Construction of N-Ferrocene Substituted Benzodihydrooxazoles via a Catalyst-Free Aza-Michael Addition/C(sp3)-O Bond Formation Tandem Reaction.

A catalyst-free aza-Michael addition/C(sp3)-O bond formation tandem reaction of substituted amino ferrocenes with quinone esters was developed, which provided a green and efficient strategy for the construction of a C(sp3)-O bond from C(sp3)-H, and a series of N-ferrocene-substituted benzodihydrooxazoles were smoothly produced in moderate to excellent yields (up to >99% yield). The mechanism experiments showed that quinone esters performed as both substrate and oxidant. The salient features of this transformation include good functional group tolerance, broad substrate scope and mild conditions.

Synthesis of Ferrocene 1,3-Derivatives by Distal C-H Activation.

The third position of cyclopentadienyl ring of a monosubstituted ferrocene has remained as an inaccessible chemical space for direct functionalization. Until recently, functionalizing the C(3)-position while bypassing the predominantly active C(2)-position is the most challenging task. Herein, we report a distal C-H functionalization of monosubstituted ferrocenes using an easily removable directing group with precise site-selectivity, under a PdII / mono-N-protected amino-acid ligand catalytic system. The robust synthetic protocol leads to the synthesis of ferrocene 1,3-derivatives with broad scope in olefins while functionalizing ferrocenyl methylamine in moderate to good yields via a highly strained ferrocene appended 12-membered palladacycle intermediate.

Mechanochemical Rhodium-Catalyzed C-H Bond Amidation of Ferrocenes by Ball Milling.

A direct protocol for Rh-catalyzed C-H amidation of ferrocenes in a ball mill using dioxazolones as the amide source under solvent-free conditions was developed. The corresponding ortho-aminated products were formed in 3 hours and the yields were up to 99% in the absence of base. This method could be a typically sustainable and environmental-friendly alternative method to traditional methodologies, with the advantages of wide substrate range, good functional group tolerance and gram-scale synthesis.

As-Grown Miniaturized True Zero-Order Waveplates Based on Low-Dimensional Ferrocene Crystals.

As basic optical elements, waveplates with anisotropic electromagnetic responses are imperative for manipulating light polarization. Conventional waveplates are manufactured from bulk crystals (e.g., quartz and calcite) through a series of precision cutting and grinding steps, which typically result in large size, low yield, and high cost. In this study, a bottom-up method is used to grow ferrocene crystals with large anisotropy to demonstrate self-assembled ultrathin true zero-order waveplates without additional machining processing, which is particularly suited for nanophotonic integration. The van der Waals ferrocene crystals exhibit high birefringence (Δn (experiment) = 0.149  ±  0.002 at 636 nm), low dichroism Δκ (experiment) = -0.0007 at 636 nm), and a potentially broad operating range (550 nm to 20 µm) as suggested by Density Functional Theory (DFT) calculations. In addition, the grown waveplate's highest and the lowest principal axes (n1 and n3 , respectively) are in the a-c plane, where the fast axis is along one natural edge of the ferrocene crystal, rendering them readily usable. The as-grown, wavelength-scale-thick waveplate allows the development of further miniaturized systems via tandem integration.

Self-Immolative Amphiphilic Poly(ferrocenes) for Synergistic Amplification of Oxidative Stress in Tumor Therapy.

Amphiphilic self-immolative polymers (SIPs) can achieve complete degradation solely through one triggerable event, which potentially optimize the blood clearance and uncontrollable/inert degradability for therapeutic nanoparticles. Herein, we report self-immolative amphiphilic poly(ferrocenes), BPnbs -Fc, composed by self-immolative backbone and aminoferrocene (AFc) side chains as well as end-capping poly(ethylene glycol) monomethyl ether. Upon triggering by tumor acidic milieu, the BPnbs -Fc nanoparticles readily degrade to release azaquinone methide (AQM) moieties, which can rapidly deplete intracellular glutathione (GSH) to cascade release AFc. Furthermore, both AFc and its product Fe2+ can catalyze intracellular hydrogen peroxide (H2 O2 ) into highly reactive hydroxyl radicals (⋅OH), thus amplifying the oxidative stress of tumor cells. Rational synergy of GSH depletion and ⋅OH burst can efficiently inhibit tumor growth by the SIPs in vitro and in vivo. This work provides an elegant design to adopt innate tumor milieu-triggerable SIPs degradation to boost cellular oxidative stress, which is a promising candidate for precision medicine.

Enantioseparation of planar chiral ferrocenes on cellulose-based chiral stationary phases: Benzoate versus carbamate pendant groups.

In this study, the enantioseparation of 14 planar chiral ferrocenes containing halogen atoms, and methyl, iodoethynyl, phenyl, and 2-naphthyl groups, as substituents, was explored with a cellulose tris(4-methylbenzoate) (CMB)-based chiral column under multimodal elution conditions. n-Hexane/2-propanol (2-PrOH) 95:5 v/v, pure methanol (MeOH), and MeOH/water 90:10 v/v were used as mobile phases (MPs). With CMB, baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.24 to 1.77, whereas only three analytes could be enantioseparated with 1.14 ≤ α ≤ 1.51 on a cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC)-based column, used as a reference for comparison, under the same elution conditions. Pendant group-dependent reversal of the enantiomer elution order was observed in several cases by changing CMB to CDMPC. The impact of analyte and chiral stationary phase (CSP) structure, and MP polarity on the enantioseparation, was evaluated. The two cellulose-based CSPs featured by different pendant groups were also compared in terms of thermodynamics. For this purpose, enthalpy (ΔΔH°), entropy (ΔΔS°) and free energy (ΔΔG°) differences, isoenantioselective temperatures (Tiso ), and enthalpy/entropy ratios (Q), associated with the enantioseparations, were derived from van 't Hoff plots by using n-hexane/2-PrOH 95:5 v/v and methanol/water 90:10 v/v as MPs. With the aim to disclose the functions of the different substituents in mechanisms and noncovalent interactions underlying analyte-selector complex formation at molecular level, electrostatic potential (V) analysis and molecular dynamics simulations were used as computational techniques. On this basis, enantioseparations and related mechanisms were investigated by integrating theoretical and experimental data.

Design and Synthesis of a Ferrocene-Based Diol Library and Application in the Hetero-Diels-Alder Reaction.

Diol scaffolds have been utilized as highly effective catalysts and ligands in a wide range of catalytic asymmetric transformations. For scaffolds to be successful as broadly used motifs, they should be prepared cheaply through facile routes and be easily handled. Herein, the synthesis of a family of planar chiral diols based on a modular and robust three-step route is described, which yields catalytically active diols in >99 % de and >99 % ee, with up to seven different chiral elements. These diols have been characterized by X-ray crystallographic analysis, which provides clear evidence for the likely transition state when applied in the asymmetric hetero-Diels-Alder reaction. Without altering the stereochemistry of the catalyst backbone, it is possible to access both enantiomers of the product by varying the substitution of the catalyst at the α-position.

Ferrocene derivatives with planar chirality and their enantioseparation by liquid-phase techniques.

In the last decade, planar chiral ferrocenes have attracted a growing interest in several fields, particularly in asymmetric catalysis, medicinal chemistry, chiroptical spectroscopy and electrochemistry. In this frame, the access to pure or enriched enantiomers of planar chiral ferrocenes has become essential, relying on the availability of efficient asymmetric synthesis procedures and enantioseparation methods. Despite this, in enantioseparation science, these metallocenes were not comprehensively explored, and very few systematic analytical studies were reported in this field so far. On the other hand, enantioselective high-performance liquid chromatography has been frequently used by organic and organometallic chemists in order to measure the enantiomeric purity of planar chiral ferrocenes prepared by asymmetric synthesis. On these bases, this review aims to provide the reader with a comprehensive overview on the enantioseparation of planar chiral ferrocenes by discussing liquid-phase enantioseparation methods developed over time, integrating this main topic with the most relevant aspects of ferrocene chemistry. Thus, the main structural features of ferrocenes and the methods to model this class of metallocenes will be briefly summarized. In addition, planar chiral ferrocenes of applicative interest as well as the limits of asymmetric synthesis for the preparation of some classes of planar chiral ferrocenes will also be discussed with the aim to orient analytical scientists towards 'hot topics' and issues which are still open for accessing enantiomers of ferrocenes featured by planar chirality.

Remote Editing of Stacked Aromatic Assemblies for Heteroannular C-H Functionalization by a Palladium Switch between Aromatic Rings.

An approach allowing remote editing of stacked aromatic assemblies for heteroannular C-H functionalization would represent a transformative chemical toolbox that may make the diversification of complex molecules in a straightforward manner. However, such a C-H activation is usually less kinetically and thermodynamically favorable than homoannular ortho C-H activation and remains a fundamental challenge. Herein we disclose an engineer's approach, using a transient ligand as an interim bridge between two aryl rings (analogues to mountaintops) to anchor the metal center on the remote heteroannular C-H bond. As a proof-of-concept, we present the palladium-catalyzed heteroannular C-H olefination of stacked aromatic assemblies with olefins and allylation with vinyl acetates using L-tert-leucine acid as a transient ligand. Mechanistic investigations suggest an unusual olefin coordination-promoted interannular palladium migration process determinative for reversal of the site-selectivity.

Separation of planar chiral ferrocenes by capillary electrokinetic chromatography and liquid chromatography.

Capillary electrokinetic chromatography (CEKC) and liquid chromatography (LC) methods were explored for the enantiomeric separation of six unsymmetrically disubstituted ferrocene derivatives. In normal-phase mode liquid chromatography, the use of n-heptane, ethanol or isopropanol with 1% n-butylamine as mobile phase on six polysaccharide-based columns, allowed to fully separate the enantiomers of three compounds out of the six (i.e 7-chloro-N-(2-((dimethylamino)methyl)ferrocenyl)quinolin-4-amine (ferroquine) (compound 1), 1-[(1S)-(1-Aminoethyl)]-2-(diphenylphosphino)ferrocene (compound 5) and 1-[(1R)-1-(Dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene (compound 6). Among the columns used, the Lux i-Cellulose-5 was the most effective. In capillary electrokinetic chromatography, a phosphate buffer of 25 mM concentration and pH equal to 2.5 was chosen as background electrolyte, leading to cationic ferrocene derivatives. The addition of neutral cyclodextrins was undertaken first and native ß- or γ-cyclodextrins were found to resolve the enantiomers of two derivatives. Then, 15 mM of anionic cyclodextrins were added to the background electrolyte. The use of SBE-ß-CD, S-ß-CD or S-γ-CD have allowed the separation of the enantiomers for most of the ferrocene derivatives studied with high resolution values in short migration time. For instance, for 1-(R)-2-(Diphenylphosphino)ethyldi-tert-butylphosphine ferrocene (compound 2), the migration times were less than 2 minutes and the resolution value was equal to 3.52 in short-end mode with 15 mM S-ß-CD, at 25 kV and 25°C. Finally, a dual cyclodextrins system was tested using 15 mM of S-ß-CD plus 15 mM HP-γ-CD in the phosphate buffer. This system allowed the improved separation of two ferrocene derivatives with an unusual resolution value equal to 41.5 in long-end mode. Overall, CEKC showed better enantioseparating power of the six chiral ferrocenes studied than liquid chromatography.

Direct Enantioselective Addition of Alkynes to Imines by a Highly Efficient Palladacycle Catalyst.

Enantiopure propargylic amines are highly valuable synthetic building blocks. Much effort has been devoted to develop methods for their preparation. The arguably most important strategy is the 1,2-addition of alkynes to imines. Despite remarkable progress, the known methods using Zn and Cu catalysts suffer from the need for high catalyst loadings, typically ranging from 2-60 mol % for neutral aldimine substrates. Here we report a planar chiral Pd complex acting as very efficient catalyst for direct asymmetric alkyne additions to imines, requiring very low catalyst loadings. Turnover numbers of up to 8700 were accomplished. Our investigation suggests that a Pd-acetylide complex is generated as a catalytically relevant intermediate by the aid of an acac ligand acting as internal catalytic base. It is shown that the catalyst is quite stable under the reaction conditions and that product inhibition is not an issue. A total of 39 examples is shown which all yielded almost enantiopure products.

Supercritical fluid chromatography for separation of chiral planar metallocenes.

Unsymmetrically disubstituted metallocene derivatives, characterized as the first sandwich structure, have found interest in asymmetrical synthesis and in medicinal chemistry as well. Besides, they present a particular case of chirality. Twenty original and six commercially available molecules presenting either i) a planar chirality or ii) an asymmetrical carbon containing group or iii) being symmetrically substituted were analyzed in supercritical fluid chromatography on eleven polysaccharide-based chiral stationary phases with carbon dioxide containing 30% of methanol or 2-propanol as a co-solvent mobile phase. A basic additive, either diethylamine, triethylamine or n-butylamine was also required at 1% to the co-solvent for elution. While some of the tested chiral stationary phases provided enantioseparation for the racemates, chlorinated cellulosic phases proved to be both highly retentive and highly enantioselective towards these particular species with the highest rate of success compared to their non-chlorinated counterparts. For instance, the resolution value was equal to 14.1 for one ferrocene derivative in one-hour analysis time on cellulose tris(3,5-dichlorophenylcarbamate) column with 30% 2-propanol/1% n-butylamine while a single peak was observed under the same conditions on cellulose tris(3,5-dimethylphenylcarbamate) column. Experimental parameters were arbitrarily set at 150 bar outlet pressure, 40 °C temperature and 3 mL/min flow-rate.

ON/OFF receptor-like enantioseparation of planar chiral 1,2-ferrocenes on an amylose-based chiral stationary phase: The role played by 2-propanol.

A set of nine planar chiral 1,2-ferrocenes was analyzed by high-performance liquid chromatography (HPLC) on the amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase. The enantioseparations were carried out using neat methanol, ethanol, 1-propanol, and 2- propanol as well as mixtures of n-hexane-2-propanol as mobile phases. The differences in retention times between the second eluted (Rp)-enantiomers and the first eluted (Sp)-enantiomers were significantly influenced by elution modes and the steric hindrance of substituents at the aromatic rings of the ferrocene backbone. It has been demonstrated an ON/OFF switching of receptor-like chiral discrimination through the employment of different alcohols as mobile phases. In particular, the presence of pure 2-propanol triggers exceptional conditions of enantioselectivity that for some ferrocenes result in values of the enantioseparation factor higher than 80.

Spectroscopic investigation on 1,2-substituted ferrocenes with only planar chirality: How chiroptical data are related to absolute configuration and to substituents.

Single enantiomers of three 1,2-substituted ferrocene derivatives, i.e. 1-methoxymethyl-2-hydroxymethylferrocene (1), 1-formyl-2-hydroxymethylferrocene (2) and 1-iodo-2-hydroxymethylferrocene (3), sharing the common hydroxymethyl substituent and the presence of planar chirality only, were investigated for their spectroscopic (IR and UV) and chiroptical (VCD and ECD) properties. Both enantiomers of 1 were obtained for the first time in optically pure form by lipase-catalyzed kinetic resolution of the corresponding racemate (±)-1 and separately converted into formyl derivatives (+)-2 and (-)-2. The experimental spectroscopic and chiroptical data were compared with DFT calculated spectra and excellent correspondence was found for all compounds, allowing one to confirm the previously assigned absolute configurations. The common features in the VCD spectra of a doublet between 940 and 965 cm-1 and the short-wavelength (about 200 nm) doublet and the longest wavelength band in the ECD spectra were analyzed to test whether they may be taken as markers of the absolute configuration (AC). The predominance of conformers with intramolecular hydrogen bond for the first two investigated compounds is predicted by conformational analysis and also confirmed by NMR.

Comparative enantioseparation of planar chiral ferrocenes on polysaccharide-based chiral stationary phases.

Planar chiral ferrocenes are well-known compounds that have attracted interest for application in synthesis, catalysis, material science, and medicinal chemistry for several decades. In spite of the fact that asymmetric synthesis procedures for obtaining enantiomerically enriched ferrocenes are available, sometimes, the accessible enantiomeric excess of the chiral products is unsatisfactory. In such cases and for resolution of racemic planar chiral ferrocenes, enantioselective high-performance liquid chromatography (HPLC) on polysaccharide-based chiral stationary phases (CSPs) has been used in quite a few literature articles. However, although moderate/high enantioselectivities have been obtained for planar chiral ferrocenes bearing polar substituents, the enantioseparation of derivatives containing halogens, or exclusively alkyl groups, remains rather challenging. In this study, the enantioseparation of ten planar chiral 1,2- and 1,3-disubstituted ferrocenes was explored by using five polysaccharide-based CSPs under multimodal elution conditions. Baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.20 to 2.92. The presence of π-extended systems in the analyte structure was shown to impact affinity of the most retained enantiomer toward amylose-based selectors, observing retention times higher than 80 min with methanol-containing mobile phases (MPs). Electrostatic potential (V) analysis and molecular dynamics (MD) simulations were used in order to study interaction modes at the molecular level.

An Electrochemical Evaluation of Novel Ferrocene Derivatives for Glutamate and Liver Biomarker Biosensing.

Here, we present an evaluation of two new monosubstituted ferrocene (Fc) derivatives, 3-(1H-pyrrol-1-yl)propanamidoferrocene and 1-hydroxy-2-[2-(thiophen-3-yl)-ethylamino]ethylferrocene, as glutamate oxidase mediators, together with their preparation and characterisation. Taking into consideration the influence of the electronic effects of substituents on the redox potentials of the Fc species, two candidates with pyrrole or thiophene moieties were proposed for investigation. Film studies involved potential sweeping in the presence of pyrrole or 3,4-ethylenedioxythiophene monomers resulting in stable electroactive films with % signal loss upon cycling ranging from 1 to 7.82% and surface coverage (Γ) 0.47-1.15 × 10-9 mol/cm2 for films formed under optimal conditions. Construction of a glutamate oxidase modified electrode resulted in second-generation biosensing with the aid of both cyclic voltammetry and hydrodynamic amperometry, resulting in glutamate sensitivity of 0.86-1.28 µA/mM and Km (app) values over the range 3.67-5.01 mM. A follow-up enzyme assay for liver biomarker γ-glutamyl transpeptidase realised unmediated and mediated measurement establishing reaction and incubation time investigations and a realising response over <100 U/L γ-glutamyl transpeptidase with a sensitivity of 5 nA/UL-1.

Chalcogen-Transfer Rearrangement: Exploring Inter- versus Intramolecular P-P Bond Activation.

tert-Butyl-substituted diphospha[2]ferrocenophane has been used as a stereochemically confined diphosphane to explore the addition of O, S, Se and Te. Although the diphosphanylchalcogane has been obtained for tellurium, all other chalcogens give diphosphane monochalcogenides. The latter transform via chalcogen-transfer rearrangement to the corresponding diphosphanylchalcoganes upon heating. The kinetics of this rearrangement has been followed with NMR spectroscopy supported by DFT calculations. Intermediates during rearrangement point to a disproportionation/synproportionation mechanism for the S and Se derivatives. Cyclic voltammetry together with DFT studies indicate ferrocene-centred oxidation for most of the compounds presented.

A new P,S-coordinating ferrocenyl ligand: synthesis of a precursor and its coordination compounds with PdII and PtII. Corrigendum.

In the paper by Mouas Toma et al. [Acta Cryst. (2014), C70, 460-464], there was an error in the name of the first author.

Gold(I) Complexes Nuclearity in Constrained Ferrocenyl Diphosphines: Dramatic Effect in Gold-Catalyzed Enyne Cycloisomerization.

Di-tert-butylated-bis(phosphino)ferrocene ligands bearing phosphino substituents R (R=phenyl, cyclohexyl, iso-propyl, mesityl, or furyl) allow tuning the selective formation of Au(I) halide complexes. Thus, dinuclear linear two-coordinate, but also rare mononuclear trigonal three-coordinate and tetrahedral four-coordinate complexes were formed upon tuning of the conditions. Both Au(I) chloride and rarer Au(I) iodide complexes were synthesized, and their X-ray diffraction analysis are reported. The significance of the control of structure and nuclearity in Au(I) complexes is further illustrated herein by its strong effect on the efficiency and selectivity of gold-catalysed cycloisomerization. Cationic linear digold(I) bis(dicyclohexylphosphino) ferrocenes outperform other catalysts in the demanding regioselective cycloisomerization of enyne sulphonamides into cyclohexadienes. Conversely, tetrahedral and trigonal cationic monogold(I) complexes were found incompetent for enyne cycloaddition. We used the two-coordinate linear electron-rich Au(I) complex 2 b (R=Cy) to extend the scope of selective intramolecular cycloaddition of different 1,6-enyne sulfonylamines with high activity and excellent selectivity to the endo cyclohexadiene products.

Comparative Study of the Supercapacitive Performance of Three Ferrocene-Based Structures: Targeted Design of a Conductive Ferrocene-Functionalized Coordination Polymer as a Supercapacitor Electrode.

As redox-active based supercapacitors are known as highly desirable next-generation supercapacitor electrodes, the targeted design of two ferrocene-functionalized (Fc(COOH)2 ) clusters based on coinage metals, [(PPh3 )2 AgO2 CFcCO2 Ag(PPh3 )2 ]2 ⋅7 CH3 OH (SC1 : super capacitor) and [(PPh3 )3 CuO2 CFcCO2 Cu(PPh3 )3 ]⋅3 CH3 OH (SC2 ), is reported. Both structures are fully characterized by various techniques. The structures are utilized as energy storage electrode materials, giving 130 F g-1 and 210 F g-1 specific capacitance at 1.5 A g-1 in Na2 SO4 electrolyte, respectively. The obtained results show that the presence of CuI instead of AgI improves the supercapacitive performance of the cluster. Further, to improve the conductivity, the PSC2 ([(PPh3 )2 CuO2 CFcCO2 ]∞ ), a polymeric structure of SC2 , was synthesized and used as an energy storage electrode. PSC2 displays high conductivity and gives 455 F g-1 capacitance at 3 A g-1 . The PSC2 as a supercapacitor electrode presents a high power density (2416 W kg-1 ), high energy density (161 Wh kg-1 ), and long cycle life over 4000 cycles (93 %). These results could lead to the amplification of high-performance supercapacitors in new areas to develop real applications and stimulate the use of the targeted design of coordination polymers without hybridization or compositions with additive materials.