Therapeutic coordination polymers: tailoring drug release through metal-ligand interactions.

Developing tunable materials which exhibit sustained drug release is a considerable challenge. Herein, we report the concept of Therapeutic Coordination Polymers (TCPs); non-porous coordination polymers constructed from biocompatible components which demonstrate tunable zero-order drug release kinetics upon degradation of metal-ligand bonds. TCPs were constructed from three principal components: (i) a cationic metal center (M = Mg2+, Mn2+, Zn2+, or Cu2+); (ii) an anionic drug (Diclofenac); and (iii) an alkyl bis-imidazole organic ligand which behaves as a "linker" between metal centers. Most drug-release materials, such as amorphous polymer dispersions, or metal-organic frameworks rely on a diffusion-based mechanism for drug release, but the degradation-controlled release of drugs from non-porous one-periodic coordination polymers has been largely unexplored. TCPs described herein exhibit a high wt% of pharmaceutical (>62%), tailorable zero-order drug release rate kinetics which span over three orders of magnitude, and stimuli-responsive drug release behavior making them well suited for extended drug-release applications.

Reversible mechanical protection: building a 3D "suit" around a T-shaped benzimidazole axle.

The T-shaped benzimidazolium/crown ether recognition motif was used to prepare suit[1]anes. These novel mechanically interlocked molecules (MIMs) were fully characterized by 1H and 13C NMR spectroscopy, single-crystal X-ray diffraction, UV-vis absorption and fluorescence spectroscopy. By conversion to a suit[1]ane, a simple benzimidazole was shown to be protected from deprotonation by strong base. Moreover, it was demonstrated that this unique three-dimensional encapsulation can be made reversible, thus introducing the concept of "reversible mechanical protection"; a protecting methodology that may have potential applications in synthetic organic chemistry and the design of molecular machinery.

Optical Distinction between "Slow" and "Fast" Translational Motion in Degenerate Molecular Shuttles.

A series of six [2]rotaxane molecular shuttles was designed which contain an axle with a benzo-bis(imidazole) core (in either a neutral or dicationic form) and a single 24-membered, crown ether wheel (24C6, B24C6, or DMB24C6), and the shuttling rates of the ring along the axle were determined. The charged versions showed much slower shuttling rates as a result of the increase in noncovalent interactions between the axle and wheel. The [2]rotaxane with a B24C6 wheel shows a difference in fluorescence between the charged and neutral species, while the [2]rotaxane with a DMB24C6 wheel exhibits a difference in color between the charged and neutral compounds. These changes in optical properties can be attributed to the structural differences in the co-conformations of the [2]rotaxane as they adapt to the changes in acid/base chemistry. This allowed the relative rate of the translational motion of a molecular shuttle to be determined by observation of a simple optical probe.

Acid-Base Switchable [2]- and [3]Rotaxane Molecular Shuttles with Benzimidazolium and Bis(pyridinium) Recognition Sites.

For the purpose of developing higher level mechanically interlocked molecules (MIMs), such as molecular switches and machines, a new rotaxane system was designed in which both the 1,2-bis(pyridinium)ethane and benzimidazolium recognition templating motifs were combined. These two very different recognition sites were successfully incorporated into [2]rotaxane and [3]rotaxane molecular shuttles which were fully characterized by 1 H NMR, 2D EXSY, single-crystal X-ray diffraction and VT NMR analysis. By utilizing benzimidazolium as both a recognition site and stoppering group it was possible to create not only an acid/base switchable [2]rotaxane molecular shuttle (energy barrier 20.9 kcal⋅mol-1 ) but also a [3]rotaxane molecular shuttle that displays unique dynamic behavior involving the simultaneous motion of two macrocyclic wheels on a single dumbbell. This study provides new insights into the design of switchable molecular shuttles. Due to the unique properties of benzimidazoles, such as fluorescence and metal coordination, this new type of molecular shuttle may find further applications in developing functional molecular machines and materials.

Conformational Study of N,N'-Diacyl Bispidines and Dioxo Bis-bispidines: Planar Chirality and Molecular Switching.

N,N'-Diacyl bispidines exhibit chirality in the absence of a chiral center and axis. Conformational analysis indicates planar chirality in the molecular structure as a result of open-ended chiral planes, which has been confirmed by X-ray diffraction studies. Substantial chiral-achiral molecular switching is observed in di(haloacetyl) bispidines upon changing the solvent polarity. Tethering the chiral planes with a bispidine linker alters the planar chirality significantly and renders the resulting bis-bispidine macrocycles achiral.

Mechanically Interlocked Linkers inside Metal-Organic Frameworks: Effect of Ring Size on Rotational Dynamics.

A series of metal-organic framework (MOF) materials has been prepared, each containing a mechanically interlocked molecule (MIM) as the linker and a copper(II) paddlewheel as the secondary building unit (SBU). The MIM linkers are [2]rotaxanes with varying sizes of crown ether macrocycles ([22]crown-6, 22C6; [24]crown-6, 24C6; [26]crown-6, 26C6; benzo[24]crown-6, B24C6) and an anilinium-based axle containing four carboxylate donor groups. Herein, the X-ray structures of MOFs UWCM-1 (no crown) and UWDM-1(22) are compared and demonstrate the effect of including a macrocycle around the axle of the linker. The rotaxane linkers are linear and result in nbo-type MOFs with void space that allows for motion of the interlocked macrocycle inside the MOF pores, while the macrocycle-free linker is bent and yields a MOF with a novel 12-connected bcc structure. Variable temperature (2)H solid-state nuclear magnetic resonance showed that the macrocycles in UWDM-1(22), UWDM-1(24), and UWDM-1(B24) undergo different degrees and rates of rotation depending on the size and shape of the macrocycle.

A molecular shuttle that operates inside a metal-organic framework.

A 'molecular shuttle' is an interlocked molecular assembly in which a macrocyclic ring is able to move back and forth between two recognition sites. This large-amplitude translational motion was first characterized in solution in 1991. Since that report, many mechanically interlocked molecules (MIMs) have been designed, synthesized and shown to mimic the complex functions of macroscopic switches and machines. Here, we show that this fundamental concept-the translational motion of a molecular shuttle-can be organized, initiated and made to operate inside a crystalline, solid-state material. A metal-organic framework (MOF) designated UWDM-4 was prepared that contains a rigid linker that is a molecular shuttle. It was demonstrated by variable-temperature (1)H-(13)C cross-polarization/magic-angle spinning (CP/MAS) and (13)C 2D exchange correlation spectroscopy (EXSY) solid-state NMR at 21.1 T on a (13)C-enriched sample that the macrocyclic ring undergoes rapid shuttling along the rigid axle built between struts of the framework.

Assembly of a M4L4 "folded-cube" using a T-shaped, right-angled ligand.

A new bipyridine ligand based on a T-shaped 2,4,7-trisubstituted benzimidazole framework was synthesized with a 90° angle between the two nitrogen donors. When combined with convergent [Pt(dppp)](2+) corners, eight right angles (four metal and four ligand) combine to form a M4L4 cluster with an unusual folded-cube structure.

Metal-organic frameworks with mechanically interlocked pillars: controlling ring dynamics in the solid-state via a reversible phase change.

Metal-organic framework (MOF) materials have been prepared that contain a mechanically interlocked molecule (MIM) as the pillaring strut between two periodic Zn-carboxylate layers. The MIM linker is a [2]rotaxane with a [24]crown-6 (24C6) macrocycle and an aniline-based axle with terminal pyridine donor groups. The single-crystal X-ray structures of MOFs UWDM-2 (1,4-diazophenyl-dicarboxylate) and UWDM-3 (1,4-biphenyl-dicarboxylate) show that both frameworks are large enough to contain the free volume required for rotation of the interlocked 24C6 macrocycle, but the frameworks are interpenetrated (UWDM-2, three-fold, and UWDM-3, two-fold). In particular, for UWDM-3 the 24C6 rings of the pillaring MIM are positioned directly inside the square openings of neighboring zinc dicarboxylate layers. Variable-temperature (VT) (2)H SSNMR demonstrated that the 24C6 macrocycles in UWDM-2 and UWDM-3 can only undergo restricted motions related to ring flexibility or partial rotation but are incapable of undergoing free rotation. VT-powder X-ray diffraction studies showed that upon activation of UWDM-3, by removing solvent, a phase change occurs. The new ß-phase of UWDM-3 retained crystallinity, and (2)H SSNMR demonstrated that the 24C6 macrocyclic ring of the pillared MIM strut is now free enough to undergo full rotation. Most importantly, the phase change is reversible; the ß version of the MOF can be reverted to the original α state by resolvation, thus demonstrating, for the first time, that the dynamics of a MIM inside a solid material can be controlled by a reversible phase change.

Coordination polymers containing rotaxane linkers.

A class of coordination polymers in which the linking ligands are mechanically interlocked rotaxane molecules is reviewed. To date, four different, axle - wheel templating motifs have been used to create the [2]pseudorotaxane linkers for these unique solid-state materials; (1) protonated diaminoalkane axles with cucurbit[6]uril wheels, (2) 1,2-bis(4,4'-bipyridinio)ethane axles with dibenzo[24]crown-8 wheels, (3) 2,6-naphthalene dicarboxylate axles with tetra-imidazolium macrocycle wheels and (4) a Cu(I) complex of a 1,10-phenanthroline containing dicarboxylate axle with a 1,10-phenanthroline containing crown ether wheel. The synthesis and solid state structure of each coordination polymer is described. The future directions of this area of research and some designs for the next generation of these compounds are discussed.

[2]Pseudorotaxanes from T-shaped benzimidazolium axles and [24]crown-8 wheels.

A new templating motif for the formation of [2]pseudorotaxanes is described in which T-shaped axles with a benzimidazolium core and aromatic substituents at the 2-, 4-, and 7-positions interact with [24]crown-8 ether wheels ([24]crown-8, dibenzo[24]crown-8, and dinaphtho[24]crown-8). The T-shape greatly enhances the association between axle and wheel when compared to simple imidazolium or benzimidazolium cations. A series of interpenetrated molecules are characterized by (1)H NMR spectroscopy and single crystal X-ray crystallography.

Metal-organic frameworks with dynamic interlocked components.

The dynamics of mechanically interlocked molecules such as rotaxanes and catenanes have been studied in solution as examples of rudimentary molecular switches and machines, but in this medium, the molecules are randomly dispersed and their motion incoherent. As a strategy for achieving a higher level of molecular organization, we have constructed a metal-organic framework material using a [2]rotaxane as the organic linker and binuclear Cu(II) units as the nodes. Activation of the as-synthesized material creates a void space inside the rigid framework that allows the soft macrocyclic ring of the [2]rotaxane to rotate rapidly, unimpeded by neighbouring molecular components. Variable-temperature (13)C and (2)H solid-state NMR experiments are used to characterize the nature and rate of the dynamic processes occurring inside this unique material. These results provide a blueprint for the future creation of solid-state molecular switches and molecular machines based on mechanically interlocked molecules.

A tetrapyridine ligand with a rigid tetrahedral core forms metal-organic frameworks with PtS type architecture.

A new tetradentate, pyridine ligand with a rigid tetrahedral core can be prepared in good yield by a cross-coupling methodology. Two metal organic framework structures of Cu(II) with PtS-type topology having a carbon atom as the tetrahedral node have been characterized utilising this ligand.

Linking [2]rotaxane wheels to create a new type of metal organic rotaxane framework.

Three new [2]rotaxanes with aromatic nitrogen donors appended to the crown ether wheel have been synthesized and used as ligands to coordinate Cd(II) ions. One of these yields a new type of 2-periodic, metal organic rotaxane framework in which the wheel rather than the axle is used to link the metal nodes.

One-, two- and three-periodic metal-organic rotaxane frameworks (MORFs): linking cationic transition-metal nodes with an anionic rotaxane ligand.

A new singly charged pyridinium axle was prepared and combined with disulfonated dibenzo[24]crown-8 ether to form a [2]pseudorotaxane. The reaction of this new, anionic ligand with Zn(II) ions, under various crystallization conditions, resulted in the formation of three metal-organic rotaxane framework (MORF) solids; a one-periodic ML coordination polymer and two, two-periodic ML(2) square grid frameworks. The layers of square grids can be pillared to create full three-periodic MORF structures, which have completely neutral frameworks and are porous. These three-periodic materials represent the first examples of neutral porous MOFs in which one (or more) of the linkers is a mechanically interlocked molecule (MIM).

Eliminating the need for independent counterions in the construction of metal-organic rotaxane frameworks (MORFs).

The combination of a disulfonated-dibenzo-24crown-8 ether wheel and a dicationic 1,2-bis(pyridinium)ethane axle yields a neutral [2]pseudorotaxane which in combination with neutral metallic units such as a Cu(II)benzoate paddlewheel or Cu(I)Br unit yields one-dimensional coordination polymers (linear and bent) which are the first examples of charge neutral, metal-organic rotaxane frameworks.