Wenjing Meng

A Self‐Assembled M8L6 Cubic Cage that Selectively Encapsulates Large Aromatic Guests

Biological encapsulants such as ferritin, lumazine synthase, and viral capsids achieve their selective separation and sequestration of substrates by providing: 1) a guest microenvironment isolated from the surroundings, 2) favorable interactions complementing a size and shape match with the encapsulated guests, and 3) sufficient flexibility to allow guests to be incorporated and released. These biological hosts self-assemble from multiple copies of identical protein subunits, the symmetries and connection properties of which dictate the hollow polyhedral structures of the encapsulant. In order to create abiological molecular systems that are capable of expressing functions of similar complexity to biological systems and to explore new applications of synthetic hosts, there is a need to create synthetic capsules capable of tightly and selectively binding large substrates. Taking inspiration from natural systems and from other previously reported metal–organic capsules, we report the design and synthesis of a series of metallo-supramolecular cage molecules capable of selectively encapsulating large aromatic guests. The necessary features to achieve this function are: 1) small pore sizes to isolate guests from the environment, 2) large cavity sizes to ensure sufficient volume for the guests of interest, 3) enough flexibility and lability to allow guests to enter and exit the host, and 4) regions of the cage walls rich in p-electron density to provide favorable interactions with targeted guests. The selective encapsulation of large aromatic molecules is an attractive goal since their physicochemical properties are similar, which can render their separation difficult. The higher fullerenes represent particularly attractive targets because their potential applications remain difficult to explore because of the challenges associated with their separation, despite recent advances. Employing principles of geometric analysis, we determined that combination of the C4-symmetric tetrakis-bidentate ligand shown in Figure 1 with the C3-symmetric iron(II) tris(pyridylimine) center would result in the formation of an O-symmetric cubic structure of general formula M8L6, in which the corners of the cube are defined by the metal centers and the faces by the ligands (Figure 1). This cage represents the first example of a new class of closed-face metallosupramolecular cubic hosts to be synthesized. In order to provide favorable binding sites for our target guests we incorporated porphyrin moieties, which have previously been demonstrated to interact with large aromatic molecules, into our design. This design also provides for small pore sizes and the potential to create new chemical functionality through the introduction of different metal ions into the centers of the N4 macrocycle and by substituting these metals axial ligands. We chose to employ labile iron(II) centers with pyridylimine ligands as chelating agents to allow for the formation of the ligand in situ through the subcomponent self-assembly approach. The reaction between tetrakis(4-aminophenyl)porphyrin (H2-tapp), 2-formylpyridine, and iron(II) trifluoromethanesulfonate (triflate, OTf ) in DMF produced cage [H21]·16OTf (Figure 1) as the uniquely observed product, as verified by NMR spectroscopy (Figure 3b), electrospray mass spectrometry (ESI-MS), and elemental analysis. Substitution of nickel(II) tetrakis(4-aminophenyl)porphyrin (Ni-tapp) or zinc(II) tetrakis(4-aminophenyl)porphyrin (Zn-tapp) for H2tapp under identical conditions yielded the nickel-containing (Ni-1) and zinc-containing (Zn-1) congeners of H2-1 (Figures S2a and S3a in the Supporting Information), respectively, suggesting the formation of such capsules to be a general feature of tetrakis(4-aminophenyl) porphyrins (Figure 1). Vapor diffusion of diethyl ether into a DMF/acetonitrile solution of Ni-1 resulted in the isolation of block-shaped dark purple crystals. Single-crystal X-ray diffraction revealed a solid-state structure (Figure 2) consistent with the O-symmetric NMR spectra recorded in solution. Each face of Ni-1 is covered by one porphyrin ligand and each corner is defined by a six-coordinate low-spin Fe ion. All of the Fe centers within each cage adopt the sameL or D configuration; both enantiomers of Ni-1 are present in the crystal lattice. The Ni–Ni distance between opposite faces is 15 , and the internal cavity volume is 1340 3 (Figure S2e). [*] W. Meng, Dr. B. Breiner, Prof. J. D. Thoburn, Dr. J. K. Clegg, Dr. J. R. Nitschke University of Cambridge, Department of Chemistry Lensfield Road, Cambridge, CB2 1EW (UK) E-mail: jrn34@cam.ac.uk Homepage: http://www-jrn.ch.cam.ac.uk/

Transformations within a network of cadmium architectures.

CdII transformer: By using a linear dialdehyde, CdII ions, and different amines, different architectures were constructed, including an M2L3 4+ triple helicate, an M 3L3 6+ triangle, an M4L8+ cryptate, as well as an M12L18 24+ hexagonal prism. These structures could be interconverted in a complex network by dynamic imine exchange, the addition of a template, or a change in the pH value of the solution.

Symmetry breaking in self-assembled M4L6 cage complexes

Here we describe the phenomenon of symmetry breaking within a series of M4L6 container molecules. These containers were synthesized using planar rigid bis-bidentate ligands based on 2,6-substituted naphthalene, anthracene, or anthraquinone spacers and FeII ions. The planarity of the ligand spacer favors a stereochemical configuration in which each cage contains two metal centers of opposite handedness to the other two, which would ordinarily result in an S4-symmetric, achiral configuration. Reduction of symmetry from S4 to C1 is achieved by the spatial offset between each ligand’s pair of binding sites, which breaks the S4 symmetry axis. Using larger CdII or CoII ions instead of FeII resulted, in some cases, in the observation of dynamic motion of the symmetry-breaking ligands in solution. NMR spectra of these dynamic complexes thus reflected apparent S4 symmetry owing to rapid interconversion between energetically degenerate, enantiomeric C1-symmetric conformations.

An autonomous molecular assembler for programmable chemical synthesis

Molecular machines that assemble polymers in a programmed sequence are fundamental to life. They are also an achievable goal of nanotechnology. Here, we report synthetic molecular machinery made from DNA that controls and records the formation of covalent bonds. We show that an autonomous cascade of DNA hybridization reactions can create oligomers, from building blocks linked by olefin or peptide bonds, with a sequence defined by a reconfigurable molecular program. The system can also be programmed to achieve combinatorial assembly. The sequence of assembly reactions and thus the structure of each oligomer synthesized is recorded in a DNA molecule, which enables this information to be recovered by PCR amplification followed by DNA sequencing.

Transformative Binding and Release of Gold Guests from a Self‐Assembled Cu8L4 Tube

The highly specific binding, transformation and protection of chemical compounds are functions associated with biomolecular systems inner phases, pockets of space that are wellisolated from the external environment. A growing number of abiological host molecules have been developed to emulate these functions. Container molecules have been developed that can encapsulate xenon and sulfur hexafluoride with the specificity that hemoglobin and myoglobin exhibit when binding and transporting dioxygen within the body. The ability of enzymes to transform substrates by binding to the transition state of a reaction has inspired the use of container molecules to catalyze reactions and the protection of the highly reactive active sites of nitrogenases from atmospheric oxidation, has been mimicked, allowing sensitive compounds to be stabilized within synthetic hosts. Whereas nature makes use of narrow tubular channels for purposes ranging from carbon monoxide reduction to ion transport, most synthetic capsules have compact binding cavities. 12] In order to investigate the specific binding and transformation of linear substrates within rigid tubular hosts, we designed and synthesized tetramine subcomponent A (Figure 1). Based on modeling studies and our prior experience with copper(I)-templated subcomponent selfassembly, we predicted A to have the correct geometry to assemble into a Cu8L4 8+ host with a narrow central channel. Indeed, A, 6-methyl-2-formylpyridine and tetrakis(acetonitrile)copper(I) tetrafluoroborate reacted in the ratios shown in Figure 1 to form the deep red-purple product 1 in acetonitrile. Electrospray ionization mass spectra (ESI-MS) and elemental analysis of 1 were consistent with the formula [Cu8L4](BF4)8, but H and C NMR spectra indicated the presence of two distinct product structures. Vapor diffusion of diethyl ether into an acetonitrile solution of 1 led to the isolation of opaque crystals having two different crystalline aspects. Single-crystal X-ray diffraction experiments revealed that two isomeric structures had crystallized separately, allowing the structures of both to be determined (Figure 2). In both isomers, four self-assembled ligands, each formed from one residue of A and four 2-formyl6-methylpyridine residues, are observed to wrap around eight Cu template ions to create tube-like complexes with approximate D2d and D4 point symmetries, in which the copper(I) ions form an elongated cuboidal structures. The ligands adopt different conformations in these two diastereomers of 1, as shown in Figure 1. In 1-D2d, the long faces of the cuboid form isosceles trapezoids, with the shorter faces forming rectangles. The parallel ligands of 1-D2d thus come together in such a way as to eliminate internal void volume, as shown in Figure 2c and d. In 1-D4, the cuboid approximates a right square prism in which one of the square faces is twisted by 408 with respect to the other. This ligand arrangement results in a narrow tubular channel having a radius of ca. 2.1 and a volume of 193 . In the crystal structure two acetonitrile molecules were found encapsulated in this channel (Figure 2a and b). The 1-D2d and 1-D4 diastereomers in the solid state were also observed in solution by H and C NMR spectroscopy. The different symmetries of these isomers led to different NMR peak multiplicities. Kinetic studies (described in the Supporting Information) revealed activation enthalpies and entropies of 148 5 kJmol 1 and 134 15 J K 1 mol 1 respectively for the isomerization from 1-D4 to 1-D2d, and 85 7 kJmol 1 and 62 21 J K 1 mol 1 for the reverse transformation (from 1-D2d to 1-D4). The rate constants for both transformations were identical at 323 K, marking 1-D4 as the dominant species in solution below this temperature, and 1D2d above. As the interior of 1-D4 was observed to accommodate two acetonitrile molecules in the crystal, we reasoned that other linear guests might also bind within this host. No new peaks were observed in the H NMR spectrum, however, following the addition to an acetonitrile solution of 1 (1.8 mm) of either: 1) the potassium salts of Ag(CN)2 , Cu(CN)2 , CN , OCN , SCN , SeCN , N3 , H2F , or F (1 equiv in each case), 2) CuCN, Ni(CN)2, Hg(CN)2, CS2, 1,4-dichlorobut-2-yne, succinonitrile, butyronitrile, C6F6, or but-2-yne (5 equiv), or 3) N2O, C2H4, or C2H2, (by bubbling the gas through the acetonitrile solution for 5 min at 25 8C), suggesting that no guest binding occurred. Despite these other guests failure to bind, the addition of KAu(CN)2 to an acetonitrile solution of 1 produced a new host–guest complex 2, as identified by NMR spectroscopy (Figure S40, Supporting Information) and ESI-MS. Mass spectra indicated that the dicyanoaurate adduct of 1 was not a simple 1:1 complex, however, but rather that the guest species was the complex anion Cu(Au(CN)2)2 , leading to the formulation of 2 as [Cu(Au(CN)2)2 1-D4] (Figure 3). The [*] W. Meng, Dr. J. K. Clegg, Dr. J. R. Nitschke University of Cambridge, Department of Chemistry Lensfield Road, Cambridge, CB2 1EW (UK) E-mail: jrn34@cam.ac.uk Homepage: http://www-jrn.ch.cam.ac.uk/

Empirical and Theoretical Insights into the Structural Features and Host–Guest Chemistry of M8L4 Tube Architectures

We demonstrate a general method for the construction of M8L4 tubular complexes via subcomponent self-assembly, starting from Cu(I) or Ag(I) precursors together with suitable elongated tetraamine and 2-formylpyridine subcomponents. The tubular architectures were often observed as equilibrium mixtures of diastereomers having two different point symmetries (D2d or D2 ⇄ D4) in solution. The equilibria between diastereomers were influenced through variation in ligand length, substituents, metal ion identity, counteranion, and temperature. In the presence of dicyanoaurate(I) and Au(I), the D4-symmetric hosts were able to bind linear Au(Au(CN)2)2(-) (with two different configurations) as the best-fitting guest. Substitution of dicyanoargentate(I) for dicyanoaurate(I) resulted in the formation of Ag(Au(CN)2)2(-) as the optimal guest through transmetalation. Density functional theory was employed to elucidate the host-guest chemistries of the tubes.

Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.

Design Principles for the Optimization of Guest Binding in Aromatic-Paneled FeII4L6 Cages

A series of aromatic-paneled FeII4L6 cages was synthesized through iron(II)-templated subcomponent self-assembly of 2-formylpyridine and C2-symmetric diamine building blocks having differing geometries, including many with a large degree of lateral offset between metal-binding sites. The new cages were characterized using X-ray crystallography, NMR spectroscopy, and mass spectrometry. Investigations of the guest binding properties of the cages provided insights into the structural factors important for the observation of guest binding. Both the size and arrangement of the aromatic panels were shown to be crucial for achieving effective encapsulation of large hydrophobic guests, including fullerenes, polycyclic aromatic hydrocarbons, and steroids, with subtle differences in the structure of subcomponents resulting in incommensurate effects on the binding abilities of the resulting hosts. Cages with large, offset aromatic panels were observed to be the most effective hosts as a result of a preference for a ligand conformation where the aromatic panels lie tangent to the edges of the tetrahedron, thus maximizing cavity enclosure.