SYNTHESIS, CHARACTERIZATION AND CATALYTIC ACTIVITY OF IRON, RUTHENIUM AND COBALT PORPHYRIN COMPLEXES

The insertion of a nitrene \u201cRN\u201d functionality into a C-H bond represents a valuable tool achieving a wide variety of nitrogen-containing fine chemicals, which frequently present pharmaceutical and/or biological properties. The key point to perform sustainable amination reactions are: i) The selection of a selective, active and stable catalytic system ii) The use of nitrene sources presenting high reactivity and atom efficiency. The last characteristic is well exhibited by organic azides (RN3)1 which transfer a nitrene functionality to an organic skeleton by yielding eco-friendly N2 as the only stoichiometric by-product. The reaction of RN3 with organic compounds can be thermally or photochemically promoted2 but, to improve the reaction selectivity, the presence of a metal catalyst is required. Amongst the catalysts used to achieve these chemical transformations,3, 4 metal porphyrins show a good catalytic efficiency coupled with a very high chemical stability.5 In the last decade, in our research group, we have studied the efficiency of cobalt6, 7 and ruthenium8 porphyrin complexes in catalysing the amination of a wide class of substrates by using ayl azides as nitrene sources. In this research project we have in-depth investigated the behavior of these catalysts in allylic9, inter10- and intra11 benzilic aminations. First, we have explored the catalytic activity of Ru(TPP)CO (TPP = dianion of tetraphenylporphyrin) in intermolecular benzylic amination reactions10, several benzylic substrates were reacted with different aryl azides employing the hydrocarbon as the reaction solvent and the catalytic ratio Ru(TPP)CO/azide = 4:50. It was observed that Ru(TPP)CO was also active in the amination of benzylic substrates containing an endocyclic benzylic C-H bond. The corresponding amines have been isolated in good yields. To investigate the mechanism of the benzylic amination catalyzed by Ru(TPP)CO, a kinetic study was undertaken. The analysis of kinetics and reaction selectivities indicated the formation of an active ruthenium (VI) imido complex as a catalytic intermediate. More in-depth studies will be necessary to better clarify the reaction mechanism of the amination of benzylic C-H bonds. Since Ru(TPP)CO has demonstrated to be a good catalyst in benzylic amination reactions we have subsequently studied the activity of this catalyst in allylic amination reactions9. Believing that an important step for the improvement of the catalytic efficiency of the reported methodology is the comprehension of the reaction mechanism, we first studied the catalyst reactivity towards the components of a model reaction, cyclohexene and azide. No catalyst modification was observed by 1H NMR when Ru(TPP)CO was suspended in cyclohexene and refluxed for a couple of hours, on the other hand, the reaction between Ru(TPP)CO and an 3,5(CF3)2C6H3N3 excess yielded the bis imido complex Ru(TPP)(NAr)2 which showed a catalytic activity similar or even better than that described for Ru(TPP)CO, his precursor. To assess if the formation of a bis-imido complex is a general reaction, we have also studied the reactivity of Ru(TPP)CO towards other aryl azides discovering that the nature of the active intermediate strongly depends on the electronic nature of the employed azide. We discovered the formation of another bis-imido complex in the reaction of Ru(TPP)CO with 4 CF3C6H4N3 but several experimental evidences indicate also the existence of a mono-imido ruthenium (IV) intermediate. This mono-imido complex can react with another molecule of aryl azide generating the bis-imido complex, or can form the complex Ru(TPP)(ArNH2)CO by hydrogen atom abstraction reactions. To shed some light into the Ru(TPP)CO catalysed allylic amination of cyclohexene, a kinetic study was undertaken employing two different arylazides as nitrogen source: 4 CF3C6H4N3 and 3,5-(CF3)2C6H4N3. In the first case the observed kinetics indicates the rate determine step of the reaction being the formation of the mono-imido complex that very quickly reacts with the olefin forming the allylic amine and regenerating Ru(TPP)CO. We suggest that Ru(TPP)CO is in equilibrium with the mono-amino complex for the presence of the aniline as reaction side-product. In the second case the kinetic was more complex than the previous discussed, in fact, the first order dependence was observed only for low concentrations of olefin. This behaviour indicates the coexistence of at least two mechanisms that contemporaneously occur with the prevalence of one or the other depending on the olefin concentration. The existence of two mechanisms was also supported by a DFT investigation.13 The theoretical study confirms that the first step of the cycle is the formation of a mono-imido complex RuIV(TPP)(NAr)(CO) which can undergo a singlet\uf0aetriplet interconversion to confer a diradical character to the \u201cArN\u201d ligand. Hence, the activation of the allylic C-H bond of cyclohexene (C6H10) occurs through a C H\u2022\u2022\u2022N adduct detected as a Transition State. The formation of the desired allylic amine follows a \u201crebound\u201d mechanism in which the nitrogen and carbon atoms radicals couple to yield the organic product. The release of the allylic amine restores the initial Ru(TPP)(CO) complex and allows the catalytic cycle to resume by the activation of another azide molecule. On the singlet PES, the CO ligand may be however dismissed from the mono-imido complex RuIV(TPP)(NAr)(CO)SN opening the way to an alternative catalytic cycle which also leads to allylic amine through comparable key steps. A second azide molecule occupies the freed coordination site of Ru(TPP)(NAr)SN to form the bis-imido complex Ru(TPP)(NAr)2, which is also prone to the intersystem crossing with the consequent C-H radical activation. The process continues till the azide reactant is present. The interconnected cycles have similarly high exergonic balances. The reaction scope of the benzylic amination has been then explored studying the intramolecular amination reaction of biphenyl azides containing benzylic C-H bonds.11 This reaction allows the synthesis of N heterocyclic compounds such as dihydrophenanthridines and phenanthridines. Phenanthridines are an important class of compounds from a biological point of view. They present a significant antitumor activity and are the basis of DNA-binding. Several challenges remain to be overcome to efficiently synthesise this class of molecules, in fact, whilst many methods to access five-membered rings are known, methodologies to yield six and seven-nitrogen membered rings in few steps remain rare. In this research project we have also studied the development of new synthetic methodologies to obtain new porphyrin frameworks and this part of my work has been developed in collaboration with Dr. Bernard Boitrel (University of Rennes, France). Some years ago we reported on the catalytic efficiency of chiral cobalt(II)-binaphthyl porphyrins in asymmetric cyclopropanations, and recorded positive data encouraging us to synthesise a structurally related chiral porphyrin. This new porphyrin has one C2 axis within the porphyrin plane and exhibits an open space on each side for substrate access and at the same time a steric chiral bulk surrounding the N-core. The reaction of the opprhyrin with FeBr2 afforded the FeIII(OMe) complex by the initial formation of the iron (II) porphyrin complex which was oxidised by the atmospheric oxygen in the presence of CH3OH yielding the desired complex in a quantitative yield. The catalytic activity of the iron complex was initially tested in the model reaction of \u3b1 methylstyrene with ethyl diazoacetate (EDA). This new chiral iron porphyrin-based catalyst performed olefin stereoselective cyclopropanations with excellent yields (up to 99%), enantio- and diasteroselectivities (eetrans up to 87%, trans/cis ratios up to 99:1) and outstanding TON and TOF values (up to 20,000 and 120,000/h respectively). To the best of our knowledge, the outstanding values of TON and TOF (20,000 and 120,000/h respectively) have never been reported for metallo-porphyrin catalysed cyclopropanations and the robustness of the catalyst under an inert atmosphere allowed three catalytic recycles. Finally, high cyclopropane yields were obtained without using an olefin excess in accordance with the industrial request for sustainable processes, especially when expensive olefins are involved. Studies are ongoing to expand the reaction scope, including testing the cyclopropanation of several olefins by differently substituted diazo derivatives. References 1. S. Cenini, E. Gallo, A. Caselli, F. Ragaini, S. Fantauzzi and C. Piangiolino, Coord. Chem. Rev., 2006, 250, 1234-1253. 2. B. C. G. Soderberg, Curr. Org. Chem., 2000, 4, 727-764. 3. T. G. Driver, Org. Biomol. Chem., 2010, 8, 3831-3846. 4. S. Cenini, F. Ragaini, E. Gallo and A. Caselli, Curr. Org. Chem., 2011, 15, 1578-1592. 5. S. Fantauzzi, A. Caselli and E. Gallo, Dalton Trans., 2009, 5434-5443. 6. A. Caselli, E. Gallo, S. Fantauzzi, S. Morlacchi, F. Ragaini and S. Cenini, Eur. J. Inorg. Chem., 2008, 3009-3019. 7. P. Zardi, D. Intrieri, A. Caselli and E. Gallo, J. Organomet. Chem., 2012, 716, 269-274. 8. S. Fantauzzi, E. Gallo, A. Caselli, C. Piangiolino, F. Ragaini and S. Cenini, Eur. J. Org. Chem., 2007, 6053-6059. 9. D. Intrieri, A. Caselli, F. Ragaini, P. Macchi, N. Casati and E. Gallo, Eur. J. Inorg. Chem., 2012, 569-580. 10. D. Intrieri, A. Caselli, F. Ragaini, S. Cenini and E. Gallo, J. Porphyrins Phthalocyanines, 2010, 14, 732-740. 11. D. Intrieri, M. Mariani, A. Caselli, F. Ragaini and E. Gallo, Chem. Eur. J., 2012, 18, 10487-10490. 12. F. Ragaini, A. Penoni, E. Gallo, S. Tollari, C. L. Gotti, M. Lapadula, E. Mangioni and S. Cenini, Chem. Eur. J., 2003, 9, 249-259. 13. G. Manca, E. Gallo, D. Intrieri, C. Mealli; ACS, manuscript submitted 14. D. Intrieri, S. Le Gac, A. Caselli, E. Rose, B. Boitrel, E. Gallo; Chem.Commun.,manuscript submitted