Charge-assisted Hydrogen Bonds Research Articles

Simultaneous membrane transport of two active pharmaceutical ingredients by charge assisted hydrogen bond complex formation

Using permeation through a model membrane in a Franz diffusion cell, we have demonstrated that acidic and basic active pharmaceutical ingredients (APIs) in deep eutectic ‘liquid co-crystal’ form can be held tightly together, even in solution, via strong hydrogen bonds or partially ionized interactions, providing simultaneous transport at rates much higher than solutions of their corresponding, commercially available crystalline salts, albeit at rates that are lower than the neutral forms of the individual molecules. It was also shown that the deep eutectic APIs do not have to be premade, but hydrogen-bonded complexes can be formed in situ by mixing the corresponding API–solvent solutions. To understand the behavior, we have extensively studied a range of nonstoichiometric mixtures of lidocaine and ibuprofen spectroscopically and via membrane transport. The data demonstrates the nature of the interactions between the acid and base and provides a route to tune the rate of membrane transport.

Molecular Networks Created by Charge-Assisted Hydrogen Bonding in Phosphonate, Phosphate, and Sulfonate Salts of Bis(amidines)

Two bis(amidines), 2,2′-bi-2-imidazoline (BI) and fluoflavin (FF), were treated with phosphonic, phosphoric, and sulfonic acids in an effort to produce crystalline salts composed of ions linked by networks of charge-assisted hydrogen bonds. As intended, mixing bis(amidine) BI with 1,4-benzenediphosphonic acid and 1,3,5-benzenetriphosphonic acid yielded crystals of phosphonate salts of dication H2BI+2. Structural analyses showed that such salts tend to incorporate tapes composed of alternating dications and anions linked by multiple charge-assisted N–H···O hydrogen bonds of type R22(9) and R21(7). Typically, the ionic tapes are further connected to form sheets or other assemblies by additional O–H···O hydrogen bonds involving phosphonate anions. An analogous reaction of the more weakly basic bis(amidine) FF with 1,4-benzenedisulfonic acid yielded only a sulfonate salt of monocation HFF+; however, diprotonation could be achieved by phosphoric acid to produce a crystalline salt built from stacks of H2FF+2 dications linked to phosphate anions by charge-assisted N–H···O hydrogen bonds of type R22(8). Together, these results demonstrate that acids with multiple PO(OH)2 and SO2OH groups can react with bis(amidines) to produce salts with structural features resulting predictably from the geometry of the ions and their ability to engage in multiple charge-assisted hydrogen bonds according to standard patterns.

ChemInform Abstract: Beyond Click Chemistry — Supramolecular Interactions of 1,2,3‐Triazoles

AbstractReview: 583 refs.

Halogen-Bond Interactions Enhanced by Charge-Assisted Hydrogen Bonds: An Ab Initio Study

Abstract The NH4+···NCX···NCY (X = F, Cl, and Br; Y = H, F, and OH) complexes are theoretically investigated to find ways to enhance the halogen-bond interaction. Cooperative effects are observed when a charge-assisted hydrogen bond (CAHB) and halogen bond coexist in the same complex. These effects are studied in terms of equilibrium geometry, interaction energy, charge-transfer properties, and 14N nuclear quadrupole coupling constant of the complexes at the MP2/aug-cc-pVTZ level. In all triads studied, a favorable cooperativity is found with values that range between −1.44 and −4.04 kcal mol−1. However, the increased percentage of the interaction energy depends on the interaction strength. To investigate the role of different energy terms in cooperativity between hydrogen and halogen bonds, the scheme of decomposition of the interaction energy is applied. The electrostatic interaction is found to be a dominant factor in enhancing both types of interactions.

Structural insight into cocrystallization with zwitterionic co-formers: cocrystals of S-naproxen

The screening of S-naproxen, S-oxiracetam, S-diprophylline, and levetiracetam with a series of essential and nonessential amino acid co-formers has yielded cocrystals only for S-naproxen, thus showing that amino acids seem to have a preference for forming cocrystals with compounds containing a carboxyl group. Herein, we report the crystal structures of four S-naproxen cocrystals: S-naproxen/L-alanine, S-naproxen/D-alanine, S-naproxen/D-tyrosine, and S-naproxen/D-tryptophan monohydrate. All of the described cocrystals show similar structural motifs, i.e., amino acids form head-to-tail chains with strong charge-assisted hydrogen bonding, which are similar to those found in the individual amino acids, with S-naproxen molecules grafted on them. According to the systematic search of the Cambridge Structural Database for other cocrystals that involve zwitterionic co-formers, charge-assisted hydrogen bonds between amino acid molecules play an essential role, being present in the majority of structures. The results of this work provide an insight into structural aspects of cocrystallization with zwitterionic co-formers, offer new possibilities for S-naproxen pharmaceutical formulations, and can serve as guidelines when developing new cocrystals involving zwitterionic co-formers.

A combined experimental and computational study of the molecular interactions between anionic ibuprofen and water.

In this work, we report a detailed study of the microsolvation of anionic ibuprofen, Ibu(-). Stochastic explorations of the configurational spaces for the interactions of Ibu(-) with up to three water molecules at the DFT level lead to very rich and complex potential energy surfaces. Our results suggest that instead of only one preponderant structure, a collection of isomers with very similar energies would have significant contributions to the properties of the solvated drug. One of these properties is the shift on the vibrational frequencies of the asymmetric stretching band of the carboxylate group in hydrated Ibu(-) with respect to the anhydrous drug, whose experimental values are nicely reproduced using the weighted contribution of the structures. We found at least three types of stabilizing interactions, including conventional CO2(-)⋯H2O, H2O⋯H2O charge assisted hydrogen bonds (HBs), and less common H2O⋯H-C and H2O⋯π interactions. Biological water molecules, those in direct contact with Ibu(-), prefer to cluster around the carboxylate oxygen atoms via cyclic or bridged charge assisted hydrogen bonds. Many of those interactions are strongly affected by the formal carboxylate charge, resulting in "enhanced" HBs with increased strengths and degree of covalency. We found striking similarities between this case and the microsolvation of dymethylphosphate, which lead us to hypothesize that since microsolvation of phosphatidylcholine depends mainly on the formal charge of its ionic PO2(-) group in the polar head, then microsolvation of anionic ibuprofen and interactions of water molecules with eukaryotic cell membranes are governed by the same types of physical interactions.

Fourier transform infrared detection of a polarizable proton trapped between photooxidized tyrosine YZ and a coupled histidine in photosystem II: relevance to the proton transfer mechanism of water oxidation.

The redox-active tyrosine YZ (D1-Tyr161) in photosystem II (PSII) functions as an immediate electron acceptor of the Mn4Ca cluster, which is the catalytic center of photosynthetic water oxidation. YZ is also located in the hydrogen bond network that connects the Mn4Ca cluster to the lumen and hence is possibly related to the proton transfer process during water oxidation. To understand the role of YZ in the water oxidation mechanism, we have studied the hydrogen bonding interactions of YZ and its photooxidized neutral radical YZ(•) together with the interaction of the coupled His residue, D1-His190, using light-induced Fourier transform infrared (FTIR) difference spectroscopy. The YZ(•)-minus-YZ FTIR difference spectrum of Mn-depleted PSII core complexes exhibited a broad positive feature around 2800 cm(-1), which was absent in the corresponding spectrum of another redox-active tyrosine YD (D2-Tyr160). Analyses by (15)N and H/D substitutions, examination of the pH dependence, and density functional theory and quantum mechanics/molecular mechanics (QM/MM) calculations showed that this band arises from the N-H stretching vibration of the protonated cation of D1-His190 forming a charge-assisted strong hydrogen bond with YZ(•). This result provides strong evidence that the proton released from YZ upon its oxidation is trapped in D1-His190 and a positive charge remains on this His. The broad feature of the ~2800 cm(-1) band reflects a large proton polarizability in the hydrogen bond between YZ(•) and HisH(+). QM/MM calculations further showed that upon YZ oxidation the hydrogen bond network is rearranged and one water molecule moves toward D1-His190. From these data, a novel proton transfer mechanism via YZ(•)-HisH(+) is proposed, in which hopping of the polarizable proton of HisH(+) to this water triggers the transfer of the proton from substrate water to the luminal side. This proton transfer mechanism could be functional in the S2 → S3 transition, which requires proton release before electron transfer because of an excess positive charge on the Mn4Ca cluster.

New 7-arylpiperazinylalkyl-8-morpholin-4-yl-purine-2,6-dione derivatives with anxiolytic activity – Synthesis, crystal structure and structure–activity study

On the basis of our earlier studies with serotonin (5-HT) receptor ligands in the group of long-chain arylpiperazines (LCAPs), a new series of 7-arylpiperazinylalkyl-8-morpholin-4-yl-purine-2,6-dione derivatives (5–12) has been designed, synthesised and studied in vitro for their affinity for 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. The introduction of o-OCH3 and m-Cl into the phenylpiperazinyl moiety as well as the elongation of the linker between purine-2,6-dione core and arylpiperazine fragment modified the affinity for the tested 5-HT receptors. The structures of compounds 9–11 (hydrochloride salts) were confirmed by an X-ray diffraction method. All molecules adopted a different conformation in the crystal. The strongest observed type of interaction is a charge assisted hydrogen bond N+–H⋯Cl−. Additionally, the π–π interactions between 1,3-dimethyl-3,7-dihydropurine-2,6-dione cores of the neighbouring molecules were also observed. As it is observed in the presented crystal structures, the morpholine ring (a potential donor and acceptor of the hydrogen bonds) seems to be an attractive substituent, that may support binding to the non-specific sites of 5-HT receptors. Another interesting feature is the mutual orientation of rings in the arylpiperazine fragment, with plausible influence on ligand-receptor recognition. For compound 10, with strong 5-HT1A binding affinity, the mutual orientation of rings is determined by the intramolecular weak C–H⋯O hydrogen bond. This observation may contribute to a better understanding of the more selective binding of o-OCH3 arylpiperazine derivatives to the 5-HT1A receptor.

Use of Charge-Assisted Hydrogen Bonding in the Supramolecular Assembly of Hybrid Uranyl Materials

Supramolecular assembly of U(VI) materials can be limited by the passivation of the uranyl oxo group and the propensity of the metal center to hydrolyze, resulting in the formation of extended two-dimensional (2D) structures. To overcome these barriers, the use of charge-assisted H-bonding was explored using amino acids (glycine [Gly] and l-alanine [Ala]), resulting in the formation of three novel compounds {[(UO2)3(Gly)2(O)2(OH)2](H2O)6 (1), [(UO2)5(Gly)4(O)3(OH)3](NO3)(H2O)12 (2), and [(UO2)3(Ala)2O(OH)3](NO3)(H2O)3 (3)} that have been characterized by X-ray diffraction, elemental analysis, TGA, and vibrational spectroscopy. Hydrolysis of the uranyl cation (UO22+) chelated by bridging zwitterionic amino acids results in the formation of infinite chains when synthesized from mildly acidic aqueous solutions. While positively charged chains form densely packed structures, the neutral UO2-glycine chains support a nanoporous (internal diameter ∼1.35 nm) supramolecular architecture through multifurcated charge-assisted hydrogen bonding. These interactions occur directly between the protonated amine of glycine and the uranyl’s oxo moiety, representing a unique supramolecular synthon for the assembly of hybrid porous uranyl materials. The zwitterionic glycine ligands also assist in the helical assembly of water molecules that are hydrogen bonded to the interior walls of the nanopores, resulting in the formation of an empty 0.85 nm channel through the pore space.

Supramolecular association in proton-transfer adducts containing benzamidinium cations. III. Three molecular salts of 3-methoxy-, 4-methoxy- and 3,4,5-trimethoxybenzoates with benzamidine

Three molecular salts, benzamidinium 3-methoxybenzoate, C7H9N2(+)·C8H7O3(-), (I), benzamidinium 4-methoxybenzoate, C7H9N2(+)·C8H7O3(-), (II), and benzamidinium 3,4,5-trimethoxybenzoate monohydrate, C7H9N2(+)·C10H11O5(-)·H2O, (III), were formed from the proton-transfer reactions of 3-methoxy, 4-methoxy- and 3,4,5-trimethoxybenzoic acids with benzamidine (benzenecarboximidamide, benzam). Monoclinic salts (I) and (II) have a 1:1 ratio of cation to anion. In monoclinic salt (III), two cation-anion pairs and two water molecules constitute the asymmetric unit. In all three molecular salts, the amidinium fragments and the carboxylate groups are completely delocalized, and the delocalization favours the aggregation of the molecular components into nonplanar dimers with an R(2)(2)(8) graph-set motif by N(+)-H···O(-) (±) charge-assisted hydrogen bonding (CAHB). Of the three molecular salts, (I) and (II) show similar conformations of the anionic components and exhibit bidimensional isostructurality, which consists of alternating R(2)(2)(8) and R(6)(4)(16) rings resulting in a corrugated sheet propagated parallel to the crystallographic ab plane. In molecular salt (III), the R(2)(2)(8) synthon is retained but the supramolecular structure is different, due to the presence of three bulky methoxy substituents and a water molecule. The structures reported here further demonstrate the robustness of R(2)(2)(8) hydrogen-bonded synthons having the benzamidinium cation as a building block, whereas N(+)-H···O(-) hydrogen bonds external to the salt bridge contribute to the overall structure organization.

Engineering Switchable Rotors in Molecular Crystals with Open Porosity

The first example of a porous molecular crystal containing rotors is presented. The permanently porous crystal architecture is sustained by rotor-bearing molecular rods which are connected through charge-assisted hydrogen bonds. The rotors, as fast as 10(8) Hz at 240 K, are exposed to the crystalline channels, which absorb CO2 and I2 vapors at low pressure. The rotor dynamics could be switched off and on by I2 absorption/desorption, showing remarkable change of material dynamics by the interaction with gaseous species and suggesting the use of molecular crystals in sensing and pollutant management.

Beyond click chemistry – supramolecular interactions of 1,2,3-triazoles

The research on 1,2,3-triazoles has been lively and ever-growing since its stimulation by the advent of click chemistry. The attractiveness of 1H-1,2,3-triazoles and their derivatives originates from their unique combination of facile accessibility via click chemistry and truly diverse supramolecular interactions, which enabled myriads of applications in supramolecular and coordination chemistry. The nitrogen-rich triazole features a highly polarized carbon atom allowing the complexation of anions by hydrogen and halogen bonding or, in the case of the triazolium salts, via charge-assisted hydrogen and halogen bonds. On the other hand, the triazole offers several N-coordination modes including coordination via anionic and cationic nitrogen donors of triazolate and triazolium ions, respectively. After CH-deprotonation of the triazole and the triazolium, powerful carbanionic and mesoionic carbene donors, respectively, are available. The latter coordination mode even features non-innocent ligand behavior. Moreover, these supramolecular interactions can be combined, e.g., in ion-pair recognition, preorganization by intramolecular hydrogen bond donation and acceptance, and in bimetallic complexes. Ultimately, by clicking two building blocks into place, the triazole emerges as a most versatile functional unit allowing very successful applications, e.g., in anion recognition, catalysis, and photochemistry, thus going far beyond the original purpose of click chemistry. It is the intention of this review to provide a detailed analysis of the various supramolecular interactions of triazoles in comparison to established functional units, which may serve as guidelines for further applications.

The Utility of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a Hydrogen Bond Acceptor in the Design of Novel Superbasic Guanidines – A Computational Study

New guanidine-derived superbases with TBD-functionalized alkyl side chains have been developed using a computational DFT approach. Exploiting the high hydrogen bond basicity of TBD allowed access to systems with strong charge-assisted intramolecular hydrogen bonds in the protonated state. The enhanced stability of such guanidines is mirrored in their gas-phase basicities, which cover the range from 1044−1168 kJ mol−1, depending on the number of alkyl side chains, the type of alkyl spacer and the hydrogen-bonding pattern.

Crystal structure and packing energy calculations of (+)-6-aminopenicillanic acid

The X-ray single-crystal structure of (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, commonly known as (+)-6-aminopenicillanic acid (C8H12N2O3S) and a precursor of a variety of semi-synthetic penicillins, has been determined from synchrotron data at 150 K. The structure represents an ordered zwitterion and the crystals are nonmerohedrally twinned. The crystal structure is composed of a three-dimensional network built by three charge-assisted hydrogen bonds between the ammonium and carboxylate groups. The complementary analysis of the crystal packing by the PIXEL method brings to light the nature and ranking of the energetically most stabilizing intermolecular interaction energies. In accordance with the zwitterionic nature of the structure, PIXEL lattice energy calculations confirm the predominance of the Coulombic term (-379.1 kJ mol(-1)) ahead of the polarization (-141.4 kJ mol(-1)), dispersion (-133.7 kJ mol(-1)) and repulsion (266.3 kJ mol(-1)) contributions.

Self-Assembly of Rigid Three-Connecting Mesitylenetribenzoic Acid: Multifarious Supramolecular Synthons and Solvent-Induced Supramolecular Isomerism

We have explored O–H···O hydrogen bonded self-assembly of rigid three-connecting mesitylenetribenzoic acid (H3MTB). The triacid is shown to exploit the acid dimer motif and self-assemble, in the solid state, into a 6-fold interpenetrated (6,3) honeycomb net with the pores of the dimension of ca. 24–26 Å. It is shown that crystallization of H3MTB with K+/NH4+ salts in the presence of 18-crown-6 leads to mono-deprotonation followed by self-assembly of the resultant H2MTB– into multicomponent crystals of different network structures sustained by charge-assisted hydrogen bonds. The X-ray crystal structure analyses reveal that the solvent employed to access the multicomponent crystals plays the role of a chaperon in modifying the supramolecular structures adopted. Crystallization of H3MTB in the presence of dibenzo-18-crown-6 is found to lead likewise to a (6,3) net that is 6-fold interpenetrated with K+⊂dibenzo-18-crown-6 occupying the voids. Thus, the strategy involving partial deprotonation of rationally designed polycarboxylic acids with KX/crown is shown to lead to multicomponent crystals sustained by charge-assisted hydrogen bonds. The structural studies have led to identification of water-mediated paddlewheel and carboxylate···carboxylate dimer synthons.

Highly Selective Fluorescent Recognition of Sulfate in Water by Two Rigid Tetrakisimidazolium Macrocycles with Peripheral Chains

The reinforced molecular recognition of two rigid tetrakisimidazolium macrocycles resulted in highly selective fluorescent recognition of sulfate dianion in water with an unprecedentedly high association constant of 8.6 × 10(9) M(-2). Besides the electrostatic interaction, the single crystal X-ray analysis revealed that sulfate was encapsulated in a pseudohexahedral cavity of a sandwich structure by two orthogonally packed macrocycles via eight hydrogen bonds between the C2 hydrogen atoms of the imidazolium units and the oxygen atoms of sulfate. This sandwich structure was reinforced by the π-π stacking between the phenyl and the triazinonide rings and multiple charge-assisted hydrogen bonds between the peripheral chains and the rigid backbones. Notably, these peripheral-backbone hydrogen bonds rendered the flexible peripheral chains to coil around the sandwich structure to shield sulfate inaccessible to water. This binding process was visible by fluorescence enhancement, which was attributed to a restrained rotation and better conjugation of the macrocycle backbone upon binding to sulfate.

Self-Assembling of Zwitterionic Squaramides through Electrostatically Compressed Face-to-Face π-Stacking: A New Supramolecular Synthon

We report, herein, a novel supramolecular synthon based on the electrostatic compression phenomenon. A zwitterionic squaric acid/squaramide compound serves as a model for the design of new face-to-face π-stacked architectures in the crystalline state which, in combination with charge-assisted hydrogen bonds, can be used to synthesize multicomponent crystals.

Benzamidinium 2-methoxybenzoate

The title mol­ecular salt, C7H9N2 +.C8H7O3 −, was synthesized by reaction between benzamidine (benzene­carboximidamide) and 2-meth­oxy­benzoic acid. In the cation, the amidinium group has two similar C—N bonds [1.3070 (17) and 1.3145 (16) Å] and is almost coplanar with the benzene ring, making a dihedral angle of 5.34 (12)°. In the anion, the meth­oxy substituent forces the carboxyl­ate group to be twisted by 69.45 (6)° with respect to the plane of the aromatic fragment. In the crystal, the components are connected by two N+—H⋯O− (±)CAHB (charge-assisted hydrogen bonds), forming centrosymmetric ionic dimers with graph-set motif R 2 2(8). These ionic dimers are then joined in ribbons running along the b-axis direction by another R 4 2(8) motif involving the remaining N+—H⋯O− hydrogen bonds. Remarkably, at variance with the well known carb­oxy­lic dimer R 2 2(8) motif, the carboxyl­ate–amidinium pair is not planar, the dihedral angle between the planes defined by the CN2 + and CO2 − atoms being 18.57 (12)°.

Pentane-1,5-diaminium dibromide

The crystal structure of the title salt, C5H16N2(2+)·2Br(-), with Z = 12 and more unusually Z' = 3, forms part of a small group of crystal structures in the Cambridge Structural Database that are ammonium bromide salts. One of the diaminium cation chains in the asymmetric unit exhibits positional disorder, which was modelled using a suitable disorder model. This compound also exhibits organic-inorganic layering in its packing arrangement that is typical of this class of compound. An extensive complex three-dimensional hydrogen-bonding network is also identified. The hydrogen bonds evident in this crystal structure were identified as being most likely strong charge-assisted hydrogen bonds.

Molecular Networks Created by Charge-Assisted Hydrogen Bonding in Carboxylate Salts of a Bis(amidine)

Amidines can be protonated by carboxylic acids to give amidinium carboxylates, and the ions can associate by forming multiple charge-assisted hydrogen bonds according to reliable motifs. Extended hydrogen-bonded networks can be constructed by treating suitable bis(amidines) with acids containing multiple carboxyl groups. To further explore the potential of this strategy, we have determined the structures of salts produced by treating 2,2′-bi-2-imidazoline, a cyclic bis(amidine), with oxalic, fumaric, terephthalic, and trimesic acids. The structures of the salts proved to incorporate features resulting predictably from the geometry of the ions and their ability to engage in charge-assisted hydrogen bonds.