In contrast to metal centered 17 valence electron radicals, such as [Mn(CO) 5 ] • , ferrocenium ions [Fe(C 5 H 5 ) 2 ] + (1 + ), [Fe(C 5 Me 5 ) 2 ] + (2 + ), [Fe(C 5 H 5 )(C 5 H 4 Et)] + (3 + ), [Fe(C 5 H 5 )-(C 5 H 4 NHC(O)Me)] + (4 + ), and [Fe(C 5 H 5 )(C 5 H 4 NHC(S)Me)] +(5 + ) do not add to nitrosobenzene PhNO to give metal-coordinated stable nitroxyl radicals. In the presence of the strong and oxidatively stable phosphazene base tert-butylimino-tris(dimethylamino)phosphorane, the quite acidic ferrocenium ions 1 + −5 + are deprotonated to give a pool of transient and persistent radicals with different deprotonation sites• , deprotonated at the nitrogen atom, has been detected by rapid-freeze EPR spectroscopy at 77 K. This iron-centered radical• appear to rapidly abstract hydrogen atoms from the adjacent base or the solvent to regenerate the corresponding ferrocenes 1−5. These transient radicals are only present in trace amounts (<1%). However, some of the transient carbon-centered radicals in the radical pool can be trapped by 1−1.2 equiv of PhNO, even at room temperature. The corresponding resulting stable nitroxyl radicals [6] • −[10] • were studied by EPR spectroscopy at room temperature and at 77 K. The hyperfine coupling pattern to protons close to the spin center allows one to assign the site of PhNO attack in radicals [6] • −[10] • , namely, at the C 5 H 5 ring in [6] • , [9 Cp ] • , and [10 Cp ] • , at a methyl group in [7] • , and at the methylene group in [8 1 ] • . These studies give a deeper insight into the stability and reactivity of radicals derived from ferrocene derivatives which might also be relevant for the biological activity of high-potent antitumor and antimalaria ferrocene-based drugs and prodrugs such as ferrocifen or ferroquine.

The conformations and redox chemistry of ferrocenyl amides have been investigated in considerable depth in the last few years, while ferrocenyl thioamides have attracted less interest so far, although distinctly different conformations and reactivity patterns are expected. Monoferrocenyl amides Fc-NHC(O)CH3 (1) and 1,1′-CH3O(O)C-Fn-NHC(O)CH3 (2) and diferrocenyl amides Fc-NHC(O)-Fc (5) and Fc-NHC(O)-Fn-NHC(O)CH3 (6) are easily transformed into the corresponding thioamides (3, 4, 7, 8) by treatment with Lawesson’s reagent (2,4-bis(p-methoxyphenyl)-1,3-dithiaphosphetane-2,4-disulfide) (Fc = Fe(C5H4)(C5H5), Fn = Fe(C5H4)2). The thioamide conformations (cis/trans) in 3, 4, 7, and 8 and the hydrogen bond determined secondary structure of dithioamide 8 have been elucidated by IR and NMR spectroscopy as well as by DFT calculations (B3LYP, LANL2DZ, PCM CH2Cl2) and contrasted with the corresponding amides 1, 2, 5, and 6. The electronic communication via the thioamide bridge in 7 + and 8 + in comparison to the interaction in the parent mixed-valence amides 5 + and 6 + has been probed by cyclic voltammetry, square wave voltammetry, UV/vis spectroelectrochemistry, EPR spectroscopy, and paramagnetic NMR spectroscopy. Additional chemical reactivity of the thioamide unit has been detected by electrochemical analysis.

The mode of anticancer activity of simple ferrocenes often relies on their intracellular oxidation with the formation of cytotoxic ferrocenium species. The former compounds should be considered as prodrugs and derived from them ferroceniums as drugs. The drugs are 17e − organometallic species. Therefore, they are chemically unstable and decompose with formation of free cyclopentadienyl ligands (which are further transformed to more stable species) and iron ions. The short lifetime of ferrocenium drugs limits the anticancer effect of ferrocene prodrugs. In this paper we prepared a series of acylated aminoferrocene monomers, dimers, and higher oligonuclear complexes Fc N (where N = 1−4). Drugs [Fc N ] + derived from Fc N (N > 1) are more stable than monomeric [Fc] + , provided that the ferrocene units are electronically coupled. Correspondingly, we expected that Fc N species will be more potent anticancer agents in comparison to the related monomers. These assumptions were confirmed for dimer 10. We observed that this prodrug has sufficient solubility in aqueous solution (100 μM) and favorable lipophilicity (log P = 2.2 ± 0.2). Ferrocene units in 10 are efficiently electronically coupled via a −C(O)NH− linker according to cyclic voltammetry, differential pulse voltammetry, and spectroelectrochemistry. We observed that 10 is the most efficient catalyst of the production of reactive oxygen species (ROS) and the most active anticancer agent in comparison to control monomers and their mixtures.

In the presence of oxidant (Ag­[SbF6]) and base, N-ferrocenyl thioamide Fc-NHC­(S)­CH3 (H-1; Fc = Fe­(η5-C5H5)­(η5-C5H4)) converts in an unexpected multistep reaction sequence to a novel N,S-heterocyclic ring, which initiates an oligomerization reaction. Key intermediates toward the resulting complicated material are Ag 6 (1) 6 silver clusters of the anionic N,S-chelating ligand 1 − and EPR-active piano stool complexes resulting from ring-slipped cyclopentadienyl ligands, as well as electrophilic N-ferrocenyl ketenimine Fc-NCCH2 (2) and its ferrocenium cation 2 •+ formed by hydrosulfide elimination. Mechanistic insight is achieved using X-ray diffraction and mass spectrometry, as well as EPR and NMR spectroscopic studies, combined with DFT calculations. In addition to the fundamental mechanistic insight, the results could have implications for smart oligomers/polymers, heterocycle synthesis, and controlled-release materials.