Synthesis, structure, and computational studies of soluble conjugated multidentate macrocycles

[Chemical reaction: See text] Conjugated, shape-persistent macrocycles based on [3 + 3] Schiff-base condensation are of interest for supramolecular materials. In an effort to develop new discotic liquid crystals based on these compounds, a series of macrocycles with peripheral alkoxy groups of varying length have been prepared. The synthesis and mechanism of formation have been probed by isolation of oligomeric intermediates. A single-crystal X-ray diffraction study of one macrocycle revealed a nonplanar, strongly hydrogen-bonded structure. To our surprise, even with very long substituents, the macrocycles were not liquid crystalline. This has been rationalized by ab initio calculations that indicate the macrocycles are undergoing rotation of the dihydroxydiiminobenzene rings that may not allow a stable discotic liquid crystalline phase. These results provide new insight into the formation and properties of these large macrocycles and may provide guidance to developing stable liquid crystalline materials in the future.     

Surface supramolecular organization of a terbium(III) double-decker complex on graphite and its single molecule magnet behavior

The two-dimensional self-assembly of a terbium(III) double-decker phthalocyanine on highly oriented pyrolitic graphite (HOPG) was studied by atomic force microscopy (AFM), and it was shown that it forms highly regular rectangular two-dimensional nanocrystals on the surface, that are aligned with the graphite symmetry axes, in which the molecules are organized in a rectangular lattice as shown by scanning tunneling microscopy. Molecular dynamics simulations were run in order to model the behavior of a collection of the double-decker complexes on HOPG. The results were in excellent agreement with the experiment, showing that-after diffusion on the graphite surface-the molecules self-assemble into nanoscopic islands which align preferentially along the three main graphite axes. These low dimension assemblies of independent magnetic centers are only one molecule thick (as shown by AFM) and are therefore very interesting nanoscopic magnetic objects, in which all of the molecules are in interaction with the graphite substrate and might therefore be affected by it. The magnetic properties of these self-assembled bar-shaped islands on HOPG were studied by X-ray magnetic circular dichroism, confirming that the compounds maintain their properties as single-molecule magnets when they are in close interaction with the graphite surface.     

Axial-bundle phases--new modes of 2D, 3D, and helical columnar self-assembly in liquid crystalline phases of bolaamphiphiles with swallow tail lateral chains

Two series of polyphilic molecules composed of a rigid and linear p-terphenyl core, terminated at both ends with polar glycerol groups capable of hydrogen bonding, and two branched swallow tail-type lateral chains, composed of a fluorinated and a nonfluorinated branch or two fluorinated branches, were synthesized and investigated by differential scanning calorimetry, polarizing microscopy, and X-ray diffraction (XRD) with respect to their self-assembly in thermotropic liquid crystalline (LC) phases. Hexagonal columnar phases were formed by all molecules, at least at the highest temperature. In these phases the columns are composed of a core of aromatic rods and an aliphatic shell. The aromatic rods form bundles which are rotationally averaged and lie parallel to the column long axis. This unique organization is proven by different optical and XRD methods. The aromatic and glycerol groups inside the rod bundles are segregated into alternating segments. Depending on temperature and molecular structure, long-range intercolumnar correlation of this periodicity could take place, leading to a 3D-ordered LC phase with rhombohedral R ?3m symmetry. The bundles are embedded in the matrix of the lateral chains, which is divided into fluoroalkyl- and aliphatic-rich regions. In the 2D columnar phase the fluorinated regions take the form of either straight columns running along the edges of the hexagonal Voronoi cells or, for compounds with a higher degree of fluorination, fuse to a hexagonal honeycomb enclosing the aromatic cores. In the R ?3m phase the fluorine-rich chains are preferentially found along right- and left-handed helices wound around the 3(1) screw axes between the main aromatic columns.     

Liquid crystalline order from ortho-phenylene ethynylene macrocycles

Triangular ortho-phenylene ethynylene (o-PE) cyclic trimers represent a novel member of shape-persistent macrocycles. Shape-persistent cyclic structures remain of great interest as molecular components in the fields of supramolecular materials, host-guest chemistry, and materials science. Novel discotic liquid crystalline properties are reported from triangular-shaped o-PE macrocycles containing branched alkoxy- and/or triethylene glycol (TEG) side chains using polarized optical microscopy (POM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The macrocycles self-assemble into thermotropic rectangular columnar (Colr) (for M1), hexagonal columnar (Colh) (for M2), and discotic nematic (for M3) mesophases at room temperature. This work shows clearly that electron-rich PE macrocycles can form LC materials. Alkyl side chains in M1 promote order, while hydrophilic side chains of M2 generate an amphiphilic structure that provides a different driving force for organization. The ability to create ordered self-assembling materials from these novel electron-rich macrocycles is important in nanotechnology.     

Evidence for a new ferroelectric switching liquid crystalline phase formed by a carbosilane based dendrimer with banana-shaped mesogenic units

The first carbosilane dendrimer with peripheral bent-core mesogenic units is reported. This material forms a liquid crystalline phase which is stable over a wide temperature range and forms an LC glass on cooling. Polarizing microscopy, X-ray diffraction, and dielectric and electrooptic investigations reveal the presence of a novel liquid crystalline phase, in which the molecules are tilted and adapt a polar order within the layers, but without long-range correlation between the layers. By applying external electric fields, switching into a ferroelectric organization can be achieved. Once formed the ferroelectric states are stable and can be switched between the different polarization states.     

Macrocyclic sulfamides: synthesis, hybridization, and metal binding properties

Four cyclophanes incorporating the cyclosulfamide sub-unit have been synthesised in high yield. The X-ray crystal structures of three of them, and of cyclosulfamide itself, provide useful insight into the hybridisation of such compounds. The ionophoric properties of the macrocycles are also reported, with the sulfamides showing unusual selectivity for rubidium (benzyl trimer), barium (pyridyl dimer) and silver (pyridyl dimer and trimer).     

Gold(I)-carbenes derived from 4-pyridylisocyanide complexes: supramolecular macrocycles supported by hydrogen bonds, and luminescent behavior

Monomeric gold(I) carbenes of the type [AuR[C(NR1R2)(NHPy-4)]] (Py-4 = 4-pyridyl) have been prepared with R = C6F5, Fmes (2,4,6-tris(trifluoromethyl)phenyl) by reaction of the corresponding isocyanide compounds [AuR(CNPy-4)] with primary or secondary amines. The single crystal X-ray diffraction structures of [Au(C6F5)[C(NEt2)(NHPy-4)]].OH2, [Au(Fmes)[C(NEt2)(NHPy-4)]], and [Au(Fmes)[C(NHMe)(NHPy-4)]] show that the presence of the NHPy-4 moiety formed induces the formation of supramolecular macrocycles only supported by hydrogen bond interactions, either with N-H groups of other molecules (tetrameric macrocycles), or with water molecules (dimeric macrocycles). Dimeric gold(I) carbenes were also produced using a diamine to form a bridging carbene, or using octafluorobiphenyl to form a Au-C6F4-C6F4-Au bridge, but the solid state structures of these dimers could not be solved. Most of the complexes herein described display luminescent properties.     

Macrocycles: lessons from the distant past,recent developments,and future directions

A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that “are up to the task” to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles'' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality.     

Quinoxaline-bridged porphyrinoids

Quinoxaline-bridged porphyrinoids (3), the first macrocycles containing dipyrrolylquinoxaline (DPQ, 1) subunits, were synthesized from the condensation of the diformyl-substituted DPQ derivatives (2) and 1,8-diaminoanthracene. The resulting structures were confirmed by X-ray analyses, which showed encapsulation of CHCl(3) molecules within the columnar channels established by the stacked arrangement of the individual macrocycles. The solution phase interactions with fluoride and dihydrogenphosphate anions were studied in the case of the unsubstituted system 3a in CH(2)Cl(2). The binding affinities for these anions, studied at the tetrabutylammonium salts, were found to be enhanced relative to those of the simple, unsubstituted monomeric DPQ "parent" system (1a), presumably as the result of the combined effects of preorganization and cooperative binding permitted by the pyrrole NH donor groups. Positive homotropic allosteric anion binding was observed and is ascribed to the structurally coupled nature of the two binding cavities present in the macrocycles. Support for this latter contention came from energy minimization studies.     

Aromatically functionalized cyclic tricholate macrocycles: aggregation, transmembrane pore formation, flexibility, and cooperativity

The aggregation of macrocyclic oligocholates with introverted hydrophilic groups and aromatic side chains was studied by fluorescence spectroscopy and liposome leakage assays. Comparison between the solution and the membrane phase afforded insight into the solvophobically driven aggregation. The macrocycles stacked over one another in lipid membranes to form transmembrane nanopores, driven by a strong tendency of the water molecules in the interior of the amphiphilic macrocycles to aggregate in a nonpolar environment. The aromatic side chains provided spectroscopic signatures for stacking, as well as additional driving force for the aggregation. Smaller, more rigid macrocycles stacked better than larger, more flexible ones because the cholate building blocks in the latter could rotate outward and diminish the conformation needed for the water-templated hydrophobic stacking. The acceptor-acceptor interactions among naphthalenediimide (NDI) groups were more effective than the pyrene-NDI donor-acceptor interactions in promoting the transmembrane pore formation of the oligocholate macrocycles.     

Cyclic tetraureas with variable flexibility--synthesis, crystal structures and properties

Macrocyclic molecules containing several amide or urea functions may serve as anion receptors. We describe the synthesis of 32-membered macrocycles, in which four rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All six possible combinations of these units (XXXX, XXXD, XXDD, XDXD, XDDD and DDDD) were synthesized and two examples were characterised by single-crystal X-ray analyses (DDDD and two structures for XXXD). Both macrocycles showed distinct differences in their overall conformation and consequently in their hydrogen-bonding pattern. Hydrogen-bonded solvent molecules are found for both compounds and intramolecular hydrogen bonds for the two structures of XXXD, but surprisingly no direct intermolecular hydrogen bonds between the macrocyclic tetraurea molecules. The interaction with various anions was studied by (1)H NMR spectroscopy. Stability constants for all tetramers were determined by UV spectroscopy for complexes with chloride, bromide, acetate and dihydrogenphosphate in acetonitrile-THF (3:1). The strongest binding was found for XXXD and acetate (log beta = 7.4 +/- 0.2), the weakest for XXXX and acetate (log beta = 5.1 +/- 0.5). MD simulations in chloroform and acetonitrile boxes show that all molecules except DDDD adopt very similar conformations characterized by an up-down-up-down arrangement of the spacer groups. Clustered solvation shells of acetonitrile molecules around XXXX and DDDD suggest their preorganization for spherical/planar and tetrahedral/bidentate anions, respectively, which in turn was corroborated by simulation of the corresponding complexes with chloride and dihydrogenphosphate.     

Size-Induced Highly Selective Synthesis of Organometallic Rectangular Macrocycles and Heterometallic Cage Based on Half-Sandwich Rhodium Building Block

The controlled synthesis of organometallic supramolecular macrocycles cages remains interesting and challenging work in the field of supramolecular chemistry. Here, two tetranuclear rectangular macrocycles and an octuclear cage were designed and synthesized utilizing a rigid and functionalized pillar linker, 2,6-bis(pyridin-4-yl)-1,7-dihydrobenzo [1,2-d:4,5-d′]diimidazole (BBI4PY) based on three half-sandwich rhodium building blocks bearing different sizes. X-ray crystallography in combination with ¹H NMR spectroscopy elucidated that the two building blocks with shorter spacers only result in rectangular macrocycles. However, the building block of bulkier size to avoid the π-π stacking interactions between two ligands BBI4PY led to the formation of an octuclear cage complex. The latter cage contains two types of metal ions, namely Rh³⁺ and Cu²⁺, showing significant characteristics of heterogeneous metal-assembling compounds. In addition, the cage accommodates two free isopropyl ether solvent molecules, thus displaying host–guest behavior.     

Liquid crystalline 3-, 4- and 6-armed star molecules based on nitromethane-trispropanol or pentaerythritol without mesogen spacers

Some molecules of unusual shape and apparently non-linear geometry, with mesogens tied directly to a central unit (for example, tetrahedral pentaerythritol), have been investigated for liquid crystalline behaviour. It was found that these three-, four- and six-armed 'star' molecules generated liquid crystalline mesophases, which were characterized by DSC, optical microscopy and X-ray diffraction. The temperature ranges of the fluid mesophases for the thermotropic compounds were above 158°C for the three-armed molecules and above 219°C for the four-and six-armed 'stars'. All the liquid crystalline compounds exhibited a smectic phase, which appears to be smectic A, with the molecules in their fully extended conformations within the layers. Some of the compounds also had a smectic phase of higher order or a nematic phase.     

Non-covalent columnar cyclodextrin-based structures

Examples of the formation of ordered ensembles of α-, β-, and γ-cyclodextrins (CDs) molecules with a columnar packing of macrocycles are reported. These ensembles are formed by (1) the supramolecular dissociation of polymer inclusion complexes under the action of organic solvents that are selective with respect to a polymer guest and (2) the fixation of columnar CD aggregates self-organized in aqueous solutions at high temperatures upon the precipitation from water into organic solvents. Specific features of the organization of cyclodextrins in the thus-synthesized structures are studied by X-ray diffraction. Preliminarily oriented polymer inclusion complexes based on corresponding CDs are used as a model with the columnar arrangement of macrocycles.     

Effect of substituents on redox, spectroscopic and structural properties of conjugated diaryltetrazines--a combined experimental and theoretical study

Two series of new soluble conjugated compounds containing tetrazine central ring have been synthesized. The three-ring compounds have been synthesized by the reaction of aryl cyanide (where aryl = thienyl, alkylthienyl, phenyl or pyridyl) with hydrazine followed by oxidation of the intermediate product with diethyl azodicarboxylate. The five-ring compounds have been prepared using two pathways: (i) reaction of 5-cyano-2,2'-bithiophene (or its alkyl derivative) with hydrazine; (ii) via Suzuki or Stille coupling of 3,6-bis(5-bromo-2-thienyl)-1,2,4,5-tetrazine with a stannyl or boronate derivative of alkylthiophene. UV-vis spectroscopic properties of the synthesized compounds are strongly dependent on the nature of the aryl group, the position of the solubilizing substituent and the length of the molecule, showing the highest bathochromic shift (λ(max) > 440 nm) for five-ring compounds with alkyl groups attached to C(α) carbon in the terminal thienyl ring. An excellent linear correlation has been found for spectroscopically determined and theoretically calculated (TD-B3LYP/6-31G*) excitation energies. With the exception of dipyridyl derivative, the calculated lowest unoccupied molecular orbital (LUMO) level of the investigated molecules changes within a narrow range (from -2.63 to -2.41 eV), in line with the electrochemical data, which show a reversible reduction process with the redox potential varying from -1.23 V to -1.33 V (vs. Fc/Fc(+)). The electrochemically determined positions of the LUMO levels are consistently lower by 0.9 to 1.2 eV with respect to the calculated ones. All molecules readily crystallize. Single crystal studies of 3,6-bis(2,2'-bithien-5-yl)-1,2,4,5-tetrazine show that it crystallizes in a P2(1)/c space group whose structural arrangement is not very favorable to the charge carriers flow within the crystal. Powder diffraction studies of other derivatives have shown that their structural organization is sensitive to the position of the solubilizing substituent. In particular, the presence of alkyl groups attached to C(α) carbon in the terminal thienyl ring promotes the formation of a lamellar-type supramolecular organization.     

Bis(azobenzocrown ether)s—synthesis and ionophoric properties

Novel biscrowns were successfully synthesized from azobenzocrown ethers containing hydroxyl groups in para position relative to the azo group. The synthesized host molecules, differing in the size of the macrocycles, the length of the linker and their potential to act as sodium or potassium ionophores, were characterized and used as ionophores in classic and miniature (screen-printed) ion-selective electrodes. Metal cation complexation for selected macrocycles was carried out with the use of UV–vis spectroscopy in acetonitrile. The structural features of novel complex have been deduced by X-ray crystallography. X-ray analysis indicated the formation of sandwich structures with two sodium cations encapsulated between two macrocyclic molecules of 13C2.     

Calix[4]pyrrole Schiff base macrocycles. Novel binucleating ligands for mu-oxo iron complexes

New bimetallic mu-oxo diferric complexes of several previously reported calix[4]pyrrole Schiff base macrocycles are described. The synthesis of a new member of this class of macrocycles is also reported; it was prepared via an acid-catalyzed condensation between 1,9-bisformyl-5,5-dipropyldipyrromethane and o-phenylenediamine. Reactions of the free base macrocycles or their bis-HCl salts with Fe(II) mesitylene, followed by air oxidation, gave the binuclear mu-oxo bis-Fe(III) compounds 6-10 in moderate yield. X-ray crystallography data reveal two different coordination environments for the Fe-O-Fe subunit in 6-10 that it is suggested can be controlled by altering the reaction conditions. Structural properties of these metalated pyrrolic macrocycles are also compared to those of mu-oxo diferric porphyrins and mu-oxo diferric texaphyrin. Complexes 6-10 exhibit two distinct types of M-N bonds that are similar in length to the bonds observed in metallotexaphyrin complexes. However, the electronics of the present systems are very different from those of texaphyrins and porphyrins in that no delocalized bonding patterns are observed within the ligands as a whole.     

Supermolecular self organization via molecular aggregation. Non-discotic three chain diols displaying a hexagonal columnar phase

A new class of mesogen formed by three chain diols is described. These compounds consist of a central part to which three aliphatic chains of various length (n = 4-14) are attached at one end and two hydroxy groups at the other. X-ray scattering, dilatometric measurements, dielectric and Kerr relaxation studies were carried out. Both X-ray investigations, dielectric and electro-optic studies revealed that the molecules are aggregated in the isotropic fluid state and that hydrogen bonding and dipole correlation contribute to this aggregation. Columnar assemblies of up to several hundred molecules are orientationally correlated in the isotropic fluid phase. Correlated reorientations occur in the presence of external electric fields. The X-ray data show that the aggregates pack in a hexagonal way at lower temperatures giving a structure which strongly resembles that of the hexagonal disordered columnar phase. This anisotropic phase can be quenched to a glassy liquid-crystalline state. It is evident that the mesogenic properties of this new class of compounds are a function of the disc-like shape of the aggregates rather than the shapes of the individual molecules.     

Effect of molecular mass on supramolecular organisation of poly(4,4'-dioctyl-2,2':5',2'-terthiophene)

The effect of the chain length on the type and extent of the 2D supramolecular organization in poly(4,4'-dioctyl-2,2':5',2'-terthiophene) (PDOTT) monomolecular layers deposited on highly oriented pyrolytic graphite (HOPG) is studied by scanning tunneling microscopy (STM) and analyzed in terms of molecular modeling. The strictly monodispersed fractions of increasing molecular mass used in this study were obtained by chromatographic fractionation of the crude product of 4,4'-dioctyl-2,2':5',2'-terthiophene oxidative polymerization. STM investigations of PDOTT layers, deposited on HOPG from poly- and monodispersed fractions, show that polydispersity can be considered as a key factor seriously limiting supramolecular ordering. This is a consequence of significant differences in the type of supramolecular order observed for molecules of different chain length. It has been demonstrated that shorter molecules (consisting of 6 and 9 thiophene units) form well-defined two-dimensional islands, while the interactions between longer molecules (consisting of 12 and 15 thiophene units) become anisotropic. Consequently, for higher molecular mass fractions, the supramolecular organization is one-dimensional and consists of more or less separated rows of ordered macromolecules. In this case an increase of the chain length leads to amplification of the intermolecular interactions proceeding via interdigitation of the alkyl substituents of adjacent molecules. Polydispersed fractions show much less ordered organization because of the incompatibility of the supramolecular structures of molecules of different molecular masses. This finding is of crucial importance for the application of polythiophene derivatives in organic and molecular electronics since ordered supramolecular organization constitutes the condition sine qua non of good electrical transport properties.     

Large ring-forming alkylations provide facile access to composite macrocycles

Macrocyclic compounds have potential to enable drug discovery for protein targets with extended, solvent-exposed binding sites. Crystallographic structures of peptides bound at such sites show strong surface complementarity and frequent aromatic side-chain contacts. In an effort to capture these features in stabilized small molecules, we describe a method to convert linear peptides into constrained macrocycles based upon their aromatic content. Designed templates initiate the venerable Friedel–Crafts alkylation to form large rings efficiently at room temperature – routinely within minutes – and unimpeded by polar functional groups. No protecting groups, metals, or air-free techniques are required. Regiochemistry can be tuned electronically to explore diverse macrocycle connectivities. Templates with additional reaction capabilities can further manipulate macrocycle structure. The chemistry lays a foundation to extend studies of how the size, shape and constitution of peptidyl macrocycles correlate with their pharmacological properties.