperativity between the two βCD components of 3 causes 3··4 to be 18 times more stable than βCD·4. These conclusions are supported by 1H NMR spectroscopic studies.