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.     

Facile Synthesis of 3‐Hydroxyglutamic Acids via Cyanation of Chiral N‐Acyliminium Cation Derived From (S)‐Malic Acid

Facile synthesis of 3‐hydroxyglutamic acids via cyanation of an N‐acyliminium intermediate derived from (S)‐malic acid is described. The chiral cyclic imide derived from (S)‐malic acid was converted to an acetoxylactam by reduction with sodium borohydride followed by acetylation. The obtained acetoxylactam was treated with trimethylsilyl cyanide in the presence of boron trifluoride etherate to give the corresponding cyanolactam in high yield, even though the diastereoselectivity of the cyanation reaction was moderate. The diastereomers of the cyanolactam were chromatographically separable and were independently converted to (2R,3S)‐ and (2S,3S)‐3‐hydroxyglutamic acids.     

Ligand-Enabled Auxiliary-Free meta-C−H Arylation of Phenylacetic Acids

The meta-C−H arylation of free phenylacetic acid was realized using 2-carbomethoxynorbornene (NBE-CO₂Me) as a transient mediator. Both the modified norbornene and the mono-protected 3-amino-2-hydroxypyridine type ligand are crucial for this auxiliary-free meta-C−H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta-arylated products in high yields.     

A Convenient Synthesis of N‐Aryl Benzamides by Rhodium‐Catalyzed ortho‐Amidation and Decarboxylation of Benzoic Acids

The rhodium‐catalyzed amidation of substituted benzoic acids with isocyanates by directed C?H functionalization followed by decarboxylation to afford the corresponding N‐aryl benzamides is demonstrated, in which the carboxylate serves as a unique, removable directing group. Notably, less common meta‐substituted N‐aryl benzamides are generated readily from more accessible para‐ or ortho‐substituted groups by employing this strategy.     

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.     

Preparation and evaluation of novel chiral stationary phases based on quinine derivatives comprising crown ether moieties

The C9‐position of quinine was modified by meta‐ or para‐substituted benzo‐18‐crown‐6, and immobilized on 3‐mercaptopropyl‐modified silica gel through the radical thiol‐ene addition reaction. These two chiral stationary phases were evaluated by chiral acids, amino acids, and chiral primary amines. The crown ether moiety on the quinine anion exchanger provided a ligand‐exchange site for primary amino groups, which played an important role in the retention and enantioselectivity for chiral compounds containing primary amine groups. These two stationary phases showed good selectivity for some amino acids. The complex interaction between crown ether and protonated primary amino group was investigated by the addition of inorganic salts such as LiCl, NH₄Cl, NaCl, and KCl to the mobile phase. The resolution results showed that the simultaneous interactions between two function moieties (quinine and crown ether) and amino acids were important for the chiral separation.     

Generation of gas‐phase sodiated arenes such as [(Na3(C6H4)+] from benzene dicarboxylate salts

Upon collision‐induced activation, gaseous sodium adducts generated by electrospray ionization of disodium salts of 1,2‐ 1,3‐, and 1,4‐benzene dicarboxylic acids (m/z 233) undergo an unprecedented expulsion of CO₂ by a rearrangement process to produce an ion of m/z 189 in which all three sodium atoms are retained. When isolated in a collision cell of a tandem‐in‐space mass spectrometer, and subjected to collision‐induced dissociation (CID), only the m/z 189 ions derived from the meta and para isomers underwent a further CO₂ loss to produce a peak at m/z 145 for a sodiated arene of formula (Na₃C₆H₄)⁺. This previously unreported m/z 145 ion, which is useful to differentiate meta and para benzene dicarboxylates from their ortho isomer, is in fact the sodium adduct of phenelenedisodium. Moreover, the m/z 189 ion from all three isomers readily expelled a sodium radical to produce a peak at m/z 166 for a radical cation [(^?C₆H₄CO₂Na₂)⁺], which then eliminated CO₂ to produce a peak at m/z 122 for the distonic cation (^?C₆H₄Na₂)⁺. Copyright © 2009 John Wiley & Sons, Ltd.     

Can be Azo Dyes Obtained by Grinding under Solvent‐Free Conditions?

The solid‐solid reactions of some electron‐donors with sulfanilic acid in the presence of solid sodium nitrite afford azo dyes by self‐catalyzed diazotization of sulfanilic acid (2) under solvent‐free conditions with moderate yields. Also the reactions of some electron‐donors with diazotization of o‐nitroaniline (5), m‐nitroaniline (6) and p‐nitroaniline (7) in the presence of solid sodium nitrite catalyzed by p‐toluenesulfonic acid (PTSA) afford azo dyes under solvent‐free conditions in good yields. This new method totally avoids the use of acids, alkalies, and toxic and/or expensive solvents in diazotization and diazo coupling reactions.     

Direct CH Amidation of Benzoic Acids to Introduce meta‐ and para‐Amino Groups by Tandem Decarboxylation

The Ir‐catalyzed mild C?H amidation of benzoic acids with sulfonyl azides was developed to give reactions with high efficiency and functional‐group compatibility. Subsequent protodecarboxylation of ortho‐amidated benzoic acid products afforded meta‐ or para‐substituted (N‐sulfonyl)aniline derivatives, the latter being inaccessible by other C?H functionalization approaches. The decarboxylation step was compatible with the amidation conditions, enabling a convenient one‐pot, two‐step process.     

Ion‐pair‐based hollow‐fiber liquid‐phase microextraction combined with high‐performance liquid chromatography for the simultaneous determination of urinary benzene,toluene, and styrene metabolites

In the current study, a novel technique for extraction and determination of trans,trans‐muconic acid, hippuric acid, and mandelic acid was developed by means of ion‐pair‐based hollow fiber liquid‐phase microextraction in the three‐phase mode. Important factors affecting the extraction efficiency of the method were investigated and optimized. These metabolites were extracted from 10 mL of the source phase into a supported liquid membrane containing 1‐octanol and 10% w/v of Aliquat 336 as the ionic carrier followed by high‐performance liquid chromatography analysis. The organic phase immobilized in the pores of a hollow fiber was back‐extracted into 24 μL of a solution containing 3.0 mol/L sodium chloride placed inside the lumen of the fiber. A very high preconcentration of 212‐ to 440‐fold, limit of detection of 0.1–7 μg/L, and relative recovery of 87–95% were obtained under the optimized conditions of this method. The relative standard deviation values for within‐day and between‐day precisions were calculated at 2.9–8.5 and 4.3–11.2%, respectively. The method was successfully applied to urine samples from volunteers at different work environments. The results demonstrated that the method can be used as a sensitive and effective technique for the determination of the metabolites in urine.     

Synthesis and characterisation of polymethacrylates containing para-, meta- and ortho-monosubstituted azobenzene moieties in the side chain

Three sets of novel side-chain liquid crystalline polymers with monosubstituted azobenzene moieties in the side-chain have been studied. These are poly(p-(4′-methoxy-4-oxyhexyloxy azobenzene) benzyl methacrylate) (PPHABM), poly(m-(4′-methoxy-4-oxyhexyloxy azobenzene) benzyl methacrylate) (PMHABM) and poly(o-(4′-methoxy-4-oxyhexyloxy azobenzene) benzyl methacrylate) (POHABM). The chemical structure of the monomers was confirmed by ¹H NMR, ¹³C NMR spectroscopy and elemental analysis. The structural characterisation of the polymers was performed by ¹H NMR spectroscopy and gel permeation chromatography, and their phase behaviour and liquid crystalline properties were studied using differential scanning calorimetry, polarised optical microscopy and wide-angle X-ray diffraction. The results show that the transitional behaviour of side-chain liquid crystalline polymers containing monosubstituted azobenzene moieties depends strongly on the position of the substituent on the azobenzene moiety; for example, the ortho-monosubstituted polymers do not form liquid crystalline phases, but all the para- and meta-monosubstituted polymers exhibit a smectic A phase. Furthermore, the glass transition temperature (T_g ) of the polymers decreases in the order, para > meta > ortho. For the PPHABM and PMHABM polymers the isotropic temperature (T_i ) and liquid crystalline range (ΔT, from T_g to T_i ) are found to be in the order, para > meta, although it is surprising that the associated enthalpy changes in these polymers is the opposite order, meta > para.     

Kinetics and mechanism of the oxidation of substituted benzaldehydes by hexamethylenetetramine‐bromine

The oxidation of thirty‐six monosubstituted benzaldehydes by hexa‐methylenetetramine‐bromine (HABR), in aqueous acetic acid solution, leads to the formation of the corresponding benzoic acids. The reaction is first order with respect to HABR. Michaelis‐Menten–type kinetics were observed with respect to aldehyde. The reaction failed to induce the polymerization of acrylonitrile. There is no effect of hexamethylenetetramine on the reaction rate. The oxidation of [²H]benzaldehyde (PhCDO) indicated the presence of a substantial kinetic isotope effect. The effect of solvent composition indicated that the reaction rate increases with an increase in the polarity of the solvent. The rates of oxidation of meta‐ and para‐substituted benzaldehydes showed excellent correlations in terms of Charton's triparametric LDR equation, whereas the oxidation of ortho‐substituted benzaldehydes correlated well with tetraparametric LDRS equation. The oxidation of para‐substituted benzaldehydes is more susceptible to the delocalization effect but the oxidation of ortho‐ and meta‐substituted compounds displayed a greater dependence on the field effect. The positive value of γ suggests the presence of an electron‐deficient reaction center in the rate‐determining step. The reaction is subjected to steric acceleration when ortho‐substituents are present. © 2000 John Wiley & Sons, Inc. Int J Chem Kinet 32: 615–622, 2000     

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.     

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.     

Effect of Substituent Orientation on Selectivity between Polymerization and Cyclization: Polycondensation of (Alkylamino)benzoic Acid Dimer Phenyl Esters

Summary: The polymerization characteristics of (octylamino)benzoic acid dimer phenyl esters with para‐meta ( 2 ), meta‐para ( 3 ), and meta‐meta ( 4 ) orientation of the amino and carbonyl groups were investigated. While treatment of 2 or 3 with a base gave the cyclic dimer 6 as the main product, condensation of 4 with an initiator in the presence of a base afforded polymers with narrow molecular weight distributions.

The condensation of 4 with an initiator in the presence of a base afforded polymers with narrow molecular weight distribution.     

The ortho‐Substituent Effect on the Ag‐Catalysed Decarboxylation of Benzoic Acids

A combined experimental and computational investigation on the Ag‐catalysed decarboxylation of benzoic acids is reported herein. The present study demonstrates that a substituent at the ortho position exerts dual effects in the decarboxylation event. On one hand, ortho‐substituted benzoic acids are inherently destabilised starting materials compared to their meta‐ and para‐substituted counterparts. On the other hand, the presence of an ortho‐electron‐withdrawing group results in an additional stabilisation of the transition state. The combination of both effects results in an overall reduction of the activation energy barrier associated with the decarboxylation event. Furthermore, the Fujita–Nishioka linear free energy relationship model indicates that steric bulk of the substituent can also exert a negative effect by destabilising the transition state of decarboxylation.     

LC‐MS identification of derivatized free fatty acids from adipocere in soil samples

Free fatty acids were derivatized as amides (DFFA) by reaction with (R)‐(+)‐1‐phenylethylamine, using a simple, fast and robust reaction scheme. A HPLC method with diode array and ESI MS detection was developed for the analysis of the derivatized substances. Six fatty acids were used in the method development: myristic, linoleic, palmitic, oleic, margaric and stearic acids. Under these conditions the elution of the DFFA are well resolved with retention times raging from 6.9 to 16.0 min. Fatty acids were extracted from cemetery soil and from adipocere formation experimental soils using a Soxhlet extraction, using as solvent ether/dichloromethane (1:1). Each DFFA is characterized by three m/z peaks: molecular weight of the substance; molecular weight of a dimer of the substance; the molecular weight of the dimer plus the atomic mass of sodium. The analysis of soil samples detected the six fatty acids used in the method developed plus palmitoleic and pentadecanoic. Beside this set of eight fatty acids other 13 fatty acids were detected in trace quantities or only in some soils and some were tentatively assigned as: 10‐hydroxystearic, myristoleic, heptadecenoic and arachidic acids.     

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.     

Synthesis,Molecular Structure and Coordination Chemistry of the First 1‐Aza‐3,7‐diphosphacyclooctanes

The first representatives of a novel type of cyclic bis‐phosphines, namely, 1‐aza‐3,7‐diphosphacyclooctanes ( 4 , 5 ), were synthesized by condensation of 1,3‐bis(arylphosphino)propanes ( 2 , 3 ; aryl = phenyl or mesityl), formaldehyde and 5‐aminoisophthalic acid. Only the meso isomers were obtained, in good to satisfactory yield. The cyclic bis‐phosphines readily form P,P chelate complexes ( 6 , 7 ) with [PtCl₂(cod)] (cod = 1,5‐cyclooctadiene). The bisphosphine 4 and the corresponding complex 6 are soluble in water in the presence of two equivalents of alkali metal hydroxide. The molecular structures of 1‐(meta‐dicarboxyphenyl)‐3,7‐dimesityl‐1‐aza‐3,7‐diphosphacyclooctanes ( 5 ) and cis‐{P,P‐1‐(meta‐dicarboxyphenyl)‐3,7‐diphenyl‐1‐aza‐3,7‐diphosphacyclooctane}dichloroplatinum(II) ( 6 ) are reported.     

Diverse meta‐C−H Functionalization of Arenes across Different Linker Lengths

Arenes containing conformationally flexible long alkyl chains have been successfully functionalized at the meta‐position. Good to excellent meta selectivity is achieved for systems with up to 20 atoms between the target C?H bond and the coordinating heteroatom of the directing group. The palladium‐catalyzed functionalization reactions include alkylation, cyanation, olefination, and acetoxylation. The meta selectivity is exclusively governed by the design of flexible pyrimidine‐based scaffolds.