Application of capillary electrophoresis technique for the enantioseparation of bioactive ferrocene-based compounds versus DFT calculated data.

Herein, a series of bioactive ferrocene-modified N-heterocycles with alkyl linkers was prepared in good to quantitative yields starting from easy accessible ferrocene alcohols and heterocycles under acidic or neutral (for imidazole) conditions in racemic forms. The analytical resolution of a number of bioactive racemic ferrocene azoles 1-6 (where azole = imidazole, pyrazole, and benzotriazole derivatives) into enantiomers was first carried out by CE using sulfobuthylether-ß-CD (captisol) as a chiral selector. The analytical approaches to highly enantiomeric-enriched ferrocene derivatives are based on the formation of their inclusion complexes. The best chiral separation was achieved using zone CE in a quartz capillary. The ACE was used to evaluate the stability constants of captisol complexes with enantiomeric forms of two ferrocene derivatives 1, FcCHMe-imidazole, and 6, FcCHMe-benzotriazole. The optimal conditions for the resolution of the studied (R, S)-ferrocene compounds 1, 2, and 6 were predicted on the basis of the performed quantum chemical calculations and then implemented by the electrophoretic method. A high correlation between density functional theory calculation results and experimental electrophoresis data were obtained. Successful enantioseparation of racemic mixtures is of great importance for the characterization and further applications of drug candidates in enantiopure forms and in the development of clinical treatment. The advantages of the CE procedure make it possible to have important practical value and significance for determining the purity and enantiomeric excess of other ferrocene-containing compounds.

Enantiomeric-Enriched Ferrocenes: Synthesis, Chiral Resolution, and Mathematic Evaluation of CD-chiral Selector Energies with Ferrocene-Conjugates.

Enantiomeric-enriched ferrocene-modified pyrazoles were synthesized via the reaction of the ferrocene alcohol, (S)-FcCH(OH)CH3 (Fc = ferrocenyl), with various pyrazoles in acidic conditions at room temperature within several minutes. X-ray structural data for racemic (R,S)-1N-(3,5-dimethyl pyrazolyl)ethyl ferrocene (1) and its (S)-enantiomer (S)-1 were determined. A series of racemic pyrazolylalkyl ferrocenes was separated into enantiomers by analytical HPLC on ß- and γ-cyclodextrins (CD) chiral stationary phases. The quantum chemical calculations of interaction energies of ß-CD were carried out for both (R)- and (S)-enantiomers. A high correlation between experimental HPLC data and calculated interaction energies values was obtained.

Letter: Influence of experimental conditions on electrospray ionization mass spectrometry of ferrocenylalkylazoles.

Influence of experimental conditions on electrospray/ionization (ESI) mass spectra of ferrocene derivatives FcCHRAz (Fc = eta5-C5H5-Fe-eta5- C5H4; R = H, Az = benzimidazole; R = Ph, Az = 2-methylimidazole) has been investigated. The spectra of all the compounds revealed [M]+*, product of its fragmentation [FcCHR]+ as well as products of ion/molecular interactions (protonated molecule [MH]+, binuclear ion [(FcCHR)2 Az]+, dimeric ion [M2]+* and its protonated form [M2H]+). Relative abundances of these ions appreciably (more than one order) depend on experimental conditions: analyte concentration, temperature of heated capillary, spray voltage, flow rate of mobile phase and polarity of solvents. Established correlations allow the selection of optimum experimental conditions for registration of ESI mass spectra, as required by the application. If an unknown compound is to be identified, it is necessary to operate by using polar solvents, small concentration, low temperature of heated capillary, high spray voltage and flow rates. There are high-intensity binuclear and protonated dimeric ions in mass spectra under other conditions. It can give rise to wrong interpretation of the structure of investigated compound. At the same time, for study of ion-molecular processes by ESI-MS it is necessary to use concentrated samples in non-polar solvents. In this case the dependence of reaction products yields on temperature and flow rate of mobile phase must be investigated.