Second-Coordination Sphere Effects on Selectivity and Specificity of Heme and Nonheme Iron Enzymes

Mononuclear iron-containing enzymes are highly versatile oxidants that often react stereospecifically and/or regioselectively with substrates. Combined experimental and computational studies on heme monooxygenases, nonheme iron dioxygenases and halogenases have revealed the intricate details of the second-coordination sphere, which determine this specificity and selectivity. These second-coordination sphere effects originate from the positioning of the substrate and oxidant, which involve the binding of the co-factors and substrate into the active site of the protein. In addition, some enzymes affect the selectivity and reactivity through charge-stabilization from nearby bound cations/anions, an induced electric field or through the positioning of salt bridges and hydrogen-bonding interactions to first-coordination sphere iron ligands and/or the substrate. Examples of all of these second-coordination sphere effects in iron-containing enzymes and how these influence structure and reactivity are given.     

Oxovanadium(IV)‐Salen Ion Catalyzed H2O2 Oxidation of Tertiary Amines to N‐Oxides– Critical Role of Acetate Ion as External Axial Ligand

The oxovanadium(IV)‐salen ion catalyzed H₂O₂ oxidation of N,N‐dimethylaniline forms N‐oxide as the product of the reaction. The reaction follows Michaelis–Menten kinetics and the rate of the reaction is accelerated by electron donating groups present in the substrate as well as in the salen ligand. This peculiar substituent effect is accounted for in terms of rate determining bond formation between peroxo bond of the oxidant and the N‐atom of the substrate in the transition state. Trichloroacetic acid (TCA) shifts the λ_max value of the oxidant to the red region and catalyzes reaction enormously. The cleavage of N? O bond by vanadium complex leads to moderate yield of the product. But the percentage yield of the product becomes excellent in the presence of TCA.     

Steric Effects in Nucleophilic Aromatic Substitution reactions with aromatic amines 12th communication on nucleophilic aromatic substitution reactions

The kinetics of the S_NAr reactions of aniline and N-methylaniline with a variety of substituted nitrochlorobenzenes in acetonitrile demonstrate that the formation of the intermediate σ-complex is rate determining. The ratio of the rate constants of the aniline and the N-methylaniline reactions (k_A/k_M) increases with increasing size of the 6-substituent; with picryl chloride k_A/k_M reaches a value of over 20 000. The reaction of aniline with 4-X-2,6-dinitrochlorobenzenes is subject to considerably larger para-substituent effects than the corresponding reactions with N-methylaniline. These results are interpreted in terms of two effects: (i) A primary steric effect, which renders the approach of N-methylaniline to the substrate difficult. (ii) A shift towards earlier, more reactant-like transition state structures caused by the primary steric effect. In early transition states the activating power of the electron-withdrawing substituents in the substrate is expected to be relatively small. An early transition state for the slow N-methylaniline reaction and a late transition state for the fast aniline reaction is in apparent contradiction to what would be expected on the basis of the Hammond postulate.     

Reductive elimination of ArCF3 from bidentate Pd(II) complexes: a computational study

The reductive eliminations of ArCF(3) from Pd(II) complexes bearing small- and large-bite-angle phosphane ligands have been investigated using computational methods. QM/QM' and QM/MM studies were applied and complemented with CP2K molecular dynamics investigations. The ligand substituents were varied and a decomposition analysis was performed to allow us to gain insights into the steric and electronic properties of the ligands. The greater reactivity of Xantphos-derived (Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) complexes in the reductive elimination of ArCF(3) is primarily due to the lower repulsive effect of the phoshine substituents in the transition state than in the reactant complex, combined with the increased electronic interaction in the transition state. For DPPE (1,2-bis(diphenylphosphino)ethane), the steric effect of the ligand substituents is greater in the transition state, leading to a higher reaction barrier overall for reductive elimination. There is no direct correlation of the reactivity with the bite angle of the reactant complexes. Only for complexes with large ligand substituents may the bite angle of the Pd complexes be used as a guide for reactivity.     

Kinetics of the Ligand Exchange of Bipyridine in Tetradentate Nickel Complexes

An investigation into the ligand exchange reaction of bipyridine with Ni(EDDA) and Ni(trien) has led to proposed mechanisms based on steric and electronic effects. Kinetic studies show that the rate order dependence of bipyridine is different for the two reactions implying a slightly different mechanism for the bulkier trien. Both mechanisms involve unwrapping of the tetradentate ligand as the rate-determining step. This unwrapping is faster in acidic solution, because protonation of the amine groups inhibits recoordination of the ligand to the nickel. The rates for bipyridine exchange were significantly faster than for phenanthroline, suggesting an electronic ligand effect.     

Synthesis and the crystal structures of N-(2-nitroxyethyl)isonicotinamide and its complexes with PdCl2 and PtCl2 as potential antitumor medicines

Previously unknown N-(2-nitroxyethyl)isonicotinamide was synthesized by the reaction of isonicotinoyl chloride with 2-nitroxyethylamine and was used as a ligand in the reactions with PdCl₂ and PtCl₂ to prepare new complexes, viz., trans-bis[(2-nitroxyethyl)isonicotinamide-N]dichloropalladium(ii) and cis-bis[(2-nitroxyethyl)isonicotinamide-N]dichloroplatinum(ii), respectively. The structures of the ligand and the resulting complexes were established by X-ray diffraction analysis.     

Palladium-Catalyzed Hydrosilylation of Unactivated Alkenes and Conjugated Dienes with Tertiary Silanes Controlled by Hemilabile Hybrid P,O Ligand

Novel P,O-type ligands, N-disulfonyl bicyclic bridgehead phosphorus triamides, were synthesized and utilized in Pd-catalyzed hydrosilylation involving tertiary silanes, unactivated alkenes, and conjugated dienes. The ligand displayed a remarkable level of reactivity for alkene hydrosilylation with tertiary silanes and its use resulted in a significant improvement in the regioselectivity of diene hydrosilylation towards 1,2-hydrosilylation. X-ray crystallographic analysis confirmed the bidentate nature of the ligand, with coordination of phosphorus and oxygen. Control experiments provided evidence for the formation of Pd⁰ species and the reversibility of Pd−H insertion in the reaction mechanism. Density functional theory (DFT) computations supported the importance of the hemilabile P,O ligand in stabilizing both the rate-determining transition state of Pd−H insertion and the transition state of reductive elimination that determines the regioselectivity.     

Aryl- and hetaryl-containing amide anions in reactions of aromatic nucleophilic substitution

The results of kinetic studies of S_NAr reactions ofp-nitrohalobenzenes, hexafluorobenzene, and pentafluoropyridine with aryl-, diaryl-, and hetarylamide anions under homogeneous conditions (in dimethyl sulfoxide) and under conditions of phase transfer catalysis (in toluene) are analyzed. The increase in the Brönsted coefficient _Nu in reactions of amide anions in DMSO as the electrophilicity of the substrate increases and steric hindrance in nucleophiles decreases may result from a higher degree of charge transfer from a nucleophile to a substrate in the transition state. The possibility of replacement of the S_NAr by the SET mechanism in these reaction is discussed.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2315–2319, December, 1995.     

Kinetics of chlorination of some Ortho-, Meta-, and Para-substituted phenols by N-chloro-3-methyl-2,6-diphenylpiperidin-4-one: A LFER study

The kinetics of chlorination of a number of ortho-, meta-, and para-substituted phenols by N-chloro-3-methyl-2,6-diphenylpiperidin-4-one (NCP) in acid medium have been investigated. The reaction is of first order with respect to oxidant and the order with respect to the substrate varies depending on the nature of the substituent present in the ring. With cresols and m-chlorophenol the order is unity, with p-methoxyphenol, zero and with the other phenols, a fraction. Isokinetic and Exner plots give straight lines with fine correlation coefficients. But the Hammett plot gives a curve that was concave downwards, instead of a straight line. The observed Hammett plot deviation has been accounted for suitably. Regression analyses of the rate data of ortho-substituted phenols by using Taft and Charton equations to separate steric effects from electronic effects have been carried out. In this reaction, the localized electronic effect plays a major role while steric and resonance effects play a minor role.     

Studies on the mechanism of allylic coupling reactions: a hammett analysis of the coupling of aryl silicate derivatives

Hammett analysis of the palladium-catalyzed allyl-aryl coupling reaction has demonstrated that the rate of the coupling reaction is enhanced by electron-withdrawing groups on the aryl siloxane. The positive slope of the Hammett plot indicated involvement of a charged transition state in which negative charge on the aryl ring is stabilized inductively. This result is consistent with either transmetalation or reductive elimination being the rate-determining step in the coupling process. Furthermore, the influence of ligand on the metal site has been assessed from competition studies as a function of ligand type, cone angle, and electronic effects. From the relative ratios of coupling products produced in the Hammett study, it is possible to gather insight into the role of the electronic as well as the steric effects of ligands on the mechanism of the coupling reaction.     

Rhodium(II)‐Catalyzed Dehydrogenative Silylation of Biaryl‐Type Monophosphines with Hydrosilanes

A rhodium‐catalyzed system is introduced for in situ modification of biaryl‐type monophosphines with hydrosilanes through a P^III‐chelation‐assisted dehydrogenative silylation reaction. A series of ligands containing silyl groups with different steric and electronic properties were obtained with excellent regioselectivities. This method offers many advantages, including the use of commercially available phosphines, no requirement for an external ligand or oxidant, a broader substrate scope, high efficiency, and access to a single regioisomer. Based on the outstanding properties of the parent scaffolds, the silyl‐substituted phosphines serve as excellent ligands in Pd‐catalyzed asymmetric Suzuki coupling reactions.     

Homogeneous and heterogeneous olefin epoxidation catalyzed by a binuclear Mn(II)Mn(III) complex

The synthesis and characterization of a binuclear carboxylated bridged manganese complex containing the heptadentate ligand N,N′-bis(2-hydroxybenzyl)-N,N′-bis(2-methylpyridyl)-2-ol-1,3-propanediamine (H₃bbppnol) is reported. This complex was characterized by elemental analysis; infrared, electronic (UV–vis) and EPR spectroscopy; and conductivity measurements. The complex was immobilized on silica by either adsorption or entrapment via a sol–gel route. The obtained solids were characterized by thermogravimetric analyses (TG and DSC), UV–vis and infrared spectroscopy, and X-ray diffraction. The catalytic performance of the binuclear manganese complex in epoxidation reactions was evaluated for both homogeneous and heterogeneous systems. The catalytic investigation revealed that the complex performs well as an epoxidation catalyst for the substrates cyclohexene (26–39%) and cyclooctene (29–74%). The solids containing the immobilized complex can be recovered from the reaction medium and reused, maintaining good catalytic activity.     

Dehydrogenative α-Oxygenation of Cyclic Ethers by a High-Valent Manganese(IV)-Oxo Species

High-valent metal-oxo species are typical catalytic cycle intermediates in mono-oxygenases and dioxygenases and commonly react through oxygen atom transfer to substrates. In this work we study a biomimetic model complex with a 1,1’-bis((3,5-dimethylpyridin-2-yl)methyl)-2,2’-bipiperidine ligand system bound to a manganese(IV)-oxo(hydroxo) species and study its formation from manganese(II)-hydroxo and H₂O₂ as well as its reaction with (S)-1-phenylisochromane through dehydrogenative α-oxygenation. The work utilizes density functional theory methods to explore its catalytic cycle and its reactivity patterns. We show that the manganese(IV)-oxo(hydroxo) species is an active oxidant and preferentially the oxo group abstracts a hydrogen atom from substrate with barriers well lower in energy than those found for hydrogen atom abstraction by the hydroxo group. Interestingly, the rate-determining step is the OH rebound rather than the hydrogen atom abstraction, which would imply they would have limited kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium.     

Reversible N-Heterocyclic Carbene-Induced α-H Abstraction in Tungsten(VI) Imido Dialkyl Dialkoxide Complexes

The first reversible N-heterocyclic carbene (NHC) induced α-H abstraction in tungsten(VI) imido-dialkyl dialkoxide complexes is reported. Treatment of W(NAr)(CH₂Ph)₂(OtBu)₂ (Ar=2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl) with different NHCs leads to the formation of complexes of the type W(NAr)(CHPh)(NHC)(CH₂Ph)(OtBu) in excellent isolated yields of up to 96 %. The highly unusual release of the tert-butoxide ligand as tBuOH in the course of the reaction was observed. The formed alkylidene complexes and tBuOH are in an equilibrium with the NHC and the dialkyl complexes. Reaction kinetics were monitored by ¹H NMR spectroscopy. A correlation between the steric and electronic properties of the NHC and the reaction rates was observed. Kinetics of a deuterium-labeled complex in comparison to its non-deuterated counterpart revealed the presence of a strong primary kinetic isotope effect (KIE) of 4.2, indicating that α-H abstraction is the rate-determining step (RDS) of the reaction.     

Equilibria and kinetics for p H-dependent axial ligation of alkyl(aquo) cobaloximes with aromatic and aliphatic N-donor ligands

Equilibria and kinetics of the reaction of bromomethyl(aquo) cobaloxime with histamine, histidine, glycine and ethyl glycine ester and iodomethyl(aquo) cobaloxime with cyanide, imidazole and substituted imidazoles were studied as a function ofpH at 25°C, 10 M ionic strength (KCl) by spectrophotometry technique. The rate of substitution of H₂O varies with thepKa of the incoming ligand, thus establishing the existence of nucleophilic participation of the ligand in the transition state. Dissociation kinetic reactions were also studied as a function ofpH. Binding and kinetic data were interpreted based on the basicity, steric crowd of the entering ligand and HSAB principle. To compare the rate constants of the entering ligandspH independent second-order rate constants were calculated.     

Regioselectivity and diasteroselectivity in Pt(II)-mediated "green" catalytic epoxidation of terminal alkenes with hydrogen peroxide: mechanistic insight into a peculiar substrate selectivity

Recently developed electron-poor Pt(II) catalyst 1 with the "green" oxidant 35% hydrogen peroxide displays high activity and complete substrate selectivity in the epoxidation of terminal alkenes because of stringent steric and electronic requirements. In the presence of isolated dienes bearing terminal and internal double bonds, epoxidation is completely regioselective toward the production of terminal epoxides. Insight into the mechanism is gained by means of a reaction progress kinetic analysis approach that underlines the peculiar role of 1 in activating both the alkene and H2O2 in the rate-determining step providing a rare example of nucleophilic oxidation of alkenes by H2O2.     

Structure and Functional Differences of Cysteine and 3-Mercaptopropionate Dioxygenases: A Computational Study

Thiol dioxygenases are important enzymes for human health; they are involved in the detoxification and catabolism of toxic thiol-containing natural products such as cysteine. As such, these enzymes have relevance to the development of Alzheimer's and Parkinson's diseases in the brain. Recent crystal structure coordinates of cysteine and 3-mercaptopropionate dioxygenase (CDO and MDO) showed major differences in the second-coordination spheres of the two enzymes. To understand the difference in activity between these two analogous enzymes, we created large, active-site cluster models. We show that CDO and MDO have different iron(III)-superoxo-bound structures due to differences in ligand coordination. Furthermore, our studies show that the differences in the second-coordination sphere and particularly the position of a positively charged Arg residue results in changes in substrate positioning, mobility and enzymatic turnover. Furthermore, the substrate scope of MDO is explored with cysteinate and 2-mercaptosuccinic acid and their reactivity is predicted.     

The Equatorial Ligand Effect on the Properties and Reactivity of Iron(V) Oxo Intermediates

High-valent metal oxo oxidants are common catalytic-cycle intermediates in enzymes and known to be highly reactive. To understand which features of these oxidants affect their reactivity, a series of biomimetic iron(V) oxo oxidants with peripherally substituted biuret-modified tetraamido macrocyclic ligands were synthesized and characterized. Major shifts in the UV/Vis absorption as a result of replacing a group in the equatorial plane of the iron(V) oxo species were found. Further characterization by EPR spectroscopy, ESI-MS, and resonance Raman spectroscopy revealed differences in structure and the electronic configuration of these complexes. A systematic reactivity study with a range of substrates was performed and showed that the reactions are affected by electron-withdrawing substituents in the equatorial ligand, which enhance the reaction rate by almost 10¹⁶ orders of magnitude. Thus, the long-range electrostatic perturbations have a major influence on the rate constant. Finally, computational studies identified the various electronic contributions to the rate-determining reaction step and explained how the equatorial ligand periphery affects the properties of the oxidant.     

Iron-catalyzed oxidation of thioethers by iodosylarenes: stereoselectivity and reaction mechanism

Catalytic properties of a series of iron(III)-salen (salen=N,N'-bis(salicylidene)ethylenediamine dianion) and related complexes in asymmetric sulfoxidation reactions, with iodosylarenes as terminal oxidants, have been explored. These catalysts have been found to efficiently catalyze oxidation of alkyl aryl sulfides to sulfoxides with high chemoselectivity (up to 100 %) and moderate-to-high enantioselectivity (up to 84 % with isopropylthiobenzene and iodosylmesitylene), the TON (TON=turnover number) approaching 500. The influence of the ligand (electronic and steric effects of the substituents), oxidant, and substrate structures on the oxidation stereoselectivity has been investigated systematically. The structure of the reactive intermediates (complexes of the type [Fe(III)(ArIO)(salen)] and the reaction mechanism have been revealed by both mechanistic studies with different iodosylarenes and direct in situ (1)H NMR observation of the formation of the reactive species and its reaction with the substrate.     

Steric and Electronic Effects of Bidentate Phosphine Ligands on Ruthenium(II)‐Catalyzed Hydrogenation of Carbon Dioxide

The reactivity difference between the hydrogenation of CO₂ catalyzed by various ruthenium bidentate phosphine complexes was explored by DFT. In addition to the ligand dmpe (Me₂PCH₂CH₂PMe₂), which was studied experimentally previously, a more bulky diphosphine ligand, dmpp (Me₂PCH₂CH₂CH₂PMe₂), together with a more electron‐withdrawing diphosphine ligand, PN^MeP (Me₂PCH₂N^MeCH₂PMe₂), have been studied theoretically to analyze the steric and electronic effects on these catalyzed reactions. Results show that all of the most favorable pathways for the hydrogenation of CO₂ catalyzed by bidentate phosphine ruthenium dihydride complexes undergo three major steps: cis–trans isomerization of ruthenium dihydride complex, CO₂ insertion into the Ru?H bond, and H₂ insertion into the ruthenium formate ion. Of these steps, CO₂ insertion into the Ru?H bond has the lowest barrier compared with the other two steps in each preferred pathway. For the hydrogenation of CO₂ catalyzed by ruthenium complexes of dmpe and dmpp, cis–trans isomerization of ruthenium dihydride complex has a similar barrier to that of H₂ insertion into the ruthenium formate ion. However, in the reaction catalyzed by the PN^MePRu complex, cis–trans isomerization of the ruthenium dihydride complex has a lower barrier than H₂ insertion into the ruthenium formate ion. These results suggest that the steric effect caused by the change of the outer sphere of the diphosphine ligand on the reaction is not clear, although the electronic effect is significant to cis–trans isomerization and H₂ insertion. This finding refreshes understanding of the mechanism and provides necessary insights for ligand design in transition‐metal‐catalyzed CO₂ transformation.