Structure of the Dioxygenase AsqJ: Mechanistic Insights into a One‐Pot Multistep Quinolone Antibiotic Biosynthesis

Multienzymatic cascades are responsible for the biosynthesis of natural products and represent a source of inspiration for synthetic chemists. The Fe^II/α‐ketoglutarate‐dependent dioxygenase AsqJ from Aspergillus nidulans is outstanding because it stereoselectively catalyzes both a ferryl‐induced desaturation reaction and epoxidation on a benzodiazepinedione. Interestingly, the enzymatically formed spiro epoxide spring‐loads the 6,7‐bicyclic skeleton for non‐enzymatic rearrangement into the 6,6‐bicyclic scaffold of the quinolone alkaloid 4′‐methoxyviridicatin. Herein, we report different crystal structures of the protein in the absence and presence of synthesized substrates, surrogates, and intermediates that mimic the various stages of the reaction cycle of this exceptional dioxygenase.     

Multi‐Functional Oxidase Activity of CYP102A1 (P450BM3) in the Oxidation of Quinolines and Tetrahydroquinolines

Tetrahydroquinoline, quinoline, and dihydroquinolinone are common core motifs in drug molecules. Screening of a 48‐variant library of the cytochrome P450 enzyme CYP102A1 (P450BM3), followed by targeted mutagenesis based on mutation‐selectivity correlations from initial hits, has enabled the hydroxylation of substituted tetrahydroquinolines, quinolines, and 3,4‐dihydro‐2‐quinolinones at most positions around the two rings in good to high yields at synthetically relevant scales (1.5 g L^?1 day^?1). Other oxidase activities, such as C?C bond desaturation, aromatization, and C?C bond formation, were also observed. The enzyme variants, with mutations at the key active site residues S72, A82, F87, I263, E267, A328, and A330, provide direct and sustainable routes to oxy‐functionalized derivatives of these building block molecules for synthesis and drug discovery.     

Investigation of the Substrate Range of CYP199A4: Modification of the Partition between Hydroxylation and Desaturation Activities by Substrate and Protein Engineering

The cytochrome P450 enzyme CYP199A4, from Rhodopseudomonas palustris HaA2, can efficiently demethylate 4‐methoxybenzoic acid. It is also capable of oxidising a range of other related substrates. By investigating substrates with different substituents and ring systems we have been able to show that the carboxylate group and the nature of the ring system and the substituent are all important for optimal substrate binding and activity. The structures of the veratric acid, 2‐naphthoic acid and indole‐6‐carboxylic acid substrate‐bound CYP199A4 complexes reveal the substrate binding modes and the side‐chain conformational changes of the active site residues to accommodate these larger substrates. They also provide a rationale for the selectivity of product oxidation. The oxidation of alkyl substituted benzoic acids by CYP199A4 is more complex, with desaturation reactions competing with hydroxylation activity. The structure of 4‐ethylbenzoic acid‐bound CYP199A4 revealed that the substrate is held in a similar position to 4‐methoxybenzoic acid, and that the C^β C? H bonds of the ethyl group are closer to the heme iron than those of the C^α (3.5 vs. 4.8 Å). This observation, when coupled to the relative energies of the reaction intermediates, indicates that the positioning of the alkyl group relative to the heme iron may be critical in determining the amount of desaturation that is observed. By mutating a single residue in the active site of CYP199A4 (Phe185) we were able to convert the enzyme into a 4‐ethylbenzoic acid desaturase.     

Combined Experimental and Theoretical Study on the Reactivity of Compounds I and II in Horseradish Peroxidase Biomimetics

For the exploration of the intrinsic reactivity of two key active species in the catalytic cycle of horseradish peroxidase (HRP), Compound I (HRP‐I) and Compound II (HRP‐II), we generated in situ [Fe^IV?O(TMP^+.)(2‐MeIm)]⁺ and [Fe^IV?O(TMP)(2‐MeIm)]⁰ (TMP=5,10,15,20‐tetramesitylporphyrin; 2‐MeIm=2‐methylimidazole) as biomimetics for HRP‐I and HRP‐II, respectively. Their catalytic activities in epoxidation, hydrogen abstraction, and heteroatom oxidation reactions were studied in acetonitrile at ?15 °C by utilizing rapid‐scan UV/Vis spectroscopy. Comparison of the second‐order rate constants measured for the direct reactions of the HRP‐I and HRP‐II mimics with the selected substrates clearly confirmed the outstanding oxidizing capability of the HRP‐I mimic, which is significantly higher than that of HRP‐II. The experimental study was supported by computational modeling (DFT calculations) of the oxidation mechanism of the selected substrates with the involvement of quartet and doublet HRP‐I mimics (^2,4Cpd I) and the closed‐shell triplet spin HRP‐II model (³Cpd II) as oxidizing species. The significantly lower activation barriers calculated for the oxidation systems involving ^2,4Cpd I than those found for ³Cpd II are in line with the much higher oxidizing efficiency of the HRP‐I mimic proven in the experimental part of the study. In addition, the DFT calculations show that all three reaction types catalyzed by HRP‐I occur on the doublet spin surface in an effectively concerted manner, whereas these reactions may proceed in a stepwise mechanism with the HRP‐II mimic as oxidant. However, the high desaturation or oxygen rebound barriers during C?H bond activation processes by the HRP‐II mimic predict a sufficient lifetime for the substrate radical formed through hydrogen abstraction. Thus, the theoretical calculations suggest that the dissociation of the substrate radical may be a more favorable pathway than desaturation or oxygen rebound processes. Importantly, depending on the electronic nature of the oxidizing species, that is, ^2,4Cpd I or ³Cpd II, an interesting region‐selective conversion phenomenon between sulfoxidation and H‐atom abstraction was revealed in the course of the oxidation reaction of dimethylsulfide. The combined experimental and theoretical study on the elucidation of the intrinsic reactivity patterns of the HRP‐I and HRP‐II mimics provides a valuable tool for evaluating the particular role of the HRP active species in biological systems.     

Pathway from N‐Alkylglycine to Alkylisonitrile Catalyzed by Iron(II) and 2‐Oxoglutarate‐Dependent Oxygenases

N‐alkylisonitrile, a precursor to isonitrile‐containing lipopeptides, is biosynthesized by decarboxylation‐assisted ‐N≡C group (isonitrile) formation by using N‐alkylglycine as the substrate. This reaction is catalyzed by iron(II) and 2‐oxoglutarate (Fe/2OG) dependent enzymes. Distinct from typical oxygenation or halogenation reactions catalyzed by this class of enzymes, installation of the isonitrile group represents a novel reaction type for Fe/2OG enzymes that involves a four‐electron oxidative process. Reported here is a plausible mechanism of three Fe/2OG enzymes, Sav607, ScoE and SfaA, which catalyze isonitrile formation. The X‐ray structures of iron‐loaded ScoE in complex with its substrate and the intermediate, along with biochemical and biophysical data reveal that ‐N≡C bond formation involves two cycles of Fe/2OG enzyme catalysis. The reaction starts with an Fe^IV‐oxo‐catalyzed hydroxylation. It is likely followed by decarboxylation‐assisted desaturation to complete isonitrile installation.     

Non‐Heme Dioxygenase Catalyzes Atypical Oxidations of 6,7‐Bicyclic Systems To Form the 6,6‐Quinolone Core of Viridicatin‐Type Fungal Alkaloids

The 6,6‐quinolone scaffold of the viridicatin‐type of fungal alkaloids are found in various quinolone alkaloids which often exhibit useful biological activities. Thus, it is of interest to identify viridicatin‐forming enzymes and understand how such alkaloids are biosynthesized. Here an Aspergillal gene cluster responsible for the biosynthesis of 4′‐methoxyviridicatin was identified. Detailed in vitro studies led to the discovery of the dioxygenase AsqJ which performs two distinct oxidations: first desaturation to form a double bond and then monooxygenation of the double bond to install an epoxide. Interestingly, the epoxidation promotes non‐enzymatic rearrangement of the 6,7‐bicyclic core of 4′‐methoxycyclopenin into the 6,6‐quinolone viridicatin scaffold to yield 4′‐methoxyviridicatin. The finding provides new insight into the biosynthesis of the viridicatin scaffold and suggests dioxygenase as a potential tool for 6,6‐quinolone synthesis by epoxidation of benzodiazepinediones.     

Drug Metabolism by Cytochrome P450 Enzymes: What Distinguishes the Pathways Leading to Substrate Hydroxylation Over Desaturation?

Cytochrome P450 enzymes are highly versatile biological catalysts in our body that react with a broad range of substrates. Key functions in the liver include the metabolism of drugs and xenobiotics. One particular metabolic pathway that is poorly understood relates to the P450 activation of aliphatic groups leading to either hydroxylation or desaturation pathways. A DFT and QM/MM study has been carried out on the factors that determine the regioselectivity of aliphatic hydroxylation over desaturation of compounds by P450 isozymes. The calculations establish multistate reactivity patterns, whereby the product distributions differ on each of the spin‐state surfaces; hence spin‐selective product formation was found. The electronic and thermochemical factors that determine the bifurcation pathways were analysed and a model that predicts the regioselectivity of aliphatic hydroxylation over desaturation pathways was established from valence bond and molecular orbital theories. Thus, the difference in energy of the O?H versus the O?C bond formed and the π‐conjugation energy determines the degree of desaturation products. In addition, environmental effects of the substrate binding pocket that affect the regioselectivities were identified. These studies imply that bioengineering P450 isozymes for desaturation reactions will have to include modifications in the substrate binding pocket to restrict the hydroxylation rebound reaction.     

Remote Radical Desaturation of Unactivated C−H Bonds in Amides

Desaturation of inert aliphatic C−H bonds in alkanes to form the corresponding alkenes is challenging. In this communication, a new and practical strategy for remote site-selective desaturation of amides via radical chemistry is reported. The readily installed N-allylsulfonylamide moiety serves as an N radical precursor. Intramolecular 1,5-hydrogen atom transfer from an inert C−H bond to the N-radical generates a translocated C-radical which is subsequently oxidized and deprotonated to give the corresponding alkene. The commercially available methanesulfonyl chloride is used as reagent and a Cu/Ag-couple as oxidant. The remote desaturation is realized on different types of unactivated sp³-C−H bonds. The potential synthetic utility of this method is further demonstrated by the dehydrogenation of natural product derivatives and drugs.     

Synthesis,Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.     

Site-Selective Pd-Catalyzed C(sp3)−H Arylation of Heteroaromatic Ketones

A ligand-controlled site-selective C(sp³)−H arylation of heteroaromatic ketones has been developed using Pd catalysis. The reaction occurred selectively at the α- or β-position of the ketone side-chain. The switch from α- to β-arylation was realized by addition of a pyridone ligand. The α-arylation process showed broad scope and high site- and chemoselectivity, whereas the β-arylation was more limited. Mechanistic investigations suggested that α-arylation occurs through C−H activation/oxidative addition/reductive elimination whereas β-arylation involves desaturation and aryl insertion.     

The Fluorination of C−H Bonds: Developments and Perspectives

This Review summarizes advances in fluorination by C(sp²)?H and C(sp³)?H activation. Transition‐metal‐catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp²) and C(sp³) sites, exploiting the reactivity of high‐oxidation‐state transition‐metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp³)?H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition‐metal‐catalyzed processes as they allow for undirected C(sp³)?H fluorination. To date, radical C?H fluorinations mainly employ electrophilic N?F fluorination reagents but a unique Mn^III‐catalyzed oxidative C?H fluorination using fluoride has been developed. Overall, the field of late‐stage nucleophilic C?H fluorination has progressed much more slowly, a state of play explaining why C?H ¹⁸F‐fluorination is still in its infancy.     

Solid‐state nuclear magnetic resonance investigation of neurosteroid compounds and magnesium interactions

The neurosteroid trans‐dehydroandrosterone (DHEA) and its analogs with slightly different modifications in the side chain attached to C17, that is, (3S)‐acetoxypregn‐5‐en‐20‐one ( 1 ) and (3S,20R)‐acetoxypregn‐5‐en‐20‐ol ( 2 ), have been synthesized to investigate DHEA–cation interactions. In this study, we applied solid‐state ¹H/¹³C cross‐polarization/magic‐angle spinning (CP/MAS) nuclear magnetic resonance (NMR) spectroscopy to a series of DHEA analog/Mg²⁺ mixtures at different Mg²⁺ concentrations. The high‐resolution ¹³C NMR spectra of 1 /Mg²⁺ mixtures exhibit two distinct ¹³C spectral patterns, one attributable to 1 free from Mg²⁺, and the other attributable to 1 with bound Mg²⁺. For 2 , the ¹³C NMR spectra exhibit three distinct spectral patterns; besides that of the free form, the other two can be assigned to Mg²⁺‐bound forms. Based on the analysis of the chemical shift deviations (CSDs), we conclude that both 1 and 2 might be subject to a cation–π interaction via the C5–C6 double bond, in contrast to that observed previously for DHEA. As demonstrated, DHEA possesses two Mg²⁺ binding sites, that is, C17–O and C5–C6 double bond, in which the binding affinity of the former is at least three times stronger than that of the latter. The solid‐state ¹³C NMR investigation allows better understanding of the underlying cation binding effects of neurosteroid molecules in vitro.     

Impact of Oxidation State on Reactivity and Selectivity Differences between Nickel(III) and Nickel(IV) Alkyl Complexes

Described is a systematic comparison of factors impacting the relative rates and selectivities of C(sp³)?C and C(sp³)?O bond‐forming reactions at high‐valent Ni as a function of oxidation state. Two Ni complexes are compared: a cationic octahedral Ni^IV complex ligated by tris(pyrazolyl)borate and a cationic octahedral Ni^III complex ligated by tris(pyrazolyl)methane. Key features of reactivity/selectivity are revealed: 1) C(sp³)?C(sp²) bond‐forming reductive elimination occurs from both centers, but the Ni^III complex reacts up to 300‐fold faster than the Ni^IV, depending on the reaction conditions. The relative reactivity is proposed to derive from ligand dissociation kinetics, which vary as a function of oxidation state and the presence/absence of visible light. 2) Upon the addition of acetate (AcO^?), the Ni^IV complex exclusively undergoes C(sp³)?OAc bond formation, while the Ni^III analogue forms the C(sp³)?C(sp²) coupled product selectively. This difference is rationalized based on the electrophilicity of the respective M?C(sp³) bonds, and thus their relative reactivity towards outer‐sphere S_N2‐type bond‐forming reactions.     

Synthesis and characterization of aluminum complexes based on amino‐benzotriazole phenoxide ligand: luminescent properties and catalysis for ring‐opening polymerization

Aluminum complexes coordinated by a ^C1DEABTP ligand (^C1DEABTP‐H = 2‐(2H‐benzotriazol‐2‐yl)‐6‐((diethylamino)methyl)‐4‐methylphenol) were synthesized and structurally characterized. The formation of Al complexes is dependent on the stoichiometry of AlMe₃ to ^C1DEABTP ligand ratio. The reaction of ^C1DEABTP‐H with AlMe₃ (1.0 molar equiv.) in hexane produced mono‐adduct aluminum complex [(^C1DEABTP)AlMe₂] (1), but treatment of ^C1DEABTP‐H with 2.0 molar equiv. of AlMe₃ afforded mixtures of [(^C1DEABTP)Al₂Me₅] (2) and [(^C1DEABTP)Al₃Me₈] (3). The penta‐coordinated bis‐adduct aluminum complex [(^C1DEABTP)₂AlMe] (4) was synthesized through the reaction of AlMe₃ with ^C1DEABTP‐H (2.0 molar equiv.) in hexane. Tri‐adduct Al complex [(^C1DEABTP)₃Al] (5) resulted from treatment of AlMe₃ with ^C1DEABTP‐H (3.0 equiv.); the Al center is hexa‐coordinated with three N,O‐bidentate ^C1DEABTP ligands. X‐ray diffraction of single crystals indicates that the bonding modes of the ^C1DEABTP ligands in complexes 2–3 are greatly affected when excess AlMe₃ is coordinated. The optical properties and catalysis for lactone polymerizations of ^C1DEABTP coordinated to Al complexes were tested. Tri‐adduct Al complex 5 produced an intense green fluorescence in both solution and the solid state. Complex 4 is an active catalyst for the ring‐opening polymerization of ε‐caprolactone (ε‐CL) and L‐lactide (L‐LA) in the presence of 9‐anthracenemethanol (9‐AnOH). In ε‐CL polymerization, Al complex 4 catalyzes efficiently in both a 'controlled' and 'immortal' manner, giving polymers with the expected molecular weights and narrow polydispersity indexes. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of 1‐silacyclopent‐2‐ene derivatives using 1,2‐hydroboration, 1,1‐organoboration and protodeborylation

The reaction of di(alkyn‐1‐yl)vinylsilanes R¹(H₂C═CH)Si(C≡C―R)₂ (R¹ = Me ( 1 ), Ph ( 2 ); R = Bu (a), Ph (b), Me₂HSi (c)) at 25°C with 1 equiv. of 9‐borabicyclo[3.3.1]nonane (9‐BBN) affords 1‐silacyclopent‐2‐ene derivatives ( 3a , 3b , 3c , 4a , 4b ), bearing one Si―C≡C―R function readily available for further transformations. These compounds are formed by consecutive 1,2‐hydroboration followed by intramolecular 1,1‐carboboration. Treated with a further equivalent of 9‐BBN in benzene they are converted at relatively high temperature (80–100°C) into 1‐alkenyl‐1‐silacyclopent‐2‐ene derivatives ( 5a , 5b 6a , 6b ) as a result of 1,2‐hydroboration of the Si―C≡C―R function. Protodeborylation of the 9‐BBN‐substituted 1‐silacyclopent‐2‐ene derivatives 3 , 4 , 5 , 6 , using acetic acid in excess, proceeds smoothly to give the novel 1‐silacyclopent‐2‐ene ( 7 , 8 , 9 , 10 ). The solution‐state structural assignment of all new compounds, i.e. di(alkyn‐1‐yl)vinylsilanes and 1‐silacyclopent‐2‐ene derivatives, was carried out using multinuclear magnetic resonance techniques (¹H, ¹³C, ¹¹B, ²⁹Si NMR). The gas phase structures of some examples were calculated and optimized by density functional theory methods (B3LYP/6‐311+G/(d,p) level of theory), and ²⁹Si NMR parameters were calculated (chemical shifts δ²⁹Si and coupling constants ⁿJ(²⁹Si,¹³C)). Copyright © 2014 John Wiley & Sons, Ltd.     

1,2‐, 1,7‐ and 1,12‐Dicarba‐closo‐dodecaborane(12) Derivatives Revisited by 13C NMR Spectroscopy and DFT Calculations. First Observation of Isotope‐Induced Chemical Shifts 1Δ10/11B(13C), and the Signs and Magnitudes of Coupling Constants 1J(13C,13C) and 1J(13C,11B)

The origin of broadening of ¹³C(carborane) NMR signals of 1,2‐, 1,7‐ and 1,12‐dicarba‐closo‐dodecaboranes(12) and several diphenylsilyl derivatives has been examined in detail and could be traced only partially to unresolved ¹³C–¹¹B spin‐spin coupling. Other contributions to the line widths arise from ¹³C–¹H dipole‐dipole interactions and, in particular, from isotope‐induced chemical shifts ¹Δ^10/11B(¹³C), observed here for carboranes for the first time. In the case of 1‐diphenylsilyl‐1,2‐dicarba‐closo‐dodecaborane(12), the coupling constant ¹J(¹³C,¹³C) = 9.3 Hz was measured in natural abundance of ¹³C. The small value of this coupling constant and its negative sign is predicted by calculations based on optimised structures [B3LYP/6‐311+G(d,p) level of theory] of the parent carboranes and 1‐silyl‐1,2‐dicarba‐closo‐dodecaborane(12) as a model compound [calcd. ¹J(¹³C,¹³C) = –10.5 Hz]. Calculated coupling constants ¹J(¹³C,¹¹B) are small (<7 Hz), in contrast to published assumptions, and of either sign, whereas ¹J(¹¹B,¹¹B) are all positive and range up to 15 Hz.     

A Sequential Homologation of Alkynes and Aldehydes for Chain Elongation with Optional 13C‐Labeling

Terminal alkynes (RCCH) are homologated by a sequence of ruthenium‐catalyzed anti‐Markovnikov hydration of alkyne to aldehyde (RCH₂CHO), followed by Bestmann–Ohira alkynylation of aldehyde to chain‐elongated alkyne (RCH₂CCH). Inverting the sequence by starting from aldehyde brings about the reciprocal homologation of aldehydes instead. The use of ¹³C‐labeled Bestmann–Ohira reagent (dimethyl ((1‐¹³C)‐1‐diazo‐2‐oxopropyl)phosphonate) for alkynylation provides straightforward access to singly or, through additional homologation, multiply ¹³C‐labeled alkynes. The labeled alkynes serve as synthetic platform for accessing a multitude of specifically ¹³C‐labeled products. Terminal alkynes with one or two ¹³C‐labels in the alkyne unit have been submitted to alkyne–azide click reactions; the copper‐catalyzed version (CuAAC) was found to display a regioselectivity of >50 000:1 for the 1,4‐ over the 1,5‐triazine isomer, as shown analytically by ¹³C NMR spectroscopy.     

Effect of methoxyl groups on the NMR spectra: configuration and conformation of natural and synthetic indanic and tetralinic structures

Here, we studied the influence of the methoxyl groups attached at C‐7 and C‐2′ of natural and synthetic 1‐arylindanes on the chemical shift of the signal of bibenzylic hydrogen and carbon atoms and J_1,2 coupling constants. This influence was also analysed in natural 1‐aryltetralins and related compounds that possess methoxyl and/or hydroxyl groups bound at C‐8 and C‐2′. The methoxyl groups attached at C‐7 in indanes or at C‐8 in tetralins produce a deshielding signal at H‐1 and shield at C‐1 and a strong decrease in the value of J_1,2 due to the pseudoequatorial location adopted by the aryl group bound at C‐1, avoiding an ‘A^1,3 strain’. Furthermore, compounds with hydroxyl or methoxyl groups in C‐2′, in the absence of substituents of C‐7 or C‐8, present a strong deshielding signal at H‐1, strong shield of the C‐1 signal and a decrease in the value of J_1,2. This is attributed to the stereoelectronic effects of the methoxyl or hydroxyl groups, which we have called ‘Asarone effect’. NOESY experiments were conducted to confirm the configuration and conformation of some of the compounds included in this work. This study shows that both effects, A^1,3 strain and Asarone effect, must be taken into account when the structure of natural indanes and tetralins is analysed by using ¹H‐NMR and ¹³C‐NMR spectra. Copyright © 2016 John Wiley & Sons, Ltd.     

Theoretical insights into the relative bonding of normal and abnormal N‐heterocyclic carbenes in [PdCl2(NHCR)2] and [PdCl2(NHCR)(aNHCR)] (R = H,Ph, Mes)

Quantum chemical insights into normal Pd‐C2(NHC^R) and abnormal Pd‐C5(aNHC^R) bonding, dominated by dispersion interactions in N‐hetereocyclic carbene complexes [PdCl₂(NHC^R)₂] ( I , R = H; II , R = Ph; III , R = Mes (2,4,6‐trimethyl)phenyl)) and [PdCl₂(NHC^R)(aNHC^R] ( IV , R = H; V , R = Ph; VI , R = Mes) have been investigated at DFT and DFT‐D3(BJ) level of theory with particular emphasis on the effects of the noncovalent interactions on the structures and the nature of Pd‐C2(NHC^R) and Pd‐C5(aNHC^R) bonds. The optimized geometries are good agreement with the experimental values. The Pd‐C bonds are essentially single bond. Hirshfeld charge distributions indicate that the abnormal aNHC^R carbene ligand is relatively better electron donor than the normal NHC^R carbene ligand. The C2 atom has larger %s contribution along Pd‐C2 bond than the C5 atom along Pd‐C5 bond. As a consequence the Pd‐C2(NHC^R) bonds are relative stronger than the Pd‐C5(aNHC^R) bonds. Thus, the results of natural hybrid orbital analysis support the key point of the present study. Calculations predict that for bulky substituent (R = Ph, Mes) at carbene, the Pd‐C2(NHC^R) bond is stronger than Pd‐C5(aNHC^R) bond due to large dispersion energy in [PdCl₂(NHC^R)₂] than in [PdCl₂(NHC^R)(aNHC^R)]. However, in case of non‐bulky substituent with small and almost equal contribution of dispersion energy, the Pd‐C2(NHC^R) bond is relative weaker than Pd‐C5(aNHC^R) bond. The bond dissociation energies are dependent on the R substituent, the DFT functional and the inclusion of dispersion interactions. Major point of this study is that the abnormal aNHCs are not always strongly bonded with metal center than the normal NHCs. Effects of dispersion interaction of substituent at nitrogen atoms of carbene ligand are found to play a crucial role on estimation of relative bonding strengths of the normal and abnormal aNHCs with metal center. © 2016 Wiley Periodicals, Inc.     

Directed C−H Activation and Tandem Cross‐Coupling Reactions Using Palladium Nanocatalysts with Controlled Oxidation

Controlled oxidation of palladium nanoparticles provided high‐valent Pd^IV oxo‐clusters which efficiently promote directed C−H halogenation reactions. In addition, palladium nanoparticles can undergo changes in oxidation states to provide both high‐valent Pd^IV and low‐valent Pd⁰ species within one system, and thus a tandem reaction of C−H halogenation and cross‐coupling (C−N, C−C, and C−S bond formation) was successfully established.