Two new Zn4L6 cages composed of diamine subcomponents containing either naphthalene diimide (NDI) or porphyrin moieties are described. Their structural differences allow these cages to exhibit distinct interactions with different chemical stimuli, yielding different supramolecular products. The electron-poor NDI subunits of the first cage were observed to thread through electron-rich aromatic crown-ether macrocycles, forming mechanically-interlocked species up to a [3]catenane, whereas the porphyrin ligands of the second cage interacted favourably with C70, causing it to be bound as a guest. When mixed, the two cages were observed to form a dynamic combinatorial library (DCL) of seven constitutionally distinct mixed-ligand Zn4L6 cages. The DCL was observed to reconstitute in opposing ways when treated with either the crown ether or C70: the electron-rich macrocycle templated the formation of heteroleptic catenanes, whereas C70 caused the DCL to self-sort into homoleptic structures.

A homochiral naphthalenediimide-based building block forms in water a disulfide library of macrocycles containing topological isomers. We attempted to identify each of these isomers, and explored the mechanisms leading to their formation. The two most abundant species of the library were assigned as a topologically chiral Solomon link (60% of the library, as measured by high-performance liquid chromatography (HPLC)) and a topologically achiral figure eight knot (18% by HPLC), competing products with formally different geometries but remarkably similar 4-fold symmetries. In contrast, a racemic mixture of building blocks gives the near-quantitative formation of another new and more stable structure, assigned as a meso figure eight knot. Taken together, these results seem to uncover a correlation between the point chirality of the building block used and the topological chirality of the major structure formed. These and the earlier discovery of a trefoil knot also suggest that the number of rigid components in the building block may translate into corresponding knot symmetry and could set the basis of a new strategy for constructing complex topologies.

We present the first polymorph interconversion study that uses solid-state dynamic covalent chemistry (DCC). This system exhibits unexpected and rich behavior, including the observation that under appropriate conditions the polymorph interconversion of a heterodimer proceeds through reversible covalent chemistry intermediates, and this route is facilitated by one of the two disulfide homodimers involved in the reaction. Furthermore, we demonstrate experimentally that in all cases a dynamic equilibrium is reached, meaning that changing the milling conditions affects the free energy difference between the two polymorphs and thus their relative stability. We suggest that this effect is due to the surface solvation energy combined with the high surface to volume ratio of the nanocrystalline powder.

We describe here the use of disulfide exchange reactions to generate distinct supramolecular topologies within a dynamic combinatorial library (DCL) derived from tri- and mono-functionalised thiol components in water. This approach allows for the effective expansion of structural diversity within a DCL, and also provides a sensitive probe for weak supramolecular interactions.

Since its inception in the mid-1990s, dynamic combinatorial chemistry (DCC), the chemistry of complex systems under thermodynamic control, has proved valuable in identifying unexpected molecules with remarkable binding properties and in providing effective synthetic routes to complex species. Essentially, in this approach, one designs the experiment rather than the molecule. DCC has also provided us with insights into how some chemical systems respond to external stimuli. Using examples from the work of our laboratory and others, this Account shows how the concept of DCC, inspired by the evolution of living systems, has found an increasing range of applications in diverse areas and has evolved conceptually and experimentally.A dynamic combinatorial library (DCL) is a thermodynamically controlled mixture of interconverting species that can respond to various stimuli. The Cambridge version of dynamic combinatorial chemistry was initially inspired by the mammalian immune system and was conceived as a way to create and identify new unpredictable receptors. For example, an added template can select and stabilize a strongly binding member of the library which is then amplified at the expense of the unsuccessful library members, minimizing the free energy of the system. But researchers have exploited DCC in a variety of other ways: over the past two decades, this technique has contributed to the evolution of chemistry and to applications in the diverse fields of catalysis, fragrance release, and responsive materials. Among these applications, researchers have built intricate and well-defined architectures such as catenanes or hydrogen-bonded nanotubes, using the ability of complex chemical systems to reach a high level of organization. In addition, DCC has proved a powerful tool for the study of complex molecular networks and systems.The use of DCC is improving our understanding of chemical and biological systems. The study of folding or self-replicating macrocycles in DCLs has served as a model for appreciating how complex organisations such as life can emerge from a pool of simple chemicals. Today, DCC is no longer restricted to thermodynamic control, and new systems have recently appeared in which kinetic and thermodynamic control coexist. Expanding the realm of DCC to unexplored and promising new territories, these hybrid systems show that the concept of dynamic combinatorial chemistry continues to evolve.

We report the first dynamic combinatorial synthesis in water of an all-acceptor [2]catenane and of different types of donor–acceptor [2] and [3]catenanes. Linking two electron-deficient motifs within one building block using a series of homologous alkyl chains provides efficient and selective access to a variety of catenanes and offers an unprecedented opportunity to explore the parameters that govern their synthesis in water. In this series, catenane assembly is controlled by a fine balance between kinetics and thermodynamics and subtle variations in the building block structure, such as the linker length and building block chirality. A remarkable and unexpected odd–even effect with respect to the number of atoms in the alkyl linker is reported.

We describe here the discovery of a new class of organic cages assembled from simple tri- and dithiol building blocks using dynamic combinatorial chemistry (DCC). These water-soluble disulfide-linked architectures containing up to eleven components are only generated upon templation by positively charged polyamine guests of appropriate shape and length such as spermine and spermidine. The overall response of the system as expressed in the pattern of peaks in an HPLC trace provides an unusual tool for the identification of the templating analyte.

Six new lanthanide complexes of two 44-membered macrocycles have been prepared and characterised in solution. An analysis of the conformations of the free macrocycles and their lanthanide complexes both in solution (2D NMR) and in solid state (X-ray crystallography) demonstrate that the complexation induces changes in folding of the macrocycles.

We present the use of hydrazone dynamic combinatorial libraries (DCLs) to identify macrocyclic receptors that are selective for alkaline earth metal ions over alkali metal ions. In particular, the toxic heavy metal ions Sr2+ and Ba2+ induce characteristic changes in the DCLs. Four macrocycles were isolated and characterised by LCMS, HRMS, NMR and X-ray crystallography; binding studies by UV-Vis spectroscopy confirm the selectivity observed in the DCLs.

We describe the use of dynamic combinatorial chemistry to discover a new series of linear hydrazone-based receptors that bind multiple dihydrogen phosphate ions. Through the use of a template-driven, selection-based approach to receptor synthesis, dynamic combinatorial chemistry allows for the identification of unexpected host structures and binding motifs. Notably, we observed the unprecedented selection of these linear receptors in preference to competing macrocyclic hosts. Furthermore, linear receptors containing up to nine building blocks and three different building blocks were amplified in the dynamic combinatorial library. The receptors were formed using a dihydrazide building block based on an amino acid-disubstituted ferrocene scaffold. A detailed study of the linear pentamer revealed that it forms a helical ditopic receptor that employs four acylhydrazone hydrogen-bond donor motifs to cooperatively bind two dihydrogen phosphate ions.

The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor−acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor−acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor−acceptor interactions when building such complex architectures.

Amino-acid functionalized naphthalenediimides self-assemble into hydrogen-bonded supramolecular helical nanotubes via a noncooperative, isodesmic process; the self-assembly of ordered helical systems is usually realized through a cooperative process. This unexpected behavior was rationalized as a manifestation of entropy–enthalpy compensation. Fundamental insights into the thermodynamics governing this self-assembly were obtained through the fitting of the isodesmic model to 1H NMR spectrometry and circular dichroism spectroscopy measurements. Furthermore, we have extended the application of this mathematical model, for the first time, to quantitatively estimate the effect of guests, solvents, and side chains on the stability of the supramolecular nanotube; most significantly, we demonstrate that C60 acts as a template to stabilize the nanotube assembly and thereby substantially increase the degree of polymerization.

We report the synthesis of a family of new macrocyclic hydrazone-based anion receptors. Formed from the reaction between isophthalaldehyde and a helical amino acid-disubstituted ferrocene dihydrazide, these macrocycles contain from one to eight ferrocene moieties. The isolation of the four smallest of the macrocycles and their characterisation by UV-Vis, CD and NMR spectroscopy is described. The conformation of the macrocycles is explored, particularly with reference to the formation of a helical intramolecularly hydrogen-bonded structure. An investigation of the use of these macrocycles as anion-receptors shows that they are all effective hosts; the larger macrocycles show the highest affinities for anions. Studies using NMR spectroscopy suggest that the anion-recognition results primarily from the formation of multiple hydrogen bonds between the anions and the electropositive N–H protons of the acylhydrazones.

Thermodynamic control over kinetically-trapped mixtures of hydrazone-based macrocycles is achieved by addition of an aromatic monohydrazide to generate dynamic combinatorial libraries (DCLs) of linear and macrocyclic oligomers.

A new [2+2] tetra-hydrazone macrocyclic receptor was significantly amplified in a dynamic combinatorial library upon templation with alkaline earth metal ions. After optimisation the product could be isolated in 95% yield and its interaction with ions was investigated by NMR and UV-Vis spectroscopy.

Three new N-desymmetrised naphthalenediimides (NDIs) are described, each containing one chiral and one achiral centre. The ability of such ‘monochiral’ NDIs to self-assemble into hydrogen-bonded helical nanotubes, to act as a sergeant in a ‘sergeants-and-soldiers’ system and to form a hexameric receptor for C70 was examined. Small differences at the achiral centre were found to have significant effects on the supramolecular properties of the NDI. All three new NDIs form nanotubes that bind C60, but with different efficiencies, and one is a better sergeant than any of the dichiral NDIs investigated to date.

We describe here the assembly of new types of donor−acceptor [2]catenanes from dynamic combinatorial libraries (DCL) in water. These new catenanes contain both the donor and acceptor components in at least one of the interlocked rings, thereby possessing unusual and unexpected DAAD or DADD stacking sequences of the π units in their structures. The efficiency of the catenane assembly process can be enhanced by manipulating the DCL equilibrium in a variety of ways: adding a guest, changing the building block stoichiometries, or increasing the library concentration or the ionic strength of the solvent. The formation of catenanes and their constitutions are found to be dependent on subtle differences in the geometry, dimension, and flexibility of the donor building blocks.

The behaviour of aqueous dynamic combinatorial libraries (DCLs) containing either electron-rich donor building blocks based on dioxynaphthalene (DN), or electron-deficient acceptor building blocks based on naphthalenediimide (NDI) are described. The influence of concentration and ionic strength on library distribution and diversity, together with the responses to electronically-complementary templates have been explored in detail, establishing the principles to be employed in more complex libraries leading to a new generation of catenanes.

We expand the possibilities in hydrazone based dynamic combinatorial chemistry with a series of new building blocks incorporating heterocyclic motifs. The synthetic procedure allows efficient access to building blocks with the general structure (MeO)2CH-Heterocycle-C(O)NHNH2, originating from heterocycles with an amine and an ester functionality. The equilibrium distribution of macrocyclic N-acyl hydrazones formed upon deprotection of the building blocks with TFA in organic solvents is reported. The mixing behaviour of these heterocycle-based building blocks with our cholate-based building blocks is described, particularly the observation of kinetic intermediates that disappear following ‘proof-reading’.

We describe an efficient and general strategy for the synthesis of dimethyl acetal functionalised steroidal hydrazides based on the cholic acid skeleton with the aim of using these compounds as building blocks for dynamic combinatorial chemistry. Deprotection of the acetal protected building blocks with TFA leads to formation of libraries containing macrocyclic N-acyl hydrazone oligomers. The isolation of several of these, and their characterisation using NMR is described. The effects on the equilibrium library distribution by varying the substituents at C-7 and C-12, extending the side-chain with glycine, and inverting the configuration at C-3 are discussed. Finally, we report the exchange properties of these macrocycles and demonstrate new examples of proof-reading and self-sorting in dynamic combinatorial libraries.

Two donor−acceptor [2]catenanes have been synthesized and characterized from a single dynamic combinatorial library in water. One of these catenanes is different from earlier related interlocked molecules in that two donor units stack on each other in an unexpected order. Shifting the equilibrium by choosing the right conditions resulted in a significant increase in the yields of the individual catenanes.

The discovery, in a two-phase dynamic combinatorial library, of an unexpected linear receptor and transporter for spermine is described.

We report a dynamic combinatorial library that, upon binding of an electronically-complementary guest, produces in high yield a tetrameric receptor with flat hydrophobic, electron-deficient surfaces and flexible, water-soluble disulfide-containing linkers; analysis of the dependence of library composition on template concentration gives insight into the binding behaviours of the species involved.

A new type of neutral donor–acceptor [2]-catenane, containing both complementary units in the same ring was synthesized from a dynamic combinatorial library in water. The yield of the water soluble [2]-catenane is enhanced by increasing either building-block concentrations or ionic strength, or by the addition of an electron-rich template. NMR spectroscopy demonstrates that the template is intercalated between the 2 electron-deficient naphthalenediimide units of the catenane.

A two-phase approach to dynamic combinatorial chemistry is described using disulfide exchange chemistry; the use of two phases significantly increases the possibilities and the scope of dynamic combinatorial chemistry by facilitating the combination of otherwise incompatible building blocks.

Two different macrocyclic members of a pseudo-peptidehydrazone dynamic combinatorial library were amplified using the diastereomeric templates quinine and quinidine.

Expanding on our earlier building block architecture [(MeO)2CH–Linker–Pro–X–NHNH2 where X = Phe, Cha], we have produced a series of new pseudo-dipeptides [(MeO)2CH–Linker–Pro–X–NHNH2 where X = Val, Leu, Ile, Ala] for use in hydrazone-based dynamic combinatorial libraries (DCLs); reverse order analogues [Phe-Pro and Val-Pro] and two enantio-analogues [Pro-Phe and Pro-Val] were also prepared. The behaviours of these building blocks in DCLs, as single components and in mixtures, were studied systematically using HPLC and mass spectrometry in order to gain insight into the relationship between building block structure and good library diversity. Subtle changes in building block structure lead to significant changes in library distribution and in the ability to produce diverse libraries in mixtures.

3,4-Tetramethylpyridiniumporphyrazines bind strongly and selectively to human telomeric G-quadruplex DNA, inducing the formation of an antiparallel quadruplex in a process that mimics molecular chaperones.

Aluminium(III) porphyrin–carboxylate complexes, including a porphyrin pentamer, have been characterised by NMR spectroscopy, MALDI spectrometry and single crystal X-ray diffraction; these complexes can also be coordinated by a sixth, nitrogenous, ligand to the aluminium(III) centre.

Suzuki and Sonogashira couplings have been used in short and efficient sequences to give access to a new family of porphyrin trimers on a practical scale.

A series of cationic porphyrins carrying 1–3 meso-N-pyridinium groups has been synthesised, and their binding to G-quadruplex DNA has been explored by surface plasmon resonance (SPR) and circular dichroism spectroscopy. Two trans substituents appear to be sufficient for tight binding; preferential binding to the anti-parallel intramolecular human telomeric DNA was observed for the A2trans and A3 porphyrins. The A2trans is able to induce the formation of an anti-parallel G-quadruplex in a K+ free solution, mimicking the effect of a molecular chaperone.

Abstract

Directed chemical synthesis can produce a vast range of molecular structures, but the intended product must be known at the outset. In contrast, evolution in nature can lead to efficient receptors and catalysts whose structures defy prediction. To access such unpredictable structures, we prepared dynamic combinatorial libraries in which reversibly binding building blocks assemble around a receptor target. We selected for an acetylcholine receptor by adding the neurotransmitter to solutions of dipeptide hydrazones [proline-phenylalanine or proline-(cyclohexyl)alanine], which reversibly combine through hydrazone linkages. At thermodynamic equilibrium, the dominant receptor structure was an elaborate [2]-catenane consisting of two interlocked macrocyclic trimers. This complex receptor with a 100 nM affinity for acetylcholine could be isolated on a preparative scale in 67% yield.

Dynamic combinatorial libraries have been prepared which feature two simultaneous covalent exchange reactions in aqueous solution at neutral pH. This allows for diversity, not only of the subunits that are linked, but also of the linkage itself.

New macrocycles incorporating a porphyrin and a π electron-rich aromatic were prepared from a dynamic disulfide library. The outcome could be influenced by use of templates.

A new, highly flexible porphyrin dimer was isolated in preparative scale from a dynamic disulfide library; this receptor adjusts to fit guests with a wide range of steric requirements and, whilst C60 proved to be an unsuitable template for this library, a new C60-porphyrin complex was isolated and characterised.

Formation of a series of pseudorotaxanes from an electron-rich crown ether (host 1), pyromellitic diimide (guest 2) and alkali salt templates MX, where M = Li+ and Na+, and X− = Br−, I−, CF3SO3−, [B(C6F5)4]− and [B{3,5-(CF3)2(C6H3)}4]−, is reported. Mixing of 1 and 2 in CH2Cl2 or a mixture of CHCl3 and MeOH (98∶2) gave a pale yellow solution indicative of a very weak charge-transfer interaction. Upon addition of MX, brightly coloured solutions were obtained, resulting from a red shift and an increase in the intensity of the charge-transfer band. Structural and kinetic studies of the pseudorotaxanes were performed by NMR. The solution-phase structures of [M2·1·2]2+ are in good agreement with the solid-phase structure determined by X-ray crystallography. The remarkable templating properties of Li+ for the 1·2 donor-acceptor complex are due to the almost perfect coincidence of coordinative geometries in [Li2·1]2+ and [Li2·1·2]2+.

Primary alkynyl phosphine porphyrins were prepared by AlHCl2 reduction of the corresponding alkynyl phosphonates. Dephosphorylation of the alkyne proved to be a major side reaction. Using LiAlH4 as reducing agent, the alkyne was found to be partially reduced to give the trans-alkenyl phosphine selectively. The primary phosphines coordinate to both ruthenium(II) and rhodium(III) porphyrins and readily form bis-phosphine complexes. The 1H and 31P NMR spectra for the ruthenium complexes show a pattern characteristic of an [AX2]2 spin system with an unusually large 2JPP coupling constant of 620.6 Hz. The IR spectrum of the complex (PAPH2)Ru(CO)(porphyrin) (PAPH2=phenylacetylenephosphine) indicates weak σ-donor properties of the ligand. In contrast to the corresponding tertiary phosphine complexes, the bis-phosphine complexes with both ruthenium(II) and rhodium(III) porphyrins are more stable than the mono-phosphine complexes, as judged by NMR spectroscopy, and they can also be detected in the gas phase by LDI-TOF MS. In all cases the complexes could not be isolated and they degrade within hours at ambient temperatures when kept in solution. These compounds may therefore not be suitable for the construction of larger multiporphyrin systems, but their accessibility makes it possible to study their coordination behaviour with other transition metals.

Disulfide-linked cyclic porphyrin oligomers from dimer to tetramer can be selected and amplified virtually quantitatively from a dynamic combinatorial library using bis-thiol substituted zinc(II) porphyrin units with appropriate amine donor templates.

Three building blocks of general structure (MeO)2CH–aromatic linker–Pro–amino acid–NHNH2 have been prepared and tested in acid-catalysed dynamic combinatorial libraries. Exposure of these libraries to LiI and NaI led to the amplification of three macrocyclic pseudopeptide receptors. The receptors were isolated and their interactions with LiI and NaI were analysed using NMR, IR and ITC. Binding of the metal ions to the receptors is invariably entropy-driven. Nevertheless, all receptors were found to be flexible with substantial conformational rearrangements accompanying guest binding. This type of receptor is extremely difficult to access through rational design and the fact that dynamic combinatorial chemistry allows facile access to these challenging molecules underlines the power of the dynamic approach.

Generating combinatorial libraries under equilibrium conditions has the important advantage that the libraries are adaptive (i.e. they can respond to exterior influences in the form of molecular recognition events). Thus, a ligand will direct and amplify the formation of its ideal receptor and vice versa. Proof of principle of this approach has been established using small libraries showing highly efficient amplification of selected receptors. The approach has recently been extended to address folding of macromolecules, including peptides.

The demonstration that an immobilised template can simultaneously select, amplify and purify a receptor is a key step forward in the development of dynamic combinatorial chemistry.

A cyclic porphyrin tetramer, consisting of two bis-phosphine substituted zinc(II) porphyrin units and two Rh(III)TPP units, is selected and amplified virtually quantitatively from a dynamic combinatorial library using 4,4′-bipy as a scaffold and using orthogonal binding modes.

The binding constants between the pyridine ligands 1–3 and the metalloporphyrin hosts 4, 6, and 7 were measured at various temperatures in toluene. The binding constants and the thermodynamic parameters found for the various complexes indicate that the cyclic nature of hosts 6 and 7 enhances binding of the substituted pyridine ligands 1 and 2, due to enthalpic factors with the smaller host 6, or entropic factors with the larger host 7. This enhanced binding is likely to lead to an increase in the reactive complex concentration in host-induced accelerated reactions; these cavity effects, which are not present in linear templates, could contribute to the greater efficiency of cyclic hosts. A plot of the enthalpic energetic gain vs. the entropic energetic cost measured for binding ligands 1–3 to hosts 4, 6 and 7 shows an enthalpy–entropy compensation effect.

Analysis of a representative series of metalloporphyrins and of their supramolecular assemblies using laser desorption/ionisation time of flight mass spectrometry (LDI-TOF MS) revealed that non-covalent metal–ligand interactions in the complexes remain effective in the gas phase. Detectable assemblies range from simple ruthenium( II) porphyrin complexes with N- or P-donor ligands, or tin( IV) and zirconium( IV) porphyrin complexes with O-donor ligands, up to trimeric arrays. Crucial to successful recording of intact complexes is avoiding protic matrices which interfere with Lewis acidic analytes and which may induce ligand exchange reactions to form complexes with the matrix itself. Also described is the in situ generation of a series of ruthenium( II) porphyrin dimers via laser induced vaporisation of the corresponding monomers and the suppression of dimerisation by nitrogen and phosphorus ligands. Careful adjustment of instrument parameters such as incident laser energy requires special attention. Relative affinities in complexation reactions are found to be consistent with liquid phase chemistry, therefore LDI-MS can provide a fast and simple, yet effective screening method for reactivity exploration. However, it also induces side-reactions such as iodine abstraction/transfer reactions. Furthermore, structurally different porphyrins show variations up to 90% in relative ion formation. Extreme caution is therefore required in the interpretation, and particularly in the quantitation, of such mass spectra.

Cyclic zinc-porphyrin dimers have been synthesised using reversible π-allyl palladium chemistry in the presence of bidentate pyridyl ligand templates.

A trace component within a dynamic combinatorial library of pseudo-peptide hydrazones has been dramatically amplified in a reversible manner through recognition by [18]crown-6.

A route to alkyne-phosphine-substituted metalloporphyrins is presented. The X-ray structure of the methanol adduct of a diphenylphosphine Zn(II) porphyrin reveals solid state dimerisation accompanied by proton transfer from coordinated methanol to phosphine in a process reminiscent of carbonic anhydrase. The ability of the phosphine-substituted porphyrins to form non-covalent arrays with a Ru(II) porphyrin was explored using 1H/31P NMR and UV/vis spectroscopy as well as MALDI-TOF mass spectrometry.

Two different macrocyclic members of a pseudo-peptidehydrazone dynamic combinatorial library were amplified using the diastereomeric templates quinine and quinidine.

Thermodynamic control over kinetically-trapped mixtures of hydrazone-based macrocycles is achieved by addition of an aromatic monohydrazide to generate dynamic combinatorial libraries (DCLs) of linear and macrocyclic oligomers.

The behaviour of aqueous dynamic combinatorial libraries (DCLs) containing either electron-rich donor building blocks based on dioxynaphthalene (DN), or electron-deficient acceptor building blocks based on naphthalenediimide (NDI) are described. The influence of concentration and ionic strength on library distribution and diversity, together with the responses to electronically-complementary templates have been explored in detail, establishing the principles to be employed in more complex libraries leading to a new generation of catenanes.

We report the synthesis of a family of new macrocyclic hydrazone-based anion receptors. Formed from the reaction between isophthalaldehyde and a helical amino acid-disubstituted ferrocene dihydrazide, these macrocycles contain from one to eight ferrocene moieties. The isolation of the four smallest of the macrocycles and their characterisation by UV-Vis, CD and NMR spectroscopy is described. The conformation of the macrocycles is explored, particularly with reference to the formation of a helical intramolecularly hydrogen-bonded structure. An investigation of the use of these macrocycles as anion-receptors shows that they are all effective hosts; the larger macrocycles show the highest affinities for anions. Studies using NMR spectroscopy suggest that the anion-recognition results primarily from the formation of multiple hydrogen bonds between the anions and the electropositive N–H protons of the acylhydrazones.

Three new N-desymmetrised naphthalenediimides (NDIs) are described, each containing one chiral and one achiral centre. The ability of such ‘monochiral’ NDIs to self-assemble into hydrogen-bonded helical nanotubes, to act as a sergeant in a ‘sergeants-and-soldiers’ system and to form a hexameric receptor for C70 was examined. Small differences at the achiral centre were found to have significant effects on the supramolecular properties of the NDI. All three new NDIs form nanotubes that bind C60, but with different efficiencies, and one is a better sergeant than any of the dichiral NDIs investigated to date.

We expand the possibilities in hydrazone based dynamic combinatorial chemistry with a series of new building blocks incorporating heterocyclic motifs. The synthetic procedure allows efficient access to building blocks with the general structure (MeO)2CH-Heterocycle-C(O)NHNH2, originating from heterocycles with an amine and an ester functionality. The equilibrium distribution of macrocyclic N-acyl hydrazones formed upon deprotection of the building blocks with TFA in organic solvents is reported. The mixing behaviour of these heterocycle-based building blocks with our cholate-based building blocks is described, particularly the observation of kinetic intermediates that disappear following ‘proof-reading’.

Six new lanthanide complexes of two 44-membered macrocycles have been prepared and characterised in solution. An analysis of the conformations of the free macrocycles and their lanthanide complexes both in solution (2D NMR) and in solid state (X-ray crystallography) demonstrate that the complexation induces changes in folding of the macrocycles.

We describe an efficient and general strategy for the synthesis of dimethyl acetal functionalised steroidal hydrazides based on the cholic acid skeleton with the aim of using these compounds as building blocks for dynamic combinatorial chemistry. Deprotection of the acetal protected building blocks with TFA leads to formation of libraries containing macrocyclic N-acyl hydrazone oligomers. The isolation of several of these, and their characterisation using NMR is described. The effects on the equilibrium library distribution by varying the substituents at C-7 and C-12, extending the side-chain with glycine, and inverting the configuration at C-3 are discussed. Finally, we report the exchange properties of these macrocycles and demonstrate new examples of proof-reading and self-sorting in dynamic combinatorial libraries.

Expanding on our earlier building block architecture [(MeO)2CH–Linker–Pro–X–NHNH2 where X = Phe, Cha], we have produced a series of new pseudo-dipeptides [(MeO)2CH–Linker–Pro–X–NHNH2 where X = Val, Leu, Ile, Ala] for use in hydrazone-based dynamic combinatorial libraries (DCLs); reverse order analogues [Phe-Pro and Val-Pro] and two enantio-analogues [Pro-Phe and Pro-Val] were also prepared. The behaviours of these building blocks in DCLs, as single components and in mixtures, were studied systematically using HPLC and mass spectrometry in order to gain insight into the relationship between building block structure and good library diversity. Subtle changes in building block structure lead to significant changes in library distribution and in the ability to produce diverse libraries in mixtures.

We present the use of hydrazone dynamic combinatorial libraries (DCLs) to identify macrocyclic receptors that are selective for alkaline earth metal ions over alkali metal ions. In particular, the toxic heavy metal ions Sr2+ and Ba2+ induce characteristic changes in the DCLs. Four macrocycles were isolated and characterised by LCMS, HRMS, NMR and X-ray crystallography; binding studies by UV-Vis spectroscopy confirm the selectivity observed in the DCLs.

Two new Zn4L6 cages composed of diamine subcomponents containing either naphthalene diimide (NDI) or porphyrin moieties are described. Their structural differences allow these cages to exhibit distinct interactions with different chemical stimuli, yielding different supramolecular products. The electron-poor NDI subunits of the first cage were observed to thread through electron-rich aromatic crown-ether macrocycles, forming mechanically-interlocked species up to a [3]catenane, whereas the porphyrin ligands of the second cage interacted favourably with C70, causing it to be bound as a guest. When mixed, the two cages were observed to form a dynamic combinatorial library (DCL) of seven constitutionally distinct mixed-ligand Zn4L6 cages. The DCL was observed to reconstitute in opposing ways when treated with either the crown ether or C70: the electron-rich macrocycle templated the formation of heteroleptic catenanes, whereas C70 caused the DCL to self-sort into homoleptic structures.

We describe here the use of disulfide exchange reactions to generate distinct supramolecular topologies within a dynamic combinatorial library (DCL) derived from tri- and mono-functionalised thiol components in water. This approach allows for the effective expansion of structural diversity within a DCL, and also provides a sensitive probe for weak supramolecular interactions.

We describe here the discovery of a new class of organic cages assembled from simple tri- and dithiol building blocks using dynamic combinatorial chemistry (DCC). These water-soluble disulfide-linked architectures containing up to eleven components are only generated upon templation by positively charged polyamine guests of appropriate shape and length such as spermine and spermidine. The overall response of the system as expressed in the pattern of peaks in an HPLC trace provides an unusual tool for the identification of the templating analyte.

A new [2+2] tetra-hydrazone macrocyclic receptor was significantly amplified in a dynamic combinatorial library upon templation with alkaline earth metal ions. After optimisation the product could be isolated in 95% yield and its interaction with ions was investigated by NMR and UV-Vis spectroscopy.

We report a dynamic combinatorial library that, upon binding of an electronically-complementary guest, produces in high yield a tetrameric receptor with flat hydrophobic, electron-deficient surfaces and flexible, water-soluble disulfide-containing linkers; analysis of the dependence of library composition on template concentration gives insight into the binding behaviours of the species involved.

The discovery, in a two-phase dynamic combinatorial library, of an unexpected linear receptor and transporter for spermine is described.

A two-phase approach to dynamic combinatorial chemistry is described using disulfide exchange chemistry; the use of two phases significantly increases the possibilities and the scope of dynamic combinatorial chemistry by facilitating the combination of otherwise incompatible building blocks.