Modeling of the Response of Hydrogen Bond Properties on an External Electric Field: Geometry, NMR Chemical Shift, Spin-Spin Scalar Coupling.

The response of the geometric and NMR properties of molecular systems to an external electric field has been studied theoretically in a wide field range. It has been shown that this adduct under field approach can be used to model the geometric and spectral changes experienced by molecular systems in polar media if the system in question has one and only one bond, the polarizability of which significantly exceeds the polarizability of other bonds. If this requirement is met, then it becomes possible to model even extreme cases, for example, proton dissociation in hydrogen halides. This requirement is fulfilled for many complexes with one hydrogen bond. For such complexes, this approach can be used to facilitate a detailed analysis of spectral changes associated with geometric changes in the hydrogen bond. For example, in hydrogen-bonded complexes of isocyanide C≡15N-1H⋯X, 1J(15N1H) depends exclusively on the N-H distance, while δ(15N) is also slightly influenced by the nature of X.

Double Proton Tautomerism via Intra- or Intermolecular Pathways? The Case of Tetramethyl Reductic Acid Studied by Dynamic NMR: Hydrogen Bond Association, Solvent and Kinetic H/D Isotope Effects.

Using dynamic liquid-state NMR spectroscopy a degenerate double proton tautomerism was detected in tetramethyl reductic acid (TMRA) dissolved in toluene-d8 and in CD2Cl2. Similar to vitamin C, TMRA belongs to the class of reductones of biologically important compounds. The tautomerism involves an intramolecular HH transfer that interconverts the peripheric and the central positions of the two OH groups. It is slow in the NMR time scale around 200 K and fast at room temperature. Pseudo-first-order rate constants of the HH transfer and of the HD transfer after suitable deuteration were obtained by line shape analyses. Interestingly, the chemical shifts were found to be temperature dependent carrying information about an equilibrium between a hydrogen bonded dimer and a monomer forming two weak intramolecular hydrogen bonds. The structures of the monomer and the dimer are discussed. The latter may consist of several rapidly interconverting hydrogen-bonded associates. A way was found to obtain the enthalpies and entropies of dissociation, which allowed us to convert the pseudo-first-order rate constants of the reaction mixture into first-order rate constants of the tautomerization of the monomer. Surprisingly, these intrinsic rate constants were the same for toluene-d8 and CD2Cl2, but in the latter solvent more monomer is formed. This finding is attributed to the dipole moment of the TMRA monomer, compensated in the dimer, and to the larger dielectric constant of CD2Cl2. Within the margin of error, the kinetic HH/HD isotope effects were found to be of the order of 3 but independent of temperature. That finding indicates a stepwise HH transfer involving a tunnel mechanism along a double barrier pathway. The Arrhenius curves were described in terms of the Bell-Limbach tunneling model.

Combined NMR and UV-Vis Spectroscopic Studies of Models for the Hydrogen Bond System in the Active Site of Photoactive Yellow Protein: H-Bond Cooperativity and Medium Effects.

Intramolecular hydrogen bonds in aprotic media were studied by combined (simultaneous) NMR and UV-vis spectroscopy. The species under investigation were anionic and featured single or coupled H-bonds between, for example, carboxylic groups and phenolic oxygen atoms (COO···H···OC)-, among phenolic oxygen atoms (CO···H···OC)-, and hydrogen bond chains between a carboxylic group and two phenolic oxygen atoms (COO···H···(OC)···H···OC)-. The last anion may be regarded as a small molecule model for the hydrogen bond system in the active site of wild-type photoactive yellow protein (PYP) while the others mimic the corresponding H-bonds in site-selective mutants. Proton positions in isolated hydrogen bonds and hydrogen bond chains were assessed by calculations for vacuum conditions and spectroscopically for the two media, CD2Cl2 and the liquefied gas mixture CDClF2/CDF3 at low temperatures. NMR parameters allow for the estimation of time-averaged H-bond geometries, and optical spectra give additional information about geometry distributions. Comparison of the results from the various systems revealed the effects of the formation of hydrogen bond chains and changes of medium conditions on the geometry of individual H-bonds. In particular, the proton in a hydrogen bond to a carboxylic group shifts from the phenolic oxygen atom in the system COO-···H-OC to the carboxylic group in COO-H···(OC)-···H-OC as a result of hydrogen bond formation to the additional phenolic donor. Increase in medium polarity may, however, induce the conversion of a structure of a type COO-H···(OC)-···H-OC to the type COO-···H-(OC)···H-OC. Application of these results obtained from the model systems to PYP suggests that both cooperative effects within the hydrogen bond chain and a low-polarity protein environment are prerequisites for the stabilization of negative charge on the cofactor and hence for the spectral tuning of the photoreceptor.

Modeling of Solute-Solvent Interactions Using an External Electric Field-From Tautomeric Equilibrium in Nonpolar Solvents to the Dissociation of Alkali Metal Halides.

An implicit account of the solvent effect can be carried out using traditional static quantum chemistry calculations by applying an external electric field to the studied molecular system. This approach allows one to distinguish between the effects of the macroscopic reaction field of the solvent and specific solute-solvent interactions. In this study, we report on the dependence of the simulation results on the use of the polarizable continuum approximation and on the importance of the solvent effect in nonpolar solvents. The latter was demonstrated using experimental data on tautomeric equilibria between the pyridone and hydroxypyridine forms of 2,6-di-tert-butyl-4-hydroxy-pyridine in cyclohexane and chloroform.

Sensitivity of 31 P NMR chemical shifts to hydrogen bond geometry and molecular conformation for complexes of phosphinic acids with pyridines.

The results of the quantum-chemical investigation of a series of hydrogen-bonded 1:1 acid-base complexes formed by model phosphinic acids, Me2 POOH, and PhHPOOH, are reported. A series of substituted pyridines (pKa range from 0.5 to 10) was chosen as proton acceptors. Gradual changes of isotropic 31 P nuclear magnetic resonance (NMR) chemical shift, δP, were correlated with the bridging proton position in the intermolecular OHN hydrogen bond, namely, r (OH) distance; the proposed correlation could easily be extended to other phosphinic acids as well. For complexes with pyridine and 2,4,6-trimethylpyridine, we have investigated in more detail several factors influencing the δP values: (1) the proton transfer within the OHN hydrogen bond; (2) the rotation of the pyridine ring around the hydrogen bond axis (associated with the formation/breakage of additional weak PO···H-C hydrogen bond); and (3) the rotation of the phenyl substituent in phenylphosphinic acid around the P-C axis. All these factors appeared to be of similar magnitude, thus masking their individual contributions that have to be independently estimated for a reliable spectral interpretation.

Stretching force constants as descriptors of energy and geometry of F···HF hydrogen bonds.

In this work applicability of proton donor group stretching vibration force constants ks and intermolecular stretching force constants kσ for evaluations of hydrogen bond strength and geometry are discussed. For a set of 30 complexes with F···HF hydrogen bonds in a wide range 0.5-48 kcal/mol by means of quantum chemical calculations equilibrium geometries, complexation energies, vibrational frequencies and corresponding force constants were calculated (MP2/aug-cc-pVTZ). It is shown, that properties of a hydrogen bond are more strictly correlated with the values of force constants than with vibrational frequencies. Easy-to-use equations for estimations of hydrogen bond energy ∆E and geometry (rFH, rFF) based on ks and kσ values are proposed.

Lone pairs mapping by Laplacian of 3 He NMR chemical shift.

Results of approbation of a new quantum mechanical approach of lone pairs (LPs) visualization, its optimization and testing on a range of model molecules are presented. The main idea of proposed methodology is using 3 He atom as a probe for investigating electronic shells of species with LPs. As model objects, we consider "classical" examples of hydrogen cyanide, methanimine, ammonia, phosphine, formaldehyde, water, and hydrogen sulfide. It is shown that LPs can be visualized by means of 3D maps of Laplacian of 3 He chemical shift ∇2 δHe . NMR calculations could be performed using level of theory as low as B3LYP/6-31G, allowing for the reduction of computational time without significant loss of quality. Advantages of our approach are discussed in comparison with usual methods of lone pairs visualization (electron localization function, molecular electrostatic potential).

Adduct under Field-A Qualitative Approach to Account for Solvent Effect on Hydrogen Bonding.

The location of a mobile proton in acid-base complexes in aprotic solvents can be predicted using a simplified Adduct under Field (AuF) approach, where solute-solvent effects on the geometry of hydrogen bond are simulated using a fictitious external electric field. The parameters of the field have been estimated using experimental data on acid-base complexes in CDF3/CDClF2. With some limitations, they can be applied to the chemically similar CHCl3 and CH2Cl2. The obtained data indicate that the solute-solvent effects are critically important regardless of the type of complexes. The temperature dependences of the strength and fluctuation rate of the field explain the behavior of experimentally measured parameters.

Unusual behaviour of the spin-spin coupling constant 1JCH upon formation of CHX hydrogen bond.

One-bond coupling constants 1JXY are usually used as a measure of the corresponding XY interatomic distances. However, the physical nature of this correlation is not well understood and, in some cases, a counterintuitive behaviour of 1JXY upon hydrogen bonded complex formation has been reported. In this work, the behavior of 1JCH upon formation and strengthening of complexes with CHX hydrogen bonds and upon a proton transfer process is investigated by means of 1H NMR spectroscopy and quantum chemical calculations. 1H NMR spectra of 1,1-dinitroethane solution at room temperature in various solvents (carbon tetrachloride, chloroform, dichloromethane, acetone, dimethylformamide and dimethyl sulfoxide) illustrate the increase of 1JCH by several Hz upon an increase of the complex strength. Computational results (MP2/aug-cc-pVDZ) reproduce this observation and allow one to conclude that the increase of 1JCH is mainly caused by the change of the carbon hybridization (an increase of s-character), rather than by the change in interatomic distance rCH. The behavior of 1JCH was also examined computationally for a wide range of CHX hydrogen bond energies and geometries. For this purpose, quantum-chemical modeling of the partial proton transfer process for complexes formed by 1,1-dinitroethane and trinitromethane as hydrogen bond donors with acetone, pyridine and fluoride anion as hydrogen bond acceptors was performed. The obtained results have confirmed the above-mentioned idea - for rather weak complexes, the dominant impact on the change of 1JCH magnitude is the increase of the s-character of carbon atom hybridization, while for complexes with a significantly transferred proton, the exponential decrease of the Fermi-contact term dominates.

Anticooperativity of FH···Cl- hydrogen bonds in [FH)n Cl]- clusters (n = 1 6).

The change of cooperativity of FH···Cl- hydrogen bonds upon sequential addition of up to six FH molecules to the Cl- first coordination sphere is investigated. The geometry of clusters [(FH) n Cl]- (n = 1…6) was calculated (CCSD/aug-cc-pVDZ) and compared with [(FH) n F]- clusters. The geometry is determined by the symmetry-driven electrostatic requirements and also by the fact that formation of each new FH···Cl- bond creates a depression in the chlorine's electron cloud on the opposite side of Cl- (σ-hole), which limits the range of directions available for subsequent H-bond formation. The mutual influence of FH···Cl- hydrogen bonds is anticooperative-the addition of each FH molecule weakens H-bonds by 23-16% and decreases their covalent character (as seen by LMO-EDA decomposition and QTAIM analysis). Anticooperativity effects could be tracked by spectroscopic parameters (frequency of local HF mode νFH , chemical shift δH , spin-spin coupling constants 1 JFH , 1h JHCl , 2h JFCl and nuclear quadrupolar constants χ18F , χD , and χ35Cl . © 2019 Wiley Periodicals, Inc.

Conformational Mobility and Proton Transfer in Hydrogen-Bonded Dimers and Trimers of Phosphinic and Phosphoric Acids.

The monomers, H-bonded cyclic dimers, and trimers of five acids were studied by density functional theory calculations, such as hypophosphorous acid (H2POOH, 1), dimethylphosphinic acid (Me2POOH, 2), phenylphosphinic acid (PhHPOOH, 3), dimethylphosphoric acid ((MeO)2POOH, 4), and diphenylphosphoric acid ((PhO)2POOH, 5). Particular attention was paid to the conformational manifold existing due to the internal degrees of freedom: proton transfer (PT), puckering ("twist") within the ring of H-bonds, and mobility of the substituents (namely, -Ph, -OMe, and -OPh rotations). For acid 3, the number of conformers is additionally increased because of the varying relative orientation of nonequivalent substituents in cyclic complexes. We show that 31P NMR chemical shifts (δP) are very sensitive to the details of the conformation, spanning ranges from ca. 1 ppm (for trimers of acids 1 and 2) to ca. 12 ppm (for trimers of 4). The energy barriers for the transitions between conformers are rather low (<6 kcal/mol for PTs, <2.5 kcal/mol for puckerings, and ca. <3 kcal/mol for rotations of substituents), such that the fast exchange regime in the NMR timescale and subsequent δP averaging are expected. Correlations are proposed linking the change of average δP with the H-bond energy, showing the slope of ca. 4 ppm per kcal/mol. The sensitivity of δP to the OPO angle and the OPOH dihedral angle and the geometries of both H-bonds formed by the POOH moiety are analyzed.

Solvent effects on acid-base complexes. What is more important: A macroscopic reaction field or solute-solvent interactions?

Can the geometry of an acid-base complex in solution be reproduced in calculations using an implicit accounting for the solvent effect in the form of a macroscopic reaction field? The answer is, "Yes, it can." Is this field equal to the real electric field experienced by the complex in solution? The answer is, "No, it is not." How can the geometry be correct under wrong conditions? This question is answered using density functional theory modeling of geometric and NMR parameters of pyridine⋯HF⋯(HCF3)n adducts in the absence and presence of an external electric field. This adduct under field approach shows that the N⋯H distance is a function of the H-F distance whatever method is used to change the geometry of the latter. An explicit account for solute-solvent interactions is required to get a realistic value of the solvent reaction field. Besides that, this approach reveals how certain NMR parameters depend on the solvent reaction field, the solute-solvent interactions, and the geometry of the N⋯H-F hydrogen bond. For some of them, the obtained dependences are far from self-evident.

Influence of Hydrogen Bonds in 1:1 Complexes of Phosphinic Acids with Substituted Pyridines on 1H and 31P NMR Chemical Shifts.

Two series of 1:1 complexes with strong OHN hydrogen bonds formed by dimethylphosphinic and phenylphosphinic acids with 10 substituted pyridines were studied experimentally by liquid state NMR spectroscopy at 100 K in solution in a low-freezing polar aprotic solvent mixture CDF3/CDClF2. The hydrogen bond geometries were estimated using previously established correlations linking 1H NMR chemical shifts of bridging protons with the O···H and H···N interatomic distances. A new correlation is proposed allowing one to estimate the interatomic distance within the OHN bridge from the displacement of 31P NMR signal upon complexation. We show that the values of 31P NMR chemical shifts are affected by an additional CH···O hydrogen bond formed between the P═O group of the acid and ortho-CH proton of the substituted pyridines. Breaking of this bond in the case of 2,6-disubstituted bases shifts the 31P NMR signal by ca. 1.5 ppm to the high field.

Outer electronic shell visualization by NMR chemical shift laplacian of a helium probe.

A new method of visualization of lone pairs is proposed using fluorine atoms in fluoroacetylene, trifluoroethylene, and fluoroform (sp, sp2 , and sp3 hybridized carbons) as an example. The space around fluorines was probed by a helium atom and at each point 3 He NMR chemical shift δHe and its Laplacian ∇2 δHe were calculated. The ∇2 δHe isosurfaces have symmetrical toroidal shapes along CF axes; the maximum values of ∇2 δHe are reached at about 1.5 Å from fluorine atom center in the direction roughly coinciding with the lone pair localization. The absolute values of the ∇2 δHe could be used to quantify the electron-rich regions of lone pairs. The results are compared with more common visualization methods-3D maps of the molecular electrostatic potential and the electron localization function. We show that a helium atom could be used for evaluation of fine features of molecular electronic shell, since 3 He NMR spectral characteristics remain sensitive at relatively large distances. © 2018 Wiley Periodicals, Inc.

NMR Study of Solvation Effect on the Geometry of Proton-Bound Homodimers of Increasing Size.

Hydrogen bond geometries in the proton-bound homodimers of quinoline and acridine derivatives in an aprotic polar solution have been experimentally studied using 1H NMR at 120 K. The reported results show that an increase of the dielectric permittivity of the medium results in contraction of the N···N distance. The degree of contraction depends on the homodimer's size and its substituent-specific solvation features. Neither of these effects can be reproduced using conventional implicit solvent models employed in computational studies. In general, the N···N distance in the homodimers of pyridine, quinoline, and acridine derivatives decreases in the sequence gas phase > solid state > polar solvent.

Proton transfer in a short hydrogen bond caused by solvation shell fluctuations: an ab initio MD and NMR/UV study of an (OHO)(-) bonded system.

We present a joint experimental and quantum chemical study on the influence of solvent dynamics on the protonation equilibrium in a strongly hydrogen bonded phenol-acetate complex in CD2Cl2. Particular attention is given to the correlation of the proton position distribution with the internal conformation of the complex itself and with fluctuations of the aprotic solvent. Specifically, we have focused on a complex formed by 4-nitrophenol and tetraalkylammonium-acetate in CD2Cl2. Experimentally we have used combined low-temperature (1)H and (13)C NMR and UV-vis spectroscopy and showed that a very strong OHO hydrogen bond is formed with proton tautomerism (PhOH···(-)OAc and PhO(-)···HOAc forms, both strongly hydrogen bonded). Computationally, we have employed ab initio molecular dynamics (70 and 71 solvent molecules, with and without the presence of a counter-cation, respectively). We demonstrate that the relative motion of the counter-cation and the "free" carbonyl group of the acid plays the major role in the OHO bond geometry and causes proton "jumps", i.e. interconversion of PhOH···(-)OAc and PhO(-)···HOAc tautomers. Weak H-bonds between CH(CD) groups of the solvent and the oxygen atom of carbonyl stabilize the PhOH···(-)OAc type of structures. Breaking of CH···O bonds shifts the equilibrium towards PhO(-)···HOAc form.

NMR studies of active-site properties of human carbonic anhydrase†II by using (15) N-labeled 4-methylimidazole as a local probe and histidine hydrogen-bond correlations.

By using a combination of liquid and solid-state NMR spectroscopy, (15) N-labeled 4-methylimidazole (4-MI) as a local probe of the environment has been studied: 1) in the polar, wet Freon CDF3 /CDF2 Cl down to 130 K, 2) in water at pH 12, and 3) in solid samples of the mutant H64A of human carbonic anhydrase II (HCA II). In the latter, the active-site His64 residue is replaced by alanine; the catalytic activity is, however, rescued by the presence of 4-MI. For the Freon solution, it is demonstrated that addition of water molecules not only catalyzes proton tautomerism but also lifts its quasidegeneracy. The possible hydrogen-bond clusters formed and the mechanism of the tautomerism are discussed. Information about the imidazole hydrogen-bond geometries is obtained by establishing a correlation between published (1) H and (15) N chemical shifts of the imidazole rings of histidines in proteins. This correlation is useful to distinguish histidines embedded in the interior of proteins and those at the surface, embedded in water. Moreover, evidence is obtained that the hydrogen-bond geometries of His64 in the active site of HCA II and of 4-MI in H64A HCA II are similar. Finally, the degeneracy of the rapid tautomerism of the neutral imidazole ring His64 reported by Shimahara et al. (J. Biol. Chem.- 2007, 282, 9646) can be explained with a wet, polar, nonaqueous active-site conformation in the inward conformation, similar to the properties of 4-MI in the Freon solution. The biological implications for the enzyme mechanism are discussed.

NMR study of CHN hydrogen bond and proton transfer in 1,1-dinitroethane complex with 2,4,6-trimethylpyridine.

The intermolecular complex with a CHN hydrogen bond formed by 1,1-dinitroethane (DNE) and 2,4,6-trimethylpyridine (collidine) dissolved in CD2Cl2 was studied experimentally by (1)H NMR spectroscopy at 180-300 K. Equilibrium between the molecular CH···N form and the zwitterionic C(-)/HN(+) form was detected in the slow exchange regime in the NMR time scale. No sign of a direct C(-)···HN(+) bond was observed; the ion pair is likely to be held by Coulomb interactions. Moreover, there are indications that the protonated base is involved in the formation of homoconjugated (NHN)(+) collidine-collidinium hydrogen bonded complexes. The reaction pathway of proton transfer in the DNE-pyiridine complex in a vacuum was studied computationally at the B3LYP/6-31++G(d,p) level of theory. NMR chemical shifts and coupling constants were calculated for a series of snapshots along the proton transfer coordinate. While the central carbon atom has a pyramidal (sp(3)) configuration in DNE, it is flat (sp(2)) in the DNE carbanion. As a result, the most indicative computed NMR parameter reflecting hybridization of a carbon atom appeared to be (1)JCC, which starts to change rapidly as soon as a structure with a quasi-symmetric C··H··N bond is reached. Couplings within the hydrogen bridge, (1)JCH, (1h)JHN, and (2)JCN, can serve as good indicators of the degree of proton transfer.

NMR studies of protonation and hydrogen bond states of internal aldimines of pyridoxal 5'-phosphate acid-base in alanine racemase, aspartate aminotransferase, and poly-L-lysine.

Using (15)N solid-state NMR, we have studied protonation and H-bonded states of the cofactor pyridoxal 5'-phosphate (PLP) linked as an internal aldimine in alanine racemase (AlaR), aspartate aminotransferase (AspAT), and poly-L-lysine. Protonation of the pyridine nitrogen of PLP and the coupled proton transfer from the phenolic oxygen (enolimine form) to the aldimine nitrogen (ketoenamine form) is often considered to be a prerequisite to the initial step (transimination) of the enzyme-catalyzed reaction. Indeed, using (15)N NMR and H-bond correlations in AspAT, we observe a strong aspartate-pyridine nitrogen H-bond with H located on nitrogen. After hydration, this hydrogen bond is maintained. By contrast, in the case of solid lyophilized AlaR, we find that the pyridine nitrogen is neither protonated nor hydrogen bonded to the proximal arginine side chain. However, hydration establishes a weak hydrogen bond to pyridine. To clarify how AlaR is activated, we performed (13)C and (15)N solid-state NMR experiments on isotopically labeled PLP aldimines formed by lyophilization with poly-L-lysine. In the dry solid, only the enolimine tautomer is observed. However, a fast reversible proton transfer involving the ketoenamine tautomer is observed after treatment with either gaseous water or gaseous dry HCl. Hydrolysis requires the action of both water and HCl. The formation of an external aldimine with aspartic acid at pH 9 also produces the ketoenamine form stabilized by interaction with a second aspartic acid, probably via a H-bond to the phenolic oxygen. We postulate that O-protonation is an effectual mechanism for the activation of PLP, as is N-protonation, and that enzymes that are incapable of N-protonation employ this mechanism.

Solvent and H/D isotope effects on the proton transfer pathways in heteroconjugated hydrogen-bonded phenol-carboxylic acid anions observed by combined UV-vis and NMR spectroscopy.

Heteroconjugated hydrogen-bonded anions A···H···X(-) of phenols (AH) and carboxylic/inorganic acids (HX) dissolved in CD2Cl2 and CDF3/CDF2Cl have been studied by combined low-temperature UV-vis and (1)H/(13)C NMR spectroscopy (UVNMR). The systems constitute small molecular models of hydrogen-bonded cofactors in proteins such as the photoactive yellow protein (PYP). Thus, the phenols studied include the PYP cofactor 4-hydroxycinnamic acid methyl thioester, and the more acidic 4-nitrophenol and 2-chloro-4-nitrophenol which mimic electronically excited cofactor states. It is shown that the (13)C chemical shifts of the phenolic residues of A···H···X(-), referenced to the corresponding values of A···H···A(-), constitute excellent probes for the average proton positions. These shifts correlate with those of the H-bonded protons, as well as with the H/D isotope effects on the (13)C chemical shifts. A combined analysis of UV-vis and NMR data was employed to elucidate the proton transfer pathways in a qualitative way. Dual absorption bands of the phenolic moiety indicate a double-well situation for the shortest OHO hydrogen bonds studied. Surprisingly, when the solvent polarity is low the carboxylates are protonated whereas the proton shifts toward the phenolic oxygens when the polarity is increased. This finding indicates that because of stronger ion-dipole interactions small anions are stabilized at high solvent polarity and large anions exhibiting delocalized charges at low solvent polarities. It also explains the large acidity difference of phenols and carboxylic acids in water, and the observation that this difference is strongly reduced in the interior of proteins when both partners form mutual hydrogen bonds.