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1. Large transition state stabilization from a weak hydrogen bond

   https://doi.org/10.1039/D0SC02806A  

   Vik, Erik C.; Li, Ping; Maier, Josef M.; Madukwe, Daniel O.; Rassolov, Vitaly A.; Pellechia, Perry J.; Masson, Eric; Shimizu, Ken D. (July 2020, Chemical Science)

   A series of molecular rotors was designed to study and measure the rate accelerating effects of an intramolecular hydrogen bond. The rotors form a weak neutral O–H⋯OC hydrogen bond in the planar transition state (TS) of the bond rotation process. The rotational barrier of the hydrogen bonding rotors was dramatically lower (9.9 kcal mol −1 ) than control rotors which could not form hydrogen bonds. The magnitude of the stabilization was significantly larger than predicted based on the independently measured strength of a similar O–H⋯OC hydrogen bond (1.5 kcal mol −1 ). The origins of the large transition state stabilization were studied via experimental substituent effect and computational perturbation analyses. Energy decomposition analysis of the hydrogen bonding interaction revealed a significant reduction in the repulsive component of the hydrogen bonding interaction. The rigid framework of the molecular rotors positions and preorganizes the interacting groups in the transition state. This study demonstrates that with proper design a single hydrogen bond can lead to a TS stabilization that is greater than the intrinsic interaction energy, which has applications in catalyst design and in the study of enzyme mechanisms. 

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2. Transition State Stabilizing Effects of Oxygen and Sulfur Chalcogen Bond Interactions

   https://doi.org/10.1002/chem.202402011  

   Lin, Binzhou; Liu, Hao; Scott, Harrison_M; Karki, Ishwor; Vik, Erik_C; Madukwe, Daniel_O; Pellechia, Perry_J; Shimizu, Ken_D (September 2024, Chemistry – A European Journal)

   Abstract Non‐covalent chalcogen bond (ChB) interactions have found utility in many fields, including catalysis, organic semiconductors, and crystal engineering. In this study, the transition stabilizing effects of ChB interactions of oxygen and sulfur were experimentally measured using a series of molecular rotors. The rotors were designed to form ChB interactions in their bond rotation transition states. This enabled the kinetic influences to be assessed by monitoring changes in the rotational barriers. Despite forming weaker ChB interactions, the smaller chalcogens were able to stabilize transition states and had measurable kinetic effects on the rotational barriers. Sulfur stabilized the bond rotation transition state by as much as −7.2 kcal/mol without electron‐withdrawing groups. The key was to design a system where the sulfur ‐hole was aligned with the lone pairs of the chalcogen bond acceptor. Oxygen rotors also could form transition state stabilizing ChB interactions but required electron‐withdrawing groups. For both oxygen and sulfur ChB interactions, a strong correlation was observed between transition state stabilizing abilities and electrostatic potential (ESP) of the chalcogen, providing a useful predictive parameter for the rational design of future ChB systems. 

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3. Counterintuitive torsional barriers controlled by hydrogen bonding

   https://doi.org/10.1039/d0cp03285a  

   Barbero, Héctor; Meunier, Antoine; Kotturi, Kondalarao; Smith, Ashton; Kyritsakas, Nathalie; Killmeyer, Adam; Rabbani, Ramin; Nazimuddin, Md; Masson, Eric (September 2020, Physical Chemistry Chemical Physics)

   null (Ed.)

   The torsional barriers along the C aryl –C aryl axis of a pair of isosteric disubstituted biphenyls were determined by variable temperature 1 H NMR spectroscopy in three solvents with contrasted hydrogen bond accepting abilities (1,1,2,2-tetrachloroethane-d 2 , nitrobenzene-d 5 and dimethyl sulfoxide-d 6 ). One of the biphenyl scaffolds was substituted at its ortho and ortho ′ positions with N ′-acylcarbohydrazide groups that could engage in a pair of intramolecular N–H⋯O=C hydrogen bonding interactions at the ground state, but not at the transition state of the torsional isomerization pathway. The torsional barrier of this biphenyl was exceedingly low despite the presence of the hydrogen bonds (16.1, 15.6 and 13.4 kcal mol −1 in the three aforementioned solvents), compared to the barrier of the reference biphenyl (15.3 ± 0.1 kcal mol −1 on average). Density functional theory and the solvation model developed by Hunter were used to decipher the various forces at play. They highlighted the strong stabilization of hydrogen bond donating solutes not only by hydrogen bond accepting solvents, but also by weakly polar, yet polarizable solvents. As fast exchanges on the NMR time scale were observed above the melting point of dimethyl sulfoxide-d 6 , a simple but accurate model was also proposed to extrapolate low free activation energies in a pure solvent (dimethyl sulfoxide-d 6 ) from higher ones determined in mixtures of solvents (dimethyl sulfoxide-d 6 in nitrobenzene-d 5 ). 

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4. A quantitative assessment of deformation energy in intermolecular interactions: How important is it?

   https://doi.org/10.1063/5.0155895  

   Sargent, Caroline T.; Kasera, Raina; Glick, Zachary L.; Sherrill, C. David; Cheney, Daniel L. (June 2023, The Journal of Chemical Physics)

   Dimer interaction energies have been well studied in computational chemistry, but they can offer an incomplete understanding of molecular binding depending on the system. In the current study, we present a dataset of focal-point coupled-cluster interaction and deformation energies (summing to binding energies, De) of 28 organic molecular dimers. We use these highly accurate energies to evaluate ten density functional approximations for their accuracy. The best performing method (with a double-ζ basis set), B97M-D3BJ, is then used to calculate the binding energies of 104 organic dimers, and we analyze the influence of the nature and strength of interaction on deformation energies. Deformation energies can be as large as 50% of the dimer interaction energy, especially when hydrogen bonding is present. In most cases, two or more hydrogen bonds present in a dimer correspond to an interaction energy of −10 to −25 kcal mol−1, allowing a deformation energy above 1 kcal mol−1 (and up to 9.5 kcal mol−1). A lack of hydrogen bonding usually restricts the deformation energy to below 1 kcal mol−1 due to the weaker interaction energy. 

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5. Exploring Secondary Electrostatic Interactions Using Molecular Rotors: Implications for S _N 2 Reactions

   https://doi.org/10.1002/anie.202505483  

   Lin, Binzhou; Liu, Hao; Huang, Xiaolong; Scott, Harrison_M; Pellechia, Perry_J; Shimizu, Ken_D (April 2025, Angewandte Chemie International Edition)

   Abstract Benzylic and allylic electrophiles are well known to react faster in S_N2 reactions than aliphatic electrophiles, but the origins of this enhanced reactivity are still being debated. Galabov, Wu, and Allen recently proposed that electrostatic interactions in the transition state between the nucleophile (Nu) and the sp²carbon (C2) adjacent to the electrophilic carbon (C1) play a key role. To test this secondary electrostatic hypothesis, molecular rotors were designed that form similar through‐space electrostatic interactions with C2 in their bond rotation transition states without forming bonds to C1. This largely eliminates the alternative explanation of stabilizing conjugation effects between C1 and C2 in the transition state. The rotor barriers were strongly correlated with the experimentally measured S_N2 free energy. Notably, rotors where C2 was sp²or sp‐hybridized had barriers that were consistently 0.5–2.0 kcal mol⁻¹lower than those for rotors where C2 was sp³‐hybridized. Computational studies of atomic charges were consistent with the formation of stabilizing secondary electrostatic interactions. Further confirmation came from observing the benzylic effect in rotors where the first atom was varied, including oxygen, sulfur, nitrogen, and sp²‐carbon. In summary, these studies provided strong experimental support for the role of secondary electrostatic interactions in the S_N2 reaction. 

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