The cytochromes P450 are a versatile range of mono-oxygenase enzymes that catalyze a variety of different chemical reactions, of which the key reactions include aliphatic hydroxylation and C=C double bond epoxidation. To establish the fundamental factors that govern substrate epoxidation by these enzymes we have done a systematic density functional theory study on substrate epoxidation by the active species of P450 enzymes, namely the iron(IV)-oxo porphyrin cation radical oxidant or Compound I. We show here, for the first time, that the rate constant of substrate epoxidation, and hence the activation energy, correlates with the ionization potential of the substrate as well as with intrinsic electronic properties of the active oxidant such as the polarizability volume. To explain these findings we present an electron-transfer model for the reaction mechanism that explains the factors that determine the barrier heights and developed a valence bond (VB) curve crossing mechanism to rationalize the observed trends. In addition, we have found a correlation for substrate epoxidation reactions catalyzed by a range of heme and nonheme iron(IV)-oxo oxidants with the strength of the O-H bond in the iron-hydroxo complex, i.e. BDE(OH), which is supported by the VB model. Finally, the fundamental factors that determine the regioselectivity change between substrate hydroxylation and epoxidation are discussed. It is shown that the regioselectivity of aliphatic hydroxylation versus double bond epoxidation is not influenced by the choice of the oxidant but is purely substrate dependent.

Prolyl-4-hydroxylase is an important nonheme iron-containing dioxygenase in humans involved in the regioselective hydroxylation of a proline residue in a peptide chain on the C(4) position. In biosystems this process is important to create collagen cross-linking and cellular responses to hypoxia. We have performed a series of density functional theory (DFT) studies into the origin of the regioselectivity of proline hydroxylation by P4H enzymes using a minimal active site model (where substrate is unhindered in the binding site) and a larger active site model that incorporates steric hindrance of the substrate by several secondary sphere aromatic residues. Our studies show that thermodynamically the most favorable hydrogen atom abstraction position of proline is from the C(5) position; hence, the small model gives a low reaction barrier and large exothermicity for this process. However, stereochemical repulsions of the substrate with aromatic residues of Tyr(140) and Trp(243) in the second coordination sphere prevent C(5) hydroxylation and make C(4) hydroxylation the dominant mechanism, despite a lesser driving force for the reaction. These studies explain the remarkable regioselectivity of proline hydroxylation by P4H enzymes and show that the regioselectivity is kinetically controlled but not thermodynamically. In addition, we calculated spectroscopic parameters and found good agreement with experimental data.

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Studying the stepwise assembly of a four component hybrid structure on Au(111)/mica, the pores of a hydrogen bonded bimolecular network of 3,4,9,10-perylenetetracarboxylic diimide (PTCDI) and 1,3,5-triazine-2,4,6-triamine (melamine) were partitioned by three and four-armed molecules based on oligo([biphenyl]-4-ylethynyl)benzene, followed by the templated adsorption of either C60 fullerene or adamantane thiol molecules. The characterisation by ambient scanning tunneling microscopy (STM) reveals that the pore modifiers exhibit dynamics which pronouncedly depend on the molecular structure. The three-armed molecule 1,3,5-tris([1,1′-biphenyl]-4-ylethynyl)benzene (3BPEB) switches between two symmetry equivalent configurations on a time scale fast compared to the temporal resolution of the STM. Derivatisation of 3BPEB by hydroxyl groups substantially reduces the switching rate. For the four-armed molecule configurational changes are observed only occasionally. The observation of isolated fullerenes and small clusters of adamantane thiol molecules, which are arranged in a characteristic fashion, reveals the templating effect of the trimolecular supramolecular network. However, the fraction of compartments filled by guest molecules is significantly below one for both the thermodynamically controlled adsorption of C60 and the kinetically controlled adsorption of the thiol with the latter causing partial removal of the pore modifier. The experiments, on the one hand, demonstrate the feasibility of templating by nested assembly but, on the other hand, also pinpoint the requirement for the energy landscape to be tolerant to variations in the assembly process.

Trigonal molecules compartmentalise the pores of a honeycomb network of 3,4:9,10-tetracarboxylic diimide (PTCDI) and 1,3,5-triazine-2,4,6-triamine (melamine). Extending the 1,3,5-tri(phenylene-ethynylene)benzene core by a phenyl group allows for a well-defined accommodation of the molecule into two symmetry equivalent positions in the pore. The corresponding styryl or phenylene-ethynylene derivatives exceed the pore size and, thus, impede pore modification.

Recent work of Nam and co-workers [J. Yoon, S. A. Wilson, Y. K. Jang, M. S. Seo, K. Nehru, B. Hedman, K. O. Hodgson, E. Bill, E. I. Solomon and W. Nam, Angew. Chem., Int. Ed., 2009, 48, 1257] on a biomimetic iron complex implicated a mixture of iron(IV)-oxo and iron(V)-oxo intermediates but the latter could not be spectroscopically characterized, hence its involvement was postulated. To gain insight into the relative activity of these iron(IV)-oxo versus iron(V)-oxo intermediates, we have performed an extensive density functional theory (DFT) study on the chemical properties of the chemical system of Nam et al., namely [Fe(O)(BQEN)(NCCH3)](2+/3+) with BQEN = N,N'-dimethyl-N,N'-bis(8-quinolyl)ethane-1,2-diamine and their reactivity in hydrogen atom abstraction from ethylbenzene. We show that the perceived iron(V)-oxo species actually is an iron(IV)-oxo ligand cation radical, similar to cytochrome P450 compound I. Moreover, this intermediate has an extremely large electron affinity and therefore can abstract electrons from substrates readily. In our particular system, this means that prior to the hydrogen atom abstraction, an electron is abstracted to form an iron(IV)-oxo species, which subsequently abstracts a hydrogen atom from the substrate. Thus, our calculations show for the first time how some nonheme iron complexes react by long-range electron transfer and others directly via hydrogen atom abstraction. We have rationalized our results with detailed thermochemical cycles that explain the observed reactivity patterns.

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