Aerobic oxidation catalyzed by N-hydroxy compounds: new frontiers in industrial and biological applications

In recent years, intensive research efforts have pursued the development of new reliable oxidative transformations capable of combining high chemical efficiency with minimization of both waste production and energy consumption. In this context, N-hydroxy compounds, the most representative of which is NHPI, are effective organocatalysts for the oxidation of organic substrates by using dioxygen as the final oxidant. The oxidations catalyzed by NHPI and N-hydroxy compounds more in general, is affected by some limitations. The solubility of this kind of organocatalysts is often too low in apolar mediums, leading them to be unusable at mild conditions and often high temperature (>100 °C) is required in order to operate under homogeneous catalysis. In this context, I focused on the sythesis of new N-hydroxy compounds in order to improve the properties of this kind of organo-catalysts for industrial and biological applications. The corrsponding N-oxyl radicals, derived from the abstraction of the hydrogen by N-hydroxy group (initiation, Figure 1), are the active species in the catalytic cycle. N-oxyl radical is able to abstract hydrogen from hydrocarbons in order to form carbon centered radical, re-generating its protonated form (step i, Figure 1). The carbon centered radicals, under aerobic condition, reacts with oxygen and forms peroxyl radicals (step ii, Figure 1). The latter are converted to the corresponding hydroperoxides by the N-hydroxy derivatives (step iii, Figure 1), which behave also as good hydrogen donors, leading to the formation of new N-oxyl radicals. Figure 1. The catalytic cycle of NHPI in the aerobic oxidation of organic substrates. In this contest, the OH bond dissociation energy (BDE) of the N-hydroxy group plays a crucial role in order guarantee the high selectivity of the process. At mean time, the solubility, the thermal and chemical stability of the catalyst is crucial for the efficiency of the protocol. For this reasons preliminary computational screening was performed in order to provide information about OH BDE, transition state (TS) in the hydrogen abstraction and the correlated activation energy (Ea). These theoretical studies allowed to synthesize two different new families of organocatalysts bearing N-hydroxy group and their catalytic efficiency was tested in industrial and biological applications. Figure 2. Time line of the new N-hydroxy catalysts Alkyl aromatics are oxidized easly to intermediate oxidation product (hydroperoxide) under mild condition (45°C and 1 oxigen or air atmosphere). NHPI requires often a co-solvent (i.e. acetonitrile (ACN)) to maintain the polar catalyst in apolar solutions. Catalyst 4 and 5 do not require any co-solvent at room temeprature, due to their high lipophilic character. Moreover, the structural modifications on the catalysts do not modify the catalytic activity, on the contrary of alternative solutions previously reported in literature as catalyst 2. The high solubility in lipophilic mediums of 4 and 5 allowed to conduct catalytic oxidations under solvent-free conditions for the firtst time. Alkyl aromatic were converted to the corresponding hydroperoxides in higher yields in comparison with the classical oxidation using co-solvent, with a considerable increase of the productivity of the process. Moreover, by operating in the absence of polar solvents, it was possible to observe for the first time the aggregation of the catalyst in apolar mediums, due to the intermolecular hydrogen bonding (HB) between N-hydroxy and carbonyl moieties present in the structure of the catalyst (see Figure 2). Figure 3. Theoretical structure and relative electrostatic potential surface (ESP) for the most stable dimer of NHPI (1), calculated in gas phase at 298 K at B3LYP/6-311+G(d,p) level of theory. This aggregation causes the decrease of the catalytic activity, due to the involvement of the N-OH group in the intramolecular HB rather than in the hydrogen atom transfer (HAT) process. Several studies were done in order to understand the role of the co-solvent and how exploit the new revealed properties. In this direction, catalyst 6 was synthesized. Catalyst 6 in solution is in equilibrium between conformers, due to the possible intramolecular HBs between N-hydroxy group and carbonyl or urea groups. These conformers have different catalytic properties, due to the different structure, leading catalyst 6 to be the first dynamic N-hydroxy organocatalyst modulated by the temperature. The high catalytic efficiency of N-hydroxy derivatives in promoting oxidative processes and the really milder operative conditions, suggested a possible alternative use as pro-oxidants for biological applications, namely the promotion of oxidative stress in cancer cells. Methyl linoleate with its bis-allylic position was choisen like model molecule for its analogy with the phospholipids of the cellular membrane. Good results were obtained in terms of yield and selectivity of the peroxidation process. The preliminary good results on suggested to move to the oxidation of liposomes, in order to mimic the cellular membrane. The oxidation of liposomes were performed in phosphate buffer solution (PBS) at pH 7.4, biological temperature (37 °C), using air as oxidant and without the use of any radical initiator in order to simulate the real biological condition. These experiments were followed using special probes, purposely synthesized, active to UV light or fluorescence. Using these protocols, formation of hydroperoxydes was confirmed and N-hydroxy catalyst could be proposed as pro-oxidant for the oxidative therapy against tumor cells. The high numbers of advantages and the improvments using these new organo-catalysts were demostrated and confirmed in industrial and biological applications in term of solubility, efficiency and innovation.