Ferrocene carboxyl derivatives

A relatively novel class of derivatives is obtained by the covalent incorporation of organometallic moieties into cellulose. For example, cellulose ferro-cenyl derivatives have been prepared by esterification of cellulose with an intermediate derived from ferrocene carboxylic acid and triphenyl phosphite in the presence of pyridine [84]. An enzymatically cleavable cellulose ester has been developed [85], and prodrugs have been coupled to the hydroxyl or carboxyl functions of C-terminal aromatic amino acids of cellulose peptide derivatives for controlled release applications [86]. 

Now let me come back to primary substitutions at the ferrocene nucleus. Together with Vil chevskaya, we phosphorylated ferrocene and its derivatives to triferrocenylphosphine oxides [263, 264). An unusual reaction, discovered in collaboration with Perevalova and Yur eva, was the direct cyanation of ferrocene with hydrocyanic acid in the presence of ferric chloride [265,272). Initially, cyanide attacks the iron atom of the ferricinium cation, then the cyanide group transfers to the ring while the iron is simultaneously reduced. The reaction was termed by us as the ricochet (from the metal to the nucleus) substitution it may be applied to many substituted ferrocenes and to the ruthenocenium cation [273), and it is now the simplest route to ferrocene carboxylic acids through their nitriles. Further, ferrocene was studied in acid-medium reactions with oxo compounds. With aldehydes [274), the reaction was complicated by the transformation of ferro-cenylalkyl carbinol formed Initially via the carbonium ion, followed by transformation to a radical which, in its turn, was coupled to 1,2-bis-(ferrocenylalkyl)ethane (27.5). The reaction with acetone led to 2,2-di-ferrocenylpropane (276). 

In 1957, Schlogl reported the synthesis and characterization of several ferrocene amino acids, including ferrocenylala-nine (Fer, 14 Scheme 18). Other organometallic amino acids include alanine, phenylalanine (Phe), glycine derivatives, as well as further ferrocene-based amino acids, which are discussed below. The Schlogl paper also describes the reaction of ferrocene carboxylic acid and ferrocene carbaldehyde with amino acids. The chemistry was later picked up in numerous publications, and ferrocene carboxylic acid amides or ferrocene imines with basically all amino acids and many dipeptides were reported. Such conju tes may serve as ligands for other transition metal ions. " Kraatz has prepared ferrocene carboxylic acid conju tes with short peptides that serve as enzyme inhibitors. ... 

It is interesting to note that early work on ferrocene derivatives of nucleosides uses Sonogashira coupling of ethynylferrocene to 5-iodouridine or 8-bromoadenosine. This reaction was later used to synthesize ferrocenylated ODNs by solid-phase synthesis techniques. Depending on the conditions, a cyclization reaction occurs with uracil derivatives. Instead of ethynylferrocene, Grinstaff et al. used ferrocene carboxylic acid propargyl amide. 

The ferrocene derivative of PNA monomer 50 is prepared by the reaction of ferrocene carboxylic acid chloride with thymine-PNA methyl es-... 

Ferrocene is a well-known guest for CD hosts. Harada and Takashi reported that P-CD and y-CD form 1 1 stoichiometric inclusion complexes with ferrocene, while a-CD forms a 2 1 complex[4]. Electrochemical studies on the interactions of ferrocene carboxylic acid (FCAH) ith p-CD, performed by Evans and coworkers[5], showed that this CD forms inclusion complexes with the FCA anion although no evidence was found for the complexation of its oxidized form. Other reports on the complexation of ferrocene derivatives by p-CD are available, including detailed molecular mechanics investigations on the docking of... 

The half-wave potentials for the oxidation of I" " and 2+ are shifted to more anodic values by about 80 mV upon addition of 12 equivalents of p-CD. However, similar additions of either a-CD or y-CD cause much lower potential shifts (< 20 mV). The observed potential difference between the voltammetric anodic and cathodic peak potentials (AEp) for these two ferrocene derivatives in the presence of excess p-CD is about 70 mV at moderate scan rates (20-100 mV/s). Indeed, the expected value for a fully reversible one-electron couple is 57 mV. Evans and coworkers also recorded AEp > 57 mV in their voltammetric studies of ferrocene carboxylic acid oxidation in the presence of p-CD. These authors conclusively showed that the observed peak-to-peak splittings are due to the inability of the complex to undergo oxidation directly, i.e., the dissociation of the complex must precede the electron transfer step[5]. Our data parallel exactly these authors experimental findings and we conclude that a similar mechanism prevails for the oxidation of 1" or 2 when bound to P-CD. 

Two of the phenolic groups in rerr-butyl-calix[4]arene were condensed with a ferrocene carboxylic diamide bridge, to give a receptor, 91, which electrochemically recognizes the H2P04 anion in the presence of excess HS04 and Cl [180]. Many similar derivatives have also been reported [181, 182]. 

Evans and coworkers have published an interesting study of the electrochemical behavior of a ferrocene-carboxylic acid derivative in the presence of BCD [18] and a summary of general guidelines on the electrochemical methodology that can be used to assess the complexation of redox-active molecules by cyclodextrin hosts [19]. However, the amphiphilic character of the surfactant viologens used in this work prevented us from applying most of these methods because the voltammetric... 

Zotti and coworkers adsorbed several carboxylated ferrocene derivatives on ITO ferrocene-carboxylic acid (Fc(COOH)), ferrocene-dicarboxyhc add (Fc(COOH)2), and ferrocenylheptanoic acid Fc(CH2)6COOH [64]. Fc(COOH) was adsorbed from 1-mM solutions of the molecule in 5/95 ethanol/hexane for as... 

An engineered glucose oxidase made by the incorporation of ferrocene derivatives into the enzyme has a similar effect [134]. A covalent coupling of ferrocene carboxylic acids to the enzyme (12 ferrocene moieties attached [135]) enables direct tunneling of electrons through the protein from ferrocene to ferrocene and hence to a clean metal electrode surface. 

A polyamino carbonyl ferrocene dmivative formed by coupling ferrocene carboxylic acid with a BOC protected polyamine is claimed to be a mammalian excitatory neurotransmitter antagonist. Ferrocenyltetrazolylhydrozones have been prqrared from the condensation reaction of ferrocenecarboxaldehyde with a series of tetrazolylhydrazines. The reaction of ferrocoie carboxaldehyde with CH2(COR)(COR ), R = Me, R = Me, OEt in ether containing a Lewis base results in the formation of FcCH=C(COR)COR (mixture of E and Z isomers the work is extendable to diferrocenyl derivatives. Further work on the reduction of fluorine substituted methyl acetylferrocenes has been reported. "... 

The first amino acid and dipeptide ferrocenoyl derivatives of this kind, Fc-CO-Aaa-OEt (Fc = (C5H5)FeC5H4, Aaa = Gly, Leu, Phe, Met), Fc-CO-Gly-OH and Fc-CO-Gly-Leu-OEt, were reported by Schlogl as early as 1957 [1], Since then, well over two dozen similar ferrocenoyl amides have been prepared from ferrocene carboxylic acid 3 and amino acids, di-, tri- and tetrapeptides. These compoimds, as exemplified for the glycine derivative Fc-GO-Gly-OH (4, Scheme 5.1), have been studied extensively with respect to their electrochemical properties and their structure in the solid state as well as in solution. A comprehensive discussion is foimd in a recent review from my group [9]. Kraatz has also recently summarized his work in the field [10],... 

Our group published the first organometallic derivatives of PNA monomers [138]. Ferrocene carboxylic acid 3 and benzoic acid chromium tricarbonyl 50 were coupled to the amino group of PNA monomers with different nucleobases (Thymine (T) a and Z-protected Cytosine (Z-C) b) using HBTU as the coupling agent to give compounds 51 and 52, respectively (Scheme 5.27). The activation barrier AG for the rotation about the tertiary amide bond has been determined for the ferrocenylated T-PNA monomer 51a to be 75 0.5 kj moD. For the same compound 51a, a T-T self-association constant = 2.5 0.2 has been... 

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