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1. Strain Release in Hydrogen Atom Transfer from 1,4-Disubstituted Cyclohexanes to the Cumyloxy Radical

   https://doi.org/10.1055/a-2522-6204  

   Galeotti, Marco; Palone, Andrea; Salamone, Michela; Liu, Fengjiao; Yu, Yanmin; Houk, K N; Bietti, Massimo (June 2025, Synlett)

   Abstract A kinetic, product, and computational study on the reactions of the cumyloxyl radical (CumO•) with 1,4-dimethyl- and 1,4-diphenylcyclohexanes is reported. The rate constants for hydrogen atom transfer (HAT) from the C–H bonds of these substrates to CumO•, together with the corresponding oxygenation product distributions reveal the role of strain release on reaction site selectivity. Transition structures and activation barriers obtained by DFT calculations are in excellent agreement with the experimental results. Tertiary/secondary ratios of oxygenation products of 0.6, 1.0, and 3.3 were observed, for trans-1,4-dimethyl-, cis-1,4-dimethyl-, and trans-1,4-diphenylcyclohexane, respectively. With cis-1,4-diphenylcyclohexane, exclusive formation of the diastereomeric tertiary alcohol products was observed. Within the two diastereomeric couples, the tertiary equatorial C–H bond in the cis- isomer is ca. 6 and 27 times more reactive, respectively, than the tertiary axial ones, a behavior that reflects the release of 1,3-diaxial strain in the HAT transition state. The tertiary axial C–H bonds of the four substrates show remarkably similar reactivities in spite of the much greater stabilization of the benzyl radicals resulting from HAT from the 1,4-diphenylcyclohexanes. The lack of benzylic acceleration is discussed in the framework of Bernasconi’s ‘principle of nonperfect synchronization’. 

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2. A predictive journey towards trans -thioamides/amides

   https://doi.org/10.1039/D2CC04228B  

   Tomasini, Michele; Zhang, Jin; Zhao, Hui; Besalú, Emili; Falivene, Laura; Caporaso, Lucia; Szostak, Michal; Poater, Albert (September 2022, Chemical Communications)

   The cis – trans isomerization of (thio)amides was studied by DFT calculations to get the model for the higher preference for the cis conformation by guided predictive chemistry, suggesting how to select the alkyl/aryl substituents on the C/N atoms that lead to the trans isomer. Multilinear analysis, together with cross-validation analysis, helped to select the best fitting parameters to achieve the energy barriers of the cis to trans interconversion, as well as the relative stability between both isomers. Double experimental check led to the synthesis of the best trans candidate with sterically demanding t -butyl substituents, confirming the utility of predictive chemistry, bridging organic and computational chemistry. 

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3. Excited‐State Distortions Promote the Photochemical 4π‐Electrocyclizations of Fluorobenzenes via Machine Learning Accelerated Photodynamics Simulations

   https://doi.org/10.1002/chem.202200651  

   Li, Jingbai; Lopez, Steven_A (May 2022, Chemistry – A European Journal)

   Abstract Benzene fluorination increases chemoselectivities for Dewar‐benzenes via 4π‐disrotatory electrocyclization. However, the origin of the chemo‐ and regioselectivities of fluorobenzenes remains unexplained because of the experimental limitations in resolving the excited‐state structures on ultrafast timescales. The computational cost of multiconfigurational nonadiabatic molecular dynamics simulations is also currently cost‐prohibitive. We now provide high‐fidelity structural information and reaction outcome predictions with machine‐learning‐accelerated photodynamics simulations of a series of fluorobenzenes, C₆F_6‐nH_n, n=0–3, to study their S₁→S₀decay in 4 ns. We trained neural networks with XMS‐CASPT2(6,7)/aug‐cc‐pVDZ calculations, which reproduced the S₁absorption features with mean absolute errors of 0.04 eV (<2 nm). The predicted nonradiative decay constants for C₆F₄H₂, C₆F₆, C₆F₃H₃, and C₆F₅H are 116, 60, 28, and 12 ps, respectively, in broad qualitative agreement with the experiments. Our calculations show that a pseudo Jahn–Teller distortion of fluorinated benzenes leads to an S₁local‐minimum region that extends the excited‐state lifetimes of fluorobenzenes. The pseudo Jahn–Teller distortions reduce when fluorination decreases. Our analysis of the S₁dynamics shows that the pseudo‐Jahn–Teller distortions promote an excited‐statecis‐transisomerization of a π_C‐Cbond. We characterized the surface hopping points from our NAMD simulations and identified instantaneous nuclear momentum as a factor that promotes the electrocyclizations. 

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4. Effects of stereoisomeric structure and bond location on the ignition and reaction pathways of hexenes

   https://doi.org/10.1002/kin.21442  

   Barraza‐Botet, Cesar L.; Liu, Changpeng; Kim, John H.; Wagnon, Scott W.; Wooldridge, Margaret S. (September 2020, International Journal of Chemical Kinetics)

   Abstract The current work presents new experimental autoignition and speciation data on the twocis‐hexene isomers:cis‐2‐hexene andcis‐3‐hexene. The new data provide insights on the effects of carbon‐carbon double bond location and stereoisomeric structures on ignition delay times and reaction pathways for linear hexene isomers. Experiments were performed using the University of Michigan rapid compression facility to determine ignition delay times from pressure‐time histories. Stoichiometric (ϕ = 1.0) mixtures at dilution levels of inert gas to O₂ = 7.5:1 (mole basis) were investigated at an average pressure of 11 atm and temperatures from 809 to 1052 K. Speciation experiments were conducted atT = 900 K for the twocis‐hexene isomers, where fast‐gas sampling and gas chromatography were used to identify and quantify the twocis‐hexene isomers and stable intermediate species. The ignition delay time data showed negligible sensitivity to the location of the carbon‐carbon double bond and the stereoisomeric structure (cis‐trans), and the species data showed no correlation with the stereoisomeric structure, but there was a strong correlation of some of the measured species with the location of the double bond in the hexene isomer. In particular, 2‐hexene showed strong selectivity to propene, acetaldehyde, and 1,3‐butadiene, and 3‐hexene showed selectivity to propanal. Model predictions of ignition delay times were in excellent agreement with the experimental data. There was generally good agreement for the model predictions of the species data for 2‐hexene; however, the mechanism overpredicted some of the small aldehyde (C₂‐C₄) species for 3‐hexene. Reaction pathway analysis indicates the hexenes are almost exclusively consumed by H‐atom abstraction reactions at the conditions studied (P = 11 atm,T > 900 K), and not by C₃‐C₄scission as observed in high‐temperature (>1300 K) hexene ignition studies. Improved estimates for 3‐hexene + OH reactions may improve model predictions for the species measured in this work. 

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5. Helical twists and β‐turns in structures at serine–proline sequences: Stabilization of cis ‐proline and type VI β‐turns via C–H/O interactions

   https://doi.org/10.1002/prot.26701  

   Oven, Harrison_C; Yap, Glenn_P_A; Zondlo, Neal_J (May 2024, Proteins: Structure, Function, and Bioinformatics)

   Abstract Structures at serine‐proline sites in proteins were analyzed using a combination of peptide synthesis with structural methods and bioinformatics analysis of the PDB. Dipeptides were synthesized with the proline derivative (2S,4S)‐(4‐iodophenyl)hydroxyproline [hyp(4‐I‐Ph)]. The crystal structure of Boc‐Ser‐hyp(4‐I‐Ph)‐OMe had two molecules in the unit cell. One molecule exhibitedcis‐proline and a type VIa2 β‐turn (BcisD). Thecis‐proline conformation was stabilized by a C–H/O interaction between Pro C–H_αand the Ser side‐chain oxygen. NMR data were consistent with stabilization ofcis‐proline by a C–H/O interaction in solution. The other crystallographically observed molecule hadtrans‐Pro and both residues in the PPII conformation. Two conformations were observed in the crystal structure of Ac‐Ser‐hyp(4‐I‐Ph)‐OMe, with Ser adopting PPII in one and the β conformation in the other, each with Pro in the δ conformation andtrans‐Pro. Structures at Ser‐Pro sequences were further examined via bioinformatics analysis of the PDB and via DFT calculations. Ser‐Pro versus Ala–Pro sequences were compared to identify bases for Ser stabilization of local structures. C–H/O interactions between the Ser side‐chain O_γand Pro C–H_αwere observed in 45% of structures with Ser‐cis‐Pro in the PDB, with nearly all Ser‐cis‐Pro structures adopting a type VI β‐turn. 53% of Ser‐trans‐Pro sequences exhibited main‐chain CO_i•••HN_i+3or CO_i•••HN_i+4hydrogen bonds, with Ser as theiresidue and Pro as thei + 1 residue. These structures were overwhelmingly either type I β‐turns or N‐terminal capping motifs on α‐helices or 3₁₀‐helices. These results indicate that Ser‐Pro sequences are particularly potent in favoring these structures. In each, Ser is in either the PPII or β conformation, with the Ser O_γcapable of engaging in a hydrogen bond with the amide N–H of thei + 2 (type I β‐turn or 3₁₀‐helix; Serχ₁t) ori + 3 (α‐helix; Serχ₁g⁺) residue. Non‐prolinecisamide bonds can also be stabilized by C–H/O interactions. 

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