Covalent Post-Assembly Modification: A Synthetic Multipurpose Tool in Supramolecular Chemistry.

The use of covalent post-assembly modification (PAM) in supramolecular chemistry has grown significantly in recent years, to the point where PAM is now a versatile synthesis tool for tuning, modulating, and expanding the functionality of self-assembled complexes and materials. PAM underpins supramolecular template-synthesis strategies, enables modular derivatization of supramolecular assemblies, permits the covalent 'locking' of unstable structures, and can trigger controlled structural transformations between different assembled morphologies. This Review discusses key examples of PAM spanning a range of material classes, including discrete supramolecular complexes, self-assembled soft nanostructures and hierarchically ordered polymeric and framework materials. As such, we hope to highlight how PAM has continued to evolve as a creative and functional addition to the synthetic chemist's toolbox for constructing bespoke self-assembled complexes and materials.

Development and Application of Synthetic Affinity Ligands for the Purification of Ferritin-Based Influenza Antigens.

A recently developed novel recombinant influenza antigen vaccine has shown great success in preclinical studies in ferrets and mice. It provides broader protection, and is efficient to manufacture compared to the conventional trivalent influenza vaccines (TIV). Each strain of the recombinant antigen has a constant self-assembled bacterial ferritin core which, if used as a target for affinity chromatography, could lead to a universal purification method. Ferritin in silico models were used to explore potential target binding sites against ligands synthesized by the four-component Ugi reaction. Two ligands, SJ047 and SJ055, were synthesized in solution, characterized by 1H, 13C, and 2D NMR spectroscopy, and subsequently immobilized on the PEG-functionalized beads. Ligands SJ047 and SJ055 displayed apparent Kd values of 2.04 × 10-7 M and 1.91 × 10-8 M, respectively, against the ferritin. SJ047 and SJ055-functionalized resins were able to purify hemagglutinin (New Caledonia)-ferritin expressed in a crude Human Embryonic Kidney (HEK) cell supernatant in a single step to a purity of 85 ± 0.5% (97 ± 1% yield) and 87.5 ± 0.5% (95.5 ± 1.5% yield), respectively. Additionally, SJ047 and SJ055-functionalized resins purified the recombinant antigens when spiked at known concentrations into HEK supernatants. All three strains, hemagglutinin (New Caledonia)-ferritin, hemagglutinin (California)-ferritin, and hemagglutinin (Singapore)-ferritin were purified, thereby offering an ideal alternate platform for affinity chromatography. Following elution from the affinity adsorbents, absorbance at 350 nm showed that there was no aggregation of the recombinant antigens and dynamic light scattering studies further confirmed the structural integrity of the recombinant antigen. The use of Ugi ligands coupled to a PEG-spacer arm to target the ferritin core of the strain is entirely novel and provides an efficient purification of these recombinant antigens. This approach represents a potentially universal method to purify any ferritin-based vaccine.

How to make a porphyrin flip: dynamics of asymmetric porphyrin oligomers.

We present the first predictions of meso-aryl flipping pathways in porphyrin oligomers. In the context of cyclic oligoporphyrins this flipping results in a paddle rotation of each porphyrin monomer in the oligomeric ring. If the monomer porphyrin units are asymmetric, this flipping will have consequences for their supramolecular behaviour. Desymmetrisation of synthetic porphyrins leads to synthetic challenges, and hence these species are not as well studied as the more accessible, symmetric counterparts. We have both simulated and synthesized novel, desymmetrised monomeric and cyclic trimeric porphyrins and we predict that the flipping barrier for a porphyrin monomer within the trimer is 36.7 kJ mol(-1) higher than that for meso-aryl flipping in the monomer. The flipping rates estimated from Variable temperature NMR data are consistent with these results. We have also carried out a systematic investigation of how porphyrinic substituents will affect the dynamics, revealing that adding steric bulk in the right place can facilitate meso-aryl flipping. While supramolecular chemistry often focuses on highly symmetric assemblies, evolution can break molecular symmetry in subtle ways, leading to many pseudosymmetric assemblies in biology, especially protein-porphyrinic complexes that are important for energy harvesting and electron transport systems. The dynamic behaviour we have characterized can be critical for the design and function of these molecules, and hence our results will help inform future efforts in the synthesis of asymmetric porphyrinic assemblies that interact with biomolecules.

Preparation of a porphyrinic bis(pyridyl aldehyde) and its supramolecular complexes.

Shape-specific molecular assemblies require the preparation of the constituent building blocks with the necessary properties to bias exclusive formation of the proposed structures. In this work, a novel linear porphyrin dialdehyde was synthesised and used to assemble a supramolecular grid via Cu(i) heteroleptic phenanthroline/pyridyl imine complexation, and a tetrahedral cage via Fe(ii) pyridyl imine coordination.

The two-step mechanochemical synthesis of porphyrins.

Porphyrin synthesis under solvent-free conditions represents the "greening" of a traditional synthesis that normally requires large amounts of organic solvent, and has hindered the industrial-scale synthesis of this useful class of molecules. We have found that the four-fold acid-catalysed condensation of aldehyde and pyrrole to yield a tetra-substituted porphyrin is possible through mechanochemical techniques, without a solvent present. This represents one of the still-rare examples of carbon-carbon bond formation by mechanochemistry. Specifically, upon grinding equimolar amounts of pyrrole and benzaldehyde in the presence of an acid catalyst, cyclization takes place to give reduced porphyrin precursors (reversible), which upon oxidation form tetraphenylporphyrin (TPP). The approach has been found to be suitable for the synthesis of a variety of meso-tetrasubstituted porphyrins. Oxidation can occur either by using an oxidizing agent in solution, to give yields comparable to those published for traditional methods of porphyrin synthesis, or through mechanochemical means resulting in a two-step mechanochemical synthesis to give slightly lower yields that are still being optimized. We are also working on "green" methods of porphyrin isolation, including entrainment sublimation, which would hopefully further reduce the need for large amounts of organic solvent. These results hold promise for the development of mechanochemical synthetic protocols for porphyrins and related classes of compounds.

'Click' functionalised polymer resins: a new approach to the synthesis of surface attached bipyridinium and naphthalene diimide [2]rotaxanes.

Herein we describe the design and synthesis of a series of solid-tethered [2]rotaxanes utilising crown ether-naphthalene diimide or crown ether-bipyridinium host guest interactions. TentaGel polystyrene resins were initially modified in a two-stage procedure to azide functionalised beads before the target supramolecular architectures were attached using a copper catalysed "click" procedure. The final assembly was examined using IR spectroscopy and gel-phase (1)H High Resolution Magic Angle Spinning (HR MAS) NMR spectroscopy. The HR MAS technique enabled a direct comparison between the solid-tethered architectures and the synthesis and characterisation of analogous solution-based [2]rotaxanes to be made.

Synthesis of a four-component [3]catenane using three distinct noncovalent interactions.

A multicomponent assembly is described resulting in [2] and [3]catenanes using three flexible components and three distinct noncovalent interactions. Despite the possibility of competing side-products, only the desired assemblies are generated and characterized spectroscopically.

Host-guest interactions in acid-porphyrin complexes.

In this report we use the weak interactions of acid-porphyrin complexes to selectively bind competing acids to the faces of a rigid cyclic porphyrin dimer, and characterise the resulting interactions by NMR spectroscopy and nano-electrospray ionisation spectrometry.

Crown-ether- and porphyrin-attached gel-phase resins in thermodynamically controlled rotaxane assembly.

Results of gel-phase proton high resolution magic angle spinning (HR MAS) NMR spectroscopy are described for a systematic study of the reversible, thermodynamically-controlled assembly of surface-attached neutral rotaxanes and pseudorotaxanes based on a three-component system consisting of a naphthodiimide thread unit, a naphthalene crown shuttle, and metalloporphyrin stoppers. Further to the previous systems based on an immobilised thread unit, we report here on the alternative systems where firstly a crown shuttle unit, and secondly metalloporphyrin stopper units, are attached to polystyrene beads, with the other two rotaxane components supplied in the surrounding solution phases in each case. Variations in concentration, temperature, and the effects of the addition of alkali metal salts are investigated. Within some limitations imposed by the technique itself, these results confirm that for each of the single entities attached in turn to polystyrene beads, rotaxane formation parallels that observed in the analogous solution-phase systems.

Monitoring the thermodynamically-controlled formation of diimide-based resin-attached rotaxanes by gel-phase HR MAS 1H NMR spectroscopy.

The thermodynamically controlled self-assembly of rotaxane and pseudorotaxane systems consisting of (i) a naphthodiimide thread unit terminated at one end with a pyridine ligand, and covalently linked at the other to a gel-phase polystyrene resin support, (ii) a dinaphtho-crown ether shuttle unit, and (iii) a ruthenium carbonyl metalloporphyrin stopper unit, is investigated by high resolution magic angle spinning proton (HR MAS 1H) NMR spectroscopy. The effects of variable concentration of the solution-phase components, the temperature, and added Li+ and Na+ ions are described, and the limitations of the technique are addressed. The dynamic behaviour is compared directly to the solution-phase analogues, where a bulky stopper group is substituted for the polystyrene resin bead.

First observation of capping/uncapping by a ligand of a Zn porphyrin adsorbed on Ag(100).

A significant first step towards creation of catalytically active porphyrin-functionalised metal surfaces has been achieved.

Synthesis and characterization of carboxylate complexes of Sn(IV) porphyrin monomers and oligomers.

Most of the porphyrin-recognition chemistry we have investigated previously has centred on kinetically labile metal-ligand interactions, such as Z-N and Ru-N. Our interest in the broader scope of molecular recognition required a metal with the ability to specifically recognise non-nitrogen-based ligands, with a significantly different binding interaction to distinguish it from nitrogen-based analogues. In this report we describe interactions of Sn(IV) porphyrins that bind oxygen-based ligands and for which the Sn(IV)bond;O bond is in slow exchange on the NMR timescale. A series of carboxylate complexes is employed to highlight the structural/geometric features of porphyrin monomers and cyclic oligomers. Where more than one porphyrin unit is present in a molecular scaffold, we report the effect of carboxylate binding on the complex when the two porphyrins contain different metals (typically Sn(IV) and Zn(II)). The unexpected spectroscopic and structural properties of the Sn(2)(9-anthroic acid)porphyrin dimer are also reported.

A self-assembling polymer-bound rotaxane under thermodynamic control.

The thermodynamically controlled self-assembly of a neutral donor-acceptor rotaxane, stoppered via porphyrin coordination and bound to polystyrene beads is described, and the dynamic equilibrium between solid and solution phases has been examined by HR MAS nmr spectroscopy.

High Catalytic Activity of Chiral Amino Alcohol Ligands Anchored to Polystyrene Resins.

Enantiomerically pure (2S,3S)-2,3-epoxy-3-phenylpropanol (3) has been anchored to Merrifield resins with different degrees of cross-linking and functionalization. The resulting epoxy-functionalized resins 4 have been submitted to completely regioselective (C-3 attack) and stereospecific ring-opening with secondary amines [piperidine (a), N-methylpiperazine (b), and cis-2,6-dimethylpiperidine (c)] in the presence of lithium perchlorate to afford (2R,3R)-3-(dialkylamino)-2-hydroxy-3-phenylpropoxy resin ethers 5a-c. The progress of these two processes has been monitored by (13)C gel-phase NMR spectroscopy. Polymer-supported amino alcohols 5a-c have been evaluated as catalytic ligands in the enantioselective addition of diethylzinc to benzaldehyde, best results being obtained with the cis-2,6-dimethylpiperidine containing ligand 5c. Analogously, (2R,3R)-3-(cis-2,6-dimethylpiperidino)-3-phenyl-1,2-propanediol (11) has been anchored to a 2-chlorotrityl chloride resin (Barlos resin) in dichloromethane in the presence of diisopropylethylamine, and the anchoring process has been also monitored by (13)C gel-phase NMR spectroscopy. The resulting resin 12 has subsequently been used as a chiral ligand in the catalytic addition at 0 degrees C of diethylzinc to a family of fourteen representative aromatic and aliphatic aldehydes 8a-n, to afford the corresponding (S)-1-substituted 1-propanols 10a-n with a mean enantiomeric excess of 92%.

Metalloporphyrin Dendrimers with Folding Arms.

Rigid and flexible linkers are combined in the new dendrimer shown schematically in the picture, which contains nine metalloporphyrin units (Porph). The construction is such that the four "arms" of the dendrimer can fold in a cooperative and predetermined manner in response to added 1,4-diazabicyclo[2.2.2]octane (DABCO).

Stepwise Approach to Bimetalic Porphyrin Hosts: Spatially Enforced Coordination of a Nickel(II) Porphyrin.

The synthesis of the Zn(3) 1,1,2-trimer Zn(3)()3 and the NiZn(2) 1,1,2-trimer NiZn(2)()3 by a stepwise convergent route is described. A large affinity for Py(3)()T by both cyclic 1,1,2-trimers, Zn(3)()3 or NiZn(2)()3, with respect to the linear trimers, provides a thermodynamic driving force for the templated cyclization of the new host molecules, which were fully characterized by NMR spectroscopy (COSY and NOESY). The binding properties of several pyridine-containing bidentate and tridentate ligands have been investigated in order to probe the shape and the size of the cavity of the host molecule. Both Py(2)()Pr and Py(2)()Py bind very strongly to Zn(3)()3 and NiZn(2)()3 (ligand affinities in CH(2)Cl(2) at 25 degrees C, >10(8) M(-)(1)), while the tridentate ligand Py(3)()T binds to both Zn(3)()3 and NiZn(2)()3 with a very high binding constant (ligand affinities in CH(2)Cl(2) at 25 degrees C, >10(9) M(-)(1)). This unexpected result for NiZn(2)()3 suggests that the cavity-enforced effective molarity of the third pyridyl of Py(3)()T at the Ni site is high enough to form the first example of a stable 1:1 Ni(II)-pyridyl complex. The resulting Ni(II) paramagnetic complex has been characterized by NMR; the temperature dependence deviates slightly from ideal Curie behavior.