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The article reports that hydrogen bonds of RNA are stronger than those of DNA, but nuclear magnetic resonance (NMR) monitors only presence of methyl substituent in uracil/thymine. This conclusion is based on the observation that the deuterium isotope effect for H/D substitution at H3 of the pyrimidine base on the chemical shift of the adenine C2 atom is larger for A:U than for A:T. Such an isotope effect had previously been connected to hydroxyl torsional frequencies of intramolecularly hydrogen-bonded systems and empirical hydrogen-bond strengths. Although, the conclusion that A:U is more strongly bound than A:T, as already reported earlier, there is no correlation between the hydrogen-bond strength and the NMR shielding of C2.

We have investigated 44 crystal structures, found in the Cambridge Structural Database, containing the X 3 synthon (where X = Cl, Br, I) in order to verify whether three type II halogen-halogen contacts forming the synthon exhibit cooperativity. A hypothesis that this triangular halogen-bonded motif is stabilized by cooperative effects is postulated on the basis of structural data. However, theoretical investigations of simplified model systems in which the X 3 motif is present demonstrate that weak synergy occurs only in the case of the I 3 motif. In the present paper we computationally investigate crystal structures in which the X 3 synthon is present, including halomesitylene structures, that are usually described as being additionally stabilized by a synergic interaction. Our computations find no cooperativity for halomesitylene trimers containing the X 3 motif. Only in the case of two other structures containing the I 3 synthon a very weak or weak synergy, i.e. the cooperative effect being stronger than -0.40 kcal mol -1 , is found. The crystal structure of iodoform has the most pronounced cooperativity of all investigated systems, amounting to about 10% of the total interaction energy., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.)

We investigated the tunability of hydrogen bond strength by altering the charge accumulation around the frontier atoms with remote substituents. For pyridine···H 2 O with NH 2 and CN substituted at different positions on pyridine, we find that the electron-withdrawing CN group decreases the negative charge accumulation around the frontier atom N, resulting in weakening of the hydrogen bond, whereas the electron-donating NH 2 group increases the charge accumulation around N, resulting in strengthening of the hydrogen bond. By applying these design principles on DDAA-AADD, DADA-ADAD, DAA-ADD, and ADA-DAD hydrogen-bonded dimers, we find that the effect of the substituent is delocalized over the whole molecular system. As a consequence, systems with an equal number of hydrogen bond donor (D) and acceptor (A) atoms are not tunable in a predictable way because of cancellation of counteracting strengthening and weakening effects. Furthermore, we show that the position of the substituent and long-range electrostatics can play an important role as well. Overall, the design principles presented in this work are suitable for monomers with an unequal number of donor and acceptor atoms and can be exploited to tune the binding strength of supramolecular building blocks.

Halogen bonds are highly important in medicinal chemistry as halogenation of drugs, generally, improves both selectivity and efficacy toward protein active sites. However, accurate modeling of halogen bond interactions remains a challenge, since a thorough theoretical investigation of the bonding mechanism, focusing on the realistic complexity of drug-receptor systems, is lacking. Our systematic quantum-chemical study on ligand/peptide-like systems reveals that halogen bonding is driven by the same bonding interactions as hydrogen bonding. Besides the electrostatic and the dispersion interactions, our bonding analyses, based on quantitative Kohn-Sham molecular orbital theory together with energy decomposition analysis, reveal that donor-acceptor interactions and steric repulsion between the occupied orbitals of the halogenated ligand and the protein need to be considered more carefully within the drug design process.

NMR spectroscopy is one of the most useful methods for detection and characterization of hydrogen bond (H-bond) interactions in biological systems. For H bonds X-H···Y, where X and Y are O or N, it is generally believed that a decrease in 1 H-shielding constants relates to a shortening of H-bond donor-acceptor distance. Here we investigated computationally the trend of 1 H-shielding constants for hydrogen-bonded protons in a series of guanine C8-substituted GC pair model compounds as a function of the molecular structure. Furthermore, the electron density distribution around the hydrogen atom was analyzed with the Voronoi deformation density (VDD) method. Our findings demonstrate that 1 H-shielding values of the hydrogen bond are determined by the depletion of charge around the hydrogen atom, which stems from the fact that electrons obey the Pauli exclusion principle.

The nature of resonance-assisted hydrogen bonds (RAHB) is still subject of an ongoing debate. We therefore analyzed the σ and π charge redistributions associated with the formation of intramolecular hydrogen bonds in malonaldehyde (MA) and its saturated analogue 3-hydroxypropanal (3-OH) and addressed the question whether there is a resonance assistance phenomenon in the sense of a synergistic interplay between the σ and π electron systems. Our quantum chemical calculations at the BP86/TZ2P level of theory show that the π charge flow is indeed in line with the Lewis structure as proposed by the RAHB model. This typical rearrangement of charge is only present in the unsaturated system, and not in its saturated analogue. Resonance in the π electron system assists the intramolecular hydrogen bond by reducing the hydrogen bond distance, and by providing an additional stabilizing component to the net bonding energy. The σ orbital interaction plays an important role in the enhanced hydrogen bond strength in MA as well. However, there is no resonance assistance in the sense of an interplay between σ charge transfer and π polarization; σ and π contribute independently from each other.

The strength and nature of the connection in Lappert's stannylene dimer ({Sn[CH(SiMe3)2]2}2) and its smaller analogs, simplified stannylenes, as well as similar Ge complexes were studied by means of DFT-D3 calculations, energy decomposition analysis (EDA), electrostatic potential (ESP), and natural population analysis. The trans-bent structure of the investigated molecules was rationalized by means of EDA, ESP, and molecular orbital (MO) analyses. The different ESPs for the monomers studied are a result of different hybridization of the Sn (Ge) atoms. The comparably strong stabilization in the largest and the smallest systems with a dramatically different substituent size is explained by the different nature of the binding between monomers. For all complexes, it has been found that the total attractive interaction is mostly provided by the electrostatic component (>50%), followed by orbital interaction and dispersion. In the largest molecule (Lappert's stannylene), the dispersion interaction plays a more significant role in stabilization and its magnitude is comparable to that of orbital interaction; on the other hand in the smallest molecule (SnH2), where bulky substituents are replaced by H only, the dispersion energy is less important and the E-E bond is more of a charge-transfer character, caused by donor-acceptor orbital interactions. The charge transfer in Ge dimers is greater than in the Sn ones due to shorter distances between monomers, which cause better ⟨HOMO/LUMO⟩ overlaps. The easier dimerization of Lappert's stannylene as compared to Kira's ({Sn[(Me3Si)2CHCH2CH2CH(SiMe3)2-κ(2)C,C']}) stannylene is explained by the different orientation of their substituents-asymmetry promotes dimerization.

The complexes [Au(4-pyridylethynyl)(phosph)] (phosph = PTA (1), DAPTA (2)) are known to produce supramolecular aggregates and gels in water. We studied the impact of these aggregation processes in the absorption spectra, (1)H NMR (at different temperatures and concentrations), and DLS and estimated the equilibrium constant for a single step aggregation of the molecule (K = 26760 and 2590 M(-1) for 1 and 2, respectively, at 25 °C). We present spectroscopic evidence for the presence of Au···Au contacts in the aggregates: the recorded changes on (1)H NMR and the appearance of new absorption bands assigned to (σ*Au···Au-π*) have been attributed to the short (Au···Au) average distances in the aggregates. Relativistic density functional theory computations support the existence of short Au···Au distances and reveal charge-transfer in the aurophilic interactions. The free energy for a single step aggregation was calculated from the experimental data, and the value obtained (ΔG ∼ -20 kJ/mol) is in good agreement with the expected values in the order of the energies found for hydrogen bonds. The DFT computations confirm the experimental findings that aggregation of monomer 1 is stronger than the aggregation of monomer 2 and the existence of aurophilic interactions.

The redox equilibrium between dinuclear Cu(II) μ-thiolate and Cu(I) disulfide structures has been analyzed experimentally and via DFT calculations. Two new ligands, L(2)SSL(2) and L(4)SSL(4), and their Cu(II) μ-thiolate and Cu(I) disulfide complexes were synthesized. For L(2)SSL(2), these two redox-isomeric copper species are shown to be in equilibrium, which depends on both temperature and solvent. For L(4)SSL(4) the μ-thiolate species forms as the kinetic product and further evolves into the disulfide complex under thermodynamic control, which creates the unprecedented possibility to compare both species under the same reaction conditions. The energies of the μ-thiolate and disulfide complexes for two series of related ligands have been calculated with DFT; the results rationalize the experimentally observed structures, and emphasize the important role that steric requirements play in the formation of the Cu(II) thiolate structure.

The stereodivergent ring-opening of 2-phenyl oxazaphospholidines with alkyl lithium reagents is reported. N-H oxazaphospholidines derived from both (+)-cis-1-amino-2-indanol and (-)-norephedrine provide inversion products in a highly stereoselective process. In contrast, N-Me oxazaphospholidines yield ring-opening products with retention of configuration at the P center, as previously reported by Jugé and co-workers. As a result, from a single amino alcohol auxiliary, both enantiomers of key P-stereogenic intermediates could be synthesized. Theoretical studies of ring-opening with model oxazaphospholidines at the DFT level have elucidated the streochemical course of this process. N-H substrates react in a single step via preferential backside S(N)2@P substitution with inversion at phosphorus. N-methylated substrates react preferentially via a two-step frontside S(N)2@P, yielding a ring-opened product in which the nucleophilic methyl binds to P with retention of configuration. DFT calculations have shown that the BH3 unit is a potent directing group to which the methyl lithium reagent coordinates via Li in all the reactions studied.

A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a four-component reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of this four-component reaction are described. Variation of the nitrile and aldehyde inputs proved to be extensively possible, but variation of the phosphonate input remains limited. Regarding the isocyanoacetate, alpha-aryl isocyanoacetates give moderate to high yields and result in a complete diastereoselectivity for the 3,4-cis isomer. Alpha-alkyl isocyanoacetates gave the corresponding dihydropyridin-2-ones in moderate yields, most of them as mixtures of diastereomers. Elevated temperatures during cyclocondensation generally increased the yield and resulted in a change of the diastereomeric ratio in favor of the cis-diastereomer. In addition to isocyanoacetates, a limited number of other alpha-acidic esters resulted in the formation of dihydropyridin-2-ones, albeit in much lower yield. Computational studies show that the observed difference in yield cannot be simply correlated to specific physical properties (including acidity) of the different alpha-acidic esters.

Here, we address the problem of stabilizing a new helicoid ferrocene. Of course, to obtain a helical complex, it is essential to design suitable organic ligands. The ligands should possess the correct symmetry to match the geometrical requirement of the metal center. We propose in silico a beautiful helix that consists of one polycyclic hydrocarbon composed of 10 fused cyclopentadiene rings bound on opposite sides of an iron atom. The nature of the metal-ligand interactions between Fe(2+) and the ligand was investigated with energy decomposition analysis. Our results provide strong evidence for the viability of the hitherto unknown helicoid ferrocene as a target for synthesis.

We have carried out a theoretical investigation of the methylalkalimetal monomers CH3M and tetramers (CH3M)4 with M = Li, Na, K, and Rb and, for comparison, the methyl halides CH3X with X = F, Cl, Br, and I, using density functional theory (DFT) at BP86/TZ2P. Our purpose is to determine how the structure and thermochemistry (e.g., C-M bond lengths and strengths, oligomerization energies) of organoalkalimetal compounds depend on the metal atom and to understand the emerging trends in terms of quantitative Kohn-Sham molecular orbital (KS-MO) theory. The C-M bond becomes longer and weaker, both in the monomers and tetramers, if one descends the periodic table from Li to Rb. Quantitative bonding analysis shows that this trend is not only determined by decreasing electrostatic attraction but also, even to a larger extent, by the weakening in orbital interactions. The latter become less stabilizing along Li-Rb because the bond overlap between the singly occupied molecular orbitals (SOMOs) of CH3(•) and M(•) radicals decreases as the metal ns atomic orbital (AO) becomes larger and more diffuse. Thus, the C-M bond behaves as a typical electron-pair bond between the methyl radical and alkalimetal atom, and, in that respect, it is covalent. It is also shown that such an electron-pair bond can still be highly polar, in agreement with the large dipole moment. Interestingly, the C-M bond becomes less polar in the methylalkalimetal tetramers because metal-metal interactions stabilize the alkalimetal orbitals and, in that way, make the alkalimetal effectively less electropositive.