Fluorescent sensors for Hg2+ that combine aggregation-induced emission (AIE) activity of tetraarylethylenes with metal chelating 1,1-bis(2-pyridylethylene) fragments and thiophene/bithiophene substituents have been prepared and characterized. The sensors exhibit red-shifted and enhanced emission in the presence of Hg2+ in aqueous solution while exhibiting little to no change in fluorescence in the presence of other metal ions. Job plot analyses indicate 2 : 1 sensor : Hg2+ binding stoichiometries in solution. 1H-NMR spectroscopy was also employed to investigate solution phase binding interactions between the sensors and Hg(ClO4)2, and a chelated HgI2–bis(pyridyl) complex has been characterized by X-ray crystallography. The limit of detection for Hg2+ was determined to be 48 nM. In contrast, the fluorescence of structurally analogous materials possessing quinoline rings in place of pyridine groups is completely quenched in the presence of Hg(ClO4)2. The high sensitivity and selectivity displayed by these sensors for Hg2+ over other metal ions may enable monitoring of mercury in aqueous environments.

The synthesis and photophysical properties of luminescent Re(I) tricarbonyl complexes prepared from bis(pyridyl)- and bis(quinolyl) tetraarylethylene (TAE) ligands are reported. Emission wavelengths of the complexes are influenced by structural variation in the tetraarylethylene ligands, and several complexes display aggregation-induced enhanced emission in aqueous solution. A Re(I) complex prepared from an indole-functionalized TAE ligand shows significant enhancement in its luminescence intensity accompanied by a remarkable blue shift (∼95 nm) upon specific binding to site II of human serum albumin.

4-Substituted pyridines linked to iodoarene groups with alkyl amide tethers can be converted to the corresponding alkylidene dihydropyridines by treatment with ethyl chloroformate and Et3N. Subsequent exposure to Pd-catalyzed Mizoroki–Heck reaction conditions results in efficient intramolecular cyclization at the exocyclic alkene to afford isoindolinone and oxindole derivatives. Asymmetric construction of 3,3-disubstituted oxindoles and isoindolinones has also been achieved. This work demonstrates the ability to utilize reactive pyridine anhydrobases in metal-catalyzed transformations and provides the basis for design of new approaches to important heterocyclic ring systems.Keywords: asymmetric Heck reaction; heterocycles; isoindolinone; Mizoroki−Heck reaction; oxindole; palladium catalysis; pyridine

Alkylidene dihydropyridines (anhydrobases) prepared via dearomatization of N-acylated 4-(aminomethyl)pyridines participate in [3 + 2] cyclocondensation reactions with aryldiazonium cations to afford substituted 1,2,4-triazolium salts or neutral 1,2,4-triazoles in high isolated yield. The reaction proceeds in the presence of a variety of N-acyl groups and aryl-susbtituted diazonium salts and offers a general route to pyridyl-substituted 1,2,4-triazoles.

Results of model studies demonstrating a stereoselective synthetic route to tricyclic analogues of the bis(piperidine) alkaloid xestoproxamine C are presented. Dearomatization of a tricyclic pyridine derivative to afford an alkylidene dihydropyridine (anhydrobase) intermediate followed by catalytic heterogeneous hydrogenation was used to install the correct relative stereochemistry about the bis(piperidine) ring system. Other key features of these model studies include development of an efficient ring-closing metathesis procedure to prepare macrocyclic derivatives of 3,4-disusbstituted pyridines, intramolecular cyclizations of alkylidene dihydropyridines to establish pyridine-substituted pyrrolidines and piperidines, successful homologation of pyridine-4-carboxaldehydes using formaldehyde dimethyl thioacetal monoxide (FAMSO), and application of B-alkyl Suzuki coupling to assemble substituted pyridines.

Ten N-halophenylpyridinium salts (halogen = Br or I) with chloride (and in one case iodide) counterions have been prepared and structurally characterized in order to examine the degree of solid state halogen bonding exhibited in these systems. N-Halophenylpyridinium salts are easily synthesized from existing pyridines, and the cationic pyridinium group is expected to increase the halogen bond donor ability of attached halophenyl moieties. Halide anions functioning as halogen bond acceptors facilitate formation of charge-assisted halogen bonds. All five substrates featuring iodophenyl or diiodophenyl substituents displayed the expected halogen bonding interactions. In several cases halide ion acceptors were also engaged in complementary hydrogen bonding interactions with C–H groups of pyridinium rings and O–H groups of water solvates. Halogen bond donors containing a diiodophenyl group formed either an extended network or discrete supramolecular macrocyclic constructs through ArI···Cl–···IAr bridging interactions. Significantly fewer and weaker halogen bonding interactions were observed in crystals of N-bromophenylpyridinium salts. The attenuation of halogen bonding in these substrates is attributed to the inability of the activated bromoarene halogen bond donors to compete with hydrogen bond donors (C–H/O–H residues) for the halide anion.

Aggregation-induced emission (AIE) is emerging as an important design element in a variety of new fluorescent-based chemical sensors and bio-imaging agents. In particular, derivatives of tetraphenylethylene (TPE) have been widely utilized in this regard as the TPE framework is a reliable AIE-luminogen. To expand the library of AIE active tetraarylethylenes, we have explored the effects of replacing one or two of the phenyl rings in TPE with pyridine. Efficient synthetic routes that deliver mono- and bis-pyridyl tetraarylethylenes have been developed and the luminescent properties of these heterocyclic TPE analogues, along with their corresponding N-methylated pyridinium salts, have been examined.

1,2-Dialkylimidazoles can be converted to nucleophilic 2-alkylidene imidazolines upon treatment with (BOC)2O under mild conditions. Incorporation of a β-keto amide carbonyl electrophile in the 2-alkylimidazole side chain results in intramolecular aldol-like cyclization to afford imidazole-functionalized γ-lactams. Positioning of a ketone electrophile in a 1-alkyl side chain results in cyclization at the 2-position to afford fused ring imidazoles through a similar reaction manifold. Efficient transfer of a BOC group from an intermediate N-acyl imidazolium species to a nucleophilic center in the cyclized product appears to be an important feature of these reactions.

Aldehyde and ketone electrophiles incorporated into the side chains of 2- and 4-alkylpyridines participate in intramolecular aldol-like condensations with pyridine benzylic carbons in the presence of Brønsted acid catalysts. Pyridines featuring β-ketoamide side chains undergo cyclization in the presence of 10 mol% TfOH to afford pyridyl-substituted hydroxy lactams in good yield. These products were found to be resistant to further dehydration under a variety of conditions, however treatment with thionyl chloride elicited an unusual dehydration/oxidation reaction sequence. In contrast, acid-catalyzed cyclization of pyridines tethered to aliphatic aldehydes with amine linkers gives pyridyl-substituted dehydro-piperidine products. Similarly, intramolecular condensation of salicylaldehyde- and salicylketone-substituted pyridines affords pyridyl-substituted benzofurans.

Substituted tetraphenylethylenes (TPEs) have been prepared that feature four alkyl or aryl urea groups arrayed along the periphery. Exposure of these TPEs to monovalent anions (halide, carboxylate, nitrate, and azide) resulted in enhanced fluorescence emission attributed to aggregation of the TPE molecules via urea-anion hydrogen bonding. Emission enhancement correlated with anion basicity, with fluoride ion eliciting the largest fluorescence response. Increased fluorescence emission could also be detected visually in solutions viewed under UV light. This study demonstrates the feasibility of TPE-based fluorescent anion sensors/detectors, and it is envisioned that additional design modifications may afford anion-selective fluorescent sensors.

Three halogen bonded co-crystals between tetraphenylethylene derivatives with peripheral pyridine groups and 1,4- or 1,2-diiodotetrafluorobenzene have been characterized. Two crystalline networks prepared from 3-pyridyl-substituted tetraphenylethylene exhibit remarkably similar topologies, each featuring an open square grid lattice assembled from the tetraphenylethylene component that surrounds π-stacked 1,2- or 1,4-diiodoarene halogen bond donors. The ratio of tetraphenylethylene to diiodoarene is 1:2 in each case, and all pyridine and iodoarene groups are engaged in halogen bonding interactions. Co-crystals obtained from 4-pyridyl-substituted tetraphenylethylene and 1,4-diiodotetrafluorobenzene, however, exhibit a 1:1 ratio of components with only a single pyridine N⋯I halogen bond.

4-Alkylpyridines functionalized with alkynyl amide substituents can be converted to pyridyl-substituted lactams via Au-catalyzed cyclization at the pyridine benzylic carbon. These transformations proceed through alkylidene dihydropyridine (anhydrobase) intermediates and demonstrate the ability to utilize these species in metal-catalyzed C–C bond forming reactions.Figure optionsDownload full-size imageDownload as PowerPoint slide

Solid state halogen bonding interactions have been examined in structurally similar tetratopic haloarenes bearing a common tetraphenylethylene core. This study was designed with the aim of providing insight into the relative importance of fundamental solid state halogen bonding interactions (i.e., halogen···halogen, halogen···π, and halogen···carbonyl) in systems devoid of strong hydrogen bonding groups. The substrates used in this study all featured four halobenzoate substituents (halogen = Br or I) attached to the four para positions of tetraphenylethylene with conformationally flexible ester linkages. A total of nine crystal structures from five different tetraarylethylene substrates were obtained. While distinct and unique X···O and X···π halogen bonding interactions were identified in each structure, all structures displayed nominally similar packing arrangements generally consisting of one-dimensional ribbons aligned to generate non-interpenetrating two-dimensional sheets. This feature may be a consequence of extensive edge-to-face arene–arene interactions found in each structure and may indicate a greater structure-determining role for aryl-H···π interactions relative to halogen bonding contacts in this system.

4-Alkylpyridines possessing nucleophilic β-dicarbonyl side chains have been converted to spirodihydropyridines upon treatment with ethyl chloroformate and sub-stoichiometric amounts of Ti(OiPr)4. Alternatively, inclusion of mild base in the reaction medium was found to facilitate generation of anhydrobase intermediates. Subsequent aldol-like condensations with electrophilic side chain moieties followed by hydrolysis delivered benzylically cyclized pyridines in good yield. In situ hydrogenation of cyclized anhydrobase intermediates afforded 4-substituted piperidines.

Principles of crystal engineering have been applied toward the construction of supramolecular assemblies between an acid-functionalized tetraphenylethylene derivative and three different bis(pyridine)s [4,4′-bis(pyridyl)ethylene, 4,4′-bis(pyridyl)ethane, and 4,4′-bipyridine]. Each assembly was structurally characterized, and charge transfer interactions within each sample were visually apparent. Quantum chemical calculations were used to determine crystal band structure and band gap magnitude, and electrical properties of the materials were measured using conducting probe atomic force microscopy (CP-AFM). The crystals displayed charge-carrier capability, and the magnitude of semiconductivity varied systematically as a function of conjugation in the bis(pyridine) component. Crystals incorporating 4,4′-bis(pyridyl)ethylene and 4,4′-bipyridine displayed conductivities comparable to those of established organic semiconductors (μeff = 0.38 and 1.7 × 10–2 cm2/V·s, respectively).

Controlling the manner in which organic compounds and metal–organic frameworks assemble in the solid state is an attractive strategy for construction of new functional materials. Most crystal engineering studies employ geometrically well-defined and rigid molecular building blocks in order to limit modes of intermolecular association to only a few (ideally predictable) pathways. Although sacrificing a measure of control, the use of conformationally flexible molecules may provide unique opportunities to construct novel crystalline architectures exhibiting desirable attributes, such as dynamic solid state properties. In this Highlight some of the potential advantages and disadvantages encountered when using flexible components in crystal engineering are discussed. Purely organic systems as well as metal–organic constructs derived from conformationally mobile precursors are described in an effort to demonstrate the impact of molecular flexibility on solid state structure in a range of applications.

Construction of 3,9-diazaspiro[5.5]undecane derivatives can be easily achieved via intramolecular spirocyclization of 4-substituted pyridines. The reaction entails in situ activation of the pyridine ring with ethyl chloroformate followed by intramolecular addition of an attached β-dicarbonyl nucleophile in the presence of Ti(OiPr)4.

Two tetrapyridyl-substituted tetraphenylethylenes have been prepared via Suzuki coupling between tetrabromo tetraphenylethylene and 3- or 4-pyridine boronic acid. Both compounds exhibit aggregation-induced emission as determined by solid state fluorescence spectroscopy and solution phase fluorescence measurements performed in aqueous/organic solvent mixtures. Solution phase fluorescence was also found to be switchable as a function of pH. 3-Pyridyl-substituted tetraphenylethylene has been structurally characterized by X-ray crystallography.

Two tetraarylethylene derivatives symmetrically functionalized at the 4, 4′, 4″, and 4‴4‴ positions with either 4-pyridyl or 3-pyridyl groups were converted to their corresponding tetrapyridinium perchlorate salts upon exposure to Fe(ClO4)3·xH2O. These tetra-perchlorates were isolated as single crystals and their structures were determined by X-ray diffractometry. In both cases extensive hydrogen bonding networks were observed involving pyridinium N–H groups, perchlorate anions, and included water molecules. Additionally, both structures feature hydrophobic crystalline regions formed from stacking of tetraarylethylene cations in helical fashion. Polar pyridinium N–H groups are directed outward from these stacks into hydrophilic crystalline regions containing perchlorate anions and water molecules of hydration. Information obtained regarding the solid state structures of these functionalized tetraarylethylene derivatives should prove useful in design of more elaborate supramolecular architectures.Highlights► Pyridinium tetraphenylethylenes have been structurally characterized. ► Solid state H-bonding networks involving N–H+, ClO4-, and H2O. ► Tetraarylethylenes form helical stacks with polar N–H groups toward the periphery. ► Helical stacks surrounded by polar regions of ClO4- and H2O.

Pyridines substituted at the 4-position with alkyl tethers containing β-dicarbonyl moieties were converted to spirocyclic 4,4-disubstituted dihydropyridines. Optimal conditions for these transformations involved N-acylation of the pyridine substrate with a chloroformate electrophile in the presence of Ti(OiPr)4. Cyclization products could be easily converted into spiro-piperidine derivatives or elaborated into more complex heterocyclic frameworks via Au-catalyzed cycloisomerization.

A strain-induced copper-free click reaction mediated by a new and easily prepared cyclooctyne derivative was used to efficiently assemble a DOTA−biotin adduct capable of radionuclide (68Ga) uptake. This synthetic strategy offers a potentially general and convenient means of preparing targeted radiolabeling and radiotherapeutic agents.

Solid-state halogen bonding interactions present in four families of structurally similar tritopic haloarenes were examined in an effort to identify molecular features that promote halogen···carbonyl, halogen···halogen, and/or halogen···π interactions. The substrates used in this study all featured three haloarene substituents attached to a central 1,3,5-substituted arene ring with conformationally flexible linkers (ketone or ester groups) in order to systematically vary the polarization of the aryl halogen groups. Within each individual substrate type, however, there was found to be little correlation in the halogen bonding motifs exhibited as a function of halogen present (I, Br, and Cl). In general, the iodoarene derivatives examined exhibited a greater degree of halogen bonding interactions than the bromo and chloro analogues, and a unique bifurcated I···I/I···O═C halogen bonding synthon was identified in two substrates. Halogen bonding contacts observed in tritopic iodoarenes correlated nicely with electrostatic potentials of simpler model compounds determined using computational methods. This study highlights the difficulty in attempting to empirically correlate halogen bonding with molecular structure.

Attachment of DOTA to a novel monofluoro-cyclooctyne facilitates bioconjugation to an azide-modified peptide via Cu-free click chemistry. The resulting conjugate was radiolabeled with 111In to afford a potential targeted molecular imaging agent with high specific activity and an excellent radiochemical purity.

A well-defined organic polyrotaxane has been obtained from a 1,3,5-triaroylbenzene tris(carboxylic acid) derivative upon crystallization under acidic conditions.

An experimentally straightforward procedure for the synthesis of structurally elaborate cyclohexadienyl ruthenium(II) complexes has been developed along the lines of the Morita−Baylis−Hillman reaction. Coordination of (cyclopentadienyl)Ru(II) fragments to N-benzyl and N-phenethyl acrylamides was found to facilitate conversion to stable cyclohexadienyl complexes via Bu3P-mediated intramolecular cyclization. An ipso cyclization was observed in all but one case, resulting in formation of five- or six-membered spirolactams at C6 positions of cyclohexadienyl ligands. Acrylamides prepared from dihydroindene and tetrahydronaphthalene precursors were suitable substrates for this transformation, affording access to novel tricyclic cyclohexadienyl complexes. One such complex was characterized by X-ray crystallography.

Bifurcated I⋯π and I⋯OC halogen bonding interactions assist in formation of unique iodo–arene trimers leading to nanoscale channels in inclusion complexes of trimesic acid iodophenolate.

A series of four structurally related crownophanes has been prepared and characterized by X-ray crystallography. The crownophanes are based upon a 1,3,5-triaroylbenzene framework and were synthesized via enaminone/alkyne cyclotrimerization. The crownophanes differ in the identity of a peripheral substituent attached to a remote arene ring that is not part of the cyclophane macrocycle. Solid state structural characterization reveals that crownophanes with remote phenyl and phenol substituents self-assemble to form centrosymmetric dimers. Incorporation of remote alkoxy groups (methoxy or ethoxy) disrupts dimerization and leads to catameric networks. Each crownophane crystallized as an inclusion complex or a hydrate and, in one instance, water was found to occupy the macrocyclic cavity.

Monolayers of triaroylbenzene derivatives bearing three octyl groups projecting away from the molecular core and terminated by hydroxyl, carboxylic acid, and methyl ester groups have been studied using surface pressure isotherm measurements and Brewster angle microscopy. The octyl derivative lacking a terminal hydrophilic group forms a monolayer of limited stability. The derivatives with hydrophilic end-groups on the octyl chains form stable monolayers. A reorientation at the water surface under compression from a ‘face-on’ to a distorted ‘edge-on’ arrangement appears likely. At intermediate molecular areas, a phase transition occurs and aggregate formation is observed. Studies of mixtures with methyl stearate exhibit a contrast inversion between the background phase and immiscible domains of methyl stearate supporting the concept of a reorientation of the triaroylbenzene derivatives during compression.

The structures of 4-chloro- and 4-bromotribenzoylbenzene, as well as a solid solution prepared from these two components, are isomorphous and dominated by C–X⋯OC interactions, whereas type-II I⋯I interactions are important in the 4-iodo derivative.

Polypyridyl ethylenes have been prepared as heterocyclic analogues of tetraphenylethylene. In addition to conventional AIE effects, a derivative possessing a 1,1-bis(2-pyridyl)ethylene fragment displays Zn2+-selective enhanced fluorescence in aqueous solution, in contrast to the behavior of isomeric bis(3- and 4-pyridyl)ethylenes. The Zn2+-sensing capability of this material is attributed to formation of chelated Zn2+-bis(pyridyl) complexes and is supported by the X-ray crystal structure of a bis(2-pyridyl)ethylene-Zn(OAc)2 complex.

Fluorescent sensors for Hg2+ that combine aggregation-induced emission (AIE) activity of tetraarylethylenes with metal chelating 1,1-bis(2-pyridylethylene) fragments and thiophene/bithiophene substituents have been prepared and characterized. The sensors exhibit red-shifted and enhanced emission in the presence of Hg2+ in aqueous solution while exhibiting little to no change in fluorescence in the presence of other metal ions. Job plot analyses indicate 2:1 sensor:Hg2+ binding stoichiometries in solution. 1H-NMR spectroscopy was also employed to investigate solution phase binding interactions between the sensors and Hg(ClO4)2, and a chelated HgI2–bis(pyridyl) complex has been characterized by X-ray crystallography. The limit of detection for Hg2+ was determined to be 48 nM. In contrast, the fluorescence of structurally analogous materials possessing quinoline rings in place of pyridine groups is completely quenched in the presence of Hg(ClO4)2. The high sensitivity and selectivity displayed by these sensors for Hg2+ over other metal ions may enable monitoring of mercury in aqueous environments.

Aldehyde and ketone electrophiles incorporated into the side chains of 2- and 4-alkylpyridines participate in intramolecular aldol-like condensations with pyridine benzylic carbons in the presence of Brønsted acid catalysts. Pyridines featuring β-ketoamide side chains undergo cyclization in the presence of 10 mol% TfOH to afford pyridyl-substituted hydroxy lactams in good yield. These products were found to be resistant to further dehydration under a variety of conditions, however treatment with thionyl chloride elicited an unusual dehydration/oxidation reaction sequence. In contrast, acid-catalyzed cyclization of pyridines tethered to aliphatic aldehydes with amine linkers gives pyridyl-substituted dehydro-piperidine products. Similarly, intramolecular condensation of salicylaldehyde- and salicylketone-substituted pyridines affords pyridyl-substituted benzofurans.