Deciphering the origin of million-fold reactivity observed for the open core diiron [HO-FeIII-O-FeIV[double bond, length as m-dash]O]2+ species towards C-H bond activation: role of spin-states, spin-coupling, and spin-cooperation.

High-valent metal-oxo species have been characterised as key intermediates in both heme and non-heme enzymes that are found to perform efficient aliphatic hydroxylation, epoxidation, halogenation, and dehydrogenation reactions. Several biomimetic model complexes have been synthesised over the years to mimic both the structure and function of metalloenzymes. The diamond-core [Fe2(µ-O)2] is one of the celebrated models in this context as this has been proposed as the catalytically active species in soluble methane monooxygenase enzymes (sMMO), which perform the challenging chemical conversion of methane to methanol at ease. In this context, a report of open core [HO(L)FeIII-O-FeIV(O)(L)]2+ (1) gains attention as this activates C-H bonds a million-fold faster compared to the diamond-core structure and has the dual catalytic ability to perform hydroxylation as well as desaturation with organic substrates. In this study, we have employed density functional methods to probe the origin of the very high reactivity observed for this complex and also to shed light on how this complex performs efficient hydroxylation and desaturation of alkanes. By modelling fifteen possible spin-states for 1 that could potentially participate in the reaction mechanism, our calculations reveal a doublet ground state for 1 arising from antiferromagnetic coupling between the quartet FeIV centre and the sextet FeIII centre, which regulates the reactivity of this species. The unusual stabilisation of the high-spin ground state for FeIV[double bond, length as m-dash]O is due to the strong overlap of with the orbital, reducing the antibonding interactions via spin-cooperation. The electronic structure features computed for 1 are consistent with experiments offering confidence in the methodology chosen. Further, we have probed various mechanistic pathways for the C-H bond activation as well as -OH rebound/desaturation of alkanes. An extremely small barrier height computed for the first hydrogen atom abstraction by the terminal FeIV[double bond, length as m-dash]O unit was found to be responsible for the million-fold activation observed in the experiments. The barrier height computed for -OH rebound by the FeIII-OH unit is also smaller suggesting a facile hydroxylation of organic substrates by 1. A strong spin-cooperation between the two iron centres also reduces the barrier for second hydrogen atom abstraction, thus making the desaturation pathway competitive. Both the spin-state as well as spin-coupling between the two metal centres play a crucial role in dictating the reactivity for species 1. By exploring various mechanistic pathways, our study unveils the fact that the bridged µ-oxo group is a poor electrophile for both C-H activation as well for -OH rebound. As more and more evidence is gathered in recent years for the open core geometry of sMMO enzymes, the idea of enhancing the reactivity via an open-core motif has far-reaching consequences.

Are cucurbiturils better drug carriers for bent metallocenes? Insights from theory.

Bent metallocenes (BM) have anti-tumor properties but they face a serious drug efficacy problem due to poor aqueous solubility and rapid hydrolysis under physiological conditions. These two problems can be fixed by encapsulating them in host molecules such as cyclodextrin (CD), cucurbituril (CB) etc. Experimentally, CD-BM, CB-BM host-guest complexes have been investigated to check the efficiency of the drug delivery and efficiency of the encapsulated drug. CB has been reported to be a better host than CD but the reasons for this has not been figured out. This can be done by finding out the mechanism of binding and the nature of the binding forces in both the inclusion complexes. This is exactly done here by performing a DFT study at BP86/TZP level on CB-BM host-guest systems. For comparison CD-BM with ß-cyclodextrin as host have been studied. Four BMs (Cp2MCl2, M=Ti, V, Nb, Mo) and their corresponding cations (Cp2MCl+, Cp2M2+) are chosen as guests and they are encapsulated into cucurbit-[6]-uril (CB[6]) and cucurbit-[7]-uril(CB[7]) host systems. Computations reveal that CB[7] accommodates well the BMs over CB[6] due to their larger cavity size and also CB[7] is found to be a better host than ß-cyclodextrin. BMs enter vertically rather than horizontally into the CB cavity. The reversible binding of BMs within CB[7] is controlled by various non-bonding interactions and mainly by hydrogen bonding between the portal oxygen atoms and Cp protons as revealed by QTAIM analysis. On the other hand, the interaction between the wall nitrogen atoms in CB[7] and chlorine atoms attached to the metal in BM strengthens the M-Cl bonds that prevents rapid hydrolysis of M-Cl and M-Cp bonds saving the drug. Comparatively, BMs experience less electrostatic attraction and more Pauli repulsion within ß-cyclodextrin cavity and this affects the drug binding with CD. This makes ß-cyclodextrin a less suitable drug carrier for BMs than CBs. Among the four BMs, niobocene binds strongly and titanocene binds weakly with CBs. EDA clearly shows that all the interactions between the guest and host are non-covalent in nature and electrostatic interactions outperform high-repulsion resulting in stable complexes. Cations form stronger complexes than neutral BMs. FMO analysis reveals that neutral BMs are less reactive compared to their cations and complexes are more reactive in CB[6] environment due to excess strain. QTAIM analysis helps to bring out the newer insights in these types of host-guest systems.

Redox Self-Adaptation of a Nitrene Transfer Catalyst to the Substrate Needs.

The development of iron catalysts for carbon-heteroatom bond formation, which has attracted strong interest in the context of green chemistry and nitrene transfer, has emerged as the most promising way to versatile amine synthetic processes. A diiron system was previously developed that proved efficient in catalytic sulfimidations and aziridinations thanks to an FeIII FeIV active species. To deal with more demanding benzylic and aliphatic substrates, the catalyst was found to activate itself to a FeIII FeIV L. active species able to catalyze aliphatic amination. Extensive DFT calculations show that this activation event drastically enhances the electron affinity of the active species to match the substrates requirements. Overall this process consists in a redox self-adaptation of the catalyst to the substrate needs.

Sequence selectivity of azinomycin B in DNA alkylation and cross-linking: a QM/MM study.

Azinomycin B--a well-known antitumor drug--forms cross-links with DNA through alkylation of purine bases and blocks tumor cell growth. This reaction has been modeled using the ONIOM (B3LYP/6-31+g(d):UFF) method to understand the mechanism and sequence selectivity. ONIOM results have been checked for reliability by comparing them with full quantum mechanics calculations for selected paths. Calculations reveal that, among the purine bases, guanine is more reactive and is alkylated by aziridine ring through the C10 position, followed by alkylation of the epoxide ring through the C21 position of Azinomycin B. While the mono alkylation is controlled kinetically, bis-alkylation is controlled thermodynamically. Solvent effects were included using polarized-continuum-model calculations and no significant change from gas phase results was observed.

Antitumor activity of bent metallocenes: electronic structure analysis using DFT computations.

The antitumor activities of bent metallocenes [Cp-M-Cp](2+) (M = Ti, V, Nb, Mo) and complexes of them with guanine, adenine, thymine and cytosine nucleotides have been probed using electronic structure calculations. DFT/BP86 calculations have revealed that the bent metallocene-nucleotide interaction strongly depends on the stability of the hydrolyzed form of the bent metallocene dichloride [Cp(2)M](2+) species, and in turn the stability of the [Cp(2)M](2+) species strongly depends on the electronic structure of [Cp(2)M](2+). Detailed electronic structure and Walsh energy analyses have been carried out for the hydrolyzed forms of four [Cp-M-Cp](2+) (M = Ti, V, Nb, Mo) species to find out why the bent structure is unusually stable. Energy changes that occur during the bending process in frontier molecular orbitals as well as the p(π)-d(π) overlap have been invoked to account for the anticipated antitumor activities of these species. The bonding situation and the interactions in bent metallocene-nucleotide adducts were elucidated by fragment analysis. Of the four nucleotides complexed with the four bent metallocenes, adenine and guanine show better binding abilities than the other two nucleotides. Metallocenes of second-row transition metals exhibit better binding with pyrimidine-base nucleotides. In particular, the Lewis acidic bent metallocenes interact strongly with nucleotides. The antitumor activity is directly related to the binding strength of the bent metallocene with nucleotide adducts, and the computed interaction energy values correlate very well with the experimentally observed antitumor activities.