Sodiation of Arenes and Heteroarenes in Continuous Flow

The first sodiations of (hetero)arenes in continuous flow using NaDA (sodium diisopropylamide) in Me₂EtN are reported. This flow procedure enables sodiation of functionalized arenes and heteroarenes that decompose under batch‐sodiation conditions. The resulting sodiated (hetero)arenes react instantly with various electrophiles, such as ketones, aldehydes, isocyanates, alkyl bromides, and disulfides, affording polyfunctionalized (hetero)arenes in high yields. Scale‐up is possible without further optimization.     

Synthesis of Polyfunctional Diorganomagnesium and Diorganozinc Reagents through In Situ Trapping Halogen–Lithium Exchange of Highly Functionalized (Hetero)aryl Halides in Continuous Flow

We report a halogen–lithium exchange performed in the presence of various metal salts (ZnCl₂, MgCl₂⋅LiCl) on a broad range of sensitive bromo‐ or iodo(hetero)arenes using BuLi or PhLi as the exchange reagent and a commercially available continuous‐flow setup. The resulting diarylmagnesium or diarylzinc species were trapped with various electrophiles, resulting in the formation of polyfunctional (hetero)arenes in high yields. This method enables the functionalization of (hetero)arenes containing highly sensitive groups such as an isothiocyanate, nitro, azide, or ester. A straightforward scale‐up was possible without further optimization.     

Borazine‐CF3− Adducts for Rapid,Room Temperature,and Broad Scope Trifluoromethylation

A fluoroform‐derived borazine CF₃⁻ transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C−H and C−X trifluoromethylation reactions. Mechanistic analysis supports a dissociative mechanism for CF₃⁻ transfer, and cation modification afforded a reagent with enhanced stability.     

Borazine‐CF3− Adducts for Rapid,Room Temperature,and Broad Scope Trifluoromethylation

A fluoroform‐derived borazine CF₃^? transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C?H and C?X trifluoromethylation reactions. Mechanistic analysis supports a dissociative mechanism for CF₃^? transfer, and cation modification afforded a reagent with enhanced stability.     

Potassium enolates of N,N‐dialkylamides as initiators of anionic polymerization

Stable potassium enolates of N,N‐diethylacetamide [α‐potassio‐N,N‐diethylacetamide ( 1 )], N,N‐diethylpropionamide [α‐potassio‐N,N‐diethylpropionamide ( 2 )], and N,N‐diethylisobutyramide [α‐potassio‐N,N‐diethylisobutyramide ( 3 )] were prepared by the proton abstraction of the corresponding N,N‐diethylamides with diphenylmethylpotassium (Ph₂CHK) or potassium naphthalenide in THF. The relative nucleophilicity of 1 – 3 was estimated to be in the order of 1 < 3 < 2 from the results of the alkylation reaction with methyl iodide. N,N‐diethylacetamide transferred its α‐proton to 2 quantitatively in THF at 0 °C, whereas no reaction occurred between N,N‐diethylisobutyramide and 2 ; this indicated the relative basicity to be 1 < 2 ～ 3 . Anionic polymerizations of N,N‐diethylacrylamide (DEA) and methyl methacrylate were quantitatively initiated with 2 in THF at ?78 °C, whereas the initiation efficiencies of 2 for styrene and 2‐vinylpyridine were about 2 and 67%, respectively. The initiation of DEA with 1 – 3 at ?78 or 0 °C in THF gave poly (DEA)s having broad molecular weight distributions (MWDs; M_w/M_n = 2) and ill‐controlled molecular weights. In contrast, poly(DEA)s of narrow MWDs (M_w/M_n < 1.2) and predicted M_n's were obtained with 2 in the presence of diethylzinc (Et₂Zn) at ?78 °C, whereas the initiations with 1 /Et₂Zn and 3 /Et₂Zn at ?78 °C resulted in poor control of the molecular weights. At the higher temperature of 0 °C, all the binary initiator systems ( 1 – 3 /Et₂Zn) induced controlled polymerizations of DEA in terms of the conversion, molecular weight, and MWD. The poly(DEA)s produced with 1 – 3 /Et₂Zn at 0 °C showed mr‐rich configurations (mr = 76–89%), as observed for the poly(DEA) generated with Ph₂CHK/Et₂Zn. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 1260–1271, 2007     

Synthesis and thermal behavior of poly(ethylene oxide) poly(N‐substituted urethane)

Poly(N‐substituted urethane)s with an alkyl or ligo(ethylene oxide) monomethyl ether side chain were synthesized by the reaction operating in the following two‐step process: first, by metalation of the starting polymer with potassium tertiary butoxide (t‐BuOK) and then by treatment of the obtained urethane polyanion with tosylate in dimethyl sulfoxide. The thermal properties of poly(ethylene oxide) poly(N‐substituted urethane) (N‐sub PEOPU) were investigated in view of the N‐substitution degree and properties of the substituent. The chemical structures were characterized by Fourier transform infrared, ¹H NMR, and ¹³C NMR spectroscopies. DSC and thermogravimetric analysis (TGA) were used to investigate the thermal properties of N‐sub PEOPUs. As the degree of N‐methylation increased, the glass‐transition temperature (T_g) of the N‐sub PEOPUs linearly decreased from 6 to ?29 °C, and the weight‐loss temperature of 5% (T) from TGA in air increased from 278 to 360 °C. In the fully N‐substituted PEOPUs, the behavior of the thermal decomposition of the PEOPU that was processed in two stages was changed to one‐step decomposition in the temperature range of 360–440 °C. The T_g was shifted to a lower temperature with an increasing length of the substituent in N‐sub PEOPU. Improvement of the thermal stability by N‐substitution was more significant in N‐alkyl PEOPU than in N‐ethoxylate PEOPU. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 4129–4138, 2001     

Highly Regioselective Remote Lithiation of Functionalized 1,3‐bis‐Silylated Arenes

Substituted arenes flanked by two bulky triethylsilyl groups were regiospecifically lithiated at the 5‐position with nBuLi?PMDTA at 25 °C. The resulting aryllithiums reacted with a broad range of electrophiles such as ketones, isocyanates, Weinreb amides, allyl bromides, and CO₂ at 25 °C. These bis‐silylated arenes were then converted in simple reaction sequences into silyl‐free tetrasubstituted arenes. This remote lithiation was extended to 2,6‐bis(triethylsilyl)pyridine as well as 3,3′‐bis(triethylsilyl)biphenyl.     

Light‐Induced CH Arylation of (Hetero)arenes by In Situ Generated Diazo Anhydrides

Diazo anhydrides (Ar?N?N?O?N?N?Ar) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst‐free C?H arylation methodology for the preparation of bi(hetero)aryls by the one‐pot reaction of anilines with tert‐butyl nitrite and (hetero)arenes under neutral conditions. The key step in this procedure is the in situ formation and subsequent photochemical (>300 nm) homolytic cleavage of a transient diazo anhydride intermediate. The generated aryl radical then efficiently reacts with a (hetero)arene to form the desired bi(hetero)aryls producing only nitrogen, water, and tert‐butanol as byproducts. The scope of the reaction for several substituted anilines and (hetero)arenes was investigated. A continuous‐flow protocol increasing selectivity and safety has been developed enabling the experimentally straightforward preparation of a variety of substituted bi(hetero)aryls within 45 min of reaction time.     

Pyridyl Radical Cation for C−H Amination of Arenes

Electron‐transfer photocatalysis provides access to the elusive and unprecedented N‐pyridyl radical cation from selected N‐substituted pyridinium reagents. The resulting C(sp²)?H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin‐trapped N‐pyridyl radical adduct implicate SET‐triggered, pseudo‐mesolytic cleavage of the N?X pyridinium reagents mediated by visible light.     

Cyclic Amine/Borane Lewis Pairs by the Reaction of N,N‐Diallylaniline with Lancaster′s H2B‐C6F5 Reagent

Twofold hydroboration of N,N‐diallylaniline with the C₆F₅BH₂?SMe₂ reagent gave the respective hetero‐bicyclo[3.3.0]octane and hetero‐methylbicyclo[3.2.0]heptane compounds 4 and 5 as the major products, both showing strong internal N‐B amine Lewis base/borane Lewis acid adduct formation. A DFT analysis indicated their formation (and that of a small amount of several isomeric five‐membered heterocyclic products) under thermodynamic control. Compound 5 underwent fragmentation with propene liberation to form compound 7 with a formal N=B bond at 100 °C. This product was also obtained from the isomer 4 at much higher temperature (300 °C).     

Synthesis of (hetero)arylated pyridazin-3(2H)-ones via Negishi reaction involving zincated pyridazin-3(2H)-ones

Zincated pyridazin-3(2H)-ones generated via bromine-magnesium exchange followed by transmetalation using ZnCl(2) or via lactam-directed ortho C4-H zincation with TMPZnCl·LiCl have been synthesized. These in situ created organometallics can be used in Negishi reactions with iodo(hetero)arenes delivering a new approach toward (hetero)arylpyridazin-3(2H)-ones.     

Crystal Structures of the Potassium and Silver Salts of Nitroform

The solid state structures of three nitroformate (NF) salts were determined using single crystal X‐ray crystallography. The NF anion was found to be a non‐planar moiety which adopts either the commonly observed C_2v conformation or distorted propeller conformation (D₃) in the case of the silver salts, or, a C₂ conformation in the case of the potassium salt. This latter C₂ conformation has been uniquely observed for potassium nitroformate. All structures exhibit cation‐anion interactions that influence the structure of the anion. The ¹³C and ¹⁴N NMR spectra of the NF anion show broad singlets, which indicates the equivalence of the nitro groups in solution within the NMR time‐scale. In addition, the vibrational and mass spectra of potassium nitroformate and silver nitroformate monohydrate were recorded. Furthermore, the gaseous decomposition products of potassium nitroformate at 25 °C were detected using IR spectroscopy and mass spectrometry.     

Preparation and Application of Solid,Salt‐Stabilized Zinc Amide Enolates with Enhanced Air and Moisture Stability

The treatment of various N‐morpholino amides with TMPZnCl⋅LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t _1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd‐ and Cu‐catalyzed cross‐couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N‐morpholino amides were converted into various ketones by LaCl₃⋅2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti‐breast‐cancer drug candidate in six steps and 23 % overall yield.     

Beyond Friedel and Crafts: Innate Alkylation of C−H Bonds in Arenes

Alkylated arenes are ubiquitous molecules and building blocks commonly utilized in most areas of science. Despite its apparent simplicity, the regioselective alkylation of arenes is still a challenging transformation in a lot of cases. Classical methods for the introduction of alkyl groups to arenes, such as the venerable Friedel–Crafts reaction, radical additions, metalation or prefunctionalization of the arene followed by further alkylation, as well as alternatives such as the directed alkylation of C?H bonds, still suffer from severe limitations in terms of scope, efficiency, and selectivity. This can be addressed by exploiting the innate reactivity of some (hetero)arenes, in which electronic and steric properties, governed (or not) by the presence of one (or multiple) heteroatom(s), ensure high levels of regioselectivity. These innate alkylations of C?H bonds in (hetero)arenes will be overviewed comprehensively in this Review.     

Adsorption of N719 Dye on Anatase TiO2 Nanoparticles and Nanosheets with Exposed (001) Facets: Equilibrium,Kinetic, and Thermodynamic Studies

Anatase TiO₂ nanosheets (TiO₂ NS) with dominant (001) facets and TiO₂ nanoparticles (TiO₂ NP) with dominant (101) facets are fabricated by hydrothermal hydrolysis of Ti(OC₄H₉)₄ in the presence and absence of hydrogen fluoride (HF), respectively. Adsorption of N719 onto the as‐prepared samples from ethanol solutions is investigated and discussed. The adsorption kinetic data are modeled using the pseudo‐first‐order, pseudo‐second‐order, and intraparticle diffusion kinetics equations, and indicate that the pseudo‐second‐order kinetic equation and intraparticle diffusion model can better describe the adsorption kinetics. Furthermore, adsorption equilibrium data of N719 on the as‐prepared samples are analyzed by Langmuir and Freundlich models; this suggests that the Langmuir model provides a better correlation of the experimental data. The adsorption capacities (q_max) of N719 on TiO₂ NS at various temperatures, determined using the Langmuir equation, are 65.2 (30 °C), 68.2 (40 °C), and 76.6 (50 °C) mg g⁻¹, which are smaller than those on TiO₂ NP, 92.4 (30 °C), 100.0 (40 °C), and 108.2 (50 °C) mg g⁻¹, respectively. The larger adsorption capacities of N719 for TiO₂ NP versus NS are attributed to its higher specific surface areas. However, the specific adsorption capacities (q_max/S_BET) at various temperatures are 1.5 (30 °C), 1.6 (40 °C), and 1.7 (50 °C) mg m⁻² for TiO₂ NS, which are otherwise higher than those for NP, 0.9 (30 °C), 1.0 (40 °C), and 1.1 (50 °C) mg m⁻², respectively. The larger specific adsorption capacities of N719 for TiO₂ NS versus NP are because the (001) surface is more reactive for dissociative adsorption of reactant molecules compared with (101) facets. Notably, the q_max and q_max/S_BET for both TiO₂ samples increase with increasing temperature, suggesting that adsorption of N719 on the TiO₂ surface is an endothermic process, which is further confirmed by the calculated thermodynamic parameters including free energy, enthalpy, and entropy of adsorption process. The present work will provide a new understanding on the adsorption process and mechanism of N719 molecules onto TiO₂ NS and NP, and this should be of great importance for enhancing the performance of dye‐sensitized solar cells.     

Palladium‐Catalyzed Trifluoromethylation of (Hetero)Arenes with CF3Br

The CF₃ group is an omnipresent motif found in many pharmaceuticals, agrochemicals, catalysts, materials, and industrial chemicals. Despite well‐established trifluoromethylation methodologies, the straightforward and selective introduction of such groups into (hetero)arenes using available and less expensive sources is still a major challenge. In this regard, the selective synthesis of various trifluoromethyl‐substituted (hetero)arenes by palladium‐catalyzed C?H functionalization is herein reported. This novel methodology proceeds under comparably mild reaction conditions with good regio‐ and chemoselectivity. As examples, trifluoromethylations of biologically important molecules, such as melatonin, theophylline, caffeine, and pentoxifylline, are showcased.     

Combination of Silica Sol and Potassium Silicate via Isothermal Heat Conduction Microcalorimetry

Isothermal heat conduction microcalorimetry was utilized as a novel characterization method to investigate the polymerization processes of silica with both thermodynamic and kinetic parameters when the combination of silica sol and potassium silicate was stirred at temperatures of 25.0, 35.0, and 45.0°C. The silica polymerization was characterized by the greater enthalpy change at each higher temperature and by the reaction orders of the silica sol and potassium silicate, which varied rapidly, instantaneously, and constantly from low to high all the time, up and down in an alternate manner. When the reaction order of the silica sol and potassium silicate was 3.0, the maximum rate constant occurred at 25.0°C (k=1.22×10^?4mol^?2·dm⁶·s^?1). The two temperature regions (25.0–35.0°C region with a faster rate and 35.0–45.0°C region with a lower rate) reflected a two‐stage oligomerization of silica monomers with different oligomers formed in a two‐step anionic mechanism. The measurements of particle size and pH value showed that the colloidal particles in the mixed silica sol and potassium silicate first dissolved, then "active" silica in the potassium silicate redeposited to make a distinct particle size distribution (Z‐average size, 33.0–14.9 nm at 25.0°C) influenced both by pH value (9.82–11.97 at 25.0°C) and the mass fraction (53, 65, 75, and 85 mass/%) of the silica sol in the mixture. The processes of combination of the silica sol and potassium silicate did not result from acid‐base neutralization reactions but from a complex polymerization of the "active" silica components which relate to silica monomers oligomerization with heat evolved (the total enthalpy changes, 1.6234–3.3882 J).     

Catalytic C−H Trifluoromethoxylation of Arenes and Heteroarenes

The intermolecular C?H trifluoromethoxylation of arenes remains a long‐standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a novel trifluoromethoxylating reagent and redox‐active catalysts for the direct (hetero)aryl C?H trifluoromethoxylation. Our approach is operationally simple, proceeds at room temperature, uses easy‐to‐handle reagents, requires only 0.03 mol % of redox‐active catalysts, does not need specialized reaction apparatus, and tolerates a wide variety of functional groups and complex structures such as sugars and natural product derivatives. Importantly, both ground‐state and photoexcited redox‐active catalysts are effective. Detailed computational and experimental studies suggest a unique reaction pathway where photoexcitation of the trifluoromethoxylating reagent releases the OCF₃ radical that is trapped by (hetero)arenes. The resulting cyclohexadienyl radicals are oxidized by redox‐active catalysts and deprotonated to form the desired products of trifluoromethoxylation.     

Enthalpy–Entropy Correlations in Reactions of Aryl Benzoates with Potassium Aryloxides in Dimethylformamide

Temperature dependences of the relative reactivity of potassium aryloxides XC₆H₄O^?K⁺ toward 4‐nitrophenyl ( 1 ), 3‐nitrophenyl ( 2 ), 4‐chlorophenyl ( 3 ), and phenyl ( 4 ) benzoates in dimethylformamide (DMF) were studied using the competitive reactions technique. The rate constants k_X for the reactions of 1 with potassium 4‐cyanophenoxide, 2 with potassium 3‐bromophenoxide, 3 with potassium 3‐bromo‐, 4‐bromo‐, and unsubstituted phenoxides, 4 with potassium 4‐methoxy‐ and 3‐methylphenoxides were measured at 25°C. Correlation analysis of the relative rate constants k_X/k_H(3‐Me) and differences in the activation parameters (??Н^≠ and ??S^≠) of competitive reactions revealed the existence of six isokinetic series. We investigated the substituent effect of X on the activation parameters for each isokinetic series and concluded that the reactions of aryl benzoates PhCO₂C₆H₄Y with potassium aryloxides in DMF proceed via a four‐step mechanism. The large ρ⁰(Y) and ρ_XY values at 25°C obtained for the reactions of 1–3 with potassium aryloxides with an electron‐donating substituent refer to the rate‐determining formation of the spiro‐σ‐complex. The Hammett plots for the reactions of 1 and 2 exhibit a downward curvature, causing the motion of the transition state for the rate‐determining step according to a Hammond effect as the substituent in aryloxide changes from electron‐donating to electron‐withdrawing. Analysis of data in the terms of two‐dimensional reaction coordinate diagrams leads to the conclusion that significant anti‐Hammond effects arise in the cases of ortho‐substituted and unsubstituted substrates. It was shown that the isokinetic and compensation effects observed for the reactions of aryl benzoates with potassium aryloxides in DMF can be interpreted in the terms of the electrostatic bonding between the reaction centers.     

Solid‐state CP/MAS 13C NMR studies on conformational polymorphism in sertraline hydrochloride,an antidepressant drug

The C(2) isotropic chemical shift values in solid‐state CP/MAS ¹³C NMR spectra of conformational polymorphs Form I (δ 28.5) and III (δ 22.9) of (1S,4S)‐sertraline HCl ( 1 ) were correlated with a γ‐gauche effect resulting from the respective 162.6° antiperiplanar and 68.8° (+)‐synclinal C(2)? C(1)? N? CH₃ torsion angles as measured by X‐ray crystallography. The similarity of the solution‐state C(2) chemical shifts in CD₂Cl₂ (δ 22.8) and DMSO‐d₆ (δ 23.4) with that for Form III (and other polymorphs having C(2)? C(1)? N? CH₃ (+)‐synclinal angles) strongly suggests that a conformational bias about the C(1)? N bond exists for 1 in both solvents. This conclusion is supported by density functional theory B3LYP/6‐31G(d)‐calculated relative energies of C(1)? N rotameric models: (kcal) 0.00 [73.8 °C(2)? C(1)? N? CH₃ torsion angle], 0.88 (168.7°), and 2.40 (?63.4°). A Boltzmann distribution of these conformations at 25 °C is estimated to be respectively (%) 80.3, 18.3, and 1.4. Copyright © 2002 John Wiley & Sons, Ltd.