Analysis of Proton NMR in Hydrogen Bonds in Terms of Lone‐Pair and Bond Orbital Contributions

NMR spectroscopic parameters of the proton involved in hydrogen bonding are studied theoretically. The set of molecules includes systems with internal resonance‐assisted hydrogen bonds, internal hydrogen bonds but no resonance stabilization, the acetic acid dimer (AAD), a DNA base pair, and the hydrogen succinate anion (HSA). Ethanol and guanine represent reference molecules without hydrogen bonding. The calculations are based on zero‐point vibrationally averaged molecular structures in order to include anharmonicity effects in the NMR parameters. An analysis of the calculated NMR shielding and J‐coupling is performed in terms of “chemist’s orbitals”, that is, localized molecular orbitals (LMOs) representing lone‐pairs, atomic cores, and bonds. The LMO analysis associates some of the strong de‐shielding of the protons in resonance‐assisted hydrogen bonds with delocalization involving the π‐backbone. Resonance is also shown to be an important factor causing de‐shielding of the OH protons for AAD and HSA, but not for the DNA base pair. Nitromalonamide (NMA) and HSA have particularly strong hydrogen bonds exhibiting signs of covalency in the associated J‐couplings. The analysis results show how NMR spectroscopic parameters that are characteristic for hydrogen bonded protons are influenced by the geometry and degree of covalency of the hydrogen bond as well as intra‐ and intermolecular resonance.     

Evaluating the COSMO‐RS Method for Modeling Hydrogen Bonding in Solution

The ability of the Conductor‐like Screening Model for Realistic Solvation (COSMO‐RS) computational method to model hydrogen bond (HB) formation in solution is examined by comparing computational data with experimental data from literature. This is the first study of this kind where mixed solvents are also involved. Hydrogen bond formation is examined between neutral molecules, between acids and their anions, and between various anion receptor molecules and different anions in a number of aprotic solvents. HB formation equilibrium constants, the corresponding Gibbs’ free energies and, when available from the literature, enthalpies were calculated. The supermolecule (SM) approach and the contact probability (CP) approach were used. Both in the case of the SM and CP approach, good to very good correlations between the experiment and computations are found for complexes formed from neutral species, enabling quantitative predictions. When the HB acceptor is an anion, the correlations are poor and in some cases even qualitative predictions fail.     

Mutual Weakening of Hydrogen Bonds Between Hydrogen Fluoride and Proton Donors

The mutual effect of hydrogen bonds in BHF(HHal) _n complexes (Hal = F, Cl, Br, I; B = –, CH₃CN, NH₃; n = 1-3) was examined using the self-consistent field ab initio approach (6-31++G(d,p) and ECP-HW). When two and three equivalent H bonds are formed from the lone electron pairs of the fluorine atom of the HF molecule, the mutual weakening effect is 17% and 28%, respectively. The coefficients of the mutual effects of hydrogen bonds in HF(HHal)₂ and H₂O(HHal)₂ bridges are close in magnitude.     

4-羟甲基吡啶－水红移氢键的密度泛函理论研究

使用密度泛函理论B3LYP方法和6-311++G**基函数对4-羟甲基吡啶与水形成的1:1和1:2（摩尔比）氢键复合物进行了理论计算研究,分别得到稳定的4-羟甲基吡啶－H₂O和4-羟甲基吡啶－(H₂O)₂氢键复合物3个和8个。经基组重叠误差和零点振动能校正后,最稳定的1:1和1:2氢键复合物的相互作用能分别为-20.536和-44.246 kJ/mol。振动分析显示O-H···N(O)氢键的形成使复合物中O-H键对称伸缩振动频率红移(减小)。自然键轨道分析表明,4-羟甲基吡啶与水形成最稳定的1:1和1:2氢键复合物时,分子间电荷转移分别为0.02642 e 和0.03813 e 。含时密度泛函理论TD-B3LYP/ 6-311++G**计算显示,相对于4-羟甲基吡啶单体分子,氢键H-OH···N和H-OH···OH的形成分别使最大吸收光谱波长兰移8~16纳米和红移4~11纳米。     

Quantifying Homo‐ and Heteromolecular Hydrogen Bonds as a Guide for Adduct Formation

An investigation into the predictability of molecular adduct formation is presented by using the approach of hydrogen bond propensity. Along with the predictions, crystallisation reactions ( 1a – 1j ) were carried out between the anti‐malarial drug pyrimethamine ( 1 ) and the acids oxalic ( a ), malonic ( b ), acetylenedicarboxylic ( c ), adipic ( d ), pimelic ( e ), suberic ( f ), azelaic acids ( g ), as well as hexachlorobenzene ( h ), 1,4‐diiodobenzene ( i ), and 1,4‐diiodotetrafluorobenzene ( j ); seven ( 1a to 1g ) of these successfully formed salts. Five of these seven salts were found to be either hydrated or solvated. Hydrogen bond propensity calculations predict that hydrogen bonds between 1 and acids a – g are more likely to form rather than the H bonds involved in self‐association, providing a rationale for the observation of the seven new salts. In contrast, propensity of hydrogen bonds between 1 and h – j is much smaller as compared to other bonds predicted for self‐association/solvate formation, in agreement with the observed unsuccessful reactions.     

Intermolecular Weak Interactions in HTeXH Dimers (X=O,S, Se,Te): Hydrogen Bonds,Chalcogen–Chalcogen Contacts and Chiral Discrimination

A theoretical study of the HTeXH (X=O, S, Se and Te) monomers and homodimers was carried out by means of second‐order Møller‐Plesset perturbation theory (MP2) computational methods. In the case of monomers, the isomerization energy from HTeXH to H₂Te=X and H₂X=Te (X=O, S, Se, and Te) and the rotational transition‐state barriers were obtained. Due to the chiral nature of these compounds, homo and heterochiral dimers were found. The electron density of the complexes was characterized with the atoms‐in‐molecules (AIM) methodology, finding a large variety of interactions. The charge transfer within the dimers was analyzed by means of natural bond orbitals (NBO). The density functional theory‐symmetry adapted perturbation theory (DFT‐SAPT) method was used to compute the components of the interaction energies. Hydrogen bonds and chalcogen–chalcogen interactions were characterized and their influence analyzed concerning the stability and chiral discrimination of the dimers.     

Understanding Regium Bonds and their Competition with Hydrogen Bonds in Au2:HX Complexes

A theoretical study of the regium and hydrogen bonds (RB and HB, respectively) in Au₂:HX complexes has been carried out by means of CCSD(T) calculations. The theoretical study shows as overall outcome that in all cases the complexes exhibiting RB are more stable that those with HB. The binding energies for RB complexes range between −24 and −180 kJ ⋅ mol^−1, whereas those of the HB complexes are between −6 and −19 kJ ⋅ mol⁻¹. DFT-SAPT also indicated that HB complexes are governed by electrostatics, but RB complexes present larger contribution of the induction term to the total attractive forces. ¹⁹⁷Au chemical shifts have been calculated using the relativistic ZORA Hamiltonian.     

The Nature of Activated Non‐classical Hydrogen Bonds: A Case Study on Acetylcholinesterase–Ligand Complexes

Molecular recognition events in biological systems are driven by non‐covalent interactions between interacting species. Here, we have studied hydrogen bonds of the CH???Y type involving electron‐deficient CH donors using dispersion‐corrected density functional theory (DFT) calculations applied to acetylcholinesterase–ligand complexes. The strengths of CH???Y interactions activated by a proximal cation were considerably strong; comparable to or greater than those of classical hydrogen bonds. Significant differences in the energetic components compared to classical hydrogen bonds and non‐activated CH???Y interactions were observed. Comparison between DFT and molecular mechanics calculations showed that common force fields could not reproduce the interaction energy values of the studied hydrogen bonds. The presented results highlight the importance of considering CH???Y interactions when analysing protein–ligand complexes, call for a review of current force fields, and opens up possibilities for the development of improved design tools for drug discovery.     

cPCET versus HAT: A Direct Theoretical Method for Distinguishing X–H Bond‐Activation Mechanisms

Proton‐coupled electron transfer (PCET) events play a key role in countless chemical transformations, but they come in many physical variants which are hard to distinguish experimentally. While present theoretical approaches to treat these events are mostly based on physical rate coefficient models of various complexity, it is now argued that it is both feasible and fruitful to directly analyze the electronic N‐electron wavefunctions of these processes along their intrinsic reaction coordinate (IRC). In particular, for model systems of lipoxygenase and the high‐valent oxoiron(IV) intermediate TauD‐J it is shown that by invoking the intrinsic bond orbital (IBO) representation of the wavefunction, the common boundary cases of hydrogen atom transfer (HAT) and concerted PCET (cPCET) can be directly and unambiguously distinguished in a straightforward manner.     

Hydrogen Bonding between Metal‐Ion Complexes and Noncoordinated Water: Electrostatic Potentials and Interaction Energies

The hydrogen bonding of noncoordinated water molecules to each other and to water molecules that are coordinated to metal‐ion complexes has been investigated by means of a search of the Cambridge Structural Database (CSD) and through quantum chemical calculations. Tetrahedral and octahedral complexes that were both charged and neutral were studied. A general conclusion is that hydrogen bonds between noncoordinated water and coordinated water are much stronger than those between noncoordinated waters, whereas hydrogen bonds of water molecule in tetrahedral complexes are stronger than in octahedral complexes. We examined the possibility of correlating the computed interaction energies with the most positive electrostatic potentials on the interacting hydrogen atoms prior to interaction and obtained very good correlation. This study illustrates the fact that electrostatic potentials computed for ground‐state molecules, prior to interaction, can provide considerable insight into the interactions.     

Intramolecular Hydrogen Bonds in Low‐Molecular‐Weight Polyethylene Glycol

We used static DFT calculations to analyze, in detail, the intramolecular hydrogen bonds formed in low‐molecular‐weight polyethylene glycol (PEG) with two to five repeat subunits. Both red‐shifted O?H???O and blue‐shifting C?H???O hydrogen bonds, which control the structural flexibility of PEG, were detected. To estimate the strength of these hydrogen bonds, the quantum theory of atoms in molecules was used. Car–Parrinello molecular dynamics simulations were used to mimic the structural rearrangements and hydrogen‐bond breaking/formation in the PEG molecule at 300 K. The time evolution of the H???O bond length and valence angles of the formed hydrogen bonds were fully analyzed. The characteristic hydrogen‐bonding patterns of low‐molecular‐weight PEG were described with an estimation of their lifetime. The theoretical results obtained, in particular the presence of weak C?H???O hydrogen bonds, could serve as an explanation of the PEG structural stability in the experimental investigation.     

Strong CH⋅⋅⋅Halide Hydrogen Bonds from 1,2,3‐Triazoles Quantified Using Pre‐Organized and Shape‐Persistent Triazolophanes

The structures associated with halide (F^?, Cl^?, Br^?) complexation inside CH hydrogen‐bonding macrocyclic receptors, called triazolophanes, are characterized using density functional theory (DFT). The associated binding energies in the gas and solution phases are evaluated. The ruffles in the empty triazolophane become smoothed‐out upon Cl^?‐ and Br^?‐ion binding directly into the middle of the cavity. The largely pre‐organized cavity morphs into an elliptical shape to facilitate shorter hydrogen bonds in the north and south regions and longer ones west and east. The smaller F^? ion sits in, and flattens‐out, only the north (or south) region. The 1,2,3‐triazoles show shorter CH???Cl^? contacts than for the phenylenes. Both Cl^? and Br^? show the same binding geometries but Cl^? has a larger binding energy consistent with its stronger Lewis basicity. Model triads were used to decompose the overall binding energy into those of its components. In the course of this triad analysis, anion polarization was identified and its contribution to the triad???Cl^? binding energy estimated. Consequently, the binding energies for the individual aryl units within the comparatively non‐polarized triazolophanes were estimated. The 1,2,3‐triazoles are twice as strong as the phenylenes thus contributing most of the interaction energy to Cl^?‐ion binding. Therefore, the 1,2,3‐triazoles appear to approach the hydrogen bond strengths of the NH donors of pyrrole units.     

Natural Products with Anti‐Bredt and Bridgehead Double Bonds

Well over a hundred years ago, Professor Julius Bredt embarked on a career pursuing and critiquing bridged bicyclic systems that contained ring strain induced by the presence of a bridgehead olefin. These endeavors founded what we now know as Bredt’s rule (Bredtsche Regel). Physical, theoretical, and synthetic organic chemists have intensely studied this premise, pushing the boundaries of such systems to arrive at a better understood physical phenomenon. Mother nature has also seen fit to construct molecules containing bridgehead double bonds that encompass Bredt’s rule. For the first time, this topic is reviewed in a natural product context.     

Opposing Electronic and Nuclear Quantum Effects on Hydrogen Bonds in H2O and D2O

The effect of extending the O−H bond length(s) in water on the hydrogen-bonding strength has been investigated using static ab initio molecular orbital calculations. The “polar flattening” effect that causes a slight σ-hole to form on hydrogen atoms is strengthened when the bond is stretched, so that the σ-hole becomes more positive and hydrogen bonding stronger. In opposition to this electronic effect, path-integral ab initio molecular-dynamics simulations show that the nuclear quantum effect weakens the hydrogen bond in the water dimer. Thus, static electronic effects strengthen the hydrogen bond in H₂O relative to D₂O, whereas nuclear quantum effects weaken it. These quantum fluctuations are stronger for the water dimer than in bulk water.     

Competitive Halide Binding by Halogen Versus Hydrogen Bonding: Bis‐triazole Pyridinium

The binding of F^?, Cl^?, Br^?, and I^? anions by bis‐triazole‐pyridine (BTP) was examined by quantum chemical calculations. There is one H atom on each of the two triazole rings that chelate the halide via H bonds. These H atoms were replaced by halogens Cl, Br, and I, thus substituting H bonds by halogen bonds. I substitution strongly enhances the binding; Br has a smaller effect, and Cl weakens the interaction. The strength of the interaction is sensitive to the overall charge on the BTP, rising as the binding agent becomes singly and then doubly positively charged. The strongest preference of a halide for halogenated as compared to unsubstituted BTP, as much as several orders of magnitude, is observed for I^?. Both unsubstituted and I‐substituted BTP could be used to selectively extract F^? from a mixture of halides.