Synthesis and characterisation of water soluble ferrocenes: Molecular tuning of redox potentials

A range of novel water-soluble alkylated ferrocene sulfonate compounds are reported. Mono- and di-sulfonation on a series of alkyl ferrocenes produced 1,1′-dimethyl ferrocene sulfonate, 1,1′-dimethyl ferrocene disulfonate, 1,1′-diethyl ferrocene sulfonate, 1,1′-diethyl ferrocene disulfonate, t-butyl ferrocene sulfonate, t-butyl ferrocene disulfonate, ethyl ferrocene sulfonate, ethyl ferrocene disulfonate, n-butyl ferrocene sulfonate and n-butyl ferrocene disulfonate. All compounds were characterized by NMR spectroscopy, UV/Vis spectroscopy and electrochemical analysis. ¹H and ¹³C NMR studies have revealed the formation of several isomers with sulfonation occurring on positions α and β to the alkyl substituent or on the unsubstituted cyclopentadienyl ring. Variation of the alkyl group allowed the isomeric pattern to be tuned such that the final products followed either electronic or steric control. Cyclic voltammetry of the resulting products showed that the redox potential of the iron centre can be easily manipulated by changing the substituents on the cyclopentadienyl rings. This result has significant implications in the future development of homogenous redox mediators for sensing applications.     

4,4-Diorganyl-1,1,3,6-tetrachloro-1,4-tellura(IV)silafulvenes - New class of tellurium-silicon containing heterocycles

The reaction of TeCl₄ with diorganyl diethynyl silanes RR¹Si(CCH)₂ in CHCl₃ at room temperature leads to regio- and stereoselective formation of a new class of unsaturated five-membered heterocycles, 4,4-diorganyl-1,1,3,6-tetrachloro-1,4-tellura(IV)silafulvenes, in high yields. In the case of dialkyl substituents at the silicon atom the reaction proceeds with 100% stereoselectively to afford only E-isomers, while for cyclic diethynyl silanes the spiro-heterocycles formed have Z- and E-configurations, E-isomers being the predominant ones. Structures of the heterocycles have been proved by the multinuclear (¹H, ¹³C, ²⁹Si, ¹²⁵Te) NMR spectroscopy, 2D NOESY NMR spectroscopy and mass-spectrometry. Z-Isomers are characterized by a long-range spin-spin interaction of protons through five bonds with ⁵J_HH 0.2-0.5 Hz lacking in E-isomers. In the mass spectra the heterocycles manifest themselves as the fragment ions [M−Cl₂]⁺.     

Synthesis and electrochemical studies of disubstituted ferrocene/dipeptide conjugates with sulfur-containing side chains

A series of 1,1′-disubstituted ferrocenoyl peptides incorporating dipeptide sidearms has been synthesized and studied electrochemically. The target peptides include ferrocene as an electrochemical reporter, sulfur-containing amino acids (l-methionine, S-methyl-l-cysteine, S-trityl-l-cysteine, S-benzhydryl-l-cysteine) as metal binding agents, and amino acids with non-polar side chains (l-alanine, l-valine, l-phenylalanine) as spacers between reporter and metal binding groups. Ferrocene/dipeptide conjugates were prepared using solution phase peptide synthesis methods employing a BOC-protecting group strategy and HBTU- (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) mediated peptide coupling. The electrochemical properties of these 1,1′-substituted ferrocenoyl peptides have been characterized using cyclic voltammetry. All exhibit fully reversible one electron oxidation steps; forward sweep half wave peaks (E_F), reverse sweep half wave peaks (E_R), peak separations (ΔE_P) and half wave potentials (E_1/2) are reported. Finally, towards the goal of utilizing ferrocenoyl peptides to detect heavy metals in solution, the response of these ferrocene/dipeptide conjugates to metal cations (zinc(II), mercury(II), cadmium(II), lead(II), silver(I)) has been examined. Monitoring changes in the potential of the Fe(II)/Fe(III) redox couple to follow peptide/metal interactions, we have probed the influence of the spacer unit between the redox reporter and the metal-binding amino acid, and shown that these systems respond to mercury(II) more strongly than to other heavy metal ions.     

One-pot three-component reaction of C60, amino acid and fluorinated benzaldehyde to C60-pyrrolidine derivatives

A series of fluorinated 2,5-disubstituted C₆₀-pyrrolidine derivatives were synthesized via one-pot three-component reaction of C₆₀, amino acid and fluorinated benzaldehyde under reflux in toluene or microwave irradiation. The cis- and trans-isomers could be isolated by chromatography and fully confirmed by ¹H NMR.     

A simple method for desymmetrizing 1,1′-ferrocenedicarboxaldehyde

A simple chromatography-free method for desymmetrizing ferrocene is described starting from the readily available dialdehyde. Oxidation of 1,1′-ferrocenedicarboxaldehyde in a water/acetonitrile mixture with KMnO₄ produced 1′-formyl-ferrocenecarboxylic acid. The same reaction carried out in a water/acetone mixture produced 1′-[(E)-3-oxo-but-1-enyl]-ferrocenecarboxylic acid.     

Synthesis, properties, and hepatic metabolism of strongly fluorescent fluorodipyrrinones

From non-fluorescent 8-H fluorophenyldipyrrinones, highly fluorescent (?_F 0.4-0.6) analogs have been synthesized by reaction with 1,1′-carbonyldiimidazole to bridge the dipyrrinone nitrogens and form an N,N′-carbonyldipyrrinone (3H,5H-dipyrrolo[1,2-c:2′,1′-f]pyrimidine-3,5-dione). Amphiphilic, water-soluble 8-sulfonic acid derivatives are then obtained by reaction with concd H₂SO₄. The resulting fluorinated and sulfonated N,N′-carbonyl-bridged dipyrrinones, isolated as their sodium salts, are potential cholephilic fluorescence and ¹⁹F MRI imaging agents for use in probing liver and biliary metabolism. After intravenous injection in the rat they were excreted rapidly and largely unchanged in bile. ¹⁹F NMR spectroscopy of a pentafluorophenyl-tosylpyrrolinone synthetic precursor exhibited rarely seen diastereotopicity.     

Synthesis, structures and some chemical and electrochemical properties of E-1,2-diferrocenyl-3-methylthioprop-2-enone and its ketals

2,3-Diferrocenyl-1-methylthiocyclopropenylium iodide reacts with water, metal alkoxides, phenolates and with alcohols in the presence of Et₃N to give E-1,2-diferrocenyl-3-methylthioprop-2-enone or its ketals. Their structures were established based on data from ¹H and ¹³C NMR spectroscopy and X-ray diffraction analysis. The mechanistic aspects of these reactions are discussed. Electrochemical properties of 8 and 13b have been studied. The compounds present two oxidation processes (I-II), attributed to the oxidations of the ferrocenes groups, E^0′(I), E^0′(II), ΔE^0′(II-I) and comproportionation constant K_com are reported.     

Synthesis and structural characterization of mixed carbene-carboxylate complexes of palladium(II)

Mixed carbene-carboxylate complexes of Palladium(II) have been prepared by reacting {1,1^′-dimethyl-3,3^′-methylenediimidazoline-2,2^′-diylidene} palladium(II) diiodide (1) [Angew. Chem. 107 (1995) 2602; Angew. Chem. Int. Ed. Engl. 34 (1995) 2371; J. Organomet. Chem. 557 (1998) 93] with AgO₂CR, where R=CF₃, CF₂CF₃ and CF₂CF₂CF₃. In this manner, {1,1^′-dimethyl-3,3^′-methylenediimidazoline-2,2^′-diylidene} palladium(II) bis(trifluo-roacetate) (2), {1,1^′-dimethyl-3,3^′-methylenediimidazoline-2,2^′-diylidene} palladium(II) bis(pentafluoropropionate) (3) and {1,1^′-dimethyl-3,3^′-methylenediimidazoline-2,2^′-diylidene} palladium(II) bis(heptafluorobutyrate) (4) were obtained. All three complexes were fully characterized by ¹H-, ¹³C- and ¹⁹F NMR spectroscopy as well as ESI mass spectrometry. X-ray crystal structure analyses of complexes 3 and 4 reveal mononuclear species with a square planar metal center coordinated by a cis-chelating dicarbene and two monodentate carboxylate ligands. The results show that the introduction of a cis-chelating N,N-heterocyclic carbene ligand stabilizes the palladium-carboxylate moiety effectively.     

Synthesis, NMR, IR spectroscopic and X-ray study of novel [pyridazin-3(2H)-one-6-yl]ferrocenes and related ferrocenophane derivatives. Study on ferrocenes. Part 14

On treatment with glyoxylic acid and hydrazine hydrate, 1,1′-diacetylferrocene was converted into the separable mixture of 1,1′-bis [pyridazin-3(2H)-one-6-yl]ferrocene and the hydrazone as well as the azine of 1-acetyl-1′-[pyridazin-3(2H)-one-6-yl]ferrocene. Successful cyclizations of 1,1′-bis[pyridazin-3(2H)-one-6-yl]ferrocene resulting in a series of novel ferrocenophanes containing heterocyclic units were performed under phase transfer- and homogeneous catalytic (RCM) conditions by the application of versatile dialkylating agents and second generation Grubbs’ catalyst, respectively. The structures were determined by mass spectrometry, IR, ¹H and ¹³C NMR spectroscopy including 2D-COSY, HMQC and HMBC measurements. The solid phase structure of a dimer product with π-stacking interaction was revealed by X-ray analysis.     

Synthesis, structural revision, and biological activities of 4′-chloroaurone, a metabolite of marine brown alga Spatoglossum variabile

4′-Chloroaurone (1a), the only aurone reported from a marine source, Spatoglossum variabile was synthesized from 2-hydroxyacetophenone along with six structural analogs. The products obtained were Z-isomers and these were converted into E-isomers by photoisomerization. The E and Z isomers of aurones showed distinct proton and carbon chemical shifts. However, the spectroscopic data of either Z-4′-chloroaurone (1a) or its E-isomer (2a) did not match with those reported for the natural product and thus requires revision of the structure assigned. The proton NMR spectroscopic data reported for the natural product matches with those reported for a known isocoumarin (5). The synthesized E and Z aurones were evaluated for their antioxidant and antibacterial activities. The aurone, Z-2-[(3,4-dihydroxyphenyl)methylene]benzo[b]furan-3-one exhibited significant antioxidant activity. Interestingly, Z-aurones are active against Gram-positive and Gram-negative bacteria, whereas the corresponding E-aurones were inactive.     

Butylene linked palladium N-heterocyclic carbene complexes: Synthesis and catalytic properties

New bis(NHC)-Pd complexes were synthesized and characterized by elemental analysis, ¹H NMR, ¹³C NMR, and IR spectroscopy. The reaction of Pd(OAc)₂ and bis(benzimidazolium) salts in DMSO gave the monomeric palladium complex in which the N-heterocyclic carbene was bound to the metal centre. The crystal and molecular structure of the cis-dibromo{1,1′-di[2,3,4,5,6-pentamethylbenzyl]-3,3′-butylenedibenzimidazol-2,2′-diylidene}-palladium(II) complex was determined by single-crystal X-ray diffraction. The activity of the Pd(II) complexes in the direct arylation of benzothiazole with arylbromides was investigated. A preliminary catalytic study showed that these bis(NHC)-Pd complexes were highly active in the direct arylation of benzothiazole with arylbromides.     

Reaction of 1-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones with urea. Synthetic route to novel 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones, 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones, and 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones

1-Substituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with urea in boiling acetic acid to give products depending on the type of substitution in position 3 and at the nitrogen atom of the 3-amino group. Starting compounds bearing a primary amino group in position 3 give 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones. Starting compounds bearing a secondary amino group in position 3 react according to the character of the other substituent in position 3. If there is a hydrogen atom α to the carbon atom C(3), 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones arise. If a hydrogen atom is not present in this position, the reaction leads to 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. Reaction mechanisms for these transformations are proposed. All compounds were characterized by their ¹H, ¹³C, IR and atmospheric pressure chemical ionization mass spectra and some of them also by ¹⁵N NMR data.     

Synthesis and characterisation of two new binaphthyl trisilanes

The synthesis and characterisation of two binaphthyl trisilanes is described. Reaction between 2,2′-dilithio-1,1′-binaphthyl and 1,3-dichlorohexamethyltrisilane gave 3,3,4,4,5,5-hexamethyl-4,5-dihydro-3H-3,4,5-trisilacyclohepta[2,1-a;4,3-a′]binaphthalene (3). Compound 3 was characterised by ¹H, ¹³C and ²⁹Si NMR spectroscopy and a crystal structure analysis. Reaction between 2,2′-dilithio-1,1′-binaphthyl and 1,3-bis(trifluoromethanesulfonyloxy)-1,1,2,3,3-pentamethyltrisilane, generated in situ by treatment of 1,3-diphenyl-1,1,2,3,3-pentamethyltrisilane with trifluormethanesulfonic acid, gave 3,3,4,5,5-pentamethyl-4,5-dihydro-3H-3,4,5-trisilacyclohepta[2,1-a;4,3-a′]binaphthalene (7). Analysis by ¹H, ¹³C and ²⁹Si NMR spectroscopy revealed that 7 had a very similar structure to 3.     

Ferrocenoyl-amino acids: redox response towards di- and trivalent metal ions

The interaction of six ferrocene-amino acid conjugates (Fc-CO-Gly-OH (2a), Fc-CO-Asp-OH (3a), Fc-CO-Glu-OH (4a), 1,1′-Fc(CO-Gly-OH) (2b), 1,1′-Fc(CO-Asp-OH) (3b), and 1,1′-Fc(CO-Glu-OH) (4b)) with Mg²⁺, Ca²⁺, Zn²⁺, La³⁺, and Tb³⁺ was investigated in aqueous solutions using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Addition of metal ions to solutions caused, in some cases, large changes in the half-wave potential, E_1/2. Our electrochemical results show that the Gly systems, 2a and 2b, show a preference for binding Mg²⁺, whereas the Asp and Glu conjugates prefer binding Ln³⁺.     

Synthesis of enantiopure, axially chiral, C-tetrasubstituted α-amino acids with binaphthyl-based crowned side chains and 3D-structural analysis of their peptides

The syntheses of the terminally protected, crowned, C^α-tetrasubstituted α-amino acids with only axial chirality, the two diastereomers Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 2′,1′:1,2; 1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip), were performed by bis-alkylation with cyclization of racemic (R+S)-Boc-[HO]₂-Bip-OMe, possessing two phenolic OH groups at the 6,6′-positions of the biphenyl frame of Bip, using (+)-(R)- and (−)-(S)-Binol[(OCH₂CH₂)₂OTs]₂ (2,2′-bis[5-tosyloxy-3-oxa-1-pentyloxy]-1,1′-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with either l-Ala or l-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these peptides preferentially adopt folded secondary structures.     

Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-substituted isoxazoles

A novel effective method is reported for the preparation of 1-amino-1H-pyrazole-4-carboxylic acid derivatives by Fe(II)-catalyzed rearrangement of isoxazoles having (2,4-dinitrophenylhydrazono)methyl substituent at C4. The reaction proceeds smoothly for both E and Z isomers of 4-(hydrazonomethyl)isoxazoles, and this means it is not necessary to separate mixtures of E/Z-isomers of the hydrazones prepared by reaction of 5-methoxy/pirrolidino-4-carbonylisoxazoles and 2,4-dinitrophenylhydrazine. The rearrangement proceeds via the formation of an aziridine intermediate which can be isolated in certain cases. The 2-nitro group in the synthesized 1-[(2,4-dinitrophenyl)amino]-1H-pyrazole-4-carboxylic esters can be selectively reduced in two steps via acylation of the amino group followed by hydrogenation-deacylation using H₂-Pd/C.     

Reactions of a hydrido(hydrosilylene)tungsten complex with oxiranes

Reactivity of a hydrido(hydrosilylene)tungsten complex, Cp¹(CO)₂(H)WSi(H)[C(SiMe₃)₃] (1), toward oxiranes was investigated. Treatment of 1 with racemic mono-substituted oxiranes with a substituent R (R = Ph, vinyl, ^tBu, or ⁿBu) at room temperature produced dihydrido(vinyloxysilyl)tungsten complexes, (E)- and/or (Z)-Cp¹(CO)₂(H)₂W{Si(H)(OCHCHR)[C(SiMe₃)₃]} [(E/Z)-2: R = Ph, (E)-3: R = vinyl, (E)-4: R = ^tBu, (E/Z)-5: R = ⁿBu] in high yields via regioselective ring-opening of oxiranes. When the substituent R on oxirane was relatively large, (E)-isomers (2, 3, and 4) were obtained predominantly (87–97%), while the substituent was a relatively small ⁿBu group, an approximately 1:1 mixture of (E)- and (Z)-isomers [(E/Z)-5] was obtained. Reaction of 1 with 2,2-dimethyloxirane afforded the corresponding complex, Cp¹(CO)₂(H)₂W{Si(H)(OCHCMe₂)[C(SiMe₃)₃]} (6), quantitatively. A reaction mechanism is also discussed.     

Practical synthetic protocols of enantiopure 1,1-binaphthyl-2,2-dicarboxylic acid and 2,2-dicyano-1,1-binaphthyl starting from optically active dibromide precursor

Dilithiation of optically active 2,2^′-dibromo-1,1^′-binaphthyl 2 with t-BuLi followed by carboxylation of the resulting dilithio-intermediate 3 with CO₂ gave optically active 1,1^′-binaphthyl-2,2^′-dicarboxylic acid 1, which was further transformed to its dicyano derivative 4. Both of these transformations were carried out in a one-pot operation and the products were obtained in excellent yields with no observable racemization.     

Synthesis and characterization of dendrons and dendrimers skeleton-constructed with azobenzene moiety

A series of dendrons and dendrimers skeleton-constructed with azobenzene moiety based upon 4-carboxy-4′-(1,2-propanediolether)-azobenzene as an AB₂ monomer, via a convergent approach, proceeding in a repeated stepwise growth manner starting from 4-carboxy-4′-(n-butylether)-azobenzene as a peripheral monomer, were synthesized, and characterized by NMR, FTIR, and MALDI-TOF-MS analysis. Their regular molecular architecture and thus monodispersed molecular weights were confirmed by GPC. The UV-Vis absorbance and ¹H NMR spectrum study indicated that the azobenzene moieties in CHCl₃ solution took fully trans-cis isomerization under UV irradiation, and reversely isomerization back to the trans by visible light irradiation or by heat.     

Ferrocenoyl peptides with sulfur-containing side chains: synthesis, solid state and solution structures

The synthesis and full characterization of a number of amino acid and dipeptide derivatives with sulfur-containing side chains derived from ferrocene carboxylic acid and ferrocene-1,1′-dicarboxylic acid is presented. In particular, compounds Fc-CO-(Aaa)_n-OMe (4) and Fe[C₅H₄-CO-(Aaa)_n-OMe]₂ (3) with (Aaa)_n = Cys(Bzl) (a), Cys(Bzl)-Cys(Bzl) (b), Cys(p-OMe-Bzl) (c), Cys(p-OMe-Bzl)-Cys(p-OMe-Bzl) (d), Met (e), and Met-Met (f) were prepared. Also, the free acid derivatives Fe[C₅H₄-CO-Met-OH]₂ (6e) and Fc-CO-Met-OH (7e) were prepared and characterized. The solid state structures of 3a, 4b, and 4e were determined by single crystal X-ray diffraction. Compound 3a shows a 1,3′ substitution pattern on the Cp rings in the solid state. Structures in solution were determined by NMR, IR and CD spectroscopy, with particular emphasis on the question of hydrogen bonding and helical chirality of the metallocene. As an example, the full assignment for the Cp signals in the disubstituted derivative 3a was achieved by simulation of the ¹H NMR signals from the cyclopentadienyl ring in combination with 2D-NOESY spectra. In solution, 3a has the known 1,2′ substitution pattern, which is stabilized by intramolecular hydrogen bonds.