Graphene Oxide Promotes Site-Selective Allylic Alkylation of Thiophenes with Alcohols

The graphene oxide (GO) assisted allylic alkylation of thiophenes with alcohols is presented. Mild reaction conditions and a low GO loading enabled the isolation of a range of densely functionalized thienyl and bithienyl compounds in moderate to high yields (up to 90%). The cooperative action of the Bronsted acidity, epoxide moieties, and pi-surface of the 2D-promoter is highlighted as crucial in the reaction course of the present Friedel-Crafts-type protocol

C–CN vs C–H Activation: Actual Mechanism of the Reaction between [(dippe)PtH]₂ and Benzonitrile Evidenced by a DFT Computational Investigation

In this paper we have carried out a DFT computational investigation on the reaction of [(dippe)]­PtH]₂ (<b>1b</b>) with benzonitrile (PhCN) leading to the products (dippe)­Pt­(H)­(2-C₆H₄CN) (<b>2</b>) and (dippe)­Pt­(Ph)­CN (<b>5</b>), which formally result from benzonitrile C–H and C–CN activation, respectively. Actually, DFT results indicate a process following a stepwise mechanism that satisfactorily explains the experimental evidence. <b>5</b> is a very stable species (19.1 kcal mol^–1 below reactants and significantly more stable than compound <b>2</b>). Computations clearly show that <b>5</b> does not represent an intermediate of the process eventually leading to the final products (dippe)­Pt­(H)­CN (<b>3</b>) and (dippe)­Pt­(CN)­(C₆H₄CN) (<b>4</b>). The favored path leading to product <b>3</b> originates directly from <b>1b</b>, which is in equilibrium with the adduct <b>2</b>. The highest energy transition state that must be overcome to give <b>3</b> is 29.1 kcal mol^–1 above the reactants. Surmounting this transition structure can be considered a feasible task at the working temperature of 140 °C. Product <b>3</b> can be obtained only when a second PhCN molecule is involved in the process. PhCN behaves like a hydrogen carrier: it provides the hydrogen finally bonded to platinum in <b>3</b> and contributes to form a benzene molecule, which is released in the course of the reaction, as experimentally observed. This PhCN molecule can be considered as a catalyst of the process. Its involvement explains why, when <b>2</b> is heated in the absence of PhCN, no reaction is observed. Only in the presence of PhCN can <b>1b</b>, which is in equilibrium with <b>2</b>, complete the process to give <b>3</b>

Thermodynamics of Binding Between Proteins and Carbon Nanoparticles: The Case of C₆₀@Lysozyme

The analysis of the interaction between C₆₀ and lysozyme provides general rules to identify the forces that govern the thermodynamics of binding between proteins and carbon nanoparticles. The main driving force of the binding are van der Waals interactions. Polar solvation and entropy, contributions that are often neglected, are strongly detrimental to the binding. These energetically relevant terms must be taken into account when protein/CNP hybrids are designed

Cl⁽⁻⁾ Exchange S_N2 Reaction inside Carbon Nanotubes: C–H···π and Cl···π Interactions Govern the Course of the Reaction

The carbon nanotube (CNT)-confined chloride exchange S_N2 reaction for methyl chloride has been examined using either a full quantum mechanical (QM) DFT approach based on the M06-2X functional or a hybrid approach where a (6,6) CNT is satisfactorily described by the molecular mechanics (MM) UFF force field and the substrate by the M06-2X functional (M06-2X/UFF approach). We found that inside the CNT the reaction is disfavored with respect to the gas phase, the intrinsic reaction barrier <i>E</i>_a (difference between the preliminary complex <b>I</b> and transition state <b>TS</b>) being 17.9 kcal mol^–1 (13.2 kcal mol^–1 in the gas phase). The augmented barrier, with respect to the gas phase, can be ascribed to a complex interplay between Cl···π and C–H···π interactions (i.e., interactions of the two Cl atoms and the C–H bonds of the substrate with the carbon electron cloud of the tube wall). While the Cl···π interactions behave like a molecular glue which sticks the two Cl atoms to the tube wall and remain approximately constant in <b>I</b> and <b>TS</b>, the importance of the stabilizing C–H···π interactions is significantly lower in <b>TS</b> with a consequent increase of the barrier. The barrier increases with the increase of the tube length to reach the asymptotic value of 19.9 kcal mol^–1 for tube length larger than 24.4 Å. This value is the minimum length of a (6,6) CNT model system that can emulate the CNT-confined S_N2 reaction and provides useful suggestions to build reliable model systems for other S_N2 reactions and, in general, different chemical processes. Furthermore, the activation barrier <i>E</i>_a is strongly affected by the tube radius. Because of the reduced volume inside the tube causing a strong structural distortion in <b>TS</b>, <i>E</i>_a is very large for small tube radii (34.4 kcal mol^–1 in the (4,4) case). When the volume increases enough (tube (5,5)) to avoid the distortion, the barrier suddenly decreases and remains approximately constant (about 20 kcal mol^–1) for tubes in the range (5,5) to (8,8). The activation barrier grows for a (9.9) tube, and the value again remains approximately constant (about 22 kcal mol^–1) for larger tubes

CNT-Confinement Effects on the Menshutkin S_N2 Reaction: The Role of Nonbonded Interactions

We investigated the effects of CNT confinement ((6,6) tube) on the model Menshutkin reaction H₃N + H₃CCl = H₃NCH₃⁽⁺⁾ + Cl⁽⁻⁾, which is representative of chemical processes involving developing of charge separation along the reaction pathway. We used either a full QM approach or a hybrid QM/MM approach. We found that the CNT significantly lowers the activation barrier with respect to the hypothetical gas-phase reaction: The activation barrier <i>E</i>_a varies from 34.6 to 25.7 kcal mol^–1 (a value similar to that found in a nonpolar solvent) and the endothermicity Δ<i>E</i> from 31.2 to 13.5 kcal mol^–1. A complex interplay between C–H···π, N–H···π, and Cl···π nonbonded interactions of the endohedral system with the CNT wall explains the lower barrier and lower endothermicity. The hybrid QM/MM approach (MM = UFF force field) does not reproduce satisfactorily the QM energy Δ<i>E</i> (18.1 vs 13.5 kcal mol^–1), while optimum agreement is found in the barrier <i>E</i>_a (25.8 vs 25.7 kcal mol^–1). These results suggest that the simple Qeq formalism (included in the MM potential) does not describe properly the effect of CNT polarization in the presence of the net charge separation featuring the final product. A more accurate estimate of the tube polarization was obtained with single-point QM/MM computations including PCM corrections (using the benzene dielectric constant) on the QM/MM optimized structures. After PCM corrections, <i>E</i>_a changes slightly (from 25.8 to 24.5 kcal mol^–1), but a more significant variation is observed for Δ<i>E</i> that becomes 13.1 kcal mol^–1, in rather good agreement with the full QM. This level of theory (QM/MM with PCM correction, MM = UFF) represents a more general approach suitable for describing CNT-confined chemical processes involving significant charge separation. QM/MM computations were extended to CNTs of different radii: (4,4), (5,5), (7,7), (8,8), (9,9), (10,10), (12,12), (14,14) CNTs and, as a limit case, a graphene sheet. The lack of space available in the small tube (4,4) causes a strong structural distortion and a consequent increase in <i>E</i>_a and Δ<i>E</i> (40.8 and 44.0 kcal mol^–1, respectively). These quantities suddenly decrease with the augmented volume inside the (5,5) tube. For larger tubes, different structural arrangements of the endohedral system are possible, and <i>E</i>_a and Δ<i>E</i> remain almost constant until the limiting case of graphene

Computational Evidence for the Catalytic Mechanism of Tyrosylprotein Sulfotransferases: A Density Functional Theory Investigation

In this paper we have examined the mechanism of tyrosine <i>O</i>-sulfonation catalyzed by human TPST-2. Our computations, in agreement with Teramoto’s hypothesis, indicate a concerted S_N2-like reaction (with an activation barrier of 18.2 kcal mol^–1) where the tyrosine oxygen is deprotonated by Glu⁹⁹ (base catalyst) and simultaneously attacks as a nucleophile the sulfuryl group. For the first time, using a quantum mechanics protocol of alanine scanning, we identified unequivocally the role of the amino acids involved in the catalysis. Arg⁷⁸ acts as a shuttle that “assists” the sulfuryl group moving from the 3′-phosphoadenosine-5′-phosphosulfate molecule to threonine and stabilizes the transition state (TS) by electrostatic interactions. The residue Lys¹⁵⁸ keeps close the residues participating in the overall H-bond network, while Ser²⁸⁵, Thr⁸¹, and Thr⁸² stabilize the TS via strong hydrogen interactions and contribute to lower the activation barrier

Functionalization Pattern of Graphene Oxide Sheets Controls Entry or Produces Lipid Turmoil in Phospholipid Membranes

Molecular dynamics, coarse-grained to the level of hydrophobic and hydrophilic interactions, shows that graphene oxide sheets, GOSs, can pierce through the phospholipid membrane and navigate the double layer only if the hydrophilic groups are randomly dispersed in the structure. Their behavior resembles that found in similar calculations for pristine graphene sheets. If the oxidation is located at the edge of the sheets, GOSs hover over the membrane and trigger a major reorganization of the lipids. The reorganization is the largest when the radius of the edge-functionalized sheet is similar to the length of the lipophilic chain of the lipids. In the reorganization, the heads of the lipid chains form dynamical structures that pictorially resemble the swirl of water flowing down a drain. All effects maximize the interaction between hydrophobic moieties on the one hand and lipophilic fragments on the other and are accompanied by a large number of lipid flip-flops. Possible biological consequences are discussed

Blocking the Passage: C₆₀ Geometrically Clogs K⁺ Channels

Classical molecular dynamics (MD) simulations combined with docking calculations, potential of mean force estimates with the umbrella sampling method, and molecular mechanic/Poisson–Boltzmann surface area (MM-PBSA) energy calculations reveal that C₆₀ may block K⁺ channels with two mechanisms: a low affinity blockage from the extracellular side, and an open-channel block from the intracellular side. The presence of a low affinity binding-site at the extracellular entrance of the channel is in agreement with the experimental results showing a fast and reversible block without use-dependence, from the extracellular compartment. Our simulation protocol suggests the existence of another binding site for C₆₀ located in the channel cavity at the intracellular entrance of the selectivity filter. The escape barrier from this binding site is ∼21 kcal/mol making the corresponding kinetic rate of the order of minutes. The analysis of the change in solvent accessible surface area upon C₆₀ binding shows that binding at this site is governed purely by shape complementarity, and that the molecular determinants of binding are conserved in the entire family of K⁺ channels. The presence of this high-affinity binding site conserved among different K⁺ channels may have serious implications for the toxicity of carbon nanomaterials

Aromatic Bromination of <i>N</i>‑Phenylacetamide Inside CNTs. Are CNTs Real Nanoreactors Controlling Regioselectivity and Kinetics? A QM/MM Investigation

We carried out a computational investigation on the mechanism of the bromination reaction of <i>N</i>-phenylacetamide inside CNTs, in water, and in an aprotic solvent (ethylbenzene). A full QM and a QM/MM approach was used. In the aprotic solvent, a Wheland intermediate (ion pair formed by arenium ion and chloride) exists only for the attack in the <i>ortho</i> position, while the <i>para</i> attack proceeds in a concerted manner (concerted direct substitution). The reaction is catalyzed by the HCl byproduct, which lowers significantly the activation barriers. The <i>ortho</i> product is favored, in contrast to the common belief based on simple steric effects. In water solution a Wheland intermediate was located for both <i>ortho</i> and <i>para</i> attacks (the ion pair is stabilized by the polar protic solvent). The formation of the <i>para</i> product is favored with respect to the <i>ortho</i> product: 9.0 and 9.9 kcal mol^–1 are the corresponding activation barriers. Inside CNTs, as found in aprotic solvent, the Wheland-type arenium ion exists only along the <i>ortho</i> pathway. The initial production of the HCl byproduct activates rapidly the catalyzed mechanism that proceeds almost exclusively along the <i>para</i> pathway (<i>para</i> and <i>ortho</i> activation barriers are 6.1 and 17.0 kcal mol^–1, respectively). The almost exclusive <i>para</i> regioselectivity for the CNT-confined reaction and its acceleration with respect to water (in agreement with the experimental evidence) are due to noncovalent (van der Waals) interactions between the endohedral system and the electron cloud of the surrounding CNT. The effect of these interactions was estimated quantitatively within the UFF scheme used in our QM/MM computations, and we found that they are particularly stabilizing for the <i>para</i>-catalyzed process

Stacked Naphthyls and Weak Hydrogen-Bond Interactions Govern the Conformational Behavior of <i>P</i>‑Resolved Cyclic Phosphonamides: A Combined Experimental and Computational Study

<i>P</i>-Enantiomerically pure cyclic phosphonamides have been synthesized via a cyclization reaction of (<i>S</i>,<i>S</i>)-aminobenzylnaphthols with chloromethylphosphonic dichloride. The reaction is highly stereoselective and gives almost exclusively (<i>S</i>,<i>S</i>,<i>S</i>_P)-cyclic phosphonamides in good yields. Analysis of the X-ray crystal structures shows clearly that the cyclization reaction forces the two naphthyl rings into a stable parallel displaced stacking assembly and indicates also the existence of intramolecular CH···π interactions and weak forms of intermolecular hydrogen bondings, involving the oxygen and the chlorine atoms. QM computations and NMR spectra in solution confirm the stacked molecular assembly as the preferred arrangement of the two naphthyl groups