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1. From Selection to Instruction and Back: Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts

   https://doi.org/10.1002/anie.202107091  

   Pavlović, Radoslav Z. ; Lalisse, Remy F. ; Hansen, Alexandar L. ; Waudby, Christopher A. ; Lei, Zhiquan ; Güney, Murat ; Wang, Xiuze ; Hadad, Christopher M. ; Badjić, Jovica D. ( July 2021 , Angewandte Chemie International Edition)

   Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate “instructs” the host to change its shape after complexation, while CS asserts that a guest “selects” the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsuleM‐1, encompassing two conformersM‐1(+) andM‐1(−), trap CX₄(X=Cl, Br) to give CX₄⊂M‐1(+) and CX₄⊂M‐1(−), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr₄would, at its lower concentrations, bindM‐1via aM‐1(+)→M‐1(−)→CBr₄⊂M‐1(−) pathway corresponding to conformational selection. ForM‐1complexing CCl₄though, data from 2D EXSY measurements and 1D NMR line‐shape analysis suggested that lower CCl₄concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature.

    

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2. A Molecular Capsule with Revolving Doors Partitioning Its Inner Space

   https://doi.org/10.1002/chem.202003247  

   Lei, Zhiquan ; Finnegan, Tyler J. ; Gunawardana, Vageesha W. Liyana ; Pavlović, Radoslav Z. ; Xie, Han ; Moore, Curtis E. ; Badjić, Jovica D. ( November 2020 , Chemistry – A European Journal)

   Covalent capsule1was designed to include two molecular baskets linked with three mobile pyridines tucked into its inner space. On the basis of both theory (DFT) and experiments (NMR and X‐ray crystallography), we found that the pyridine “doors” split the chamber (380 ų) of1so that two equally sizeable compartments (190 ų) became joined through a conformationally flexible aromatic barrier. The compartments of such unique host could be populated with CCl₄(88 ų; PC=46 %), CBr₄(106 ų; 56 %) or their combination CCl₄/CBr₄(PC=51 %), with thermodynamic stabilities ΔG° tracking the values of packing coefficients (PC). Halogen (C−X⋅⋅⋅π) and hydrogen bonding (C−H⋅⋅⋅X) contacts held the haloalkane guests in the cavities of1. The consecutive complexations were found to occur in a negative allosteric manner, which we propose to result from the induced‐fit mode of complexation. Newly designed1opens a way for probing the effects of inner conformational dynamics on noncovalent interactions, reactivity and intramolecular translation in confined spaces of hollow molecules.

    

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3. Computational exploration of the copper(I)‐catalyzed conversion of hydrazones to dihalogenated vinyldiazene derivatives

   https://doi.org/10.1002/jcc.27433  

   Askerova, Ulviyya ; Abdullayev, Yusif ; Shikhaliyev, Namiq ; Maharramov, Abel ; Nenajdenko, Valentine G ; Autschbach, Jochen ( May 2024 , Journal of Computational Chemistry)

   This computational study explores the copper (I) chloride catalyzed synthesis of (E)‐1‐(2,2‐dichloro‐1‐phenylvinyl)‐2‐phenyldiazene (2Cl‐VD) from readily available hydrazone derivative and carbon tetrachloride (CCl₄).2Cl‐VDhas been extensively utilized to synthesize variety of heterocyclic organic compounds in mild conditions. The present computational investigations primarily focus on understanding the role of copper (I) andN¹,N¹,N²,N²‐tetramethylethane‐1,2‐diamine (TMEDA) in this reaction, TMEDA often being considered a proton scavenger by experimentalists. Considering TMEDA as a ligand significantly alters the energy barrier. In fact, it is only 8.3 kcal/mol higher compared to the ligand‐free (LF) route for the removal of a chlorine atom to form the radical·CCl₃but the following steps are almost barrierless. This intermediate then participates in attacking the electrophilic carbon in the hydrazone. Crucially, the study reveals that the overall potential energy surface is thermodynamically favorable, and the theoretical turnover frequency (TOF) value is higher in the case of Cu(I)‐TMEDA complex catalyzed pathway.

    

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4. In Vitro and In Vivo Sequestration of Phencyclidine by Me 4 Cucurbit[8]uril**

   https://doi.org/10.1002/chem.202004380  

   Murkli, Steven ; Klemm, Jared ; Brockett, Adam T. ; Shuster, Michael ; Briken, Volker ; Roesch, Matthew R. ; Isaacs, Lyle ( January 2021 , Chemistry – A European Journal)

   We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me₄CB[8] toward ten drugs of abuse (3–9,12–14) by a combination of¹H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me₄CB[8] are able to encapsulate the 1‐amino‐1‐aryl‐cyclohexane ring system of phencyclidine (PCP) and ketamine as well as the morphinan skeleton of morphine and hydromorphone withK_dvalues ≤50 nm. In vitro cytotoxicity (MTS metabolic and adenylate kinase cell death assays in HEK293 and HEPG2 cells) and in vivo maximum tolerated dose studies (Swiss Webster mice) which were performed for Me₄CB[8] indicated good tolerability. The tightest host⋅guest pair (Me₄CB[8]⋅PCP;K_d=2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me₄CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me₄CB[8] significantly reduces the locomotion levels.

    

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5. Improved complexation of paraquats with crown ether‐based pyridyl cryptands

   https://doi.org/10.1002/hc.21406  

   Price, Jr., Terry L. ; Slebodnick, Carla ; Gibson, Harry W. ( December 2017 , Heteroatom Chemistry)

   The commonly used paraquat guestN,N′‐dimethyl‐4,4′‐bipyridinium bis(hexafluorophosphate) (7) was targeted for structural alterations to improve the binding constants with crown ethers and cryptands. The association constant was improved by one order of magnitude (toK_a = 1.00 × 10⁶ mol L⁻¹) with the dibenzo‐30‐crown‐10 pyridyl cryptand host5by changing the N‐methyl groups to benzyl and the counterions from PF₆to TFSI, that is,11. Moreover, through addition of ap‐bromobenzyloxy moiety on the 4‐position of the pyridyl ring of cryptand18, an association constant ofK_a = 5.35 × 10⁶ mol L⁻¹was achieved with paraquat11.

    

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