meta‐Selective C−H Arylation of Fluoroarenes and Simple Arenes

Fluorine is known to promote ortho‐C?H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho‐palladation intermediate and is then relayed to the meta position, leading to meta‐selective C?H arylation of fluoroarenes. Deuterium experiment suggests that this meta‐arylation is initiated by ortho C?H activation and the catalytic cycle is terminated by C‐2 protonation. A dual‐ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.     

Rational Development of Remote C−H Functionalization of Biphenyl: Experimental and Computational Studies

A simple and efficient nitrile‐directed meta‐C?H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U‐shaped template to achieve a molecular U‐turn and assemble the large‐sized cyclophane transition state for the remote C?H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta‐C?H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta‐selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand‐containing Pd–Ag heterodimeric transition state (TS) favors the desired remote meta‐selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non‐directed meta‐C?H activation. Substituted 2‐pyridone ligands were found to be key in assisting the cleavage of the meta‐C?H bond in the concerted metalation–deprotonation (CMD) process.     

Synthesis of meta‐Terphenyl‐2,2′′‐diols by Anodic C−C Cross‐Coupling Reactions

The anodic C?C cross‐coupling reaction is a versatile synthetic approach to symmetric and non‐symmetric biphenols and arylated phenols. We herein present a metal‐free electrosynthetic method that provides access to symmetric and non‐symmetric meta‐terphenyl‐2,2′′‐diols in good yields and high selectivity. Symmetric derivatives can be obtained by direct electrolysis in an undivided cell. The synthesis of non‐symmetric meta‐terphenyl‐2,2′′‐diols required two electrochemical steps. The reactions are easy to conduct and scalable. The method also features a broad substrate scope, and a large variety of functional groups are tolerated. The target molecules may serve as [OCO]^3? pincer ligands.     

Rhodium‐Catalyzed Enantioselective Oxidative [3+2] Annulation of Arenes and Azabicyclic Olefins through Twofold C−H Activation

C?H bond activation is mostly limited to ortho selectivity. Activation of both ortho and meta C?H bonds constitutes a particularly important strategy for annulation, but has rarely been studied in enantioselective systems. Reported herein is rhodium(III)‐catalyzed asymmetric [3+2] transannulation of arenes with 7‐azabenzonorbornadienes. Two distinct classes of arenes have been identified as substrates, and the coupling proceeded with high enantioselectivity and excellent diastereoselectivity through sequential activation of ortho and meta C?H bonds.     

Environment‐Sensitive Probes Containing a 2,6‐Diethynylpyridine Motif for Fluorescence Turn‐On Detection and Induction of Nanoarchitectures of Human Telomeric Quadruplex

Bis(phenylethynyl)pyridylcarboxamides with amide side chains at the para position of the NH₂ group possess strong solvatochromic properties compared with the meta analogues. Fluorescence binding titrations show that these probes exhibit remarkable fluorescence turn‐on responses upon interacting with the human telomeric G‐quadruplex (h‐TELO). Förster resonance energy transfer melting analysis shows the high selectivity of these probes for h‐TELO over duplex DNA. Isothermal titration calorimetry, as well as UV/Vis and fluorescence spectroscopy studies, show that the meta analogue has a twofold binding affinity for h‐TELO over the para analogue. The noncovalent interaction of these small‐molecule probes with h‐TELO has been used to regulate the assembly of novel supramolecular nanoarchitectures.     

Ruthenium‐Catalyzed meta‐Selective CH Bromination

The first example of a transition‐metal‐catalyzed, meta‐selective C? H bromination procedure is reported. In the presence of catalytic [{Ru(p‐cymene)Cl₂}₂], tetrabutylammonium tribromide can be used to functionalize the meta C? H bond of 2‐phenylpyridine derivatives, thus affording difficult to access products which are highly predisposed to further derivatization. We demonstrate this utility with one‐pot bromination/arylation and bromination/alkenylation procedures to deliver meta‐arylated and meta‐alkenylated products, respectively, in a single step.     

Shape Selectivity by Guest‐Driven Restructuring of a Porous Material

A flexible metal‐organic framework selectively sorbs para‐ (pX) over meta‐xylene (mX) by synergic restructuring around pX coupled with generation of unused void space upon mX loading. The nature of the structural change suggests more generally that flexible structures which are initially mismatched in terms of fit and capacity to the preferred guest are strong candidates for effective molecular separations.     

Photoisomerization of Trans Ortho‐, Meta‐, Para‐Nitro Diarylbutadienes: A Case of Regioselectivity

A series of ortho‐, meta‐ and para‐substituted trans‐nitro aryl (phenyl and pyridyl) butadienes have been synthesized and characterized. The effect of substitution and positional selectivity on their fluorescence and photoisomerization were systematically investigated. Among all dienes, meta‐ and para‐nitro phenyl‐substituted derivatives exhibit remarkable solvatochromic emission shifts due to intramolecular charge transfer. On the other hand, ortho derivatives undergo regioselective isomerization upon photoexcitation in contrast to inefficient isomerization of para and meta nitro‐substituted dienes. Single crystal X‐ray analysis revealed existence of intramolecular hydrogen bonding between the nitro group and the hydrogen of the proximal double bond. This restricts the rotation of the proximal double bond thereby allowing regioselective isomerization. The observations were also supported by NMR spectroscopic studies.     

meta‐Selective C−H Activation of Arenes at Room Temperature Using Visible Light: Dual‐Function Ruthenium Catalysis

Ruthenium‐catalyzed meta‐C?H activation of arenes at room temperature is reported to proceed under blue‐light irradiation. A variety of heteroarenes are compatible with this photochemical process, which leads to the corresponding meta C?C coupling products in good to very good yields. Initial mechanistic studies suggest a single‐electron transfer process occurs between a photoexcited Ru^II‐cyclometalated complex and alkyl halides, enabling meta‐C?H functionalization reaction via carbon‐centered radicals.     

Intramolecular Charge Transfer in Kekulé‐ and Non‐Kekulé‐Bridged Bis(triarylamine) Radical Cations: Missing Key Compounds in Organic Mixed‐Valence Systems

From the viewpoint of para‐meta topological bridging effect on the electronic coupling in organic mixed‐valence (MV) systems, the optically induced and thermally assisted intramolecular charge/spin transfer (ICT/IST) processes have been investigated for three bis(triarylamine) (BTA) radical cations as missing key compounds in very basic BTA MV systems. In contrast to the case of p‐ and m‐dinitrobenzene radical anions, the difference in the strength of electronic coupling (V) was not so large for the present BTA MV radical cations, although they still fall within the paradigm of strong V for para‐linkage and weak V for meta‐linkage. Unexpectedly, it has been found that meta‐phenylenediamine radical cation has an electronic coupling comparable to those in the para‐conjugated BTA‐based MV species, and the ICT/IST rate exceeds the ESR time‐scale. This finding is very encouraging considering that sufficient electronic communication can be ensured even when the redox‐active centers are linked directly by the meta‐phenylene bridge, thus broadening the selection of π‐bridging units for molecule‐based optoelectronics.     

Palladium‐Catalyzed Directed meta‐Selective C−H Allylation of Arenes: Unactivated Internal Olefins as Allyl Surrogates

Palladium(II)‐catalyzed meta‐selective C?H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ‐donating and π‐accepting ability of pyrimidine‐based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E stereoselectivity were achieved with broad substrate scope, wide functional‐group tolerance, and good to excellent yields. Late‐stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed light on the mechanism and point to key steric control in the palladacycle, thus determining product selectivities.     

Generating Selective Saccharide Binding Affinity of Phenyl Boronic Acids by using Single‐Walled Carbon Nanotube Corona Phases

Saccharides recognition is challenging due to their low affinity for substrates, yet this recognition is critical for human immunity and glycobiology. Herein, we demonstrate that a polymer or surfactant corona phase surrounding a single‐walled carbon nanotube can substantially modify the selectivity of pre‐adsorbed phenyl‐boronic acids (PBA) for mono‐, di‐, and poly‐saccharides. A library of 17 PBAs including carboxy, nitro, and amino PBA with ortho‐, meta‐, or para‐ substitutions are used to generate 144 distinct corona phases. Six in particular demonstrate significantly increased selectivity to specific saccharides including ribose (0.42 mol per total mol), arabinose (0.36), and glucose (0.25), but unusually diminished binding to fructose (0.02). Recognition proceeds by saccharide adsorption into the corona, followed by PBA reaction in a consecutive second order reaction. The results extend to larger saccharides, such as glycosaminoglycans, suggesting promise for protein glycosylation.     

meta‐ and para‐Phenylenediamine‐Fused Porphyrin Dimers: Synthesis and Magnetic Interactions of Their Dication Diradicals

meta‐ and para‐Phenylenediamine‐fused nickel(II) porphyrin dimers were synthesized by S_NAr reaction of meso,β,β‐trichloro nickel(II) porphyrin with meta‐ and para‐phenylenediamines and subsequent Pd‐catalyzed intramolecular C?H arylation. Their tetrachlorinated dication diradicals are very stable, allowing SQUID magnetometry and revealing clear open‐shell characters for both meta and para isomers with ferro‐ and anti‐ferromagnetic interactions, respectively. The nitrogen analogue of Thiele's hydrocarbon usually displays predominant closed‐shell nature but its hidden diradical characters increase either in a twisted conformation or upon insertion of an additional phenylene spacer. The observed distinct diradical nature of the para‐congener indicates that diradical properties can be enhanced also by efficient spin delocalization.     

Highly Active and Robust Metalloporphyrin Catalysts for the Synthesis of Cyclic Carbonates from a Broad Range of Epoxides and Carbon Dioxide

Bifunctional metalloporphyrins with quaternary ammonium bromides (nucleophiles) at the meta, para, or ortho positions of meso‐phenyl groups were synthesized as catalysts for the formation of cyclic carbonates from epoxides and carbon dioxide under solvent‐free conditions. The meta‐substituted catalysts exhibited high catalytic performance, whereas the para‐ and ortho‐substituted catalysts showed moderate and low activity, respectively. DFT calculations revealed the origin of the advantage of the meta‐substituted catalyst, which could use the flexible quaternary ammonium cation at the meta position to stabilize various anionic species generated during catalysis. A zinc(II) porphyrin with eight nucleophiles at the meta positions showed very high catalytic activity (turnover number (TON)=240 000 at 120 °C, turnover frequency (TOF)=31 500 h^?1 at 170 °C) at an initial CO₂ pressure of 1.7 MPa; catalyzed the reaction even at atmospheric CO₂ pressure (balloon) at ambient temperature (20 °C); and was applicable to a broad range of substrates, including terminal and internal epoxides.     

A ‘meta effect’ in the fragmentation reactions of ionised alkyl phenols and alkyl anisoles

The competition between benzylic cleavage (simple bond fission [SBF]) and retro‐ene rearrangement (RER) from ionised ortho, meta and para RC₆H₄OH and RC₆H₄OCH₃ (R = n‐C₃H₇, n‐C₄H₉, n‐C₅H₁₁, n‐C₇H₁₅, n‐C₉H₁₉, n‐C₁₅H₃₁) is examined. It is observed that the SBF/RER ratio is significantly influenced by the position of the substituent on the aromatic ring. As a rule, phenols and anisoles substituted by an alkyl group in meta position lead to more abundant methylene‐2,4‐cyclohexadiene cations (RER fragmentation) than their ortho and para homologues. This ‘meta effect’ is explained on the basis of energetic and kinetic of the two reaction channels. Quantum chemistry computations have been used to provide estimate of the thermochemistry associated with these two fragmentation routes. G3B3 calculation shows that a hydroxy or a methoxy group in the meta position destabilises the SBF and stabilises the RER product ions. Modelling of the SBF/RER intensities ratio has been performed assuming two single reaction rates for both fragmentation processes and computing them within the statistical RRKM formalism in the case of ortho, meta and para butyl phenols. It is clearly demonstrated that, combining thermochemistry and kinetics, the inequality (SBF/RER)_meta < (SBF/RER)_ortho < (SBF/RER)_para holds for the butyl phenols series. It is expected that the ‘meta effect’ described in this study enables unequivocal identification of meta isomers from ortho and para isomers not only of alkyl phenols and alkyl anisoles but also in other alkyl benzene series. Copyright © 2012 John Wiley & Sons, Ltd.     

Visible‐Light‐Enabled Ruthenium‐Catalyzed meta‐C−H Alkylation at Room Temperature

Visible‐light‐induced ruthenium catalysis has enabled remote C?H alkylations with excellent levels of position control under exceedingly mild conditions at room temperature. The metallaphotocatalysis occurred under exogenous‐photosensitizer‐free conditions and features an ample substrate scope. The robust nature of the photo‐induced mild meta‐C?H functionalization is reflected by the broad functional group tolerance, and the reaction can be carried out in an operationally simple manner, setting the stage for challenging secondary and tertiary meta‐C?H alkylations by ruthenaphotoredox catalysis.     

Synthesis of [m.n]Cyclophanes: Regiochemistry Transfer from Vinyl Halides to Cyclophanes via Fischer Carbene Complexes

The double benzannulation of bis‐carbene complexes of chromium with α,ω‐diynes generates [m.n]cyclophanes in which all three rings are generated in a single reaction. This triple annulation process is very flexible allowing for the construction of symmetrical [n.n]cyclophanes and unsymmetrical [m.n]cyclophanes as well as isomers in which the two benzene rings are both meta bridged or both para bridged, and isomers that contain both meta and para bridges. The connectivity patterns of the bridges in the cyclophanes can be controlled by regioselectivity transfer from the bis‐vinyl carbene complexes in which the substitution pattern of the vinyl groups in the carbene complexes dictate the connectivity pattern in the [m.n]cyclophanes. This synthesis of [n.n]cyclophanes is quite flexible with regard to ring size and can be used with tether lengths ranging from n=2 to n=16 and thus to ring sizes with up to 40 member rings. The only limitation to regioselectivity transfer from the carbene complexes to the [m.n]cyclophanes was found in the synthesis of para,para‐cyclophanes with four carbon tethers for which the loss of fidelity occurred with the unexpected formation of meta,para‐cyclophanes.     

Enantiopure Double‐Helical Phenylene Ethynylene Cyclophynes with the 2,2′‐Binaphthyl Template

New types of enantiopure compounds were synthesized to gain better insight into the structural features of phenylene ethynylene cyclophynes. Besides the previously obtained meta‐substituted arylene ethynylenes, 1 , ortho‐connected phenylene ethynylene units were incorporated to give cyclophynes with ortho/meta and ortho/ortho connection modes, 2 and 3 . Furthermore, a diphenylethyne component was also accommodated in 4 . Both ab initio calculations and NMR spectra suggest a large amount of strain for 2 but less strain for 3 and 1 a , the latter having the smallest ring size among cyclophynes with the meta/meta connection mode. The CD spectra of 2 and 3 showed a characteristic shoulder at around 340 nm, similar to the case of 1 a . This implies that the aromatic acetylene bonds cross over each other in the double‐helical structure. These results indicate that chirality information is useful for probing the persistency of molecular shape.     

A new biologically active molecular scaffold: crystal structure of 7‐(3‐hydroxyphenyl)‐4‐methyl‐2H‐[1,2,4]triazolo[3,2‐c][1,2,4]triazole and selective antiproliferative activity of three isomeric triazolo–triazoles

A study of three isomeric compounds containing a phenolic moiety attached to the nitrogen‐rich triazolo–triazole bicycle is presented. In the three isomers, the phenolic OH group is in the ortho, meta and para positions. The crystal structure analysis of the meta isomer (C₁₀H₉N₅O) shows that the 2H‐tautomer is present in the crystal and that the molecule adopts a substantially planar geometry. However, the conformation found in the crystal is different compared to the monoprotonated cation of the same compound previously investigated in several salts. The packing of the meta isomer is driven by the formation of strong hydrogen bonds and shows the formation of infinite planar ribbons, parallel to a, formed around 2₁ crystallographic axes. The three isomers were tested against some cancer cell lines and also against normal cell lines. The ortho isomer shows a weak antiproliferative activity, the meta isomer shows significant antiproliferative activity against some cancer lines and no activity against healthy cell lines, and the para isomer is active against all the tested cell lines.     

Metal‐Free I2‐Catalyzed Highly Selective Dehydrogenative Coupling of Alcohols and Cyclohexenones

The I₂ catalyzed highly selective oxidative condensation of cyclohexenones and alcohols for the synthesis of aryl alkyl ethers has been described. DMSO is employed as the mild terminal oxidant. This novel methodology offers a metal‐free reaction condition, operational simplicity and broad substrate scope to afford valuable products from inexpensive reagents. Various meta‐substituted aromatic ethers which are hardly synthesized from the reported methods requiring meta‐substituted phenols, are efficiently prepared by the present protocol.