Polyether Natural Product Inspired Cascade Cyclizations: Autocatalysis on π‐Acidic Aromatic Surfaces

Anion‐π catalysis functions by stabilizing anionic transition states on aromatic π surfaces, thus providing a new approach to molecular transformation. The delocalized nature of anion–π interactions suggests that they serve best in stabilizing long‐distance charge displacements. Aiming therefore for an anionic cascade reaction that is as charismatic as the steroid cyclization is for conventional cation‐π biocatalysis, reported here is the anion‐π‐catalyzed epoxide‐opening ether cyclizations of oligomers. Only on π‐acidic aromatic surfaces having a positive quadrupole moment, such as hexafluorobenzene to naphthalenediimides, do these polyether cascade cyclizations proceed with exceptionally high autocatalysis (rate enhancements k_auto/k_cat >10⁴ m ^?1). This distinctive characteristic adds complexity to reaction mechanisms (Goldilocks‐type substrate concentration dependence, entropy‐centered substrate destabilization) and opens intriguing perspectives for future developments.     

Polyether Natural Product Inspired Cascade Cyclizations: Autocatalysis on π-Acidic Aromatic Surfaces

Anion-π catalysis functions by stabilizing anionic transition states on aromatic π surfaces, thus providing a new approach to molecular transformation. The delocalized nature of anion–π interactions suggests that they serve best in stabilizing long-distance charge displacements. Aiming therefore for an anionic cascade reaction that is as charismatic as the steroid cyclization is for conventional cation-π biocatalysis, reported here is the anion-π-catalyzed epoxide-opening ether cyclizations of oligomers. Only on π-acidic aromatic surfaces having a positive quadrupole moment, such as hexafluorobenzene to naphthalenediimides, do these polyether cascade cyclizations proceed with exceptionally high autocatalysis (rate enhancements k_auto/k_cat >10⁴ m ⁻¹). This distinctive characteristic adds complexity to reaction mechanisms (Goldilocks-type substrate concentration dependence, entropy-centered substrate destabilization) and opens intriguing perspectives for future developments.     

A New Approach to Enantiopure C3‐Symmetric Molecules

Chiral base chemistry has been used to create three chiral centres in one pot on a C₃‐symmetric substrate. The potential of this new approach to C₃‐symmetric molecules is exemplified by the creation of an enantiopure C_3v‐symmetric triol, triphosphane and tripyridine. A ruthenium complex of the last compound has been studied by X‐ray crystallography.     

Highly Efficient Synthesis of α‐Halomethylketones via Ce(SO4)2/Acid Co‐Catalyzed Hydration of Alkynes

A general atom‐economical approach for the synthesis of α‐halomethyl ketones is demonstrated through Ce(SO₄)₂/acid co‐catalyzed hydration of a wide range of haloalkynes. The reactions are conducted under convenient conditions and provide products with excellent regioselectivity in good to excellent yields, with broad substrate scope. This protocol is an alternative to conventional α‐halogenation of ketones.     

FeCl3‐Mediated Three‐Component Cascade Reaction: An Effective Approach to the Construction of Highly Functionalized Pyrrolo[1,2‐c]quinazolinones

An unexpected FeCl₃‐mediated three‐component cascade reaction has been used to construct structurally diverse pyrrolo[1,2‐c]quinazolinone derivatives with potential biological activities. This method has advantages of mild conditions, simple work‐up, as well as wide substrate scope, which makes it a powerful approach to the synthesis of diverse pyrrolo[1,2‐c]quinazolinones. This cascade reaction involves 1,3‐dipolar cycloaddition between azomethine ylides and allenoates, followed by intramolecular nucleophilic addition in the presence of FeCl₃. The obtained products could be easily transformed into derivatives with the pyrrolo[2,3‐c]quinazoline alkaloid skeleton.     

Supramolecularly Regulated Ligands for Asymmetric Hydroformylations and Hydrogenations

Herein we report the use of polyether binders as regulation agents (RAs) to enhance the enantioselectivity of rhodium‐catalyzed transformations. For reactions of diverse substrates mediated by rhodium complexes of the α,ω‐bisphosphite‐polyether ligands 1 – 5 , a – d , the enantiomeric excess (ee) of hydroformylations was increased by up to 82 % (substrate: vinyl benzoate, 96 % ee), and the ee value of hydrogenations was increased by up to 5 % (substrate: N‐(1‐(naphthalene‐1‐yl)vinyl)acetamide, 78 % ee). The ligand design enabled the regulation of enantioselectivity by generation of an array of catalysts that simultaneously preserve the advantages of a privileged structure in asymmetric catalysis and offer geometrically close catalytic sites. The highest enantioselectivities in the hydroformylation of vinyl acetate with ligand 4 b were achieved by using the Rb[B(3,5‐(CF₃)₂C₆H₃)₄] (RbBArF) as the RA. The enantioselective hydrogenation of the substrates 10 required the rhodium catalysts derived from bisphosphites 3 a or 4 a , either alone or in combination with different RAs (sodium, cesium, or (R,R)‐bis(1‐phenylethyl)ammonium salts). This design approach was supported by results from computational studies.     

Intramolecular Aryl Migration of Diaryliodonium Salts: Access to ortho‐Iodo Diaryl Ethers

By using vicinal trifluoromethanesulfonate‐substituted diaryliodonium salts, a novel approach was developed for the synthesis of ortho‐iodo diaryl ethers by intramolecular aryl migration. The reaction conditions are mild with a broad substrate scope. Mechanistic insight suggests a sulfonyl‐directed nucleophilic aromatic substitution pathway. Additionally, the product ortho‐iodo diaryl ethers serve as versatile synthons as demonstrated with several coupling reactions. Furthermore, a useful thyroxine analogue of the 3‐iodo‐l ‐thyronine (3‐T₁) derivative was synthesized by this aryl migration procedure.     

Concerted Bimetallic Nanocluster Synthesis and Encapsulation via Induced Zeolite Framework Demetallation for Shape and Substrate Selective Heterogeneous Catalysis

Bimetallic nanoparticle encapsulation in microporous zeolite crystals is a promising route for producing catalysts with unprecedented reaction selectivities. Herein, a novel synthetic approach was developed to produce PtZn_x nanoclusters encapsulated inside zeolite micropores by introducing Pt²⁺ cations into a zincosilicate framework via ion exchange, and subsequent controlled demetallation and alloying with framework Zn. The resulting zeolites featured nanoclusters with sizes of approximately 1 nm, having an interatomic structure corresponding to a PtZn_x alloy as confirmed by pair distribution function (PDF) analysis. These materials featured simultaneous shape and substrate specificity demonstrated by the selective production of p‐chloroaniline from the competitive hydrogenation of p‐chloronitrobenzene and 1,3‐dimethyl‐5‐nitrobenzene.     

Radical Alkyne peri‐Annulation Reactions for the Synthesis of Functionalized Phenalenes,Benzanthrenes, and Olympicene

Radical cyclization reactions at a peri position were used for the synthesis of polyaromatic compounds. Depending on the choice of reaction conditions and substrate, this flexible approach led to Bu₃Sn‐substituted phenalene, benzanthrene, and olympicene derivatives. Subsequent reactions with electrophiles provided synthetic access to previously inaccessible functionalized polyaromatic compounds.     

Simulaaneous ethanol and cellobiose inhibition of cellulose hydrolysis studied with integrated equations assuming constant or variable substrate concentration

The integrated forms of the Michaelis-Menten equation assuming variable substrate (depletion) or constant substrate concentration were used to study the effect of the simultaneous presence of two exoglucanase Cel7A inhibitors (cellobiose and ethanol) on the kinetics of cellulose hydrolysis. The kinetic parameters obtained, assuming constant substrate (K _m =21 mM, K _ic =0.035 mM; K _icl =1.5×10¹⁵mM; k _cat=12 h⁻¹) or assuming variable substrate (K _m =16 mM, K _ic =0.037 mM; K _icl =5.8×10¹⁴ mM; k _cat=9 h⁻¹), showed a good similarity between these two alternative methodologies and pointed out that bothethanol and cellobiose are competitive inhibitors. Nevertheless, ethanol is a very weak inhibitor, as shown by the large value estimated for the kinetic constant K _icl . In addition, assuming different concentrations of initial accessible substrate present in the reaction, both inhibition and velocity constants are at the same order of magnitude, which is consistent with the obtained values. The possibility of using this kind of methodology to determine kinetic constants in general kinetic studies is discussed, and several integrated equations of different Michaelis-Menten kinetic models are presented. Also examined is the possibility of determining inhibition constants without knowledge of the true accessible substrate concentration.     

Radical Alkyne peri‐Annulation Reactions for the Synthesis of Functionalized Phenalenes,Benzanthrenes, and Olympicene

Radical cyclization reactions at a peri position were used for the synthesis of polyaromatic compounds. Depending on the choice of reaction conditions and substrate, this flexible approach led to Bu₃Sn‐substituted phenalene, benzanthrene, and olympicene derivatives. Subsequent reactions with electrophiles provided synthetic access to previously inaccessible functionalized polyaromatic compounds.     

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.     

Region‐Selective Deposition of Core–Shell Nanoparticles for 3 D Hierarchical Assemblies by the Huisgen 1,3‐Dipolar Cycloaddition

A method for the region‐selective deposition of nanoparticles (NPs) by the Huisgen 1,3‐dipolar cycloaddition is presented. The approach enables defined stacking of various oxide NPs in any order with control over layer thickness. Thereby the reaction is performed between a substrate, functionalized with a self‐assembled monolayer of an azide‐bearing phosphonic acid (PA) and aluminum oxide (AlO_x) NPs functionalized with an alkyne bearing PA. The layer of alkyne functionalized AlO_x NPs is then used as substrate for the deposition of azide‐functionalized indium tin oxide (ITO) NPs to provide a binary stack. This progression is then conducted with alkyne‐functionalized CeO₂ NPs, yielding a ternary stack of NPs with three different NP cores. The stacks are characterized by AFM and SEM, defining the region‐selectivity of the deposition technique. Finally, these assemblies have been tested in devices as a dielectric to form a capacitor resulting in a dramatic increase in the measured capacitance.     

Photochromic Coatings Containing Ag(Cl1−xBrx) Microcrystals

Photochromic ormosil coatings containing Ag(Cl_1–x Br _x ) microcrystals were formed on a glass substrate via the sol-gel process. Methyltrimethoxysilane and 3-glycidoxypropyltrimethoxysilane were used as starting materials of the ormosil matrices. 3-chloropropyltrimethoxysilane and bromophenyltrimethoxysilane were added as halogen sources and silver colloidal dispersion was introduced into the precursor sol. The coated glass became transparent and photosensitive after Ag(Cl_1–x Br _x ) microcrystals were precipitated in the coatings above 300°C. Insertion of a SiO₂ buffer layer between the substrate and photochromic layer was effective in preventing Ag⁺ migration into the substrate. Photochromic performances were improved by the substitution of Cl with Br and the incorporation of a minute amount of Cu.     

Engineered Substrate‐Specific Delta PKC Antagonists to Enhance Cardiac Therapeutics

Most protein kinases phosphorylate multiple substrates, each of which induces different and sometimes opposing functions. Determining the role of phosphorylation of each substrate following a specific stimulus is challenging but is essential to elucidate the role of that substrate in the signaling event. Here we describe a rational approach to identify inhibitors of delta protein kinase C (δPKC), each inhibiting the phosphorylation of only one of δPKC′s substrates. δPKC regulates many signaling events and we hypothesized that a docking inhibitor of a given substrate to δPKC should selectively abrogate the phosphorylation of only that substrate, without affecting the phosphorylation of the other δPKC substrates. Here we report the development of selective inhibitors of three δPKC substrates (in vitro K_d≈3 nm ); two greatly reduced ischemia‐induced cardiac injury with an IC₅₀ of ≈200 nm and the third had no effect, indicating that its respective substrate phosphorylation by δPKC has no role in the response to cardiac ischemia and reperfusion. The three inhibitors are highly specific; even at 1 μm , the phosphorylation of other δPKC protein substrates was unaffected. The rationale we describe is likely applicable for the development of other substrate‐specific inhibitors as well.     

Controlled Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides

A chemoenzymatic approach has been developed for the preparation of diverse libraries of heparan sulfate (HS) oligosaccharides. It employs chemically synthesized oligosaccharides having a chemical entity at a GlcN residue, which in unanticipated manners influences the site of modification by NST, C5‐Epi/2‐OST and 6‐OST₁/6‐OST₃, thus resulting in oligosaccharides differing in N/O‐sulfation and epimerization pattern. The enzymatic transformations defined fine substrate requirements of NST, C5‐Epi, 2‐OST, and 6‐OST.     

Deposition of Gallium Nitride Thin Films by MOCVD in Microwave Plasma

The deposition of GaN thin films in a nitrogen–hydrogen microwave plasma using Ga(CH ₃ ) ₃ as a gallium precursor was investigated. The deposit was identified as stoichiometric GaN by XPS and XRD. The substrate was dielectrically heated in the microwave discharge and the substrate temperature was lower than that in usual thermal MOCVD. The NH radicals, which were the primary N-atoms precursors, and fragments of Ga(CH ₃ ) ₃ were identified in the plasma by OES. The NH radical formation and the decomposition of Ga(CH ₃ ) ₃ in the plasma may be one of the reasons for the lower deposition temperature of GaN. The position dependence of the substrate temperature showed similar tendency as the position dependence of the electron temperature. The plasma state contributes to the deposition of GaN thin films. The deposited GaN exhibited a wide optical band gap of 3.4eV. Material highly oriented along the c axis was detected in the deposit, and a PL spectrum which has the band head at about 450 mm was obtained.     

Can Water Act as a Nucleophile in CO Oxidation Catalysed by Mo/Cu CO-Dehydrogenase? Answers from Theory

The aerobic CO dehydrogenase from Oligotropha carboxidovorans is an environmentally crucial bacterial enzyme for maintenance of subtoxic concentration of CO in the lower atmosphere, as it allows for the oxidation of CO to CO₂ which takes place at its Mo−Cu heterobimetallic active site. Despite extensive experimental and theoretical efforts, significant uncertainties still concern the reaction mechanism for the CO oxidation. In this work, we used the hybrid quantum mechanical/molecular mechanical approach to evaluate whether a water molecule present in the active site might act as a nucleophile upon formation of the new C−O bond, a hypothesis recently suggested in the literature. Our study shows that activation of H₂O can be favoured by the presence of the Mo=O_eq group. However, overall our results suggest that mechanisms other than the nucleophilic attack by Mo=O_eq to the activated carbon of the CO substrate are not likely to constitute reactive channels for the oxidation of CO by the enzyme.     

Preliminary attempt to follow the enthalpy of an enzymatic reaction by ab initio computations: Catalytic action of papain

A new theoretical approach to study the enthalpy variations occurring during an enzymatic reaction is presented. The structural modifications of the enzyme–substrate complex along the reaction path are distinguished as macro- and microdeformations. Macrodeformations, which concern primarily the approach of the substrate to the enzyme and the release of the reaction products and arise from nonbonded interactions, are treated with an empirical method for computing the energy of a macromolecule. Microdeformations, which are local displacements driven by variations of the electronic structure and its energy and involve only a limited portion of the complex, are treated with the ab initio SCF-LCAO-MO method. The reaction path is idealized as a sequence of major steps: at each step, first the empirical program REFINE is used to calculate the geometry of the system for that step, then the energy of an appropriate subsystem is computed ab initio with the program IBMOL, using the geometry provided by REFINE and applying small concerted atomic displacements. Thus along the entire reaction path one can obtain an energy profile computed with the ab initio method and compatible with the structure of the whole complex. This approach was applied here to the first steps of the reaction of proteolysis catalyzed by papain. The formation of an ion pair ImH⁺ …S^? between the side chains of residues His-159 and Cys-25 was examined in detail. The results show that the instability of the ion pair decreases by ? 11.5 kcal/mol when the interactions with residues Asn-175 and Ala- 160 are taken into account; the instability is further decreased by ?2 kcal/mol after a partial geometry optimization. The energies of the noncovalent enzyme–substrate complex and of the tetrahedral intermediate were computed, considering N-methyl acetamide (NMA) as model substrate and representing papain with the residues Cys-25, His-159, Gln-19, and Ala-160. The interaction energy of the noncovalent complex is -3.8 kcal/mol, compared to the value of +7.4 kcal/mol for the CH₃S^? -NMA complex. The tetrahedral intermediate is found to be less stable than the noncovalent complex by 27 and 38.5 kcal/mol, respectively, for the papain–NMA and the CH₃S^? -NMA systems. While these rather large energy differences are possibly due to the incorrect geometry of the tetrahedral intermediate and optimization of the structure is required, it appears that the interactions with the various protein residues represent a very important stabilization factor, which lowers the onthalpy variations during the reaction.     

Large-Scale Molecular Dynamics Simulations of Energetic Ni Nanocluster Impact onto the Surface

On the atomic scale, Molecular Dynamics (MD) Simulation of Nano Ni cluster impact on Ni (100) substrate surface have been carried out for energies of E _a = 1–5 eV/atom and total energy of E _T = 195 eV (the total energy of cluster is E _T = nE _a, n is the number of cluster atoms) to understand quantitatively the interaction mechanisms between the cluster atoms and the substrate atoms. The many-body Embedded Atom Method (EAM) was used in this simulation. We investigated the maximum substrate temperature T _max and the time t _max within which this temperature is reached as a function of cluster sizes and the total energy E _T. The temperature T _max is linearly proportional to total cluster energy. For the constant energy per atom and for the cluster size increase, the correlated collisions rapidly transfers energy to the substrate, and the time t _max approached a constant value. For constant total energy the temperature T _max and the time t _max versus different cluster sizes was studied. We showed that the cluster implantation and sputtering atoms from the surface are affected by the cluster size and total kinetic energy of the clusters. Finally time dependence of the number N _dis of disordered atoms in the substrate was observed.