Pathways for Arene Oxidation in Non-Heme Diiron Enzymes: Lessons from Computational Studies on Benzoyl-Coenzyme A Epoxidase

Oxygenation of aromatic rings using O2 is catalyzed by several non-heme carboxylate-bridged diiron enzymes. In order to provide a general mechanistic description for these reactions, computational studies were carried out at the ONIOM(B3LYP/BP86/Amber) level on the non-heme diiron enzyme benzoyl coenzyme A epoxidase BoxB. The calculations revealed four possible pathways for attacking the aromatic ring: a) electrophilic (2e–) attack by a bis(μ-oxo)-diiron(IV) species (Q pathway); b) electrophilic (2e–) attack via the σ* orbital of a μ-η2:η2-peroxo-diiron(III) intermediate (Pσ* pathway); c) radical (1e–) attack via the π*-orbital of a superoxo-diiron(II,III) species (Pπ* pathway); d) radical (1e–) attack of a partially quenched bis(μ-oxo)-diiron(IV) intermediate (Q′ pathway). The results allowed earlier work of de Visser on olefin epoxidation by diiron complexes and QM-cluster studies of Liao and Siegbahn on BoxB to be put into a broader perspective. Parallels with epoxidation using organic peracids were also examined. Specifically for the BoxB enzyme, the Q pathway was found to be the most preferred, but the corresponding bis(μ-oxo)-diiron(IV) species is significantly destabilized and not expected to be directly observable. Epoxidation via the Pσ* pathway represents an energetically somewhat higher lying alternative; possible strategies for experimental discrimination are discussed. The selectivity toward epoxidation is shown to stem from a combination of inherent electronic properties of the thioacyl substituent and enzymatic constraints. Possible implications of the results for toluene monooxygenases are considered as well

Mono- and Binuclear Non-Heme Iron Chemistry from a Theoretical Perspective

In this minireview, we provide an account of the current state-of-the-art developments in the area of mono- and binuclear non-heme enzymes (NHFe and NHFe2) and the smaller NHFe(2) synthetic models, mostly from a theoretical and computational perspective. The sheer complexity, and at the same time the beauty, of the NHFe(2) world represent a challenge for both experimental as well as theoretical methods. We emphasize that the concerted progress on both theoretical and experimental side is a conditio sine qua non for future understanding, exploration and utilization of the NHFe(2) systems. After briefly discussing the current challenges and advances in the computational methodology, we review the recent spectroscopic and computational studies of NHFe(2) enzymatic and inorganic systems and highlight the correlations between various experimental data (spectroscopic, kinetic, thermodynamic, electrochemical) and computations. Throughout, we attempt to keep in mind the most fascinating and attractive phenomenon in the NHFe(2) chemistry which is the fact that despite the strong oxidative power of many reactive intermediates, the NHFe(2) enzymes perform catalysis with high selectivity. We conclude with our personal viewpoint and hope that further developments in quantum chemistry and especially in the field of multireference wave function methods are needed to have a solid theoretical basis for the NHFe(2) studies, mostly by providing benchmarking and calibration of the computationally efficient and easy-to-use DFT methods

Homogén katalitikus reakciók kvantumkémiai tanulmányozása = Quantum Chemical Studies of Homogeneous Catalytic Reactions

A pályázat keretében folytatott kutatási tevékenység alapvető célja homogén katalitikus folyamatok mechamizmusának kvantumkémiai módszerekkel történő feltárása volt. A pályázati időszakban közös kísérleti-elméleti tanulmányok során hazai és külföldi kutatócsoportokkal együttműködve a) jellemeztük több, a széndioxid kémiai átalakításában fontos szerepet játszó átmenetifém-komplex szerkezetét és reaktivitását; b) részletesen feltártuk egy karbamid alapú bifunkciós organokatalizátor aszimmetrikus Michael-addíciós reakciókban kifejtett katalitikus hatását; c) új mechanisztikus modellt javasoltunk az úgynevezett ""frusztrált Lewis párok"" különleges reaktivitásának értelmezésére. Eredményeink hozzájárultak új katalizátorok tervezéséhez. | The primary goal of the present project was to provide mechanistic insight into homogeneous catalytic reactions using quantum chemical calculations. In collaboration with synthetic chemists, we carried out joint experimental-theoretical investigations and succeeded in a) characterizing the structure and reactivity of a number of transition metal complexes relevant to the chemical utilization of carbon dioxide; b) exploring the catalytic effect of thiourea-based bifunctional organocatalysts in asymmetric Michael addition reactions; c) providing a new mechanistic model that accounst for the unique reactivity of ""frustrated Lewis pairs"" towards small molecules. Our results made considerable impact on the development of new catalysts

Új szintézismódszerek kidolgozása és alkalmazása célzott hatásterületen aktív heterociklusos molekulák szintézisére = Elaboration and application of new synthetic methodologies for the synthesis of heterocyclic molecules of aimed biological activity

Pályázati kutatásunk alapvető célja az volt, hogy néhány, a legutóbbi időkben felismert új szintézis-lehetőséget laboratóriumunkban meghonosítsunk, saját magunk új módszereket dolgozzunk ki, és mindezek segítségével felfedező kutatásokat végezzünk kiemelten fontos területen ható biológiailag aktív molekulák megtalálására és szintézisére. Beszámolhatunk arról, hogy palládium-katalizált C-C és C-N keresztkapcsolások segítségével új gyűrűvázakhoz jutottunk, és alapvető új átalakulásokat kezdeményeztünk az organokatalízis és fluoros technika területén. Módszereink segítségével főként a multidrog-rezisztenciát gátló vegyületek családjában értünk el figyelemre méltó eredményt. Kimutattuk, hogy néhány újszerűen szubsztituált fenotiazin-származék hatása meghaladja a kontrollként vizsgált verapamil hatását. A rezisztencia gátlása különösen a mikróbás fertőzések és tumoros betegségek leküzdésében kiemelt jelentőségű. A leghatékonyabb származékokat egy jövőbeli gyógyszerfejlesztés lead-molekulájaként tekintjük. Munkánk elvégzésébe nagy számban vontunk be graduális és posztgraduális hallgatókat. A kutatási eredményekből 7 PhD értekezés született, ezek közül 4 már sikeres védésre került, emellett két egyetemi záródolgozat is elkészült. Munkánk tudományos értékét a megjelent 18 közlemény fémjelzi, összesített hatástényezőjük 57.5. | The basic aim of the present project activity was to establish recently recognized new synthetic methodologies in our laboratory, to elaborate new procedures, and to apply these novel approaches for identification and synthesis of compounds exhibiting biological activity in important areas of drug research. It is to be emphasized that application of palladium-catalyzed C-C and C-N cross coupling reactions allowed the synthesis of new ring systems, whereas basically new transformations have been initiated in the areas of organocatalysis and fluorous techniques.. The new methods provided the most outstanding reaults in the area of multidrug resistance inhibition. Results of some phenothiazines with unusual substitution pattern exceeded the effect of verapamil used as a reference compound. Resistance inhibition is of primary importance in treatment of microbial infections and tumor diseases. Those synthesized compounds exhibiting the highest effectivity can be regarded as lead compounds for the future drug development. Great number of MSc and PhD students were involved into accomplishment of the project. Seven PhD dissertations were born, four of these have already been successfully defended and, furthermore, two master theses have also been finalized. The scientific value of the research activity is coined by the 18 scientific publications with a cumulative impact factor of 57.5

Reactivity Models of Hydrogen Activation by Frustrated Lewis Pairs: Synergistic Electron Transfers or Polarization by Electric Field?

Two alternative qualitative reactivity models have recently been proposed to interpret the facile heterolytic cleavage of H(2) by frustrated Lewis pairs. Both models assume that the reaction takes place via reactive intermediates with preorganized acid/base partners; however, they differ in the mode of action of the active centers. In the electron transfer (ET) model, the hydrogen activation is associated with synergistic electron donation processes with the simultaneous involvement of active centers and the bridging hydrogen, showing similarity to transition-metal-based and other H(2)-activating systems. In contrast, the electric field (EF) model suggests that the heterolytic bond cleavage occurs as a result of polarization by the strong electric field present in the cavity of the reactive intermediates. To assess the applicability of the two conceptually different mechanistic views, we examined the structural and electronic rearrangements as well as the electric fields along the H2 splitting pathways for a representative set of reactions. The analysis reveals that electron donations developing already in the initial phase are general characteristics of all studied reactions, and the related ET model provides qualitative interpretation for the main features of the reaction pathways. On the other hand, several arguments have emerged that cast doubt on the relevance of electric field effects as a conceptual basis in FLP-mediated hydrogen activation

Coordination and Bond Activation in Complexes of Regioisomeric Phenylpyridines with the Nickel(II) Chloride Cation in the Gas Phase

Electrospray ionization of dilute solutions of phenylpyridines (phpy) in the presence of nickel(II) chloride leads to gaseous ions of the type [Ni(phpy)m]2+ with m = 3–5 and [NiCl(phpy)n]+ with n = 1–3, which are characterized by various gas-phase experiments in combination with calculations using density functional theory. Of the regioisomeric phpy's, 2-phpy behaves drastically different compared to 3- and 4-phpy. Ion mobility mass spectrometry allows a differentiation of the gaseous ions and an elucidation of characteristic properties of the metal complexes. For 2-phpy, C–H bond activation in the [NiCl(phpy)2]+ complex is significant, whereas this route is almost suppressed for the corresponding complexes of 3- and 4-phpy and only occurs at elevated energies

Transformation of zwitterionic pyridine derivatives to a spiro fused ring system: azoniabenzo[de]fluorine. Synthesis and mechanistic rationalization

Reaction of aryl- and benzylsulfanopyridinium amidates bearing a methyl group in position 6 with two equivalents of diphenylketene afforded a spiro fused ring system: azoniabenzo[de]fluorine. By use of excess amount of ketene, a distinct reaction was observed via which a 1H-pyrrolo[3,2- b]pyridin-2(3H)-one derivative was furnished. Structure of the tetracyclic spiro-fused ring system was unambiguously confirmed by X-ray diffraction and its formation was rationalized by DFT calculations