Hydrogen Atom Transfer Reactions Research Articles

Identification, Characterization, and Electronic Structures of Interconvertible Cobalt-Oxygen TAML Intermediates.

The reaction of Li[(TAML)CoIII]·3H2O (TAML = tetraamido macrocyclic tetraanionic ligand) with iodosylbenzene at 253 K in acetone in the presence of redox-innocent metal ions (Sc(OTf)3 and Y(OTf)3) or triflic acid affords a blue species 1, which is converted reversibly to a green species 2 upon cooling to 193 K. The electronic structures of 1 and 2 have been determined by combining advanced spectroscopic techniques (X-band electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), X-ray absorption spectroscopy/extended X-ray absorption fine structure (XAS/EXAFS), and magnetic circular dichroism (MCD)) with ab initio theoretical studies. Complex 1 is best represented as an S = 1/2 [(Sol)(TAML•+)CoIII---OH(LA)]- species (LA = Lewis/Brønsted acid and Sol = solvent), where an S = 1 Co(III) center is antiferromagnetically coupled to S = 1/2 TAML•+, which represents a one-electron oxidized TAML ligand. In contrast, complex 2, also with an S = 1/2 ground state, is found to be multiconfigurational with contributions of both the resonance forms [(H-TAML)CoIV═O(LA)]- and [(H-TAML•+)CoIII═O(LA)]-; H-TAML and H-TAML•+ represent the protonated forms of TAML and TAML•+ ligands, respectively. Thus, the interconversion of 1 and 2 is associated with a LA-associated tautomerization event, whereby H+ shifts from the terminal -OH group to TAML•+ with the concomitant formation of a terminal cobalt-oxo species possessing both singlet (SCo = 0) Co(III) and doublet (SCo = 1/2) Co(IV) characters. The reactivities of 1 and 2 at different temperatures have been investigated in oxygen atom transfer (OAT) and hydrogen atom transfer (HAT) reactions to compare the activation enthalpies and entropies of 1 and 2.

Revealing the Mechanism of Alcohol Dehydroxylation and C-C Bond Formation through Concerted Catalysis by Ir/Cu Bimetallic Complexes.

The density functional theory (DFT) was employed to theoretically investigate the reaction mechanism of alcohol deoxygenation/trifluoromethylation. The substrate alcohol (R1) forms a complex (INT3) by binding with benzoxazole salts (NHCs). Under the influence of the photocatalyst ([IrIII]*) and quinuclidine, the C-H bond in INT3 is activated through either electron transfer-proton transfer (ETPT) or hydrogen atom transfer (HAT) mechanisms, resulting in the cleavage of C-O bonds and generation of deoxyalkyl radicals. The distribution of high-valent and low-valent states in the catalytic cycle of [Ir]-complexes is governed by the redox potential mechanism. Investigation was conducted on the source of hydrogen atom transfer reagents in the HAT reaction process under both optimal and nonoptimal conditions. The results demonstrate distinct reactivity among various radicals involved in the Cu-mediated radical capture process. Further investigations into INT3 activation modes, cycling facilitated by [Ir]-complexes, and understanding the role played by [Cu]-complexes in this reaction system provide a valuable theoretical foundation for comprehending and enhancing Ir/Cu bimetallic cooperative catalysis in alcohol deoxygenation/trifluoromethylation reactions. This provides anticipated theoretical support for future designs of more efficient and rational alcohol deoxygenation reactions.

Enhanced Reactivity through Equatorial Sulfur Coordination in Nonheme Iron(IV)-Oxo Complexes: Insights from Experiment and Theory.

Sulfur ligation in metalloenzymes often gives the active site unique properties, whether it is the axial cysteinate ligand in the cytochrome P450s or the equatorial sulfur/thiol ligation in nonheme iron enzymes. To understand sulfur ligation to iron complexes and how it affects the structural, spectroscopic, and intrinsic properties of the active species and the catalysis of substrates, we pursued a systematic study and compared sulfur with amine-ligated iron(IV)-oxo complexes. We synthesized and characterized a biomimetic N4S-ligated iron(IV)-oxo complex and compared the obtained results with an analogous N5-ligated iron(IV)-oxo complex. Our work shows that the amine for sulfur replacement in the equatorial ligand framework leads to a rate enhancement for oxygen atom and hydrogen atom transfer reactions. Moreover, the sulfur-ligated iron(IV)-oxo complex reacts through a different reaction mechanism as compared to the N5-ligated iron(IV)-oxo complex, where the former reacts through hydride transfer with the latter reacting via radical pathways. We show that the reactivity differences are caused by a dramatic change in redox potential between the two complexes. Our studies highlight the importance of implementing a sulfur ligand into the equatorial ligand framework of nonheme iron(IV)-oxo complexes and how it affects the physicochemical properties of the oxidant and its reactivity.

Intramolecular Hydrogen Atom Transfer from Unactivated C(sp3)−H Bond to Alkyl Radical

AbstractRegioselective C(sp3)−H bond functionalization in atom‐ and step‐economic mode has long been recognized as a prominent and challenging task due to its application in late‐stage modification of complex skeletons, natural products and drugs. As a complement to transition metal‐catalyzed C−H activation and carbene/nitrene insertion reactions, hydrogen atom transfer (HAT) emerges as a versatile tool for C(sp3)−H bond functionalization and showcases significant and distinctive superiority in terms of selectivity trend and substrate scope. Intramolecular HAT processes initiated by nitrogen‐ and oxygen‐centered radicals, aryl radicals, and vinyl radicals, have already been well developed in the past century. In contrast, the development of alkyl radical‐mediated HAT reactions lagged behind, although generation methods of corresponding alkyl radicals under mild conditions have gained rapid growth. Especially, selective and efficient HAT from unactivated C(sp3)−H to alkyl radical is highly challenging due to their comparable BDEs and radical polarity. This Concept highlights recent advance in regioselective functionalization of ubiquitous unactivated C−H bonds enabled by intramolecular H‐atom transfer to alkyl radicals.

Single-Electron Oxidation-Initiated Enantioselective Hydrosulfonylation of Olefins Enabled by Photoenzymatic Catalysis.

Controlling the enantioselectivity of hydrogen atom transfer (HAT) reactions has been a long-standing synthetic challenge. While recent advances on photoenzymatic catalysis have demonstrated the great potential of non-natural photoenzymes, all of the transformations are initiated by single-electron reduction of the substrate, with only one notable exception. Herein, we report an oxidation-initiated photoenzymatic enantioselective hydrosulfonylation of olefins using a novel mutant of gluconobacter ene-reductase (GluER-W100F-W342F). Compared to known photoenzymatic systems, our approach does not rely on the formation of an electron donor-acceptor complex between the substrates and enzyme cofactor and simplifies the reaction system by obviating the addition of a cofactor regeneration mixture. More importantly, the GluER variant exhibits high reactivity and enantioselectivity and a broad substrate scope. Mechanistic studies support the proposed oxidation-initiated mechanism and reveal that a tyrosine-mediated HAT process is involved.

Repurposing quantum chemical descriptor datasets for on-the-fly generation of informative reaction representations: application to hydrogen atom transfer reactions

In this work, we explore how existing datasets of quantum chemical properties can be repurposed to build data-efficient downstream ML models, with a particular focus on predicting the activation energy of hydrogen atom transfer reactions.

Substituting density functional theory in reaction barrier calculations for hydrogen atom transfer in proteins.

Hydrogen atom transfer (HAT) reactions are important in many biological systems. As these reactions are hard to observe experimentally, it is of high interest to shed light on them using simulations. Here, we present a machine learning model based on graph neural networks for the prediction of energy barriers of HAT reactions in proteins. As input, the model uses exclusively non-optimized structures as obtained from classical simulations. It was trained on more than 17 000 energy barriers calculated using hybrid density functional theory. We built and evaluated the model in the context of HAT in collagen, but we show that the same workflow can easily be applied to HAT reactions in other biological or synthetic polymers. We obtain for relevant reactions (small reaction distances) a model with good predictive power (R2 ∼ 0.9 and mean absolute error of <3 kcal mol-1). As the inference speed is high, this model enables evaluations of dozens of chemical situations within seconds. When combined with molecular dynamics in a kinetic Monte-Carlo scheme, the model paves the way toward reactive simulations.

Photocatalytic selective oxidation of toluene under encapsulated air conditions.

Benzaldehydes are indispensable building blocks in chemistry. However, the selective oxidation of toluene to benzaldehyde remains an ongoing challenge due to the low oxidation potential of benzaldehyde compared to toluene. We report herein a mild protocol that combines hydrogen atom transfer (HAT) with encapsulated air conditions and suitable catalyst loading for selective oxidation of toluene with high selectivity as well as good functional-group tolerance and a broad substrate scope for the synthesis of various high-value aromatic aldehydes. Moreover, the compatibility of this reaction with toluene derivatives of bioactive molecules further demonstrated the practicality of this approach. Mechanism studies have demonstrated that the collaboration between the oxygen quantity and the HAT catalytic system has a major impact on the high selectivity of the reaction. This study not only showcases the effectiveness of HAT strategies toward selective oxidation of toluene to benzaldehyde, but also provides an approach to controlling the selectivity of HAT reactions.

How Axial Coordination Regulates the Electronic Structure and C-H Amination Reactivity of Fe-Porphyrin-Nitrene?

Detailed electronic structure and its correlation with the intramolecular C-H amination reactivity of Fe-porphyrin-nitrene intermediates bearing different "axial" coordination have been investigated using multiconfigurational complete active space self-consistent field (CASSCF), N-electron valence perturbation theory (NEVPT2), and hybrid density functional theory (DFT-B3LYP) calculations. Three types of "axial" coordination, -OMe/-O(H)Me (1-Sul/2-Sul), -SMe/-S(H)Me (3-Sul/4-Sul), and -NMeIm (MeIm = 3-methyl-imidazole) (5-Sul) mimicking serine, cysteine, and histidine, respectively, along with no axial coordination (6-Sul) have been considered to decipher how the "axial" coordination of different strengths regulates the electronic integrity of the Fe-N core and nitrene-transfer reactivity of Fe-porphyrin-nitrene intermediates. CASSCF-based natural orbitals reveal two distinct classes of electronic structures: Fe-nitrenes (1-Sul and 3-Sul) with relatively stronger axial coordination (-OMe and -SMe) display "imidyl" nature and those (2-Sul, 4-Sul, and 6-Sul) with weaker axial coordination (-O(H)Me, -S(H)Me and no axial coordination) exhibit "imido-like" character. A borderline between the two classes is also observed with NMeIm axial coordination (5-Sul). Axial coordination of different strengths not only regulates the electronic structure but also modulates the Fe-3d orbital energies, as revealed through the d-d transition energies obtained by CASSCF/NEVPT2 calculations. The relatively lower energy of Fe-3dz2 orbital allows easy access to low-lying high-spin quintet states in the cases of weaker "axial" coordination (2-Sul, 4-Sul, and 6-Sul), and the associated hydrogen atom transfer (HAT) reactivity appears to involve two-state triplet-quintet reactivity through minimum energy crossing point (3,5MECP) between the spin states. In stark contrast, Fe-nitrenes with relatively stronger "axial" coordination (1-Sul and 3-Sul) undergo triplet-only HAT reactivity. Overall, this in-depth electronic structure investigation and HAT reactivity evaluation reveal that the weaker axial coordination in Fe-porphyrin-nitrene complexes (2-Sul, 4-Sul, and 6-Sul) can promote more efficient C-H oxidation through the quintet spin state.

Generation, Spectroscopic Characterization, and Computational Analysis of a Six-Coordinate Cobalt(III)-Imidyl Complex with an Unusual S = 3/2 Ground State that Promotes N-Group and Hydrogen Atom-Transfer Reactions with Exogenous Substrates.

We report the synthesis and characterization of a mononuclear nonheme cobalt(III)-imidyl complex, [Co(NTs)(TQA)(OTf)]+ (1), with an S = 3/2 spin state that is capable of facilitating exogenous substrate modifications. Complex 1 was generated from the reaction of CoII(TQA)(OTf)2 with PhINTs at -20 °C. A flow setup with ESI-MS detection was used to explore the kinetics of the formation, stability, and degradation pathway of 1 in solution by treating the Co(II) precursor with PhINTs. Co K-edge XAS data revealed a distinct shift in the Co K-edge compared to the Co(II) precursor, in agreement with the formation of a Co(III) intermediate. The unusual S = 3/2 spin state was proposed based on EPR, DFT, and CASSCF calculations and Co Kβ XES results. Co K-edge XAS and IR photodissociation (IRPD) spectroscopies demonstrate that 1 is a six-coordinate species, and IRPD and resonance Raman spectroscopies are consistent with 1 being exclusively the isomer with the NT ligand occupying the vacant site trans to the TQA aliphatic amine nitrogen atom. Electronic structure calculations (broken symmetry DFT and CASSCF/NEVPT2) demonstrate an S = 3/2 oxidation state resulting from the strong antiferromagnetic coupling of an •NTs spin to the high-spin S = 2 Co(III) center. Reactivity studies of 1 with PPh3 derivatives revealed its electrophilic characteristic in the nitrene-transfer reaction. While the activation of C-H bonds by 1 was proved to be kinetically challenging, 1 could oxidize weak O-H and N-H bonds. Complex 1 is, therefore, a rare example of a Co(III)-imidyl complex capable of exogenous substrate transformations.

Deciphering the Mechanism of Base-Triggered Conversion of Ammonia to Molecular Nitrogen and Methylamine to Cyanide.

We report an in-depth investigation into the ammonia oxidation mechanism by the catalyst [RuIII(tpy)(dmabpy)NH3]3+ ([Ru(NH3)]3+). Stoichiometric reactions of [Ru(NH3)]3+ were carried out with exogenous noncoordinating bases to trigger a proposed redox disproportionation reaction, which was followed using variable-temperature NMR spectroscopy. An intermediate species was identified as a dinitrogen-bridged complex using 15N NMR and Raman spectroscopy on isotopically labeled complexes. This intermediate is proposed to derive from coupling of nitridyl species formed upon sequential redox disproportion reactions. Acetonitrile displaces the dinitrogen bridge to yield free N2. DFT calculations support this lower-energy pathway versus that previously reported for ammonia oxidation by the parent [RuIII(tpy)(bpy)NH3]3+ complex. These experimental and computational results are consistent with the interpretation of redox disproportionation involving sequential hydrogen atom transfer reactions by an amide/aminyl intermediate, [Ru(NH2)-]+ ⇔ [Ru(NH2)•]+, formed upon deprotonation of the parent complex. Control experiments employing a large excess of ammonia as a base indicate this new proposed lower-energy pathway contributes to the oxidation of ammonia to dinitrogen in conditions relevant to electrocatalysis. In addition, analogous methylamine complexes, [Ru(NH2CH3)]2+/3+, were prepared to further test the proposed mechanism. Treating [Ru(NH2CH3)]3+ with a base cleanly yields two products [Ru(NH2CH3)]2+ and [Ru(CN)]+ in an ∼3:1 ratio, fully consistent with the proposed cascade of hydrogen atom transfer reactions by an intermediate.

A new method for determining the intrinsic resistance energy of H‐atom transfer reaction and structure–activity relationship of H‐donating ability

AbstractThe intrinsic resistance energy ΔG≠XH/X of H‐donor XH in hydrogen atom transfer (HAT) reaction is usually used to evaluate the kinetic H‐donating ability. In this article, a new method for determining ΔG≠XH/X of H‐donor in HAT reaction was proposed by the definition of thermo‐kinetic parameter ΔG≠o (XH) = 1/2[ΔG≠XH/X + ΔGo (XH)]. ΔG≠o (XH) is the characteristic physical parameter of XH to describe the H‐donating ability in a chemical reaction during a certain reaction time, ΔGo (XH) is the bond dissociation free energy. The kinetic studies of HATs between 20 alcohols, ethers, alkanes and amines (XH) with cumyloxyl radical [PhC (CH3)2O•, CumO•] were researched, and ΔGo (XH), ΔG≠XH/X, and ΔG≠o (XH) were used to investigate the H‐donating abilities of the studied substrates in thermodynamics, kinetics, and HAT reaction. The effect of structures of XH on these three parameters, the structure–activity relationship, such as the influence of electronic, steric, polar and stereoelectronic effects of substituents, heteroatoms insertion in cycloalkanes, and cis–trans configurational isomerism on the H‐donating abilities were discussed in detail. This study not only provides a new method for determining ΔG≠XH/X but also systematically studies the factors affecting the H‐donating ability, laying a foundation for the selection, design, and synthesis of more efficient antioxidants.

Photochemically Induced Hydrogen Atom Transfer and Intramolecular Radical Cyclization Reactions with Oxazolones.

Photochemically induced intramolecular hydrogen atom transfer in oxazolones is reported. An acetal or thioacetal function at the side chain acts as a hydrogen donor while the photochemical exited oxazolone is the acceptor. A one-step process─the electron and the proton are simultaneously transferred─is productive, while electron transfer followed by proton transfer is inefficient. Radical combination then takes place, leading to the formation of a C-C or C-N bond. The regioselectivity of the reaction is explained by the diradical/zwitterion dichotomy of radical intermediates at the singlet state. In the present case, the zwitterion structure plays a central role, and intramolecular electron transfer favors spin-orbit coupling and thus the intersystem crossing to the singlet state. The reaction of corresponding thioacetal derivatives is less efficient. In this case, photochemical electron transfer is competitive. The photoproducts resulting from C-C bond formation easily undergo stepwise thermal decarboxylation in which zwitterionic and polar transition states are involved. A computational study of this step has also been performed.

Polar Effects in Hydrogen Atom Transfer Reactions from a Proton-Coupled Electron Transfer (PCET) Perspective: Abstractions from Toluenes.

Rate constants for hydrogen atom transfer (HAT) reactions of substituted toluenes with tert-butyl, tert-butoxy, and tert-butylperoxyl radicals are reanalyzed here using the free energies of related proton transfer (PT) and electron transfer (ET) reactions, calculated from an extensive set of compiled or estimated pKa and E° values. The Eyring activation energies ΔGHAT‡ do not correlate with the relatively constant ΔG°HAT, but do correlate close-to-linearly with ΔG°PT and ΔG°ET. The slopes of correlations are similar for the three radicals except that the tBu• barriers shift in the opposite direction from the oxyl radical barriers─a clear example of the qualitative "polar effect" in HAT reactions. When cast quantitatively in free energy terms (ΔGHAT‡ vs ΔG°PT/ET), this effect is very small, only 5-10% of the typical Bell-Evans-Polanyi (BEP) effect of changing ΔG°HAT. This analysis also highlights connections between polar effects and the concepts of "asynchronous" or "imbalanced" HAT reactions in which the PT and ET components of ΔG°HAT contribute differently to the barrier. Finally, these observations are discussed in light of the traditional explanations of polar effects and the potential for a rubric that could predict the extent to which contra-thermodynamic selectivity may be achieved in HAT reactions.

Kinetics of direct and water‐mediated tautomerization reactions of nucleobases at low temperatures ⩽200 K

AbstractDetailed chemical kinetic mechanisms for the synthesis of complex organic molecules in the interstellar medium are at an early stage of developement. That such synthesis must take place is well‐known from chemical analysis of sampled asteroids. As molecular complexity increases the number of possible structural isomers also increases with the consequence that the nascent species may adopt a different spatial arrangement, to the lowest energy one. As part of a program of investigations of the hydrogen atom transfer reaction or tautomerization of imidic acid–amide species H‐O=C‐N‐ O=C‐N‐H we have studied the kinetics for a number of nucleobases, namely cytosine, thymine and uracil where a cyclic form of tautomerism (lactim–lactam) is encountered. Together with a fourth, 5‐aza‐uracil (1,3,5‐triazine‐2,4(1H,3H)‐dione), we report on the rates of reaction at low temperatures 50–200 K for both the direct unimolecular process and the similar transformation mediated by an additional water molecule. We show that these tautomerization reactions can be categorized into three classes, and highlight the importance of quantum mechanical tunneling on the rate constants at these low temperatures. We further present some thermochemistry data, such as formation enthalpies, entropies, isobaric heat capacities and enthalpy functions.

Structural and spectroscopic characterization of large boron heterocyclic radicals: Matrix infrared spectroscopy and quantum chemical calculations

Six boron heterocyclic radicals with different conformations or configurations were synthesized in solid neon and identified by matrix isolation infrared spectroscopy as well as quantum-chemical calculations. The ground-state boron atom selectively attacks the C = C bond of cycloheptene forming η2 (1,2)-BC7H12 complex (A), which contains a chair conformation and a boat conformation. Species A isomerizes to the 2,3,4,5,6,7-hexahydroborocine radical (B), which involves an eight-membered boron heterocyclic ring and also has two isomers observed. The 1-(prop-1-en-1-yl)-2,3,4-dihydro borole radical (C) with E-configuration and Z-configuration is generated as the final product under UV light irradiation through ring contraction reaction and the hydrogen atom transfer reaction. The observation of species A and further photo-isomerization to species C is consistent with theoretical predictions that these reactions are thermodynamically exothermic and kinetically facile. This work not only provides a possible route for future design and synthesis of corresponding borole derivatives, but also provides new insights into the structural and spectroscopic information of boron heterocyclic radicals with different conformations and configurations.

Bioinspired Cu(II) Defect Sites in ZIF-8 for Selective Methane Oxidation.

Activating the C-H bonds of alkanes without further oxidation to more thermodynamically stable products, CO and CO2, is a long-sought goal of catalytic chemistry. Inspired by the monocopper active site of methane monooxygenase, we synthesized a Cu-doped ZIF-8 metal-organic framework with 25% Cu and 75% Zn in the nodes and activated it by heating to 200 °C and dosing in a stepwise fashion with O2, methane, and steam. We found that it does oxidize methane to methanol and formaldehyde. The catalysis persists through at least five cycles, and beyond the third cycle, the selectivity improves to the extent that no CO2 can be detected. Experimental characterization and analysis were carried out by PXRD, DRUV-vis, SEM, and XAS (XANES and EXAFS). The reaction is postulated to proceed at open-coordination copper sites generated by defects, and the mechanism of methanol production was explicated by density functional calculations with the revMO6-L exchange-correlation functional. The calculations reveal a catalytic cycle of oxygen-activated CuI involving the conversion of two molecules of CH4 to two molecules of CH3OH by a sequence of hydrogen atom transfer reactions and rebound steps. For most steps in the cycle, the reaction is more favored by singlet species than by triplets.

Role of Steric Effects on Rates of Hydrogen Atom Transfer Reactions.

The influence of steric effects on the rates of hydrogen atom transfer (HAT) reactions between oxyradicals and alkanes is explored computationally. Quantum chemical density functional theory computations of transition states show that activation barriers and reaction enthalpies are both influenced by bulky substituents on the radical but very little by substituents on the alkane. The activation barriers remain roughly correlated with reaction enthalpies via the Evans-Polanyi relationship even when steric repulsion effects become important, although dispersion effects sometimes stabilize transition states. By making comparisons to previously developed Evans-Polanyi and modified Roberts-Steel relationships, we find that HAT reactions between bulky molecules remain well-described by these relationships.

Two-State Hydrogen Atom Transfer Reactivity of Unsymmetric [Cu2(O)(NO)]2+ Complexes.

We report the temperature-dependent spin switching of dicopper oxo nitrosyl [Cu2(O)(NO)]2+ complexes and their influence on hydrogen atom transfer (HAT) reactivity. Electron paramagnetic resonance (EPR) and Evans method analysis suggest that [Cu2(O)(NO)]2+ complexes transition from the S = 1/2 to the S = 3/2 state around ca. 202 K. At low temperatures (198 K) where S = 3/2 dominates, a strong correlation between the rate of HAT (kHAT) and the population of the S = 1/2 state was identified (R2 = 0.988), suggesting that the HAT by [Cu2(O)(NO)]2+ complexes proceeds by the S = 1/2 isomer. Installation of functional groups that introduce an unsymmetric secondary coordination environment accelerates the HAT rates through perturbation of the spin equilibria. Given the often unsymmetric coordination sphere of bimetallic active sites in natural proteins, we anticipate that similar strategies could be employed by metalloenzymes to control HAT reactions.

Catalysis by KDM6 Histone Demethylases - A Synergy between the Non-Heme Iron(II) Center, Second Coordination Sphere, and Long-Range Interactions.

KDM6A (UTX) and KDM6B (JMJD3) are human non-heme Fe(II) and 2-oxoglutarate (2OG) dependent JmjC oxygenases that catalyze the demethylation of trimethylated lysine 27 in the N-terminal tail of histone H3, a post-translational modification that regulates transcription. A Combined Quantum Mechanics/ Molecular Mechanics (QM/MM) and Molecular Dynamics (MD) study on the catalytic mechanism of KDM6A/B reveals that the transition state for the rate-limiting hydrogen atom transfer (HAT) reaction in KDM6A catalysis is stabilized by polar (Asn217) and aromatic (Trp369)/non-polar (Pro274) residues in contrast to KDM4, KDM6B and KDM7 demethylases where charged residues (Glu, Arg, Asp) are involved. KDM6A employs both σ- and π-electron transfer pathways for HAT, whereas KDM6B employs the σ-electron pathway. Differences in hydrogen bonding of the Fe-chelating Glu252(KDM6B) contribute to the lower energy barriers in KDM6B vs. KDM6A. The study reveals a dependence of the activation barrier of the rebound hydroxylation on the Fe-O-C angle in the transition state of KDM6A. Anti-correlation of the Zn-binding domain with the active site residues is a key factor distinguishing KDM6A/B from KDM7/4s. The results reveal the importance of communication between the Fe center, second coordination sphere, and long-range interactions in catalysis by KDMs and, by implication, other 2OG oxygenases.