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1. Can Water Trigger Room‐Temperature Formation of Benzofuran‐2( 3H )‐one Scaffolds From Vinyldiazene Derivatives? Computational Insights Into an Unusual Cyclization

   https://doi.org/10.1002/jcc.70102  

   Askerova, Ulviyya; Abdullayev, Yusif; Shikhaliyev, Namiq; Talybov, Avtandil; Autschbach, Jochen (April 2025, Journal of Computational Chemistry)

   ABSTRACT Access to benzofuran‐2(3H)‐one derivatives from readily available substrates under mild conditions is crucial in the pharmaceutical and plastics industries. We identified (Z)‐3‐(2‐phenylhydrazineylidene)benzofuran‐2(3H)‐one (P) during the recrystallization of (E)‐2‐(2,2‐dichloro‐1‐(phenyldiazenyl)vinyl)phenol using a 96% ethanol solution. The mechanism of the unexpected substrate conversion leading toPis investigated using density functional calculations. The computations revealed that ethanol is required to initiate the reaction viaTS1E, which involves a concerted deprotonation of ethanol by the basic diaza group of the substrate and an ethoxy group attacking the electrophilic center (Cl₂C), with an energy barrier of 28.3 kcal/mol. The resulting intermediate (I1E) is calculated to be unstable and can yield a cyclic chloroacetal adduct with a lower energy barrier of 2.2 kcal/mol via the ring‐closure transition state (TS2E). In the absence of water, the next steps are impossible because water is required to cleave the ether bond, yieldingP. A small amount of water (4% of the recrystallization solvent) can promote further transformation ofI2Evia the transition statesTS3E(∆G^‡ = 11.1 kcal/mol) andTS4E(∆G^‡ = 10.5 kcal/mol). A comparison of the ethanol/water‐ and only water‐promoted free energy profiles shows that the presence of ethanol is crucial for lowering the energy barriers (by about 5 kcal/mol) for the initial two steps leading to the cyclic chloroacetal (I2E), whereas water is then required to initiate product formation. 

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2. Quantifying the barrier for the movement of cyclobis(paraquat- p -phenylene) over the dication of monopyrrolotetrathiafulvalene

   https://doi.org/10.1039/d1ob02263f  

   Kristensen, Rikke; Neumann, Mathias S.; Andersen, Sissel S.; Stein, Paul C.; Flood, Amar H.; Jeppesen, Jan O. (March 2022, Organic & Biomolecular Chemistry)

   A bistable [2]pseudorotaxane 1⊂CBPQT·4PF 6 and a bistable [2]rotaxane 2·4PF 6 have been synthesised to measure the height of an electrostatic barrier produced by double molecular oxidation (0 to +2). Both systems have monopyrrolotetrathiafulvalene (MPTTF) and oxyphenylene (OP) as stations for cyclobis(paraquat- p -phenylene) (CBPQT 4+ ). They have a large stopper at one end while the second stopper in 2 4+ is composed of a thioethyl (SEt) group and a thiodiethyleneglycol (TDEG) substituent, whereas in 1⊂CBPQT 4+ , the SEt group has been replaced with a less bulky thiomethyl (SMe) group. This seemingly small difference in the substituents on the MPTTF unit leads to profound changes when comparing the physical properties of the two systems allowing for the first measurement of the deslipping of the CBPQT 4+ ring over an MPTTF 2+ unit in the [2]pseudorotaxane. Cyclic voltammetry and 1 H NMR spectroscopy were used to investigate the switching mechanism for 1⊂CBPQT·MPTTF 4+ and 2·MPTTF 4+ , and it was found that CBPQT 4+ moves first to the OP station producing 1⊂CBPQT·OP 6+ and 2·OP 6+ , respectively, upon oxidation of the MPTTF unit. The kinetics of the complexation/decomplexation process occurring in 1⊂CBPQT·MPTTF 4+ and in 1⊂CBPQT·OP 6+ were studied, allowing the free energy of the transition state when CBPQT 4+ moves across a neutral MPTTF unit (17.0 kcal mol −1 ) or a di-oxidised MPTTF 2+ unit (24.0 kcal mol −1 ) to be determined. These results demonstrate that oxidation of the MPTTF unit to MPTTF 2+ increases the energy barrier that the CBPQT 4+ ring must overcome for decomplexation to occur by 7.0 kcal mol −1 . 

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3. Methane Over‐Oxidation by Extra‐Framework Copper‐Oxo Active Sites of Copper‐Exchanged Zeolites: Crucial Role of Traps for the Separated Methyl Group

   https://doi.org/10.1002/cphc.202100103  

   Adeyiga, Olajumoke; Odoh, Samuel_O (April 2021, ChemPhysChem)

   Abstract Copper‐exchanged zeolites are useful for stepwise conversion of methane to methanol at moderate temperatures. This process also generates some over‐oxidation products like CO and CO₂. However, mechanistic pathways for methane over‐oxidation by copper‐oxo active sites in these zeolites have not been previously described. Adequate understanding of methane over‐oxidation is useful for developing systems with higher methanol yields and selectivities. Here, we use density functional theory (DFT) to examine methane over‐oxidation by [Cu₃O₃]²⁺active sites in zeolite mordenite MOR. The methyl group formed after activation of a methane C−H bond can be stabilized at a μ‐oxo atom of the active site. This μ‐(O−CH₃) intermediate can undergo sequential hydrogen atom abstractions till eventual formation of a copper‐monocarbonyl species. Adsorbed formaldehyde, water and formates are also formed during this process. The overall mechanistic path is exothermic, and all intermediate steps are facile at 200 °C. Release of CO from the copper‐monocarbonyl costs only 3.4 kcal/mol. Thus, for high methanol selectivities, the methyl group from the first hydrogen atom abstraction stepmust bestabilizedawayfrom copper‐oxo active sites. Indeed, it must be quickly trapped at an unreactive site (short diffusion lengths) while avoiding copper‐oxo species (large paths between active sites). This stabilization of the methyl group away from the active sites is central to the high methanol selectivities obtained with stepwise methane‐to‐methanol conversion. 

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4. Computational mechanistic studies of the carbon–carbon double bond difunctionalization via epoxidation and subsequent aminolysis in vegetable oils

   https://doi.org/10.1002/qua.26609  

   Abdullayev, Yusif; Abbasov, Vagif; Nasirov, Fuzuli; Rzayeva, Nigar; Nasibova, Leyla; Autschbach, Jochen (February 2021, International Journal of Quantum Chemistry)

   Abstract The industrial importance of the CC double bond difunctionalization in vegetable oils/fatty acid chains motivates computational studies aimed at helping to improve experimental protocols. The CC double bond epoxidation is studied with hydrogen peroxide, peracetic acid (CH₃CO₃H), and performic acid (HCO₃H) oxidizing agents. The epoxide ring‐opening mechanism is calculated in the presence of ZnCl₂, NiCl₂, and FeCl₂Lewis acidic catalysts. Computations show that H₂O₂(∆G^‡= 39 kcal/mol,TS1_HP) is not an effective oxidizing agent compared to CH₃CO₃H (∆G^‡= 29.8 kcal/mol,TS1_PA) and HCO₃H (∆G^‡= 26.7 kcal/mol,TS1_PF). The FeCl₂(∆G^‡= 14.7 kcal/mol,TS1_FC) coordination to the epoxide oxygen facilitates the ring‐opening via lower energy barriers compared to the ZnCl₂(∆G^‡= 19.5 kcal/mol,TS1_ZC) and NiCl₂(∆G^‡= 29.4 kcal/mol,TS1_NC) coordination. ZnCl₂was frequently utilized as a catalyst in laboratory‐scale procedures. The energetic span model identifies the FeCl₂(FC) catalytic cycle as the best option for the epoxide ring‐opening. 

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5. Assessing the Catalytic Role of Native Glucagon Amyloid Fibrils

   https://doi.org/10.1021/acscatal.4c00452  

   Nandi, Ashim; Zhang, Aoxuan; Arad, Elad; Jelinek, Raz; Warshel, Arieh (April 2024, ACS Catalysis)

   Glucagon stands out as a pivotal peptide hormone, instrumental in controlling blood glucose levels and lipid metabolism. While the formation of glucagon amyloid fibrils has been documented, their biological functions remain enigmatic. Recently, we demonstrated experimentally that glucagon amyloid fibrils can act as catalysts in several biological reactions including esterolysis, lipid hydrolysis, and dephosphorylation. Herein, we present a multiscale quantum mechanics/molecular mechanics (QM/MM) simulation of the acylation step in the esterolysis of para-nitrophenyl acetate (p-NPA), catalyzed by native glucagon amyloid fibrils, serving as a model system to elucidate their catalytic function. This step entails a concerted mechanism, involving proton transfer from serine to histidine, followed by the nucleophilic attack of the serine oxy anion on the carbonyl carbon of p-NPA. We computed the binding energy and free-energy profiles of this reaction using the protein-dipole Langevin-dipole (PDLD) within the linear response approximation (LRA) framework (PDLD/S-LRA-2000) and the empirical valence bond (EVB) methods. This included simulations of the reaction in an aqueous environment and in the fibril, enabling us to estimate the catalytic effect of the fibril. Our EVB calculations obtained a barrier of 23.4 kcal mol-1 for the enzyme-catalyzed reaction compared to the experimental value of 21.9 kcal mol-1 (and a calculated catalytic effect of 3.2 kcal mol-1 compared to the observed effect of 4.7 kcal mol-1). This close agreement together with the barrier reduction when transitioning from the reference solution reaction to the amyloid fibril provides supporting evidence to the catalytic role of glucagon amyloid fibrils. Moreover, employing the PDLD/S-LRA-2000 approach further reinforced exclusively the enzyme's catalytic role. The results presented in this study contribute significantly to our understanding of the catalytic role of glucagon amyloid fibrils, marking, to the best of our knowledge, the first-principles mechanistic investigation of fibrils using QM/MM methods. Therefore, our findings offer fruitful insights for future research into the mechanisms of related amyloid catalysis. 

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