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Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA‐approved drugs and experimental molecules, display markedly different biological activities. The time‐dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future. [ABSTRACT FROM AUTHOR]

5N‐Benzoyl‐1,5‐benzodiazepin‐2‐ones with various substituents were synthesized and their atropisomeric properties were analyzed. For the rotational isomers (E/Z) based on the amide bond [N−C(=O)], the E‐isomers were preferentially formed regardless of the substituents. Atropisomers (aR/aS) due to the Ar−N(CO) (sp2‐sp2) axis were isolated using chiral HPLC, and the rotational barrier (ΔG≠) in thermal isomerization was measured. The rotation barrier about the Ar−N(CO) axis was affected by both the substituents at the C6‐position and the p‐substituents on the benzoyl group. The substituents at C6 (R1) caused both steric and electronic effects. On the other hand, the p‐substituents (R2) on the benzoyl group caused electronic effects: the electron‐donating group (EDG) lowered the ΔG≠ value, whereas the electron‐withdrawing group (EWG) raised it. The ΔG≠ values were linearly correlated with the magnitude of the electronic effect (Hammett σ constants) of functional groups (R2). The EDG causes an increase in the electron density on the carbonyl moiety in the amide, which may disturb the planarity of the amide bond, resulting in a decrease in the ΔG≠ value. [ABSTRACT FROM AUTHOR]

This report presents the N–H and O–H bond dissociation energies (BDEs) and enthalpies (BDEts) of 27 para-substituted anilines and phenols using Density Functional Theory (DFT) with functional wB97X-D and basis set 6-31G**. The computed BDEs/ BDEts show a strong correlation with the calculated rotational barrier (RB) around phenyl–NH2 and phenyl–OH bonds of the parent neutral molecules. Electron-withdrawing (EW) substituents increased RB and BDEs/BDEts, while electron-donating (ED) substituents caused opposite behavior. Geometric, atomic, molecular, and spectroscopic properties of NH2 and OH groups in neutral anilinic and phenolic molecules exhibited excellent correlations with RB and BDEs/BDEts. The geometry around heteroatoms of the radicals displayed constant geometrical changes for all substituents. Spin density maps confirmed that the unpaired electrons in radicals are delocalized in heteroatoms and phenyl rings for all the para-substituents. Spin delocalization in both types of radicals was further enhanced in the presence of para-ED substituents. The increase in electronic density around heteroatoms of radicals with the strength of ED substituents was found proportional to that in neutral molecules. Therefore, the N–H and O–H BDE/BDEt are mainly governed by the stabilization/destabilization of the neutral molecules and, to a significantly lower extent, the stabilization of radicals in the case of strong ED groups.

Supramolecular electronics provide opportunities to integrate molecular building blocks into electronic circuits, and investigations of the mechanical properties of the non‐covalent interactions are necessary to understand the role of the assembly configuration in the electronic coupling among different assembly blocks. However, the mechanical characterization of supramolecular interactions remains experimentally challenging. We investigated the strain distribution of the supramolecular interactions through a series of single‐stacking junctions. The alpha values exhibit a clear odd‐even effect versus the numbers of thiophene rings. The theoretical calculations demonstrated that a larger rotational barrier of the single‐stacking junctions with an even number of thiophene rings leads to limited torsional freedom and thus a smaller strain distribution. These results provide new insights into the control of supramolecular interactions by the design of the basic molecular building blocks. [ABSTRACT FROM AUTHOR]

The aim of this work is to study theoretically the geometrical structure, conformational preference, and vibrational properties of rotational isomers of 2- and 3-furancarbothialdehyde. The B3YLP hybrid density functional with the standard 6-311++G basis set is used to carry out all the calculations. The potential energy profile is calculated to determine the more stable conformer. The energy differences between cis and trans conformers show that the trans conformers are the preferred conformers with 0.70 kcal/mol and 1.36 kcal/mol for both 2-furancarbothialdehyde and 3-furancarbothialdehyde respectively. Nine different solvents with the polarity ranging from ε = 1.92 to ε = 78.39 are used to study the effect of solvation on the conformational stability of the two molecules using the integral equation formalism in the polarizable continuum model (IEF-PCM). The trans conformers are found to be more stable than the cis conformers in the gas phase. For 3-furancarbothialdehyde, the stability of the cis conformer increases as the dielectric constant of the solvent increases. On the other hand, the solvent reverses the conformational stability of 2-furancarbothialdehyde. The cis conformer becomes less stable as the dielectric constant of the solvent increases. The simulated infrared spectra of the molecules, geometrical parameters, and assignments of the vibrational modes are reported. Variations of the relative energy, dipole moment, and solvation energies as a function of the dielectric constant of solvents are investigated. [ABSTRACT FROM AUTHOR]

The barrier to internal rotation around the central C2–C3 single bond of a series of (1E)-monosubstituted 1,3-butadienes and (1E,3E)-1-Y-4-X-disubstituted butadienes, with Y=NH2 or OCH3 and X=NO2, CHO, COOH, CN, CF3, Cl or F, were studied at the density functional w B97X-D/6-31G∗∗ level. The effect of substituents on π-conjugation in disubstituted 1,3-butadienes was studied by correlating the calculated internal rotational barriers with the difference in structural, atomic and molecular properties between the transition state TS and the s-trans conformers. The calculated differences in lengths of C–C, C–NH2 and C–OCH3 single bonds, N-H-N, and C-O-CH3 angles, NH2 out-of-plane angle, natural charges on amino nitrogen and methoxy oxygen, and the maximum electrostatic potential on amino hydrogens, were found to correlate strongly with the rotational barriers. The conjugative interaction was strongly stabilized in the case of strong π-electron acceptors such as NO2 or CHO and is slightly or negligibly affected with Cl and F groups. The resonance stabilization with the remaining acceptors decreases in the order COOH > CN > CF3. Acceptors X maintain their relative order of stabilization for the two donors, and NH2 is more stabilizing. Dominant resonance structures are suggested for highly and negligibly conjugated systems.

The rotational barrier around the phenyl-formyl bond between the minimum and transition states of para-substituted benzaldehydes was computationally studied for 34 electron-donating substituents. The rotational barrier exhibited very good correlation with shortening of the phenyl-formyl bond, lengthening of carbonyl bond, increase of electron density at the formyl group, increase of stabilization energy, lowering of chemical shift in the 13C NMR of the formyl carbon, and with the values of empirical Hammett sp+ constants. Therefore, rotational barrier is a useful quantum mechanical parameter for quantifying the electron-donating substituent effect and p-conjugation in parasubstituted benzaldehydes. Based upon the rotational barrier a scale has been set in this work to judge the electron donating effect of substituents. Moreover, a canonical structure has been proposed for stronger electron-donating substituents. The results of this study reveal that simultaneous presence of electron acceptor formyl group and electron-donating groups is mandatory for the extension of resonance stabilization. [ABSTRACT FROM AUTHOR]

Expressions for the rotational barrier height parameters K1 and K2 have been derived for dilute OH-impurity in KCl, KBr and KI lattices. These values are derived using an ab initio calculations using point charge point dipole model, which appears to be suited for the present systems. The obtained values are close to what is observed generally for such systems. The results explains the the energy orientational configuration direction for each system. The value of potential parameters K1 and K2 also describes the energy eigen values for the rotor. [ABSTRACT FROM AUTHOR]

3-(2-Chlorobenzylidene)-5-(p-tolyl)furan-2(3H)-one (1), C18H13ClO2, crystallizes with Z = 8 and Z′ = 2, and the structure at 100 K has orthorhombic (Pna21) symmetry. Each kind of molecule takes part in π–π stacking interactions to form infinite chains parallel to the c axis. We believe that the existence of two forms can be explained by the probable rotation around a single C–C bond. The quantum chemical modeling reveals that these molecules are almost equivalent energetically, and they can be described as the two most stable conformers (rotamers) with a minor rotational barrier of about 0.67 kcal/mol.

Highlights • Two distinct conformers (A and B) of SAG(Smo agonist) are revealed by solution NMR. • The 3D structural difference of the two conformers are elucidated by ROESY spectroscopy and MMFF94 program. • The minor conformer (conformer B) in D 2 O solution has higher affinity to Smo receptor by molecular docking. • Exchange dynamics properties of two conformers was drastically solvent dependent, revealed by NMR experiments. Abstract SAG (Smo agonist) is high specific agonist of Smo receptor, it is widely used as chemical probe to explore the therapeutic value of activating the Hh-signaling pathway. In the present work, the coexistence of two distinct conformers (A and B) of SAG are revealed by solution NMR, the 3D structural difference of the two conformers are elucidated by ROESY spectroscopy and MMFF94 program. It is discovered that both conformers are agonists of Smo receptor, and the minor conformer (conformer B) in D 2 O solution has higher affinity to Smo receptor by molecular docking. The result showed the detail about two distinct conformers of SAG are involved in activation of Smo receptor, and also provides information for designing more effective agonist of Smo by mimicking B conformer of SAG. By exchange dynamics investigation using variable-temperature NMR experiments, the ratio of two conformers has been shown to be drastically solvent dependent, so, the menstruum type is another important influence factor of SAG bioactivity, when using SAG as chemical probe. [ABSTRACT FROM AUTHOR]

The optimised molecular structures, vibrational wavenumbers and corresponding vibrational assignments of the syn- and anti-conformers of 2,2ʹ-bifuran and its nitro, fluoro, methyl and hydroxyl derivatives were obtained using density functional theory. The starting structures with C2 symmetry of all the ground state structures were considered and the transition state arising from syn-anti isomerisation was also modelled. All structures were fully optimised, and the geometries, dipole moments, charge, thermodynamic properties, and energies are reported. The calculated vibrational wavenumbers were assigned to the various fundamental modes of vibrations. The integral Equation Formalism Polarisation Continuum Model (IEF-PCM) was used to calculate the optimised geometry and the vibrational wavenumbers for all the compounds in different solvents. The results indicate that in the gas phase, the syn-conformer is more stable while in solution phases the conformational preference depends on the polarity of the solvent. [ABSTRACT FROM AUTHOR]

The reactions of electron-rich organosilicon compounds 1,4-bis(trimethylsilyl)-1,4-diaza-2,5-cyclohexadiene (1), 2,3,5,6-tetramethyl-1,4-bis(trimethylsilyl)-1,4-diaza-2,5-cyclohexadiene (2), and 1,1′-bis(trimethylsilyl)-1,1′-dihydro-4,4′-bipyridine (12) with B-amino and B-aryl dihaloboranes afforded a series of novel B=N-bond-containing compounds 3–11 and 13. The B=N rotational barriers of 7 (>71.56 kJ/mol), 10 (58.79 kJ/mol), and 13 (58.65 kJ/mol) were determined by variable-temperature 1H-NMR spectroscopy, thus reflecting different degrees of B=N double bond character in the corresponding compounds. In addition, ring external olefin isomers 11 were obtained by a reaction between 2 and DurBBr2. All obtained B=N-containing products were characterized by multinuclear NMR spectroscopy. Compounds 5, 9, 10a, 11, and 13a were also characterized by single-crystal X-ray diffraction analysis.

Abstract: Bonding is a fundamental aspect of organic chemistry, yet the magnitude of C=C bonding in [n]cumulenes as a function of increasing chain length has yet to be experimentally verified for derivatives longer than n=5. The synthesis of a series of apolar and unsymmetrically substituted tetraaryl[n]cumulenes (n=3, 5, 7, 9) was developed and rotational barriers for Z/E isomerization were measured using dynamic VTNMR spectroscopy. Both experiment and theory confirm a dramatic reduction in the rotational barrier (through estimation of ΔG≠rot for the isomerization) across the series, from >24 to 19 to 15 to 11 kcal−1 in [n]cumulenes with n=3, 5, 7, 9, respectively. The reduction in cumulenic bonding in longer cumulenes thus affords bond rotational barriers that are more characteristic of a sterically hindered single bond than that of a double bond. [ABSTRACT FROM AUTHOR]

Atropisomerism is stereochemistry arising from restricted bond rotation that creates a chiral axis. Atropisomers are subject to time-dependent inversion of chirality via bond rotation, a property which in drug molecules introduces complexity and challenges for drug discovery and development processes. Greater recognition of the occurrence of atropisomerism and improved characterization techniques have helped medicinal chemists successfully advance atropisomeric drug molecules. This review provides recent examples of atropisomerism encountered in medicinal chemistry efforts and the strategies used to address the accompanying challenges. [ABSTRACT FROM AUTHOR]

Molecular structure, conformational stability and vibrational wave numbers for the rotational isomers of 2-furoyl chloride and 3-furoyl chloride have been computed using the B3LYP method with the 6-311++G(d,p) basis set. From computations, 2-furoyl chloride was predicated to exist predominantly in cis conformation with cis- trans rotational barrier 40.40 kJ·mol, and 3-furoyl chloride was predicated to exist predominantly in the trans conformation with cis- trans rotational barrier 30.17 kJ·mol. The effects of solvents on the conformational stability of all the molecules in nine different solvents (heptane, chloroform, tetrahydrofuran, dichloroethane, acetone, ethanol, methanol, dimethylsulfoxide and water) were investigated. The integral equation formalism of the polarizable continuum model was used for all solution phase computations. The vibrational wave numbers and the corresponding vibrational assignments of the molecules in C symmetry were examined and the simulated infrared spectra of the molecules are reported. The geometrical parameters, highest occupied and lowest unoccupied molecular orbitals, Infrared intensities, and molecular electrostatic potentials results are reported. [ABSTRACT FROM AUTHOR]

As equally essential as the synthesis of new materials, maneuvering new structure configurations can endow the brand-new functional properties to existing materials, which is also one of the core goals in the synthesis community. In this respect, pressure-induced emission (PIE) that triggers photoluminescence (PL) in nonemission materials is an emerging stimuli-responsive smart materials technology. In the PIE paradigms, harvesting bright PL at ambient conditions, however, has remained elusive. Herein, a remarkable PIE phenomenon is reported in initially nonemission Zn(BDC)(DMF)(H 2 O) (MOF-2), which shows bright blue-emission at 455 nm under pressure. Intriguingly, the bright blue PL with an excellent photoluminescence quantum yield up to 70.4% is unprecedentedly retained to ambient conditions upon decompression from 16.2 GPa. The detailed structural analyses combined with density functional theory calculations reveal that hydrogen bonding cooperativity effect elevates powerfully the rotational barrier of the linker rotor to 3.87 eV mol -1 from initial 0.91 eV mol -1 through pressure treatment. The downgrade rotational freedom turns on PL of MOF-2 after releasing pressure completely. This is the first case of harvesting PIE to ambient conditions. These findings offer a new platform for the creation of promising alternatives to high-performance PL materials based on initially nonemission counterparts., (© 2023 Wiley-VCH GmbH.)

The molecular structures, conformational stabilities, and infrared vibrational wavenumbers of 2-thiophenecarboxaldehyde and 3-thiophenecarboxaldehyde are computed using Becke-3-Lee-Yang-Parr (B3LYP) with the 6-311++G** basis set. From the computations, cis-2-thiophenecarboxaldehyde is found to be more stable than the transfer conformer with an energy difference of 1.22 kcal/mol, while trans-3-thiophenecarboxaldehyde is found to be more stable than the cis conformer by 0.89 kcal/mol. The computed dipole moments, structural parameters, relative stabilities of the conformers and infrared vibrational wavenumbers of the two molecules coherently support the experimental data in the literature. The normal vibrational wavenumbers are characterized in terms of the potential energy distribution using the VEDA4 program. The effect of solvents on the conformational stability of the molecules in nine different solvents is investigated using the polarizable continuum model. [ABSTRACT FROM AUTHOR]

TcO and TcO(OH) along with their S and Se analogs, TcS , TcSe TcS(OH) and TcSe(OH), have been analyzed employing the hybrid meta-GGA functional TPSS. Charge, geometry, frontier orbital analysis based on the optimized structure have been done as a function of type of an atom bonded to Tc. The effect of addition of OH group to TcS , TcSe and TcO on geometrical and electronic properties is discussed. Rotational barrier of the O-H bond for title molecules are calculated and discussed. [ABSTRACT FROM AUTHOR]

The energy change on each Occupied Molecular Orbital as a function of rotation about the C-C bond in ethane was studied using the B3LYP, mPWB95 functional and MP2 methods with different basis sets. Also, the effect of the ZPE on rotational barrier was analyzed. We have found that σ and π energies contribution stabilize a staggered conformation. The σs molecular orbital stabilizes the staggered conformation while the stabilizes the eclipsed conformation and destabilize the staggered conformation. The πz and molecular orbitals stabilize both the eclipsed and staggered conformations, which are destabilized by the πv and molecular orbitals. The results show that the method of calculation has the effect of changing the behavior of the energy change in each Occupied Molecular Orbital energy as a function of the angle of rotation about the C–C bond in ethane. Finally, we found that if the molecular orbital energy contribution is deleted from the rotational energy, an inversion in conformational preference occurs.

The optimized molecular structures, vibrational wavenumbers and corresponding vibrational assignments of the syn and anti conformers of 2-, 3- and 4-pyridine carboxaldehydes and their sulfur and selenium analogues were calculated using the density functional theory method employing the B3LYP functional with the 6-311++G(d,p) basis set and second order Møller-Plesset Perturbation Theory (MP2) method with the cc-pVDZ basis set. The calculations were adapted to the C symmetries of all ground state structures. The transition state arising from syn-anti isomerization was also modelled. All structures were fully optimized, and the geometries, rotational constants, dipole moments, charges, thermodynamic properties and energies are reported. Energies of the optimized structures were used to obtain the energy difference between the syn and anti conformers and the rotational barrier. The calculated vibrational wavenumbers were appropriately assigned to the various fundamental modes of vibrations. The Integral Equation Formalism Polarization Continuum Model was used to calculate the optimized geometry and the vibrational wavenumbers for all of the compounds in nine solvents: heptane, chloroform, tetrahydrofuran, dichloroethane, acetone, ethanol, methanol, dimethylsulfoxide and water. In addition, the LUMO, HOMO and energy band gap are also reported. The results indicate that the anti conformer is preferred with a rotational barrier of at least 19 kJ·mol. Graphical Abstract: [ABSTRACT FROM AUTHOR]

The conformation and vibration analysis of 2-, 3- and 4-pyridinecarbonyl chlorides have been computed using B3LYP hybrid density functional with 6-311++G** basis set. All structures have been fully optimized, and the optimized geometries, dipole moments, infrared vibrational frequencies and relative energies are reported. From the computations, 2-pyridinecarbonyl chloride is predicted to exist predominantly in trans conformation, while the 3-pyridinecarbonyl chloride is predicted to exist predominantly in cis conformation with the trans-cis rotational barrier of 4.63 and 5.48 kcal/mol respectively. The two equivalent planar structures of 4-pyridinecarbonyl chloride are separated by an energy barrier of 4.55 kcal/mol. The effect of solvents on the conformational stability have been examined for nine different solvents (heptane, chloroform, THF, dichloroethane, acetone, ethanol, methanol, DSMO and water). The Integral Equation Formalism version of Polarized Continuum model (IEF-PCM) used for all solution phase computations. The trans conformer of 2-pyridinecarbonyl chloride and the cis conformer of 3-pyridinecarbonyl chloride which are more stable in gas phase remain the stable confomers in solution, but the stability decreases as the dielectric constant of the solvent increases. The variation of relative energies, dipole moments, solvation energies as function of the dielectric constant of solvents has been investigated. [ABSTRACT FROM AUTHOR]

The article deals with conformational behaviour of 2-methoxy-2′-hydroxythiobenzanilides. The CS-NH group of these compounds preferentially adopts the Z -conformation. Entropy favours the Z -conformer over the E -conformer, whereas enthalpy slightly favours the E -conformer over the Z -conformer. The rotational barrier about the CS-NH bond was determined to be (81.5±0.4) kJ/mol. No significant rotational barrier was found on the Ar–CS and Ar–NH bonds. All experimental outcomes are compared with the results of quantum-chemical calculations. [ABSTRACT FROM AUTHOR]

Two polymorph forms of 1,4-bis(triisopropylsilyl)buta-1,3-diyne were investigated by X-ray analysis. The polymorph grown from acetone solution crystallized in the monoclinic crystal system with one molecule in a general position of the asymmetric unit. A second polymorph grown from acetonitrile and ethanol solutions crystallized in the triclinic crystal system with a molecule located on an inversion center. The two polymorphs have slightly different molecular geometries and crystal packing motifs. The conformations found in these polymorphs were investigated and compared with five other rotamers as possible candidates for conformational polymorphs using DFT calculations. [ABSTRACT FROM AUTHOR]

Hydroxamic acids (HAs) perform tasks in medicine and industry that require bidentate metal binding. The two favored conformations of HAs are related by rotation around the C(=O)-N bond. The conformations are unequal in stability. Recently, we reported that the most stable conformation of a small secondary HA in water places the oxygen atoms anti to one another. The barrier to C-N bond rotation may therefore modulate metal binding by secondary HAs in aqueous media. We have now determined the activation barrier to C-N rotation from major to minor conformation of a small secondary HA in D2O to be 67.3 kJ/mol. The HA rotational barrier scales with solvent polarity, as is observed in amides, although the HA barrier is less than that of a comparable tertiary amide in aqueous solution. Successful design of new secondary HAs to perform specific tasks requires solid understanding of rules governing HA structural behavior. Results from this work provide a more complete foundation for HA design efforts. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The torsional potentials, molecular structures, conformational stability, and vibrational wavenumbers for the rotational isomers of 2-formylfuran and 3-formylfuran are computed using the density functional theory (B3LYP) method with the 6-31+G* basis set. All structures are fully optimized and the optimized geometries, rotational constants, dipole moments, and energies are presented. From the computations, both 2-formylfuran and 3-formylfuran are predicted to exist predominantly in trans conformation with a cis-trans rotational barrier of 11.19 kcal/mol and 8.10 kcal/mol, respectively. The vibrational wavenumbers and the corresponding vibrational assignments of the molecules in the C symmetry are examined and the infrared spectra of the molecules are simulated using the wavenumbers and the corresponding intensities obtained from the computations. The effect of solvents on the conformational stability of all the molecules in nine different solvents (heptane, chloroform, tetrahydrofuran, dichloroethane, acetone, ethanol, methanol, dimethylsulfoxide, and water) is investigated. The integral equation formalism in the polarizable continuum model (IEF-PCM) is used for all solution phase computations. [ABSTRACT FROM AUTHOR]