Internal charge-transfer in a metal-catalyzed oxidative addition reaction turns an inhibitive electric field stimulus to catalytic.

In a metal-catalyzed oxidative addition, an oriented external electric field (EEF) catalyzes the reaction along one direction and inhibits it when applied in the opposite direction. Beyond a threshold value, the inhibitory direction becomes catalyzing by swapping the metal-to-ligand charge transfer (MLCT) to ligand-to-metal charge-transfer (LMCT) or . The change in direction of the charge-transfer mechanism triggers the inversion of the dipole moment along the reaction axis, that results in the resurgence of catalysis.

Two-Way Catalysis in a Diels-Alder Reaction Limits Inhibition Induced by an External Electric Field.

Oriented external electric fields (EEFs) act as catalysts that can induce selectivity in chemical reactions. The responses of the Diels-Alder (DA) reaction between butadiene and ethylene (BDE-DA) as well as cyclopentadiene and ethylene (CPDE-DA) towards EEF stimuli are investigated here using density functional theory (B3LYP) calculations. EEF is a vector that catalyzes the reaction in one direction while inhibiting it in the opposite direction.

Can an external electric field switch between ethylene formation and L-arginine hydroxylation in the ethylene forming enzyme?

The non-heme Fe(II) and 2-oxoglutarate (2OG) dependent ethylene-forming enzyme (EFE) catalyzes both ethylene generation and L-Arg hydroxylation. Despite experimental and computational progress in understanding the mechanism of EFE, no EFE variant has been optimized for ethylene production while simultaneously reducing the L-Arg hydroxylation activity. In this study, we show that the two L-Arg binding conformations, associated with different reactivity preferences in EFE, lead to differences in the intrinsic electric field (IntEF) of EFE.

What Is the Catalytic Mechanism of Enzymatic Histone N-Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?

Invited for the cover of this issue are Christo Z. Christov and co-workers at Michigan Technological University and University of Oxford. The image depicts the effects of applying an external electric field on the demethylation of dimethylated arginine substrate by a non-heme Fe center Histone N-methyl arginine demethylase.

Catalysis by the JmjC histone demethylase KDM4A integrates substrate dynamics, correlated motions and molecular orbital control.

The -methyl lysine status of histones is important in the regulation of eukaryotic transcription. The Fe(ii) and 2-oxoglutarate (2OG) -dependent JmjC domain enzymes are the largest family of histone -methyl lysine demethylases (KDMs). The human KDM4 subfamily of JmjC KDMs is linked with multiple cancers and some of its members are medicinal chemistry targets.

What Is the Catalytic Mechanism of Enzymatic Histone N-Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?

Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2-oxoglutarate dependent Jumonji-C (JmjC) Nϵ-methyl lysine histone demethylases also have N-methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N-methyl arginine demethylation by human KDM4E and compare the results with those reported for N-methyl lysine demethylation by KDM4A.

Role of Structural Dynamics in Selectivity and Mechanism of Non-heme Fe(II) and 2-Oxoglutarate-Dependent Oxygenases Involved in DNA Repair.

AlkB and its human homologue AlkBH2 are Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenases that repair alkylated DNA bases occurring as a consequence of reactions with mutagenic agents. We used molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate how structural dynamics influences the selectivity and mechanisms of the AlkB- and AlkBH2-catalyzed demethylation of 3-methylcytosine (mC) in single (ssDNA) and double (dsDNA) stranded DNA. Dynamics studies reveal the importance of the flexibility in both the protein and DNA components in determining the preferences of AlkB for ssDNA and of AlkBH2 for dsDNA.

Oriented (Local) Electric Fields Drive the Millionfold Enhancement of the H-Abstraction Catalysis Observed for Synthetic Metalloenzyme Analogues.

This contribution follows the recent remarkable catalysis observed by Groves et al. in hydrogen-abstraction reactions by a) an oxoferryl porphyrin radical-cation complex [Por Fe (O)L ] and b) a hydroxoiron porphyrazine ferric complex [PyPzFe (OH)L ], both of which involve positively charged substituents on the outer circumference of the respective macrocyclic ligands. These charge-coronated complexes are analogues of the biologically important Compound I (Cpd I) and synthetic hydroxoferric species, respectively.

Catalysis by the Non-Heme Iron(II) Histone Demethylase PHF8 Involves Iron Center Rearrangement and Conformational Modulation of Substrate Orientation.

PHF8 (KDM7B) is a human non-heme 2-oxoglutarate (2OG) JmjC domain oxygenase that catalyzes the demethylation of the di/mono-N-methylated K9 residue of histone H3. Altered PHF8 activity is linked to genetic diseases and cancer; thus, it is an interesting target for epigenetic modulation. We describe the use of combined quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations to explore the mechanism of PHF8, including dioxygen activation, 2OG binding modes, and substrate demethylation steps.

Structure-function relationships in KDM7 histone demethylases.

The demethylation of lysine residues of histone proteins is a key epigenetic mechanism in cells. The enzymes that catalyze these processes are called histone demethylases (KDMs). The largest family of KDMs is the Jumonji C (JmjC) domain-containing enzymes; these includes KDM2-7 subfamily of enzymes.

Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases.

The human KDM7 subfamily histone H3 Nϵ-methyl lysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer. We describe experimentally based computational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates interdomain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity. F279S an X-linked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligands and second sphere residues.

Conformational flexibility influences structure-function relationships in nucleic acid N-methyl demethylases.

N-Methylation of DNA/RNA bases can be regulatory or damaging and is linked to diseases including cancer and genetic disorders. Bacterial AlkB and human FTO are DNA/RNA demethylases belonging to the Fe(ii) and 2-oxoglutarate oxygenase superfamily. Modelling studies reveal conformational dynamics influence structure-function relationships of AlkB and FTO, e.

Oriented-External Electric Fields Create Absolute Enantioselectivity in Diels-Alder Reactions: Importance of the Molecular Dipole Moment.

The manuscript studies the enantioselectivity and stereoselectivity of Diels-Alder (DA) cycloadditions between cyclopentadiene (CPD) and a variety of dienophiles (ranging from halo-ethenes to cyano-ethenes), under oriented external electric fields (OEEFs). Applying OEEFs oriented in the X/ Y directions, perpendicular to the reaction axis ( Z), will achieve complete isomeric and enantiomeric discrimination of the products. Unlike the Z-OEEF, which involves charge-transfer from the diene to the dienophile, and thereby brings about catalysis due to increased intramolecular bonding, an OEEF along X, aligned parallel to the C1-C4 atoms of CPD, will lead to R/ S enantiomeric discrimination by means of intramolecular-bond polarization.

Structure and reactivity/selectivity control by oriented-external electric fields.

This is a tutorial on use of external-electric-fields (EEFs) as effectors of chemical change. The tutorial instructs readers how to conceptualize and design electric-field effects on bonds, structures, and reactions. Most effects can be comprehended as the field-induced stabilization of ionic structures.

Catalysis of Methyl Transfer Reactions by Oriented External Electric Fields: Are Gold-Thiolate Linkers Innocent?

Oriented external electric fields (OEEFs) are potent effectors of chemical change and control. We show that the Menshutkin reaction, between substituted pyridines and methyl iodide, can be catalyzed/inhibited at will, by just flipping the orientation of the EEF ( F ) along the "reaction axis" ( Z), N---C---I. A theoretical analysis shows that catalysis/inhibition obey the Bell-Evans-Polanyi principle.

Oriented electric fields as future smart reagents in chemistry.

Oriented external electric fields (OEEFs) as 'smart reagents' are no longer a theoretical dream. Here, we discuss the wide-ranging potential of using OEEFs to catalyse and control a variety of non-redox reactions and impart selectivity at will. An OEEF along the direction of electron reorganization (the so-called reaction axis) will catalyse nonpolar reactions by orders of magnitude, control regioselectivity and induce spin-state selectivity.

Emergence of Function in P450-Proteins: A Combined Quantum Mechanical/Molecular Mechanical and Molecular Dynamics Study of the Reactive Species in the H2O2-Dependent Cytochrome P450SPα and Its Regio- and Enantioselective Hydroxylation of Fatty Acids.

This work uses combined quantum mechanical/molecular mechanical and molecular dynamics simulations to investigate the mechanism and selectivity of H2O2-dependent hydroxylation of fatty acids by the P450SPα class of enzymes. H2O2 is found to serve as the surrogate oxidant for generating the principal oxidant, Compound I (Cpd I), in a mechanism that involves homolytic O-O bond cleavage followed by H-abstraction from the Fe-OH moiety. Our results rule out a substrate-assisted heterolytic cleavage of H2O2 en route to Cpd I.

How does tunneling contribute to counterintuitive H-abstraction reactivity of nonheme Fe(IV)O oxidants with alkanes?

This article addresses the intriguing hydrogen-abstraction (H-abstraction) and oxygen-transfer (O-transfer) reactivity of a series of nonheme [Fe(IV)(O)(TMC)(Lax)](z+) complexes, with a tetramethyl cyclam ligand and a variable axial ligand (Lax), toward three substrates: 1,4-cyclohexadiene, 9,10-dihydroanthracene, and triphenyl phosphine. Experimentally, O-transfer-reactivity follows the relative electrophilicity of the complexes, whereas the corresponding H-abstraction-reactivity generally increases as the axial ligand becomes a better electron donor, hence exhibiting an antielectrophilic trend. Our theoretical results show that the antielectrophilic trend in H-abstraction is affected by tunneling contributions.

Mechanism and stereoselectivity of biologically important oxygenation reactions of the 7-dehydrocholesterol radical.

The mechanism of free radical oxygenation of 7-dehydrocholesterol (7-DHC), one of the biologically important sterols, is investigated by using density functional theory. The energetic origin of the product distribution and the stereoelectronic factors involved in various mechanistic pathways are delineated. The addition of triplet molecular oxygen to two types of conjugatively stabilized radicals, generated by the removal of the reactive allylic hydrogens from C9 or C14 positions, respectively denoted as H9 and H14 pathways, is studied.

On the mechanism of the dehydroaromatization of hexane to benzene by an iridium pincer catalyst.

The developments in the area of transition-metal pincer complexes have opened up new avenues for conversion of saturated hydrocarbons to more useful aromatic compounds under homogeneous reaction conditions. In the backdrop of an interesting series of conversions of unbranched alkanes to benzene, toluene, and xylene (known as the BTX family aromatics) reported by Goldman and co-workers (Nature Chem. 2011, 3, 167), we herein present a comprehensive mechanistic picture obtained by using density functional computations.

Mechanistic insights on platinum- and palladium-pincer catalyzed coupling and cyclopropanation reactions between olefins.

The mechanism of M(II)-PNP-pincer catalyzed reaction between (i) ethene, (ii) trans-butene with 2-methylbut-2-ene, 2,3-dimethylbut-2-ene and tert-butylbutene is examined by using density functional theory methods (where M = Pt or Pd). All key intermediates and transition states involved in the reaction are precisely located on the respective potential energy surfaces using the popular DFT functionals such as mPW1K, M06-2X, and B3LYP in conjunction with the 6-31+G** basis set. The reaction between these olefins can lead to a linear coupling product or a substituted cyclopropane.

On the origin of regio- and stereoselectivity in singlet oxygen addition to enecarbamates.

The reactions of excited state singlet molecular oxygen ((1)Δ(g),(1)O(2)) continue to witness interesting new developments. In the most recent manifestation, (1)O(2) is tamed to react with enecarbamates in a stereoselective manner, which is remarkable, in view of its inherently high reactivity (Acc. Chem.

Mechanism and electronic effects in nitrogen ylide-promoted asymmetric aziridination reaction.

The mechanism and stereoselectivity of the aziridination reaction between guanidinium ylide and a series of para-substituted benzaldehydes have been studied by using density functional theory methods. The mechanistic details and analyses of the key elementary steps involved in (a) the addition of nitrogen ylide to benzaldehydes and (b) subsequent fragmentation of the resulting oxaspirocyclic intermediate are presented. The relative energies of important transition states and intermediates are found to be useful toward rationalizing reported diastereoselective product formation.

Na(I)/Cu(I-II) heterometallic cages interconnected by unusual linear 2-coordinate OCN-Cu(I)-NCO links: synthesis, structural, magnetostructural correlation and computational studies.

A new Na(I)/Cu(I-II) heterometallic coordination complex [Cu(2)L(2)Na(NCO)(2)Cu](n) (1) with an unusual architecture has been synthesised. In 1 cyclic Na-O-Cu-O-Cu cages constructed by the tetradentate N(2)O(2) donor Schiff base ligand (H(2)L = N,N'-bis(2-hydroxyacetophenone)propylenediimine) are interconnected to each other by a rare singly end-to-end bridged OCN-Cu(I)-NCO link generating 1D chain. The complex has been characterised by elemental, spectral and structural analysis.

On the origin of reversible hydrogen activation by phosphine-boranes.

Mechanistic insights into the factors responsible for the reversible hydrogen-activation ability exhibited by an aryl phosphine-borane system ((CH(3))(2)P-C(6)F(4)-B(CF(3))(2)) are presented. A detailed evaluation of the energies of various intermediates, generated by the addition of molecular hydrogen, and their interconverting barriers have been carried out using ab initio and DFT methods. Several rearrangement possibilities of the H(2)-phosphino-borane adduct have been investigated so as to unravel the lower energy pathways that convert the initial adduct to a series of other intermediates.