Intramolecular hydrogen bond: Can it be part of the basis set of valence internal coordinates in normal mode analysis?

It has been shown earlier1] that the relaxed force constants (RFCs) could be used as a measure of bond strength only when the bonds form a part of the complete valence internal coordinates (VIC) basis. However, if the bond is not a part of the complete VIC basis, its RFC is not necessarily a measure of bond strength. Sometimes, it is possible to have a complete VIC basis that does not contain the intramolecular hydrogen bond (IMHB) as part of the basis. This means the RFC of IMHB is not necessarily a measure of bond strength. However, we know that IMHB is a weak bond and hence its RFC has to be a measure of bond strength. We resolve this problem of IMHB not being part of the complete basis by postulating `equivalent' basis sets where IMHB is part of the basis at least in one of the equivalent sets of VIC. As long as a given IMHB appears in one of the equivalent complete VIC basis sets, its RFC could be used as a measure of bond strength parameter.

I. The crystal structure of potassium bis(tricyanovinyl)amine. II. Nuclear magnetic resonance studies of alkali halide solutions. III. Elucidation of the intramolecular hydrogen bond in acetylacetone by the deuterium isotope effect on the chemical shift of the bridge hydrogen

Part I

Potassium bis-(tricyanovinyl) amine, K⁺N[C(CN)=C(CN)₂]₂^-, crystallizes in the monoclinic system with the space group Cc and lattice constants, a = 13.346 ± 0.003 Å, c = 8.992 ± 0.003 Å, B = 114.42 ± 0.02°, and Z = 4. Three dimensional intensity data were collected by layers perpendicular to b* and c* axes. The crystal structure was refined by the least squares method with anisotropic temperature factor to an R value of 0.064.

The average carbon-carbon and carbon-nitrogen bond distances in –C-CΞN are 1.441 ± 0.016 Å and 1.146 ± 0.014 Å respectively. The bis-(tricyanovinyl) amine anion is approximately planar. The coordination number of the potassium ion is eight with bond distances from 2.890 Å to 3.408 Å. The bond angle C-N-C of the amine nitrogen is 132.4 ± 1.9°. Among six cyano groups in the molecule, two of them are bent by what appear to be significant amounts (5.0° and 7.2°). The remaining four are linear within the experimental error. The bending can probably be explained by molecular packing forces in the crystals.

Part II

The nuclear magnetic resonance of ⁸¹Br and ¹²⁷I in aqueous solutions were studied. The cation-halide ion interactions were studied by studying the effect of the Li⁺, Na⁺, K⁺, Mg⁺⁺, Cs⁺ upon the line width of the halide ions. The solvent-halide ion interactions were studied by studying the effects of methanol, acetonitrile, and acetone upon the line width of ⁸¹Br and ¹²⁷I in the aqueous solutions. It was found that the viscosity plays a very important role upon the halide ions line width. There is no specific cation-halide ion interaction for those ions such as Mg⁺⁺, Di⁺, Na⁺, and K⁺, whereas the Cs⁺ - halide ion interaction is strong. The effect of organic solvents upon the halide ion line width in aqueous solutions is in the order acetone ˃ acetonitrile ˃ methanol. It is suggested that halide ions do form some stable complex with the solvent molecules and the reason Cs⁺ can replace one of the ligands in the solvent-halide ion complex.

Part III

An unusually large isotope effect on the bridge hydrogen chemical shift of the enol form of pentanedione-2, 4(acetylacetone) and 3-methylpentanedione-2, 4 has been observed. An attempt has been made to interpret this effect. It is suggested from the deuterium isotope effect studies, temperature dependence of the bridge hydrogen chemical shift studies, IR studies in the OH, OD, and C=O stretch regions, and the HMO calculations, that there may probably be two structures for the enol form of acetylacetone. The difference between these two structures arises mainly from the electronic structure of the π-system. The relative population of these two structures at various temperatures for normal acetylacetone and at room temperature for the deuterated acetylacetone were calculated.

SYNTHESIS AND PHASE-BEHAVIOR STUDIES OF 2 NEW CHIRAL LIQUID-CRYSTALS OF SCHIFF-BASE - THE INFLUENCE OF INTRAMOLECULAR HYDROGEN-BOND ON THE PHASE-BEHAVIOR

Two new chiral liquid crystals of schiff-base type have been synthesized. This series of compounds contain a-chloro acidic ester chain prepared from commercially available L-valine. Both of the compounds exhibit tilted smectic phases; their phase transitions were studied using DSC and polarized optical microscopy; the influence of intramolecular hydrogen bonds on the phase behavior was studied as well.

An infrared spectroscopic study of C7 intramolecular hydrogen bonds in peptides

The ir-spectra in the N-H stretching region of Piv-Pro-NHMe and Boc-Pro-NHMe have been studied in carbon tetrachloride and chloroform solutions over a wide range of concentrations. Based on the concentration dependence of the N-H stretching bands, it has been shown that the characteristic N-H stretching band due to the C7 intramolecular hydrogen bond is around 3335 cm-'. Intermolecular hydrogen bonding also occurs to a small extent in these peptides, giving rise to a slight concentration dependence of the N-H stretching bands. The band around 3335 cm-* need not necessarily be due to C7 hydrogen bonds alone as proposed by Tsuboi et al. or to intermolecular hydrogen bonding alone as proposed by Maxfield et al.; this conclusion is supported by studies on Boc-Leu-NHMe, which undergoes only intermolecular hydrogen bonding We have shown that 2-Aib-Aib-OMe and Z-Aib- Ala-OMe form C7 intramolecular hydrogen bonds in addition to C5 intramolecular hydrogen bonds. The present studies also show that all the peptides studied exist in more than one conformation in solution.

Conformational Stability and Intramolecular Hydrogen Bonding in 1,2-Ethanediol and 1,4-Butanediol

The gas-phase infrared spectra of 1,2-ED and 1,4-BD have been, recorded at three different temperatures using a multipass gas cell of 6 m optical path length. DFT calculation has also been carried out using 6-311++G** and aug-cc-pVDZ basis sets to look for the existence of intramolecular hydrogen bonding, in them from the red shift and infrared absorption intensity enhancement of the bonded O-H band compared to that of the free O-H hand. Equilibrium population analysis With 10 conformers of 1,2-ED and 1,4-BD at experimental temperatures were-carried out for the reconstruction of the Observed vibrational spectra at that temperature,using standard statistical relationships. The most abundant conformer at experimental temperatures, was identified. In 1,2-ED a red shift of 45 cm(-1) in the intramolecularly interacting O-H stretching vibrational band position and no significant intensity enhancement compared to that of-the free O-H have been observed. On the contrary, in one of the hydrogen bonded conformers of 1,4-BD, a 124 cm(-1) red shift in the O-H stretching frequency and 8.5 times-intensity enhancement for the ``bonded'' O-H compared to that of the ``free'' O-H is seen. On the basis of this comparative study, we have concluded that strong intramolecular hydrogen bonding exists in 1,4-BD. But there appears, to be weak intramolecular hydrogen bonding in 1,2-ED at temperatures of 303, 313, and 323 Km the gas phase We have found that most stable hydrogen-bonded conformers of 1,4-BD are less populated than some of the non-hydrogen-bonded conformers. Even for the 1,4-BD, the relative population of the g'GG'Gt conformer, which has a strong intramolecular,hydrogen bond, is less than what is predicted. Perhaps the intramolecular hydrogen bond plays a less Significant role in the relative stability,of the various Conformers than what has been predicted from calculations and prevails in the literature.

The change in hydrogen bond strength accompanying charge rearrangement: Implications for enzymatic catalysis

The equilibrium for formation of the intramolecular hydrogen bond (KHB) in a series of substituted salicylate monoanions was investigated as a function of ΔpKa, the difference between the pKa values of the hydrogen bond donor and acceptor, in both water and dimethyl sulfoxide. The dependence of log KHB upon ΔpKa is linear in both solvents, but is steeper in dimethyl sulfoxide (slope = 0.73) than in water (slope = 0.05). Thus, hydrogen bond strength can undergo substantially larger increases in nonaqueous media than aqueous solutions as the charge density on the donor or acceptor atom increases. These results support a general mechanism for enzymatic catalysis, in which hydrogen bonding to a substrate is strengthened as charge rearranges in going from the ground state to the transition state; the strengthening of the hydrogen bond would be greater in a nonaqueous enzymatic active site than in water, thus providing a rate enhancement for an enzymatic reaction relative to the solution reaction. We suggest that binding energy of an enzyme is used to fix the substrate in the low-dielectric active site, where the strengthening of the hydrogen bond in the course of a reaction is increased.

The 310 Helical Conformation of the Amino Terminal Decapeptide of Suzukacillin. 270 MHz 'H NMR Evidence for Eight Intramolecular Hydrogen Bonds

The amino terminal suzukacillin decapeptide fragment, Boc-Aib-Pro-Val-Aib-Val-Ala-Aib-Ala-Aib-Aitbh-eO Me, two pentapeptides Boc-AibPrc-Val-AibVal-OMe and Boc-Ala-AibAla-AibAibOMe, and the tripeptide Boc-Ala-AibAibOMe have been studied by 270-MHz 'H NMR spectroscopy. By use of solvent dependence of chemical shifts in a CDC13-(CD3),S0 system and temperature dependence of amide NH chemical shifts in (CD3),S0, the intramolecularly hydrogen bonded NH groups in these peptides have been identified. The tripeptide possesses one hydrogen bond, both pentapeptides show evidence for three intramolecular hydrogen bonds, and the decapeptide has eight NH groups participating in hydrogen bonding. An Ala( 1)-Aib(2) @ turn is proposed for the tripeptide. Both pentapeptides favor 310 helical conformations composed of three consecutive B turns. The decapeptide adopts a 310 helical conformation with some flexibility at the Va1(5)-Ala(6) segment. The proposed conformations are consistent with the known stereochemical preferences of Aib residues.

Estimation of the 2.0(5) helix type i -> i hydrogen bond energy at Aib*-Oxa motif: an isodesmic approach

Bending at the valence angle N-C-alpha-C' (tau) is a known control feature for attenuating the stability of the rare intramolecular hydrogen bonded pseudo five-membered ring C-5 structures, the so called 2.0(5) helices, at Aib. The competitive 3(10)-helical structures still predominate over the C5 structures at Aib for most values of tau. However at Aib*, a mimic of Aib where the carbonyl 0 of Aib is replaced with an imidate N (in 5,6-dihydro-4H-1,3-oxazine = Oxa), in the peptidomimic Piv-Pro-Aib*-Oxa (1), the C(5)i structure is persistent in both crystals and in solution. Here we show that the i -> i hydrogen bond energy is a more determinant control for the relative stability of the C5 structure and estimate its value to be 18.5 +/- 0.7 kJ/mol at Aib* in 1, through the computational isodesmic reaction approach, using two independent sets of theoretical isodesmic reactions. (C) 2014 Elsevier Ltd. All rights reserved.

Tautomeric Preference and Conformation Locking in Fenobam, Thiofenobam, and Their Analogues: The Decisive Role of Hydrogen Bond Hierarchy

The crystal and molecular structures of the potential antidepressant drug fenobam and its derivatives are examined in terms of the preferred form among the two possible tautomeric structures. In this study, chemical derivatization has been utilized as a means to ``experimentally simulate'' the tautomeric preference and conformational variability in fenobam. Eight new derivatives of fenobam have been synthesized, and structural features have been characterized by single-crystal X-ray diffraction and NMR spectroscopy. The specific tautomeric preference found in all of these compounds and their known crystal forms have been construed in terms of the stabilizing intramolecular N-H center dot center dot center dot O and N-H center dot center dot center dot S hydrogen bonding. The hierarchy of intramolecular hydrogen bonds evidenced as the preference of the C-H center dot center dot center dot O hydrogen bond over C-H center dot center dot center dot N and that of the C-H center dot center dot center dot N hydrogen bond over C-H center dot center dot center dot S explains the two distinct conformations adopted by fenobam and thiofenobam derivatives. The relative energy values of different molecular conformations have been calculated and compared.

Isotopic fractionation in proteins as a measure of hydrogen bond length

If a deuterated molecule containing strong intramolecular hydrogen bonds is placed in a hydrogenated solvent, it may preferentially exchange deuterium for hydrogen. This preference is due to the difference between the vibrational zero-point energy for hydrogen and deuterium. It is found that the associated fractionation factor (I) is correlated with the strength of the intramolecular hydrogen bonds. This correlation has been used to determine the length of the H-bonds (donor-acceptor separation) in a diverse range of enzymes and has been argued to support the existence of short low-barrier H-bonds. Starting with a potential energy surface based on a simple diabatic state model for H-bonds, we calculate (I) as a function of the proton donor-acceptor distance R. For numerical results, we use a parameterization of the model for symmetric 0-H. ``.0 bonds R. H. McKenzie, Chem. Phys. Lett. 535, 196 (2012)]. We consider the relative contributions of the 0-H stretch vibration, O-H bend vibrations (both in plane and out of plane), tunneling splitting effects at finite temperature, and the secondary geometric isotope effect. We compare our total (I) as a function of R with NMR experimental results for enzymes, and in particular with an earlier model parametrization (D(R), used previously to determine bond lengths. (C) 2015 AIP Publishing LLC.

NMR evidence for the participation of a low-barrier hydrogen bond in the mechanism of delta 5-3-ketosteroid isomerase.

Delta 5-3-Ketosteroid isomerase (EC 5.3.3.1) promotes an allylic rearrangement involving intramolecular proton transfer via a dienolic intermediate. This enzyme enhances the catalytic rate by a factor of 10(10). Two residues, Tyr-14, the general acid that polarizes the steroid 3-carbonyl group and facilitates enolization, and Asp-38 the general base that abstracts and transfers the 4 beta-proton to the 6 beta-position, contribute 10(4.7) and 10(5.6) to the rate increase, respectively. A major mechanistic enigma is the huge disparity between the pKa values of the catalytic groups and their targets. Upon binding of an analog of the dienolate intermediate to isomerase, proton NMR detects a highly deshielded resonance at 18.15 ppm in proximity to aromatic protons, and with a 3-fold preference for protium over deuterium (fractionation factor, phi = 0.34), consistent with formation of a short, strong (low-barrier) hydrogen bond to Tyr-14. The strength of this hydrogen bond is estimated to be at least 7.1 kcal/mol. This bond is relatively inaccessible to bulk solvent and is pH insensitive. Low-barrier hydrogen bonding of Tyr-14 to the intermediate, in conjunction with the previously demonstrated tunneling contribution to the proton transfer by Asp-38, provide a plausible and quantitative explanation for the high catalytic power of this isomerase.

Mastering the canonical loop of serine protease inhibitors : enhancing potency by optimising the internal hydrogen bond network

Background Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact β-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity. Methodology/Principal Findings In this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (Ki = 0.0386±0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion. Conclusion/Significance These findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors.

Vibration spectra of ferroelectric alkali trihydrogen selenites and the nature of the hydrogen bond potential in these crystals

Raman spectra of the ferroelectric LiH3 (SeO3)2 and NaH3(SeO3)2 and the anti-ferroelectric KH3 (SeO3)2 have been recorded at room temperature using a He-Ne and also an Ar-ion laser source. The infrared absorption spectra of these crystals and their deuterated analogues have been recorded in the region 400–4000 cm−1 both below and above the Curie temperature. From an analysis of the spectrum in the region 400–900 cm−1 it is concluded that (i) in LiH3 (SeO3)2 the protons are ordered in an asymmetric double minimum potential with a low barrier and the spectrum can be interpreted in terms of HSeO3− and H2SeO3 vibrations, (ii) in NaH3 (SeO3)2 all three protons occupy a single minimum potential at room temperature and below the transition temperature the groups HSeO3− and H2SeO3 are present, (iii) the proton at the inversion centre in KH3(SeO3)2 is in a broad troughed potential well and the low temperature spectrum is more likely to be due to H3SeO3+ and SeO32− species. This deviation of the spectrum from that of the previous two crystals is attributed to the difference in H-bond scheme and hence the absence of any cooperative motion of protons in this crystal.

The hydrogen bond: a molecular beam microwave spectroscopist's view with a universal appeal

In this manuscript, we propose a criterion for a weakly bound complex formed in a supersonic beam to be characterized as a `hydrogen bonded complex'. For a `hydrogen bonded complex', the zero point energy along any large amplitude vibrational coordinate that destroys the orientational preference for the hydrogen bond should be significantly below the barrier along that coordinate so that there is at least one bound level. These are vibrational modes that do not lead to the breakdown of the complex as a whole. If the zero point level is higher than the barrier, the `hydrogen bond' would not be able to stabilize the orientation which favors it and it is no longer sensible to characterize a complex as hydrogen bonded. Four complexes, Ar-2-H2O, Ar-2-H2S, C2H4-H2O and C2H4-H2S, were chosen for investigations. Zero point energies and barriers for large amplitude motions were calculated at a reasonable level of calculation, MP2(full)/aug-cc-pVTZ, for all these complexes. Atoms in molecules (AIM) theoretical analyses of these complexes were carried out as well. All these complexes would be considered hydrogen bonded according to the AIM theoretical criteria suggested by Koch and Popelier for C-H center dot center dot center dot O hydrogen bonds (U. Koch and P. L. A. Popelier, J. Phys. Chem., 1995, 99, 9747), which has been widely and, at times, incorrectly used for all types of contacts involving H. It is shown that, according to the criterion proposed here, the Ar-2-H2O/H2S complexes are not hydrogen bonded even at zero kelvin and C2H4-H2O/H2S complexes are. This analysis can naturally be extended to all temperatures. It can explain the recent experimental observations on crystal structures of H2S at various conditions and the crossed beam scattering studies on rare gases with H2O and H2S.