Steric desolation enhances the effective molarities of intramolecular H-bonding interactions

Free energy contributions due to intramolecular phosphonate diester-phenol H-bonds have been measured for 20 different supramolecular architectures in cyclohexanone solution. High throughput UV/Vis titrations were used in combination with chemical double mutant cycles to dissect out the contributions of different functional group interactions to the stabilities of over 100 different zinc porphyrin-pyridine ligand complexes. These complexes have previously been characterised in toluene and in 1,1,2,2-tetrachloroethane (TCE) solution. Intramolecular ester-phenol H-bonds that were measured in these less polar solvents are too weak to be detected in cyclohexanone, which is a more competitive solvent. The stability of the intermolecular phosphonate diester-phenol H-bond in cyclohexanone is an order of magnitude lower than in TCE and two orders of magnitude lower than in toluene. As a consequence, only seven of the twenty intramolecular phosphonate diester-phenol interactions that were previously measured in toluene and TCE could be detected in cyclohexanone. The effective molarities (EM) for these intramolecular interactions are different in all three solvents. Determination of the EM accounts for solvent effects on the strengths of the individual H-bonding interactions and the zinc porphyrin-pyridine coordination bond, so the variation in EM with solvent implies that differences in the solvation shells make significant contributions to the overall stabilities of the complexes. The results suggest that steric effects lead to desolvation of bulky polar ligands. This increases the EM values measured in TCE, because ligands that fail to replace the strong interactions made with this solvent are unusually weakly bound compared with ligands that make intramolecular H-bonds.     

Dissection of complex molecular recognition interfaces

The synthesis of a family of zinc porphyrins and pyridine ligands equipped with peripheral H-bonding functionality has provided access to a wide range of closely related supramolecular complexes featuring between zero and four intramolecular H-bonds. An automated UV/vis titration system was used to characterize 120 different complexes, and these data were used to construct a large of number of different chemical double mutant cycles to quantify the intramolecular H-bonding interactions. The results probe the quantitative structure-activity relationship that governs cooperativity in the assembly of complex molecular recognition interfaces. Specifically, variations in the chemical structures of the complexes have allowed us to change the supramolecular architecture, conformational flexibility, geometric complementarity, the number and nature of the H-bond interactions, and the overall stability of the complex. The free energy contributions from individual H-bonds are additive, and there is remarkably little variation with architecture in the effective molarity for the formation of intramolecular interactions. Intramolecular H-bonds are not observed in complexes where they are geometrically impossible, but there are no cases where excellent geometric complementarity leads to very high affinities. Similarly, changes in conformational flexibility seem to have limited impact on the values of effective molarity (EM). The major variation that was found for all of the 48 intramolecular interactions that were examined using double mutant cycles is that the values of EM for intramolecular carboxylate ester-phenol H-bonds (200 mM) are an order of magnitude larger than those found for phosphonate diester-phenol H-bonds (30 mM). The corresponding intermolecular phosphonate diester-phenol H-bonds are 2 orders of magnitude more stable than carboxylate ester-phenol H-bonds, and the large differences in EM may be due to some kind of compensation effect, where the stronger H-bond is harder to make, because it imposes tighter constraints on the geometry of the complex.     

Intramolecular Hydrogen Bonding Restricts Gd–Aqua-Ligand Dynamics

Aqua ligands can undergo rapid internal rotation about the M−O bond. For magnetic resonance contrast agents, this rotation results in diminished relaxivity. Herein, we show that an intramolecular hydrogen bond to the aqua ligand can reduce this internal rotation and increase relaxivity. Molecular modeling was used to design a series of four Gd complexes capable of forming an intramolecular H-bond to the coordinated water ligand, and these complexes had anomalously high relaxivities compared to similar complexes lacking a H-bond acceptor. Molecular dynamics simulations supported the formation of a stable intramolecular H-bond, while alternative hypotheses that could explain the higher relaxivity were systematically ruled out. Intramolecular H-bonding represents a useful strategy to limit internal water rotational motion and increase relaxivity of Gd complexes.     

Protein–ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein–ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein–ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.     

Elucidating the intermolecular interactions within a desolvated protein-ligand complex. An experimental and computational study

The first detailed study of the intermolecular hydrogens bonds (H-bonds) within a desolvated, noncovalent protein-ligand complex is reported. Using both experimental and computational methods, the intermolecular H-bonds stabilizing protonated and deprotonated ions of a complex composed of a single chain fragment (scFv) of a monoclonal antibody and its native trisaccharide ligand, alphaGal[alphaAbe] alphaMan (1), are characterized. Using the blackbody infrared radiative dissociation-functional group replacement (BIRD/FGR) technique, three H-bond donor-acceptor pairs within the gaseous (scFv + 1)n+ ions are identified and quantified. Additional sites of interaction on the protein and ligand, for which the binding partner could not be elucidated, are also identified. Comparison of the gas-phase interaction maps with the crystal structure suggests that at least two of the specific H-bonds are conserved upon transfer of the complex from solution to the gas phase by electrospray ionization. However, new (nonspecific) interactions can also form in the gas phase. Notably, the nature and strength of the intermolecular interactions can vary significantly with charge state, and striking differences in the structures of the (scFv + 1)n+ and (scFv + 1)n- ions are evident. Intermolecular H-bonds are also identified from molecular dynamics (MD) simulations performed at the +8 and -8 charge states. Agreement is found for a majority of intermolecular interactions predicted for the (scFv + 1)8+ ion by the MD simulation and BIRD/FGR method; the agreement is less favorable in the case of the (scFv + 1)8- ion. However, both the computational and experimental results point to structural differences between the +8 and -8 ions. The computational results also provide insights into the structural changes that accompany the loss of interfacial waters from the complex.     

Advances in the coordination chemistry of nitrogen ligand complexes of coinage metals

Coinage metals nitrogen chemistry has not been studied extensively until recently. The focus of this review is the base- and halide-free complexes of the monoanionic nitrogen ligands. This review describes how minor ligand modifications can result in a drastic change in the metal–metal interactions in multinuclear compounds. Crystal structures of these complexes show individual complexes, dimers, supramolecular columnar packing or more complex supramolecular aggregates. Bulky substituents on the ligands can prevent intermolecular metal–metal interactions or the formation of supramolecular architectures. The nuclearity and metal–metal interactions in these complexes are controlled by ligand steric and electronic factors and solvent of crystallization. Many classes of nitrogen ligand coordination compounds have given rise to advances in several fundamental and applied research aspects. Recent potential applications of nitrogen ligand complexes are highlighted particularly for those complexes included in this review.     

Solid-state supramolecular array through cooperative π-π interactions of 1-(2-methoxyphenyl)-o-carborane

Dicarba-closo-dodecaborane (carborane) has received much attention as a building block for supramolecular assemblies and bioactive compounds. Among the carborane isomers, 1,2-dicarba-closo-dodecaborane (o-carborane) has unique chemical properties, including the ability of the o-carborane C-H hydrogens to form H-bonds. We have designed and synthesized 1-(2-methoxyphenyl)-o-carborane 1a to study its ability to form an intramolecular H-bond between the o-carborane C-H hydrogen and various H-bond acceptors both in solution and in the solid state. Intramolecular H-bonding ability in solution was evaluated by means of ¹H NMR spectroscopic measurements of the C-H hydrogen signal. The signal of the C-H hydrogen of 1a showed a remarkable downfield shift in CDCl₃ and various other solvents, i.e., the shift was almost solvent-independent. We suggest that 1a forms an intramolecular H-bond in these solvents. Crystal structure analysis of 1a showed a C-H?O distance of 2.05 Å and a nearly planar torsion angle C(2)-C(1)-C(7)-C(8) of 6.5°, indicating intramolecular C-H?O H-bond formation in the solid state. The crystal packing of 1a indicates that a supramolecular array is stabilized by cooperative π-π stacking interactions among the methoxyphenyl groups and by hydrophobic interactions of the o-carborane cages. DFT calculations indicate that the strength of the intramolecular H-bond of 1a is about 3.53 kcal/mol. These observations indicate the potential value of o-carborane in supramolecular chemistry and materials chemistry; it should be possible to design novel materials by utilizing both the H-bonding ability of the o-carborane C-H hydrogen and the high hydrophobicity of the o-carborane cage.     

Acetonitrile hydration and ethyl acetate hydrolysis by pyrazolate-bridged cobalt(II) dimers containing hydrogen-bond donors

The preparation of new CoII-mu-OH-CoII dimers with the binucleating ligands 3,5-bis{bis[(N'-R-ureaylato)-N-ethyl]aminomethyl}-1H-pyrazolate ([H4PRbuam]5-, R=tBu, iPr) is described. The molecular structure of the isopropyl derivative reveals that each CoII center has a trigonal-bipyramidial coordination geometry, with a Co...Co separation of 3.5857(5) A. Structural and spectroscopic studies show that there are four hydrogen-bond (H-bond) donors near the CoII-micro-OH-CoII moiety; however, they are too far away to be form intramolecular H-bonds with the bridging hydroxo ligand. Treating [CoII2H4PRbuam(micro-OH)]2- with acetonitrile led to the formation of bridging acetamidato complexes, [CoII2H4PRbuam(micro-1,3-OC(NH)CH3)]2-; in addition, these CoII-micro-OH-CoII dimers hydrolyze ethyl acetate to form CoII complexes with bridging acetato ligands. The CoII-1,3-micro-X'-CoII complexes (X'=OAc-, [OC(NH)CH3]-) were prepared independently by reacting [CoII2H3PRbuam]2- with acetamide or [CoII2H4PRbuam]- with acetate. X-ray diffraction studies show that the orientation of the acetate ligand within the H-bonding cavity depends on the size of the R substituent appended from the urea groups. The tetradentate ligand 3-{bis[(N'-tert-butylureaylato)-N-ethyl]aminomethyl}-5-tert-butyl-1H-pyrazolato ([H2PtBuuam]3-) was also developed and its CoII-OH complex prepared. In the crystalline state, [CoIIH2PtBuuam(OH)]2- contains two intramolecular H-bonds between the urea groups of [H2PtBuuam]3- and the terminal hydroxo ligand. [nPr4N]2[CoIIH2PtBuuam(OH)] does not hydrate acetonitrile or hydrolyze ethyl acetate. In contrast, K2[CoIIH2PtBuuam(OH)] does react with ethyl acetate to produce KOAc; this enhanced reactivity is attributed to the presence of the K+ ions, which can possibly interact with the CoII-OH unit and ester substrate to assist in hydrolysis. However, K2[CoIIH2PtBuuam(OH)] was still unable to hydrate acetonitrile.     

Relationship between conformational flexibility and chelate cooperativity

A family of four biscarbamates (AA) and four bisphenols (DD) were synthesized, and H-bonding interactions between all AA?DD combinations were characterized using (1)H NMR titrations in carbon tetrachloride. A chemical double mutant cycle analysis shows that there are no secondary electrostatic interactions or allosteric cooperativity in these systems, and the system therefore provides an ideal platform for investigating the relationship between chemical structure and chelate cooperativity. Effective molarities (EMs) were measured for 12 different systems, where the number of rotors in the chains connecting the two H-bond sites was varied from 5 to 20. The association constants vary by less than an order of magnitude for all 12 complexes, and the variation in EM is remarkably small (0.1-0.9 M). The results provide a relationship between EM and the number of rotors in the connecting chains (r): EM ≈ 10r(-3/2). The value of 10 M is the upper limit for the value of EM for a noncovalent intramolecular interaction. Introduction of rotors reduces the value of EM from this maximum in accord with a random walk analysis of the encounter probability of the chain ends (r(-3/2)). Noncovalent EMs never reach the very high values observed for covalent processes, which places limitations on the magnitudes of the effects that one is likely to achieve through the use of chelate cooperativity in supramolecular assembly and catalysis. On the other hand, the decrease in EM due to the introduction of conformational flexibility is less dramatic than one might expect based on the behavior of covalent systems, which limits the losses in binding affinity caused by poor preorganization of the interaction sites.     

Intramolecular hydrogen bonding and cooperative interactions in carbohydrates via the molecular tailoring approach

In spite of many theoretical and experimental attempts for understanding intramolecular hydrogen bonding (H-bonding) in carbohydrates, a direct quantification of individual intramolecular H-bond energies and the cooperativity among the H-bonded networks has not been reported in the literature. The present work attempts, for the first time, a direct estimation of individual intramolecular O-H...O interaction energies in sugar molecules using the recently developed molecular tailoring approach (MTA). The estimated H-bond energies are in the range of 1.2-4.1 kcal mol(-1). It is seen that the OH...O equatorial-equatorial interaction energies lie between 1.8 and 2.5 kcal mol(-1), with axial-equatorial ones being stronger (2.0-3.5 kcal mol(-1)). The strongest bonds are nonvicinal axial-axial H-bonds (3.0-4.1 kcal mol(-1)). This trend in H-bond energies is in agreement with the earlier reports based on the water-water H-bond angle, solvent-accessible surface area (SASA), and (1)H NMR analysis. The contribution to the H-bond energy from the cooperativity is also estimated using MTA. This contribution is seen to be typically between 0.1 and 0.6 kcal mol(-1) when H-bonds are a part of a relatively weak equatorial-equatorial H-bond network and is much higher (0.5-1.1 kcal mol(-1)) when H-bonds participate in an axial-axial H-bond network.     

Tunable intramolecular multicenter H-bonding interactions in first-row metal complexes bearing bidentate redox-active ligands

Abstract

In this research article, we report the synthesis and structural characterization of a family of first-row metal complexes bearing redox-active ligands with tunable H-bonding donors. We observed that these coordination complexes can adopt three different geometries and that they are stabilized by intramolecular multicenter H-bonding interactions, which are systematically modified by changing the metal ion (Co, Ni, Cu, Zn), the ligand scaffold (variations in the diamine and ureanyl substituents used) and the solvent of crystallization.     

Analysis of complexes pairing hydroperoxyl radical with peroxyformic acid

Ab initio quantum calculations are used to analyze the binding of complexes pairing OOH with HOOCHO. Six minima are located on the potential energy surface, all of cyclic geometry. Of particular interest are the OH...O and CH...O H-bonds that arise in the complexes and the manner in which these interactions influence the internal properties of the subunits. The analysis is complicated by the presence of an intramolecular H-bond in the unperturbed HOOCHO molecule, which must be broken in order to form the pair of intermolecular H-bonds that are responsible for the binding in the most stable complex. The CH bond of HOOCHO is contracted, and its stretching frequency undergoes a blue shift, when this group participates in a H-bond.     

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.     

An ab initio molecular orbital study of intramolecular H-bonding: 1,3 propanediol

An ab initio molecular orbital calculation has been carried out for three different conformations of 1,3 propanediol, one of which permits intramolecular H-bond studied by ab initio quantum mechanical methods. The ΔE for H-bonding formation is compated to be 0.9 kcal/mole and the charge redistributions and molecular orbital energy changes are compared to those found in intermolecular H-bonds.     

Effects of the H-bond donor structure on the properties of supramolecular side chain liquid crystalline polymers based on poly(3-carboxypropylmethylsiloxane-co-dimethylsiloxane)s and stilbazoles

Supramolecular side chain liquid crystalline polymers (SCLCPs) based on poly(3-carboxypropylmethylsiloxane-co-dimethylsiloxane) (PSIX, X=100, 76, 60, 41 or 23, denoting the mole percentage of 3-carboxypropylmethylsiloxane unit in the polymer) and stilbazole derivatives have been obtained through intermolecular hydrogen bonding (H-bonding) interactions between the carboxylic acid and the pyridyl moieties. The formation of H-bonding and self-assembly results in the formation of new mesogenic units, in which H-bonds function as molecular connectors. FTIR shows the existence of H-bonding in the complexes. The polymeric complexes behave as single component liquid crystalline polymers and exhibit stable and enantiotropic mesophases. The liquid crystalline properties of the supramolecular SCLCPs were studied using differential scanning calorimetry, polarizing optical microscopy and X-ray diffraction, and were found to exhibit smectic A phases with focal-conic textures. The thermal stability of the SCLCP increases on increasing the carboxylic acid content in the polysiloxane and the concentration of the stilbazole derivative in the complex. However, the thermal stability decreases on increasing the chain length of the stilbazole derivative. The crystal phase was not formed even on cooling to the glass transition temperature of the polymeric complex.     

Analysis of multiple H-bond interactions in self-assembly between polyurethane with pendent carboxyl and poly(4-vinylpyridine)

As an extension study, FTIR and molecular simulation methods were combined in the present paper to analyze the H-bond interactions resulting from multiple donors and acceptors that have led to self-assembly based on segmented polyurethane with carboxyl (PUc) and poly(4-vinylpyridine) (P4VP) in our previous work. Of them, FTIR was used to analyze the H-bonding types and interactions as well as their changes before and after self-assembly; molecular mechanics (MM/COMPASS) was used to study the effect of possible conformations on the H-bonds involved and analyze the most probable H-bond patterns; quantum mechanics (QM/B3LYP) was used to help confirm the experimental FTIR band assignments and calculate the H-bond energy. It was found that two types of H-bonds exist, namely, COOH...P4VP (type I) and (OCO)NH...P4VP (type II), based on OH and NH as the strong donors in the interaction between PUc and P4VP. Strong evidence has been obtained for a type II H-bond, which is the specialty in PUc/P4VP assembly. The type I and type II H-bonding energies are -11.293 and -7.150 kcal/mol, respectively. The forming probability of the type I H-bond accounts for 95.87%, while that of the type II H-bond is 4.13%, showing the primary driving force for the assembly based on PUc and P4VP is still the H-bond between COOH and P4VP, yet the H-bonds based on NH and pyridyl in P4VP cannot be ignored.     

Molecular basis of the recognition process: hydrogen-bonding patterns in the guanine primary recognition site of ribonuclease T1

Investigation of the intrinsic H-bonding pattern of the guanine complex with a sizable segment (from Asn43 to Glu46) of the primary recognition site (PRS) in RNase T1 at the B3LYP/6-311G(d,p) level of theory enables the electronic density characteristics of the H-bonding patterns of the guanine-PRS complexes to be identified. The perfect H-bonding pattern in the guanine recognition site is achieved through the guanine complex interactions with the large segment of the PRS. Two significant short H-bonds, O epsilon 1...HN1 and O epsilon 2...HN2, have been identified. The similar short H-bond distances found in the anionic GC- base pair and in this study suggest that the short hydrogen-bond distances may be characteristic of the multiple H-bonded anionic nucleobases. The H-bonding energy distribution, the geometric analysis of the H-bonding pattern, and the electron structure characteristics of the H-bonds in the guanine PRS of RNase T1 all suggest that the O epsilon 1...HN1 and O epsilon 2...HN2 side-chain H-bonds dominate the binding at the guanine recognition site of RNase T1. Also, the geometry evidence, the electron structure characteristics, and the properties of the bond critical points of the H-bonds reveal that the side-chain H-bonding and the main-chain H-bonding are mutually intensifying. Thus the positive cooperativity between Asn43 to Tyr45 and Glu46 is proposed.     

The effect of intramolecular interactions on hydrogen bond acidity

DFT calculations on a range of molecules containing intramolecular hydrogen bonds are reported, with a view to establishing how intramolecular hydrogen bonding affects their intermolecular interactions. It is shown that properties such as the energy of the intramolecular H-bond are unrelated to the ability to form external H-bonds. Conversely, several properties of complexes with a reference base correlate well with an experimental scale of H-bond acidity, and accurate predictive models are determined. A more detailed study, using electrostatic and overlap properties of complexes with a reference base, is used to predict the location, as well as strength, of hydrogen bond acidity. The effects of intramolecular hydrogen bonding on acidity can be seen not just on O-H and N-H, where acidity is greatly reduced, but also on certain C-H groups, which in some cases become the primary source of acidity.     

Steric, electronic, and secondary effects on the coordination chemistry of ionic phosphine ligands and the catalytic behavior of their metal complexes

The effects of introducing ionic functionalities in phosphine ligands on the coordination chemistry of these ligands and the catalytic behavior of the corresponding metal complexes are reviewed. The steric and electronic consequences of such functionalizations are discussed. Apart from these steric and electronic effects, the presence of charged groups often leads to additional, supramolecular interactions that occur in the second coordination sphere of the metal complex, such as intramolecular, interligand hydrogen bonding and Coulombic repulsion. These interactions can significantly alter the behavior of the phosphine ligand in question. Such effects have been observed in phosphine-metal association/dissociation equilibria, ligand substitution reactions, and stereoisomerism in phosphine-metal complexes. By drawing general conclusions, this review offers an insight into the coordination and catalytic behavior of phosphine ligands containing ionic functionalities and their corresponding metal complexes.