Ferrocene Analogues Research Articles

Theoretically predicted ferrocene analogues with triplet aromatic CB5H5 ligands.

Three ferrocene analogues, D 5h (η5-CB5H5)2M (M=Fe2-, Co-, and Ni), with triplet aromatic CB5H5 ligands have been predicted at TPSSh/6-311+G(d,p) level. We find that the M atom interacts drastically with the two CB5H5 ligands through a nearly fully-filled 3d subshell, which is different from (η5-C5H5)2Fe. The natural population analyses suggest that (η5-CB5H5)2M have an unconventional charge distribution, i.e., the M atom is negatively charged, while the two boron rings are positively charged. The analyses of the electronic and dynamic stabilities indicate that (η5-CB5H5)2Co- is the most stable among (η5-CB5H5)2M. Thus, we theoretically confirm that the triplet aromatic CB5H5 cluster can be regarded as a potential new ligand. Our theoretical predictions are awaiting future experimental verification.

Phosphorus-Sulfur Heterocycles Incorporating an O-P(S)-O or O-P(S)-S-S-P(S)-O Scaffold: One-Pot Synthesis and Crystal Structure Study.

A new one-pot preparative route was developed to synthesize novel organophosphorus-sulfur heterocycles via the reaction of the four-membered ring thionation reagent [2,4-diferrocenyl-1,3,2,4-diathiadiphosphetane 2,4-disulfide (FcLR, a ferrocene analogue of Lawesson’s reagent)] and alkenyl/aryl-diols and I2 (or SOCl2) in the presence of triethylamine. Therefore, a series of five- to ten-membered heterocycles bearing an O-P(S)-O or an O-P(S)-S-S-P(S)-O linkage were synthesized. The synthesis features a novel application of the multicomponent reaction, providing an efficient and environmentally benign method for the preparation of the unusual phosphorus-sulfur heterocycles. Seven representative X-ray structures confirm the formation of these heterocycles.

Ruthenocenyl Glycidyl Ether: A Ruthenium-Containing Epoxide for Anionic Polymerization

Ruthenocenyl glycidyl ether (rcGE) is a novel monomer for the anionic polymerization and copolymerization with ethylene oxide to water-soluble, thermo-, and redox-responsive organometallic poly(ethylene glycol)s (PEGs). The polymers exhibit adjustable molecular weights, comonomer ratios, and narrow molecular weight distributions (typically Mw/Mn < 1.2). Real-time 1H NMR copolymerization kinetics prove random incorporation of rcGE into the polyether backbone in analogy to its ferrocene analog. The rcGE-co-EO copolymers are water-soluble with a lower critical solution temperature, depending on the rcGE content. Terpolymerization of ferrocenyl glycidyl ether, ethylene oxide, and rcGE produces the first random PEG derivatives with multiple redox response. Ruthenocenyl glycidyl ether broadens the field of organometallics, especially ruthenium-containing polymers, and these copolymers might find applications in catalysis, as redox-active surfactants, or as staining reagents in electron microscopy.

Synthesis of the ferrocenyl analogue of clotrimazole drug

The ferrocenyl analogue of clotrimazole, in which the metallocene fragment replaces one of the phenyl rings in the triphenylmethane system, and a related isomer were prepared through the direct substitution of a methoxygroup in the α-position to ferrocene with imidazole in the key step. The obtained ferrocenyl derivatives were spectroscopically characterized and in a preliminary assay for bioactivity their cell growth inhibitory activity on two different human cancer cell lines was evaluated. In comparison with the parent drug the ferrocene analogues displayed about two-fold increase of cytotoxicity on HT29 colorectal cancer cells, whereas comparable activity was displayed against MCF-7 breast cancer cell line.

Preparation, characterization and in vitro release kinetics of polyaspartamide-based conjugates containing antimalarial and anticancer agents for combination therapy

Malaria is treated by combination of two drugs in order to overcome drug resistance. Antimalarials have been found to be more effective by combining them with low doses of anticancer drugs. Polymer-drug conjugates containing aminoquinoline and ferrocene derivatives were prepared from polyaspartamides polymers. These conjugates physicochemical properties were characterized. FTIR and 1H NMR confirmed the successful incorporation of aminoquinoline and ferrocene analogues onto the polyaspartamides polymers. The XRD thermograms indicated the amorphous nature of the polymer-drug conjugates and the successful incorporation of the drugs onto the polymer carriers. It further indicated the absence of free 4-aminoquinoline and ferrocene analogues. The rate of release of the bioactive drugs was slow at pH 7.4 and fast at pH 1.2. The release mechanism of ferrocene analogue from the carrier was super case II whereas the release mechanism of the 4-aminoquinoline from the carrier was a case II. Zero order release mechanism dominated the first 24 h. The release mechanisms of the bioactive drugs and physico-chemical properties from the polyaspartamide-based carriers suggested that they are potential drug delivery which can be used to overcome drug resistance that is common with the presently used antimalarials.

Improved Syntheses of 1,2‐Disubstituted Ferrocenes

1,2‐Disubstituted ferrocenes, in particular 1,2‐dihaloferrocenes, are important starting materials. Herein, we describe significantly improved high‐yielding syntheses of 1,2‐disubstituted ferrocenes such as 1,2‐dibromo‐ and 1,2‐diiodoferrocene as well as 1‐bromo‐2‐iodoferrocene, and 1‐bromo‐2‐fluoroferrocene. DFT calculations show that 1,2‐dihaloferrocenes do not differ much in their highest occupied molecular orbital (HOMO) energies; however, their lowest unoccupied molecular orbital (LUMO) energies – and thus the HOMO/LUMO gaps – correlate with the sum of the halogen electronegativities. In addition, a synthesis of the rather sensitive 2‐aminoferrocenecarboxylic acid, the ferrocene analogue of anthranilic acid, is presented, which starts from ferrocene‐1,2‐dicarboxylic acid. However, 2‐aminoferrocenecarboxylic acid rapidly decomposed and thus could not be properly characterized. Ferrocene‐1,2‐dicarboxylic anhydride serves as the starting material for preliminary photochemical decarbonylation/decarboxylation experiments resulting in 1,2‐dideuterioferrocene when carried out in [D8]toluene.

Synthesis of Bioorganometallic Nanomolar-Potent CB2 Agonists Containing a Ferrocene Unit

A small library of ferrocene-containing amides has been synthesized using standard amide coupling chemistry with ferrocenylamine. Ferrocene analogues of known bioactive adamantylamides were shown to be effective cannabinoid receptor (CB1 and CB2) agonists, displaying, in many cases, single-digit nanomolar potency. Three final ferrocene-containing derivatives have been characterized in the solid state by X-ray crystallography and display intramolecular hydrogen bonding of the type NH---C═O. N-Methylation of the amide, confirmed by X-ray crystallography, leads to both loss of hydrogen bonding and biological activity.

One-Pot Three-Component Condensation Synthesis and Structural Features of Organophosphorus-Sulfur Macrocycles.

A new preparative route was developed to synthesize new phosphorus-sulfur [SP(═S)S moiety]-containing macrocycles via a one-pot and three-component domino reaction of four-membered ring thionation reagents such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (LR, Lawesson's reagent) and 2,4-diferrocenyl-1,3,2,4-diathiadiphosphetane 2,4-disulfide (FcLR, a ferrocene analogue of Lawesson's reagent) and alkyldithiols(aryldithols) and dihaloalkanes in the presence of sodium hydride. Therefore, a series of 12- to 18-membered macrocycles incorporating two phosphorus and six sulfur atoms were synthesized. The synthesis features a novel application of the multicomponent reaction, providing an efficient route to the preparation of the new phosphorus-sulfur-containing macrocycles. Seven representative X-ray structures confirm the formation of these macrocycles and show the presence of a number of the intramolecular C-H···S hydrogen bonding, intermolecular C-H···S, C-H···Cl, and Cl···Cl short contacts and π-stacking interactions in their 3D network structures.

One-Pot Approach to Organo-Phosphorus-Chalcogen Macrocycles Incorporating Double OP(S)SCn or OP(Se)SeCn Scaffolds: A Synthetic and Structural Study.

The development of new methodology for the preparation of functional macrocycles with practical applications is an important research area in macromolecular science. In this study, we report a new one-pot route for the synthesis of a series of macro-heterocycles by incorporating two phosphorus atoms and two chalcogen atoms and two oxygen atoms (double OP(S)SCn or OP(Se)SeCn scaffolds). The three-component condensation reactions of 2,4-diferrocenyl-1,3,2,4-diathiadiphosphetane 2,4-disulfide (FcLR, a ferrocene analogue of Lawesson's reagent) or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (LR, Lawesson's reagent), or 2,4-diphenyl-1,3,2,4-diselenadiphosphetane 2,4-diselenide (WR, Woollins' reagent), disodium alkenyl-diols, and dihalogenated alkanes are performed, giving rise to soluble and air or moisture-stable macrocycles in good-to-excellent yields (up to 92 %). This is the first systemically preparative and readily scalable example of one-pot ring opening/ring extending reaction of three-components to prepare phosphorus-chalcogen containing macrocycles. We also provide a systematic crystallographic study.

Crystal structures of [η5-C5H4CR(SCH2)2]Cr(NO)2X (R = H, X = Cl or I; R = CH3, X = Cl) and unequivocal assignments of C(2,5) and C(3,4) on the cyclopentadienyl ring of dicarbonyl(η5-cyclopentadienyl)nitrosylchromium, chloro(η5-cyclopentadienyl)dinitrosylchromium, (η5-cyclopentadienyl)iododinitrosylchromium, and (η5-cyclopentadienyl)methyldinitrosylchromium, bearing an electron-donating substituent via induction in 13C NMR spectra

After thioacetalization with 1,2-ethanedithiol complexes (η5-C5H4COR)Cr(CO)2(NO) (R=H, CH3) were converted to [η5-C5H4CR(SCH2)2]Cr(CO)2(NO). Chlorination/nitrosylation of the latter with hydrogen chloride/isoamyl nitrite gave [η5-C5H4CR(SCH2)2]Cr(NO)2Cl (R=H 2f, CH32g). Those complexes were converted to iodide analog, [η5-C5H4CR(SCH2)2]Cr(NO)2I (R=H 3f, CH33g) with potassium iodide. The diastereotopism of the two sets of methylene hydrogens on the dithiolanyl substituent was observed in 1H NMR spectra of 2f and 3f, but not in those of 2g and 3g. The environmental disparity revealed by X-ray structures may account for it. Based on the 2D HETCOR, the H(2,5) resonates at a lower field than H(3,4) on the Cp(Cr) ring in 3g, as ferrocene analog (η5-C5H4CH2CH3)FeCp, opposite to CpCr(CO)2(NO) analog (η5-C5H4CH2CH3)Cr(CO)2(NO). The electron density distribution in the cyclopentadienyl ring was discussed on the basis of 13C NMR data and was compared with calculations using the density functional B3LYP exchange–correlation method for those with X-ray diffraction studies.

Macromolecular Co-conjugate of Ferrocene and Bisphosphonate: Synthesis, Characterization and Kinetic Drug Release Study

Cancer chemotherapy often results in side effects such as high toxicity and drug resistance. Sequential and simultaneous delivery of drug combinations have been found to reduce the side effects associated with systemic delivery of anticancer drugs. An alternative approach to systemic delivery of anticancer drugs is the co-conjugation of two or more of these agents to a single polymeric carrier via biofissionable linkages. In this study, macromolecular co-conjugates of bisphosphonate and ferrocene were synthesized and the kinetic drug release studied. Phosphorus and proton NMR and FTIR were used to characterize the co-conjugates. The mass percentages incorporation of ferrocene analogue were found to be between 4–5 % and 10–12 % for bisphosphonate. Kinetic drug release results at selected pH (1.2, 5.5 and 7.4) were fitted in different mathematical drug release model to determine the mechanism of release of ferrocene and bisphosphonate from a co-conjugate pro-drug. The best model describing the release of ferrocene were found to be Korsmeyer–Peppas model at pH 1.2 and zero order model at pH 5.5 and 7.4. For bisphosphonate, Korsmeyer–Peppas, Higuchi and zero order models were found to best fit the release mechanism at pH 1.2, 5.5 and 7.4 respectively.

Acyl chloride carbon insertion into dicarbaborane cages – new route to tricarbollide cages

Abstract Reactions between the arachno-6,9-C2B8H14 dicarbaborane and acyl chlorides, RCOCl, in the presence of amine bases in CH2Cl2, followed by acidification with conc. H2SO4 at 0 °C, generate in high yields a series of neutral alkyl and aryl tricarbollides of structure 8-R-nido-7,8,9-C3B8H11 (where R=alkyls and aryls). These skeletal alkylcarbonation (SAC) reactions are consistent with an aldol-type condensation between the RCO group and open-face dicarbaborane hydrogen atoms, which is associated with the insertion of the acyl chloride RC unit into the structure under elimination of three extra hydrogen atoms as H2O and HCl. The reactions thus result in an effective cross-coupling between R and the tricarbollide cage. High-temperature reactions between 8-Ar-nido-7,8,9-C3B8H11 (where Ar=Ph, 1-C10H7, and 2-C10H7) compounds and [CpFe(CO)2]2 produced the first types of monoaryl substituted twelve-vertex ferratricarbollide complexes of general constitution [1-(CpFe)-closo-ArC3B8H10] with three different arrangements of cluster carbon vertexes. The Fe-complexation is accompanied by extensive rearrangement of the cluster carbon atoms over the twelve-vertex cage and the complexes isolated can be regarded as ferrocene analogues.

Binuclear 1,2-diaza-3,5-diborolyl iron carbonyls: Effect of replacing ring CC units with isoelectronic BN units

The recently synthesized 1,2-diaza-3,5-diborolyl ligand is a BN analog of the cyclopentadienyl ligand that has been recently used for the synthesis of a BN analog of ferrocene. The binuclear 1,2-diaza-3,5-diborolyl iron carbonyl derivatives (Me4B2N2CH)2Fe2(CO)n (n=5, 4, 3, 2) have now been investigated by density functional theory for comparison with the corresponding cyclopentadienyliron carbonyl systems, (C5H5)2Fe2(CO)n. The lowest energy (Me4B2N2CH)2Fe2(CO)n (n=4, 3, 2) structures have two bridging CO groups. For (Me4B2N2CH)2Fe2(CO)3 a triplet triply bridged (Me4B2N2CH)2Fe2(μ-CO)3 structure is analogous to the experimentally known stable compounds (η5-C5R5)2Fe2(μ-CO)3 (R=H, CH3). From the thermochemistry results, the doubly bridged singlet (Me4B2N2CH)2Fe2(CO)2(μ-CO)2 structure appears to a promising synthetic objective. The energies of the triplet (Me4B2N2CH)2Fe2(CO)3 and (Me4B2N2CH)2Fe2(CO)2 structures are lower than those of the corresponding singlet structures. The Wiberg bond indices of the iron–iron bonds determined by the NBO method correlate well with the formal bond orders suggested by the FeFe distances and electron counting. The (Me4B2N2CH)2Fe2(CO)5 structures lack an iron–iron bond and require only ∼2kcal/mol in energy for decarbonylation to (Me4B2N2CH)2Fe2(CO)4. In all of the (Me4B2N2CH)2Fe2(CO)n (n=4, 3, 2) structures, the predicted FeN and FeB distances are close to those in the ferrocene analog [η5-(CH2)3N2(BPh)2CMe]2Fe.

Oxidative Sequence of a Ruthenocene-Based Anticancer Drug Candidate in a Basic Environment

The complete oxidation sequence of ruthenociphenol (1), an organometallic ruthenocene-based analogue of ferrocifens, a promising anticancer drug series, has been investigated by cyclic voltammetry. As for the unsubstituted ruthenocene, the oxidation of 1 produced the corresponding species 1+, which engaged in a reversible dimerization reaction. The highest reversibility occurred in dichloromethane (DCM), a low-donor solvent, with the weakly coordinating supporting electrolyte anion B(C6F5)4. Under these conditions, the addition of pyridine triggered a chemical sequence through which the hydroxyl group of electrogenerated 1+ was ultimately converted into the phenoxy radical 2. Unlike analogue ferrocifen derivatives, 2 did not undergo a further electrochemical oxidation but engaged in coupling with 1+. The slow deprotonation of the resulting species appeared to be the key step leading to the quinone methide 3 after sluggish electron transfer. Again, in contrast with the ferrocifen series, 3 was not the final and stable complex of this oxidation sequence. It was indeed shown that the quinone methide spontaneously underwent a further oxidative evolution under our conditions. This led to a five-membered-ring closure and regeneration of the phenolic species 4, which could be further oxidized irreversibly, leading presumably to the new quinone methide 6. Such distinct behavior in comparison to ferrocene analogues may explain the different cytotoxic activities observed against hormone-independent breast cancer cells for ruthenocifens and ferrocifens.

Synthesis, characterization and in vitro anti-Trypanosoma cruzi and anti-Mycobacterium tuberculosis evaluations of cyrhetrenyl and ferrocenyl thiosemicarbazones

To study the electronic influence of the organometallic moieties in thiosemicarbazones, two short libraries of cyrhetrenyl thiosemicarbazone and ferrocenyl thiosemicarbazone hybrids were synthesized and tested for their antichagasic and antitubercular activities. The unreported cyrhetrenyl thiosemicarbazone derivatives of the form [(η5-C5H4)–C(R1) = NNHC(S)NHR2]Re(CO)3 (R1 = H, CH3; R2 = H, CH3, CH2CH3, C6H5) were prepared from cyrhetrenylcarbaldehyde (1a) or acetylcyrhetrene (1b) and the corresponding thiosemicarbazide. The 1H and 13C NMR spectra indicate that these compounds have the anti-(E) conformation in solution, and the X-ray crystal structure of formylcyrhetrene 4-methyl-thiosemicarbazone (2b) confirms that this complex also adopts the anti-(E) form in the solid state. The new cyrhetrenyl thiosemicarbazones and their ferrocene analogues were screened in vitro against Trypanosoma cruzi and Mycobacterium tuberculosis. The anti-T. cruzi evaluation showed that the ferrocenyl derivatives were more efficient trypanocidal agents compared to their cyrhetrenyl counterparts. The incorporation of any organometallic fragment into thiosemicarbazone scaffold showed moderate antituberculosis activity against mc27000 strain.

Ferrocene analogues of sandwich M(CrB₆H₆)₂: a theoretical investigation.

The stability and electronic structures of the new sandwich compounds M(CrB6H6)2 (M = Cr, Mn(+), Fe(2+)) are investigated by density functional theory. All the investigated sandwich complexes are in D(6d) symmetry and all of them are thermodynamically stable according to the large HOMO-LUMO gap, binding energy, vertical ionization potential and vertical electron affinity analyses, as well as Fe(C5H5)2 and Cr(C6H6)2, following the 18-electron principle. The natural bond orbital, detailed molecular orbitals and adaptive natural density partitioning analyses suggest that the spd-π interaction plays an important role in the sandwich compounds. This work challenges the traditional chemical bonding of the inorganic metal compound, investigates first the bonding style of the d atom orbital interacting with the π MO which was formed by p-d atomic orbitals, and indicates that the metal-doped borane ring can also be an ideal type π-electron donor ligand to stabilize the transition metal.

Structural Characteristics of Chloroquine-Bridged Ferrocenophane Analogues of Ferroquine May Obviate Malaria Drug-Resistance Mechanisms

Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (logP) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.

Targeting Epidermal Growth Factor Receptor with Ferrocene-Based Kinase Inhibitors

A series of ferrocene analogues based on a 6,7-dimethoxy-N-phenylquinazolin-4-amine template has been synthesized, and two compounds were characterized in the solid state by X-ray crystallography. The compounds have been tested for in vitro anticancer activity, against epidermal growth receptor (EGFR), and submicromolar IC50 values have been determined.

Synthesis, Characterization, Kinetic Release Study and Evaluation of Hydrazone Linker in Ferrocene Conjugates at Different pH Values

Hydrazone linker plays an important role in drug delivery because it is stable under physiological conditions and hydrolytically degradable in mildly acidic environment. In this research, we demonstrated the efficacy of hydrazone linker in polymer-drug conjugation by using it to incorporate an analogue of ferrocene to biodegradable polymers to form conjugates. These conjugates were characterized by NMR, IR and UV spectroscopy. The mass percentage incorporation of the analogue was found to be between 1.95-2.76 % from the NMR spectroscopy. The stability of the hydrazone linker of the selected conjugates was evaluated at various pH-values and found to cleave under acidic pH but stable at neutral pH. Various kinetic release models were used to determine the release mechanism of ferrocene analogue from polyaspartamide polymeric carriers. The release profile was found to fit best with Korsmeyer-Peppas model with a diffusion exponent of 1.1.

Unequivocal assignments of C(2,5) and C(3,4) on the cyclopentadienyl ring of dicarbonyl(η5-cyclopentadienyl)nitrosylchromium, dicarbonyl(η5-cyclopentadienyl)cobalt, and tricarbonyl(η5-cyclopentadienyl)methyltungsten derivatives bearing an electron-withdrawing carbonyl substituent in 13C NMR spectra

The chemical shifts of C(2)–C(5) carbon atoms of the series of substituted-cyclopentadienyl Cp(M) derivatives—(CO)2Co[η5-(C5H4-sub)] (1–5), (C4Ph4)Co[η5-(C5H4COOCH3)] (6), (CO)3(CH3)W[η5-(C5H4-sub)](7–9), (CO)3(Cl)W[η5-(C5H4COOCH3)] (10), (CO)2(NO)Cr[η5-(C5H4-sub)] (11–23), and (NO)2(Cl)Cr[η5-(C5H4COOCH3)] (24)—have been assigned using two-dimensional HETCOR NMR spectroscopy. The assigned chemical shifts were compared with the NMR data of their ferrocene analogs. We observed that H(3,4) resonate at a lower field than H(2,5) resonate in (CO)2Co(η5-C5H4CHO) 1. The structure of (CO)3(CH3)W[η5-(C5H4COCH3)] 8 has been determined by X-ray diffraction studies. The electron density distribution in the cyclopentadienyl ring is discussed on the basis of 13C NMR data and that of 10 and (CO)2Co[η5-(C5H4COONS)] (NS=N-succinimidyl) (25) is compared with calculations using the density functional B3LYP exchange-correlation method.