Arylation with Unsymmetrical Diaryliodonium Salts: A Chemoselectivity Study

Phenols, anilines, and malonates have been arylated under metal‐free conditions with twelve aryl(phenyl)iodonium salts in a systematic chemoselectivity study. A new “anti‐ortho effect” has been identified in the arylation of malonates. Several “dummy groups” have been found that give complete chemoselectivity in the transfer of the phenyl moiety, irrespective of the nucleophile. An aryl exchange in the diaryliodonium salts has been observed under certain arylation conditions. DFT calculations have been performed to investigate the reaction mechanism and to elucidate the origins of the observed selectivities. These results are expected to facilitate the design of chiral diaryliodonium salts and the development of catalytic arylation reactions that are based on these sustainable and metal‐free reagents.     

Mechanistic Insights into Copper‐Catalyzed Sonogashira–Hagihara‐Type Cross‐Coupling Reactions: Sub‐Mol % Catalyst Loadings and Ligand Effects

An efficient catalytic system for Sonogashira–Hagihara‐type reactions displaying ligand acceleration in the copper‐catalyzed formation of C(sp²)? C(sp) bonds is described. The structure of the ligand plays a key role for the coupling efficiency. Various copper sources show excellent catalytic activity, even in sub‐mol % quantities. A wide variety of substituents is tolerated in the substrates. Mechanistic details have been revealed by kinetic measurements and DFT calculations.     

Experimental and Computational Probes of the Nature of Halogen Bonding: Complexes of Bromine‐Containing Molecules with Bromide Anions

The nature of halogen bonding is examined via experimental and computational characterizations of a series of associates between electrophilic bromocarbons R? Br (R? Br=CBr₃F, CBr₃NO₂, CBr₃COCBr₃, CBr₃CONH₂, CBr₃CN, etc.) and bromide anions. The [R? Br, Br^?] complexes show intense absorption bands in the 200–350 nm range which follow the same Mulliken correlation as those observed for the charge‐transfer associates of bromide anions with common organic π‐acceptors. For a wide range of the associates, intermolecular R? Br???Br^? separations decrease and intramolecular C? Br bond lengths increase proportionally to the Br^?→R? Br charge transfer; and the energies of R? Br???Br^? bonds are correlated with the linear combination of orbital (charge‐transfer) and electrostatic interactions. On the whole, spectral, structural and thermodynamic characteristics of the [R? Br, Br^?] complexes indicate that besides electrostatics, the orbital (charge‐transfer) interactions play a vital role in the R? Br???Br^? halogen bonding. This indicates that in addition to controlling the geometries of supramolecular assemblies, halogen bonding leads to electronic coupling between interacting species, and thus affects reactivity of halogenated molecules, as well as conducting and magnetic properties of their solid‐state materials.     

Four‐Center Oxidation State Combinations and Near‐Infrared Absorption in [Ru(pap)(Q)2]n (Q=3,5‐Di‐tert‐butyl‐N‐aryl‐1,2‐benzoquinonemonoimine,pap=2‐Phenylazopyridine)

The complex series [Ru(pap)(Q)₂]ⁿ ([ 1 ]ⁿ–[ 4 ]ⁿ; n=+2, +1, 0, ?1, ?2) contains four redox non‐innocent entities: one ruthenium ion, 2‐phenylazopyridine (pap), and two o‐iminoquinone moieties, Q=3,5‐di‐tert‐butyl‐N‐aryl‐1,2‐benzoquinonemonoimine (aryl=C₆H₅ ( 1⁺ ); m‐(Cl)₂C₆H₃ ( 2⁺ ); m‐(OCH₃)₂C₆H₃ ( 3⁺ ); m‐(tBu)₂C₆H₃ ( 4 ⁺)). A crystal structure determination of the representative compound, [ 1 ]ClO₄, established the crystallization of the ctt‐isomeric form, that is, cis and trans with respect to the mutual orientations of O and N donors of two Q ligands, and the coordinating azo N atom trans to the O donor of Q. The sensitive C? O (average: 1.299(3) Å), C? N (average: 1.346(4) Å) and intra‐ring C? C (meta; average: 1.373(4) Å) bond lengths of the coordinated iminoquinone moieties in corroboration with the N?N length (1.292(3) Å) of pap in 1 ⁺ establish [Ru^III(pap⁰)(Q^.?)₂]⁺ as the most appropriate electronic structural form. The coupling of three spins from one low‐spin ruthenium(III) (t_2g⁵) and two Q^.? radicals in 1 ⁺– 4 ⁺ gives a ground state with one unpaired electron on Q^.?, as evident from g=1.995 radical‐type EPR signals for 1 ⁺– 4 ⁺. Accordingly, the DFT‐calculated Mulliken spin densities of 1 ⁺ (1.152 for two Q, Ru: ?0.179, pap: 0.031) confirm Q‐based spin. Complex ions 1 ⁺– 4 ⁺ exhibit two near‐IR absorption bands at about λ=2000 and 920 nm in addition to intense multiple transitions covering the visible to UV regions; compounds [ 1 ]ClO₄–[ 4 ]ClO₄ undergo one oxidation and three separate reduction processes within ±2.0 V versus SCE. The crystal structure of the neutral (one‐electron reduced) state ( 2 ) was determined to show metal‐based reduction and an EPR signal at g=1.996. The electronic transitions of the complexes 1 ⁿ– 4 ⁿ (n=+2, +1, 0, ?1, ?2) in the UV, visible, and NIR regions, as determined by using spectroelectrochemistry, have been analyzed by TD‐DFT calculations and reveal significant low‐energy absorbance (λ_max>1000 nm) for cations, anions, and neutral forms. The experimental studies in combination with DFT calculations suggest the dominant valence configurations of 1 ⁿ– 4 ⁿ in the accessible redox states to be [Ru^III(pap⁰)(Q^.?)(Q⁰)]²⁺ ( 1 ²⁺– 4 ²⁺)→[Ru^III(pap⁰)(Q^.?)₂]⁺ ( 1 ⁺– 4 ⁺)→[Ru^II(pap⁰)(Q^.?)₂] ( 1 – 4 )→[Ru^II(pap^.?)(Q^.?)₂]^? ( 1 ^?– 4 ^?)→[Ru^III(pap^.?)(Q^2?)₂]^2? ( 1 ^2?– 4 ^2?).     

Mechanism of Ketone Allylation with Allylboronates as Catalyzed by Zinc Compounds: A DFT Study

The mechanism of the allylation reaction between 4‐chloroacetophenone and pinacol allylboronates catalyzed by ZnEt₂ with alcohols was investigated using density functional theory (DFT) at the M05‐2X/6‐311++G(d,p) level. The calculations reveal that the reaction prefers to proceed through a double γ‐addition stepwise reaction mechanism rather than a Lewis acid‐catalyzed concerted one. The intermediate with a four‐coordinated boron center, which is formed through proton transfer from EtOH to the ethyl group of ZnEt₂ mediated by the boron center, is the active species and an entrance for the catalytic cycle. The latter is composed of three elementary steps: 1) boron to zinc transmetalation leading to the formation of allylzincate species, 2) electrophilic addition of ketone to allylzincate species, and 3) generation of the final product with recovery of the catalyst. The boron to zinc transmetalation step has the largest energy barrier of 61.0 kJ mol^?1 and is predicted to be the rate‐determining step. The calculations indicate that the additive EtOH plays important roles both in lowering the activation free energy for the formation of the four‐coordinated boron active intermediate and in transforming the low catalytic activity ZnEt₂ into high activity zinc alkoxide species. The alcohols with a less sterically encumbering R group might be the effective additives. The substituted groups on the allylboronates might primarily affect the boron to zinc transmetalation, and the allylboronates with substituents on the C_γ atom is poor in reactivity. The comparison of the catalytic effect between the zinc compounds investigated suggest that Zn(OEt)₂, Zn(OH)₂, and ZnF₂ exhibit higher catalytic efficiency for the boron to zinc transmetalation due to the activation of the B? C_α bond through orbital interactions between the p orbitals of the EtO, OH, F groups and the empty p orbital of the boron center.     

Cyclopalladation and Reactivity of Amino Esters through C?H Bond Activation: Experimental,Kinetic, and Density Functional Theory Mechanistic Studies

The orthopalladation, through C? H bond activation, of a large number of amino esters and amino phosphonates derived from phenylglycine, and having different substituents at the aryl ring and the C‐α atom, as well as on the N‐amine atom, has been studied. The experimental observations indicated an improvement in the yields of the orthopalladated compounds when the N‐amine and/or the C‐α atom are substituted, when compared with the unsubstituted methyl phenylglycinate derivatives. In contrast, substitutions at the aryl ring do not promote significant changes in the orthometalation results. Furthermore, the use of hydrochloride salts of the amino esters has also been shown to have a remarkably favorable effect on the process. All these observations have been fully quantified at different temperatures and pressures by a detailed kinetic study in solution in different solvents and in the presence and absence of added Brønsted acids and chloride anions. The data collected indicate relevant changes in the process depending on these conditions, as expected from the general background known for cyclopalladation reactions. An electronic mechanism of the orthopalladation has been proposed based on DFT calculations at the B3LYP level, and a very good agreement between the trends kinetically measured and the theoretically calculated activation barriers has been obtained. The reactivity of the new orthopalladated amino phosphonate derivatives has been tested and it was found that their halogenation, alkoxylation and carbonylation resulted in formation of the corresponding functionalized ortho‐haloaminophosphonates, ortho‐alkoxyaminophosphonates and oxoisoindolinylphosphonates.     

Self‐Assembled Tetragonal Prismatic Molecular Cage Highly Selective for Anionic π Guests

The metal‐directed supramolecular synthetic approach has paved the way for the development of functional nanosized molecules. In this work, we report the preparation of the new nanocapsule 3? (CF₃SO₃)₈ with a A₄B₂ tetragonal prismatic geometry, where A corresponds to the dipalladium hexaazamacrocyclic complex Pd‐1 , and B corresponds to the tetraanionic form of palladium 5,10,15,20‐tetrakis(4‐carboxyphenyl)porphyrin ( 2 ). The large void space of the inner cavity and the supramolecular affinity for guest molecules towards porphyrin‐based hosts converts this nanoscale molecular 3D structure into a good candidate for host–guest chemistry. The interaction between this nanocage and different guest molecules has been studied by means of NMR, UV/Vis, ESI‐MS, and DOSY experiments, from which highly selective molecular recognition has been found for anionic, planar‐shaped π guests with association constants (K_a) higher than 10⁹ M ^?1, in front of non‐interacting aromatic neutral or cationic substrates. DFT theoretical calculations provided insights to further understand this strong interaction. Nanocage 3? (CF₃SO₃)₈ can not only strongly host one single molecule of M(dithiolene)₂ complexes (M=Au, Pt, Pd, and Ni), but also can finely tune their optical and redox properties. The very simple synthesis of both the supramolecular cage and the building blocks represents a step forward for the development of polyfunctional supramolecular nanovessels, which offer multiple applications as sensors or nanoreactors.     

Theoretical Aspects of Hydrolysis of Peptide Bonds by Zinc Metalloenzymes

Activation and reaction energies for four model systems capturing the essential physicochemical features of the hydrolysis of the peptide bond have been calculated at various level of theory, including the presumably accurate CCSD(T) calculations. The models studied covered a part of the spectrum encountered in biological systems: the hydrolysis in the absence of metal ions (represented by formamide and Ala–Ala) and the hydrolysis in the presence of one and two zinc(II) ions, mimicking the active sites of mono‐ and dizinc metallopeptidases, respectively (by using thermolysin and glutamate carboxypeptidase II as the model catalytic systems and formamide as the model substrate). The results obtained using CCSD(T)/def2‐TZVP and CCSD(T)/aug‐cc‐pVTZ calculations were used as the benchmark values to which the set of cheaper methods, such as (RI‐)DFT, (RI‐)MP2, and SCS‐MP2, were referenced. It was shown that deviations of 3–5 kcal mol^?1 (translating to 2–3 orders in reaction constants) with respect to the reference CCSD(T) barriers are frequently encountered for many correlated methods and most of studied DFT functionals. It has been concluded that from the set of wave‐function methods, both MP2 and SCS‐MP2 methods can be recommended for smaller models (measured by the mean absolute deviation of the activation barriers over the four systems studied), whereas among the popular DFT functionals, B3LYP and especially M06‐2X are likely to be reasonable choices for calculating the activation barriers of zinc metallopeptidases. Finally, with the model of glutamate carboxypeptidase II, issues related to the convergence of the calculated barriers with the size of the model system used as the representative of the enzyme active site were addressed. The intricacies related to system truncation are demonstrated, and suggest that the correlated wave‐function methods may suffer from problems, such as intramolecular BSSE, which make their usage for the larger system questionable. Altogether, the presented data should contribute to efforts to understand enzymatic catalysis more deeply and to gain control of the accuracy and deficiencies of the available theoretical methods and computational approaches.     

The Aqueous Ca2+ System,in Comparison with Zn2+, Fe3 +, and Al3 +: An Ab Initio Molecular Dynamics Study

Herein, we report on the structure and dynamics of the aqueous Ca²⁺ system studied by using ab initio molecular dynamics (AIMD) simulations. Our detailed study revealed the formation of well‐formed hydration shells with characteristics that were significantly different to those of bulk water. To facilitate a robust comparison with state‐of‐the‐art X‐ray absorption fine structure (XAFS) data, we employ a 1st principles MD‐XAFS procedure and directly compare simulated and experimental XAFS spectra. A comparison of the data for the aqueous Ca²⁺ system with those of the recently reported Zn²⁺, Fe³⁺, and Al³⁺ species showed that many of their structural characteristics correlated well with charge density on the cation. Some very important exceptions were found, which indicated a strong sensitivity of the solvent structure towards the cation′s valence electronic structure. Average dipole moments for the 2nd shell of all cations were suppressed relative to bulk water.     

Structural and Dynamic Basis of Human Cytochrome P450 7B1: A Survey of Substrate Selectivity and Major Active Site Access Channels

Cytochrome P450 (CYP) 7B1 is a steroid cytochrome P450 7α‐hydroxylase that has been linked directly with bile salt synthesis and hereditary spastic paraplegia type 5 (SPG5). The enzyme provides the primary metabolic route for neurosteroids dehydroepiandrosterone (DHEA), cholesterol derivatives 25‐hydroxycholesterol (25‐HOChol), and other steroids such as 5α‐androstane‐3β,17β‐diol (anediol), and 5α‐androstene‐3β,17β‐diol (enediol). A series of investigations including homology modeling, molecular dynamics (MD), and automatic docking, combined with the results of previous experimental site‐directed mutagenesis studies and access channels analysis, have identified the structural features relevant to the substrate selectivity of CYP7B1. The results clearly identify the dominant access channels and critical residues responsible for ligand binding. Both binding free energy analysis and total interaction energy analysis are consistent with the experimental conclusion that 25‐HOChol is the best substrate. According to 20 ns MD simulations, the Phe cluster residues that lie above the active site, particularly Phe489, are proposed to merge the active site with the adjacent channel to the surface and accommodate substrate binding in a reasonable orientation. The investigation of CYP7B1–substrate binding modes provides detailed insights into the poorly understood structural features of human CYP7B1 at the atomic level, and will be valuable information for drug development and protein engineering.