Hyperfine-shifted 13C resonance assignments in an iron-sulfur protein with quantum chemical verification: aliphatic C-H···S 3-center-4-electron interactions

Although the majority of noncovalent interactions associated with hydrogen and heavy atoms in proteins and other biomolecules are classical hydrogen bonds between polar N-H or O-H moieties and O atoms or aromatic π electrons, high-resolution X-ray crystallographic models deposited in the Protein Data Bank show evidence for weaker C-H···O hydrogen bonds, including ones involving sp(3)-hybridized carbon atoms. Little evidence is available in proteins for the (even) weaker C-H···S interactions described in the crystallographic literature on small molecules. Here, we report experimental evidence and theoretical verification for the existence of nine aliphatic (sp(3)-hybridized) C-H···S 3-center-4-electron interactions in the protein Clostridium pasteurianum rubredoxin. Our evidence comes from the analysis of carbon-13 NMR chemical shifts assigned to atoms near the iron at the active site of this protein. We detected anomalous chemical shifts for these carbon-13 nuclei and explained their origin in terms of unpaired spin density from the iron atom being delocalized through interactions of the type: C-H···S-Fe, where S is the sulfur of one of the four cysteine side chains covalently bonded to the iron. These results suggest that polarized sulfur atoms in proteins can engage in multiple weak interactions with surrounding aliphatic groups. We analyze the strength and angular dependence of these interactions and conclude that they may contribute small, but significant, stabilization to the molecule.     

Hydrogen Bonds with Fluorine in Ligand–Protein Complexes-the PDB Analysis and Energy Calculations

Fluorine is a common substituent in medicinal chemistry and is found in up to 50% of the most profitable drugs. In this study, a statistical analysis of the nature, geometry, and frequency of hydrogen bonds (HBs) formed between the aromatic and aliphatic C–F groups of small molecules and biological targets found in the Protein Data Bank (PDB) repository was presented. Interaction energies were calculated for those complexes using three different approaches. The obtained results indicated that the interaction energy of F-containing HBs is determined by the donor–acceptor distance and not by the angles. Moreover, no significant relationship between the energies of HBs with fluorine and the donor type was found, implying that fluorine is a weak HB acceptor for all types of HB donors. However, the statistical analysis of the PDB repository revealed that the most populated geometric parameters of HBs did not match the calculated energetic optima. In a nutshell, HBs containing fluorine are forced to form due to the stronger ligand–receptor neighboring interactions, which make fluorine the “donor’s last resort”.     

Nature of the Hydrogen Bond Enhanced Halogen Bond

The factors responsible for the enhancement of the halogen bond by an adjacent hydrogen bond have been quantitatively explored by means of state-of-the-art computational methods. It is found that the strength of a halogen bond is enhanced by ca. 3 kcal/mol when the halogen donor simultaneously operates as a halogen bond donor and a hydrogen bond acceptor. This enhancement is the result of both stronger electrostatic and orbital interactions between the XB donor and the XB acceptor, which indicates a significant degree of covalency in these halogen bonds. In addition, the halogen bond strength can be easily tuned by modifying the electron density of the aryl group of the XB donor as well as the acidity of the hydrogen atoms responsible for the hydrogen bond.     

Density functional theory and topological analysis on the hydrogen bonding interactions in cysteine‐thymine complexes

Hydrogen bonding interactions between amino acids and nucleic acid bases constitute the most important interactions responsible for the specificity of protein binding. In this study, complexes formed by hydrogen bonding interactions between cysteine and thymine have been studied by density functional theory. The relevant geometries, energies, and IR characteristics of hydrogen bonds (H‐bonds) have been systematically investigated. The quantum theory of atoms in molecule and natural bond orbital analysis have also been applied to understand the nature of the hydrogen bonding interactions in complexes. More than 10 kinds of H‐bonds including intra‐ and intermolecular H‐bonds have been found in complexes. Most of intermolecular H‐bonds involve O (or N) atom as H‐acceptor, whereas the H‐bonds involving C or S atom usually are weaker than other ones. Both the strength of H‐bonds and the structural deformation are responsible for the stability of complexes. Because of the serious deformation, the complex involving the strongest H‐bond is not the most stable structures. Relationships between H‐bond length (ΔR_X‐H), frequency shifts (Δv), and the electron density (ρ_b) and its Laplace (?²ρ_b) at bond critical points have also been investigated. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Structures,vibrational frequencies,topologies, and energies of hydrogen bonds in cysteine‐formaldehyde complexes

The hydrogen bonding interactions between cysteine (Cys) and formaldehyde (FA) were studied with density functional theory regarding their geometries, energies, vibrational frequencies, and topological features of the electron density. The quantum theory of atoms in molecules and natural bond orbital analyses were employed to elucidate the interaction characteristics in the Cys‐FA complexes. The intramolecular hydrogen bonds (H‐bonds) formed between the hydroxyl and the N atom of cysteine moiety in some Cys‐FA complexes were strengthened because of the cooperativity. Most of intermolecular H‐bonds involve the O atom of cysteine/FA moiety as proton acceptors, while the strongest H‐bond involves the O atom of FA moiety as proton acceptor, which indicates that FA would rather accept proton than providing one. The H‐bonds formed between the CH group of FA and the S atom of cysteine in some complexes are so weak that no hydrogen bonding interactions exist among them. In most of complexes, the orbital interaction of H‐bond is predominant during the formation of complex. The electron density (ρ_b) and its Laplace (?²ρ_b) at the bond critical point significantly correlate with the H‐bond parameter δR, while a linearly relationship between the second‐perturbation energy E(2) and ρ_b has been found as well. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

A novel hydrogen-bonding N-oxide–sulfonamide–nitro N—H…O synthon determining the architecture of benzenesulfonamide cocrystals

The structures of novel cocrystals of 4-nitropyridine N-oxide with benzenesulfonamide derivatives, namely, 4-nitrobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C₅H₄N₂O₃·C₆H₆N₂O₄S, and 4-chlorobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C₆H₆ClNO₂S·C₅H₄N₂O₃, are stabilized by N—H…O hydrogen bonds, with the sulfonamide group acting as a proton donor. The O atoms of the N-oxide and nitro groups are acceptors in these interactions. The latter is a double acceptor of bifurcated hydrogen bonds. Previous studies on similar crystal structures indicated competition between these functional groups in the formation of hydrogen bonds, with the priority being for the N-oxide group. In contrast, the present X-ray studies indicate the existence of a hydrogen-bonding synthon including N—H…O(N-oxide) and N—H…O(nitro) bridges. We present here a more detailed analysis of the N-oxide–sulfonamide–nitro N—H…O ternary complex with quantum theory computations and the Quantum Theory of Atoms in Molecules (QTAIM) approach. Both interactions are present in the crystals, but the O atom of the N-oxide group is found to be a more effective proton acceptor in hydrogen bonds, with an interaction energy about twice that of the nitro-group O atoms.     

Direct evaluation of individual hydrogen bond energy in situ in intra- and intermolecular multiple hydrogen bonds system

The results of evaluating the individual hydrogen bond (H-bond) strength are expected to be helpful for the rational design of new strategies for molecular recognition or supramolecular assemblies. Unfortunately, there is few obvious and unambiguous means of evaluating the energy of a single H-bond within a multiple H-bonds system. We present a local analytic model, ABEEMσπ H-bond energy (HBE) model based on ab initio calculations (MP2) as benchmark, to directly and rapidly evaluate the individual HBE in situ in inter- and intramolecular multiple H-bonds system. This model describes the HBE as the sum of electrostatic and van der Waals (vdW) interactions which all depend upon the geometry and environment, and the ambient environment of H-bond in the model is accounted fairly. Thus, it can fairly consider the cooperative effect and secondary effect. The application range of ABEEMσπ HBE model is rather wide. This work has discussed the individual H-bond in DNA base pair and protein peptide dimers. The results indicate that the interactions among donor H atom, acceptor atom as well as those atoms connected to them with 1,2 or 1,3 relationships are all important for evaluating the HBE, although the interaction between the donor H atom and the acceptor atom is large. Furthermore, our model quantitatively indicates the polarization ability of N, O, and S in a new style, and gives the percentage of the polarization effect in HBE, which can not be given by fixed partial charge force field.     

Hydrogen‐bonded complexes of nicotine with simple alcohols

Ab initio and density functional theory studies have been performed on the hydrogen‐bonded complexes of neutral and protonated nicotine with ethanol, methanol, and trifluromethanol to explore their relative stability in a systematic way. Among all the hydrogen‐bonded nicotine complexes considered here, protonated forms in nicotine–ethanol and nicotine–methanol, and neutral form in nicotine–trifluromethanol complexes have been found to be the most stable. In the former two complexes, the proton attached to the pyrrolidine nitrogen acts as a strong hydrogen bond donor, whereas the pyrrolidine nitrogen atom acts as a hydrogen bond acceptor in the latter case. Neutral complex of nicotine with trifluromethanol has been found to possess a very short hydrogen bond (1.57 Å) and basis set superposition error corrected hydrogen bond energy value of 19 kcal/mol. The nature of the various hydrogen bonds formed has been investigated through topological aspects using Bader's atoms in molecules theory. From the calculated topological results, excellent linear correlation is shown to exist among the hydrogen bond length, electron density, and its Laplacian at the bond critical points for all the complexes considered. The natural bond orbital analysis has been carried out to investigate the charge transfer in the nicotine alcohol complexes. In contrast to the blue shifting behavior that is generally exhibited by other C? H···O hydrogen bonds involving sp³ carbon atom, the C? H···O hydrogen bond in the protonated nicotine–ethanol and methanol complexes has been found to be proper with red shifting in nature. © 2011 Wiley Periodicals, Inc.     

Crystal Structure Investigations on Imines derived from 3‐Ferrocenyl‐prop‐2‐enal Crystallizing in Non‐centrosymmetric Space Groups

The condensation of 3‐ferrocenyl‐prop‐2‐enal with primary amines leads to the formation of the corresponding imines in good yields. The crystal structures of imines derived from p‐dimethylamino‐aniline and furfurylamine are determined by the ability of the functional groups to act as hydrogen bond donor or acceptor sites. Although N, N‐dimethyl‐N′‐(3‐ferrocenyl‐allylidene)‐benzene‐1, 4‐diamine and furan‐2‐ylmethyl‐(3‐ferrocenyl‐allylidene)‐amine are achiral molecules they crystallize in the non‐centrosymmetric space groups P2₁ and Pca2₁, respectively. The molecular architecture of N, N‐dimethyl‐N′‐(3‐ferrocenyl‐allylidene)‐benzene‐1, 4‐diamine is realized by the incorporation of dichloromethane acting as hydrogen bond donor and acceptor with both hydrogen and both chlorine atoms. On the other hand, the molecules of furan‐2‐ylmethyl‐(3‐ferrocenyl‐allylidene)‐amine are linked by hydrogen bonds towards the centroid of one of the cyclopentadienyl ligands and towards the oxygen atom of the furan ring to produce infinite chains.     

Interplay between hydrogen-bond formation and multicenter pi-electron delocalization: intramolecular hydrogen bonds

The specific case of intramolecular hydrogen bonds assisted by pi-electron delocalization is thoroughly investigated using multicenter delocalization analysis. The effect of the pi-electron delocalization on the intramolecular hydrogen-bond strength is determined by means of the relative molecular energies of "open" and "closed" structures, calculated at the B3LYP/6-311++G(d,p) level of theory. These relative energies are compared to variations in the multicenter electron delocalization indices and covalent hydrogen-bond indices, which are shown to correlate very well with the relative strength of the intramolecular hydrogen bonds studied. The multicenter electron delocalization indices and covalent bond indices have been computed using the quantum theory of atoms in molecules approach. The hydrogen bonds are formed with oxygen, nitrogen, or sulfur as acceptor atom, which are also the atoms considered to be bonded to the donor hydrogen. Malonaldehyde is taken as reference; the substitution of oxygen by other atoms at the acceptor and donor positions and the effect of the aromaticity have been studied. The results shown here match perfectly with the qualitative expectations derived from the resonance models. In addition, they provide a quantitative picture of the role played by the pi-electron delocalization on the relative strength of intramolecular hydrogen bonds.     

取代基对N—H…O＝C氢键三聚体中氢键强度的影响

使用MP2方法研究了氢键三聚体中N-H…O=C氢键强度,探讨了氢键受体分子中不同取代基对N-H…O=C氢键强度的影响.研究表明,不同取代基对氢键三聚体中N-H…O=C氢键强度的影响是不同的:取代基为供电子基团,氢键键长r(H…O)缩短,氢键强度增强;取代基为吸电子基团,氢键键长r(H…O)伸长,氢键强度减弱.自然键轨道(NBO)分析表明,N-H…O=C氢键强度越强,氢键中氢原子的正电荷越多,氧原子的负电荷越多,质子供体和受体分子间的电荷转移越多.供电子基团使N-H…O=C氢键中氧原子的孤对电子n(O)对N-H的反键轨道σ~*(N-H)的二阶相互作用稳定化能增加,吸电子基团使这种二阶相互作用稳定化能减小.取代基对与其相近的N-H…O=C氢键影响更大.     

The coordination chemistry of the proton

It is well known that an acidic hydrogen atom can form hydrogen bonds to a hydrogen bond acceptor, a Lewis base. It is considerably less known that the proton can coordinate two or more atoms conveniently in bonding modes that cannot be described as hydrogen bonding. Agostic interactions, bridging hydrides, 3-centre-2-electron bonds in boranes, bifurcated hydrogen atoms, they are all elements of the coordination chemistry of the proton and, of course, the hydrogen bond comes in more than one facette as well.     

Computational studies of σ-type weak interactions between NCO/NCS radicals and XY(X = H,Cl;Y = F,Cl,and Br)

The triatomic radicals NCO and NCS are of interest in atmospheric chemistry,and both the ends of these radicals can potentially serve as electron donors during the formation of σ-type hydrogen/halogen bonds with electron acceptors XY(X = H,Cl;Y = F,Cl,and Br).The geometries of the weakly bonded systems NCO/NCS···XY were determined at the MP2/aug-cc-pVDZ level of calculation.The results obtained indicate that the geometries in which the hydrogen/halogen atom is bonded at the N atom are more stable than those where it is bonded at the O/S atom,and that it is the molecular electrostatic potential(MEP)-not the electronegativity-that determines the stability of the hydrogen/halogen bond.For the same electron donor(N or O/S) in the triatomic radical and the same X atom in XY,the bond strength decreases in the order Y = F > Cl > Br.In the hydrogen/halogen bond formation process for all of the complexes studied in this work,transfer of spin electron density from the electron donor to the electron acceptor is negligible,but spin density rearranges within the triatomic radicals,being transferred to the terminal atom not interacting with XY.     

Classification of So-Called Non-Covalent Interactions Based on VSEPR Model

The variety of interactions have been analyzed in numerous studies. They are often compared with the hydrogen bond that is crucial in numerous chemical and biological processes. One can mention such interactions as the halogen bond, pnicogen bond, and others that may be classified as σ-hole bonds. However, not only σ-holes may act as Lewis acid centers. Numerous species are characterized by the occurrence of π-holes, which also may play a role of the electron acceptor. The situation is complicated since numerous interactions, such as the pnicogen bond or the chalcogen bond, for example, may be classified as a σ-hole bond or π-hole bond; it ultimately depends on the configuration at the Lewis acid centre. The disadvantage of classifications of interactions is also connected with their names, derived from the names of groups such as halogen and tetrel bonds or from single elements such as hydrogen and carbon bonds. The chaos is aggravated by the properties of elements. For example, a hydrogen atom can act as the Lewis acid or as the Lewis base site if it is positively or negatively charged, respectively. Hence names of the corresponding interactions occur in literature, namely hydrogen bonds and hydride bonds. There are other numerous disadvantages connected with classifications and names of interactions; these are discussed in this study. Several studies show that the majority of interactions are ruled by the same mechanisms related to the electron charge shifts, and that the occurrence of numerous interactions leads to specific changes in geometries of interacting species. These changes follow the rules of the valence-shell electron-pair repulsion model (VSEPR). That is why the simple classification of interactions based on VSEPR is proposed here. This classification is still open since numerous processes and interactions not discussed in this study may be included within it.     

气相中O3与HSO自由基间的氢键复合物

气相中O3与HSO自由基之间的相互作用及其反应在大气化学中非常重要.在DFT-B3LYP/6-311++G**和MP2/6-311++G**水平上求得O3+HSO复合物势能面上的稳定构型,B3LYP方法得到了三种构型(复合物Ⅰ,Ⅱ和Ⅲ),而MP2方法只能得到一种构犁(复合物Ⅱ).在复合物Ⅰ和Ⅲ中,HSO单元中的1H原子作为质子供体.与O3分子中的端基O原子作为质子受体相互作用,形成红移氢键复合物;而在复合物Ⅱ中,虽与复合物Ⅰ和Ⅲ中具有相间的质子供体和质子受体,却形成了蓝移氢键复合物.B3LYP/6-311++G**水平上计算的单体间相互作用能的计算考虑了基组重甍误差(BSSE)和零点振动能(ZPVE)校正,其值在-3.37到-4.55 kJ·mol-1之间.采用自然键轨道理论(NBO)对单体间相互作用的本质进行了考查,并通过分子中原子理论(AIM)分析了三种复合物中氢键的电子密度拓扑性质.     

气相中O3与HSO自由基间的氢键复合物

气相中O3与HSO自由基之间的相互作用及其反应在大气化学中非常重要. 在DFT-B3LYP/6-311++G**和MP2/6-311++G**水平上求得O3+HSO复合物势能面上的稳定构型, B3LYP方法得到了三种构型(复合物I, II和III), 而MP2方法只能得到一种构型(复合物II). 在复合物I和III中, HSO单元中的1H原子作为质子供体, 与O3分子中的端基O原子作为质子受体相互作用, 形成红移氢键复合物; 而在复合物II中, 虽与复合物I和III中具有相同的质子供体和质子受体, 却形成了蓝移氢键复合物. B3LYP/6-311++G**水平上计算的单体间相互作用能的计算考虑了基组重叠误差(BSSE)和零点振动能(ZPVE)校正, 其值在-3.37到-4.55 kJ·mol-1之间. 采用自然键轨道理论(NBO)对单体间相互作用的本质进行了考查, 并通过分子中原子理论(AIM)分析了三种复合物中氢键的电子密度拓扑性质.     

Halogen Bonds in Adenine-5-Bromouracil Complexes

Ab initio and density functional calculations were employed to investigate the bonding patterns in theadenine-5-bromouracil (AT+) complexes. It is shown that the Br atom in 5-bromouracil (T+) is involved in bonding both with the hydrogen atom of the amino group of adenine (A) and with N7(A) (or N1(A)). With this motif, the Br atom interacts with a nucleophile (H) in a "head-on" fashion and an electrophile(N) in a "side-on" fashion, forming both hydrogen and halogen bonds. Electrostatic attraction between the Br atom in T+ and N7 (or N1) of adenine was found via the electrostatic potential analysis. The existence of the Br···N interactions in the pairs was further conˉrmed by means of Bader's atoms in molecules theory. A bond critical point is identiˉed for the halogen bonds and the topological parameters at the bond critical point indicate the typical closed-shell interactions in the pairs. Natural bond orbital analysis suggests that the charge transfer from the lone pair of the nitrogen atom of adenine is mainly directed to the C-Br antibonding orbital. Finally, halogen bonds in the T+AT+A tetrads were also explored.     

Interplay between hydrogen bond formation and multicenter pi-electron delocalization: intermolecular hydrogen bonds

The interplay between aromatic electron delocalization and intermolecular hydrogen bonding is thoroughly investigated using multicenter delocalization analysis. The effect on the hydrogen bond strength of aromatic electron delocalization within the acceptor and donor molecules is determined by means of the interaction energies between monomers, calculated at the B3LYP/6-311++G(d,p) level of theory. This magnitude is compared to variations of multicenter electron delocalization indices and covalent hydrogen bond indices, which are shown to correlate perfectly with the relative values of the interaction energies for the different complexes studied. The multicenter electron delocalization indices and covalent bond indices have been computed using the quantum theory of atoms in molecules approach. All the hydrogen bonds are formed with oxygen as the acceptor atom; however, the atom bonded to the donor hydrogen has been either oxygen or nitrogen. The water-water complex is taken as reference, where the donor and acceptor molecular environments are modified by substituting the hydrogens and the hydroxyl group by phenol, furan, and pyrrole aromatic rings. The results here shown match perfectly with the qualitative expectations derived from the resonance model.     

C-H⋯O, O-H⋯C, and C-H⋯C interactions in complexes of carbocations and carboanions

Molecular complexes formed by different forms of carbocations (carbenium ions) and carboanions with water, acetylene, and methane molecules have been calculated by the MP2/6-311++G(2df,2pd) method. In complexes with water where the carbon atom of the carbocation (carboanion) acts as the proton donor (acceptor), the energies of the C-H?O and O-H?C hydrogen bonds turn out to be approximately the same being 13–20 kcal/mol for carbocation (carboanion) species differing in the valence state of the carbon atom. Two types of C-H?C interactions have been revealed depending on the charge at the bridging hydrogen atom, which is determined by the hybridization of the donor carbon atom. The C-H?C interaction energy in molecular complexes with the positively charged hydrogen atom (carboanion complexes with acetylene) is an order of magnitude higher than in the complexes where the bridging hydrogen atom has an excess of electron density (carbocation complexes with methane). In all the complexes under consideration, the covalent C-H bond involved in interaction is elongated, and the negative charge is transferred from the acceptor to the donor.     

Rate constants and isotope effects for the reaction of H-atom abstraction from RH substrates by PINO radicals

The kinetics of the reactions of hydrogen atom abstraction from the C–H bonds of substrates of different structures by phthalimide-N-oxyl radicals is studied. The rate constants of this reaction are measured and the kinetic isotope effects are determined. It is shown that in addition to the thermodynamic factor, Coulomb forces and donor–acceptor interactions affect the reaction between phthalimide-N-oxyl radicals and substrate molecules, altering the shape of the transition state. This favors the tunneling of hydrogen atoms and leads to a substantial reduction in the activation energy of the process.