Ricerc@Sapienza

Precise and predictable control of C-H activation sites is essential to disclose novel and straightforward synthetic pathways. However, the great similarity in strength and properties of C-H bonds in any organic molecules makes such control very challenging to achieve. In natural enzymes, the problem of targeting a specific C-H bond for oxidation is solved by precisely positioning the substrates inside the active sites by means of multiple weak interactions with aminoacidic residues and/or cofactors within the cavity. The elaborated architecture required for optimal substrate-catalyst binding (often with multiple attachment points) makes this approach challenging to replicate in synthetic systems. The development of biomimetic supramolecular catalysts, which represent good models of artificial enzymes, provides a highly innovative approach to the accomplishment of regio- and stereoselective oxidative transformations. In this context, a special attention has been recently dedicated to reactions involving HAT from C-H bonds which are useful from a synthetic and industrial point of view. In previous works, several C-H oxidation catalysts were designed with recognition motifs able to engage in reversible pre-association with a substrate by means of weak interactions that orient the substrate, enabling site selective C-H oxidation, overcoming the requirement of stoichiometric directing groups. However, in most cases the structurally highly elaborated nature of these catalysts have limited the generality and scope of recognition to few, well-crafted substrates responding to precise geometric and shape constraints. In addition, these catalysts oxidize activated and relatively weak C-H bonds in substrates that contain at most two sites susceptible to oxidation. Along this line, in order to accomplish the site selective oxidation of methylenic chains in our previous work we synthetized a ditopic catalysts (1) made up of a core catalytic center (manganese or iron PDP complexes) known to promote effective hydroxylation of aliphatic C-H bonds via a highly reactive yet selective oxidizing species formed upon reaction with H2O2 and carboxylic acids, decorated with two benzo-18-crown-6 ethers, known to have high affinity for ammonium ions and metal cations, as receptors. The molecular recognition of substrates containing primary ammonium groups with the binding sites directly linked to the nonheme metal complex allowed the control of the specific position to be functionalized in the oxidative processes. These catalytic systems, however, form unstable FeV=O or MnV=O oxidants and do not allow a quantitative analysis of the reactivity enhancement due the intramolecularity of the HAT reaction. Therefore, a complete understanding of recognition-driven C-H oxidation catalyzed by nonheme Fe and Mn complexes is still lacking.
The synthesis of the (N4Py)FeIV=O complex, stable enough to be easily generated and handled, decorated with a supramolecular receptor (benzo-18-crown-6 ether), able to bind protonated primary amines, will allow to measure and compare the rates of HAT from C-H bonds to the FeIV=O unit in the presence and absence of substrate binding. The knowledge of the effective molarities (EM) as determined by the ratio of k1 (intramolecular HAT rate constants) and k2 (rate constants for the intermolecular HAT promoted by (N4Py)FeIV=O lacking of the supramolecular receptor unit) will provide for the first time useful information on the effect of intramolecularity on the reactivity in HAT promoted by metal-oxo complexes. In addition a possible explanation of the reactivity difference between the catalytic efficiency of natural enzymatic FeIV=O and biomimetic systems containing the same iron-oxo moiety will be provided by these studies.
Supramolecular catalysts 3 and 4 containing the 18-crown-6 ether recognition unit linked to N-hydroxy derivatives may represents a significant innovation with great advantages with respect to the previously synthetized catalytic systems where the same recognition units have been linked to nonheme iron or manganese complexes. The presence of an aminoxyl radical in the catalytic core and the lack of a metal ion in these supramolecular catalysts, will expand the substrate scope allowing the oxidation of substrates containing functional groups (e.g. carboxylates) which can inhibit catalysts such as 1 by effect of the coordination to the iron or manganese metal center. A lower level of deactivation and a higher catalytic turnover number should be also expected in view of the lack of possible product binding.