Pyridine Hydrogen Bonds Research Articles

N‐H⋅⋅⋅O, O‐H⋅⋅⋅O hydrogen bonded supramolecular formation in the cocrystal of salicylic acid with N‐containing bases

Cocrystals of salicylic acid (derived from reaction between aspirin and coformers) with 4,4′dipyridyl, nicotinamide, isonicotinamide, N,N′‐diacetylpiperazine and piperazine have been examined with intent to improve physicochemical properties of antipyretic agent. All of the resulting cocrystals, salicylic acid/4,4′dipyridyl (2:1), salicylic acid/nicotinamide (1:1), salicylic acid/isonicotinamide (1:1), salicylic acid/piperazine (1:0.5) and salicylic acid/ N,N′‐diacetylpiperazine (2:1) (derived from reaction between aspirin and piperazine) are obtained solution cooling/evaporation experiments. The structural analysis has shown that the well‐known COOH⋅⋅⋅N heterosynthon was considered the key element in the cocrystals design strategy. The carboxylic acid⋅⋅⋅pyridine hydrogen bond is an often used supramolecular synthon. The results from X‐ray Powder Diffraction, DSC, Raman and single‐crystal X‐ray analysis revealed the formation of cocrystal of salicylic acid with several coformers.

Interplay of Packing, Proton Transfer and Hydrogen Bonding on Crystal Properties

The designed creation of crystalline materials with desired physical properties is a key objective of crystal engineering. Currently the development of multi-component crystals such as salts and co-crystals as a route for the modification of physicochemical properties has been a major focus within the field. However, while the creation of such materials has been repeatedly demonstrated, understanding the structure-property relationships between the component molecules and the final crystal form is great challenge, so limiting the ability to design new materials. Controlling the proton transfer process is vital for the designed creation of protonic conductive materials but also important in other fields as the proton location alters the physical properties of other systems such as pharmaceutical or photochromic materials. The interaction between chemical structure and local crystallographic environment has been shown to alter the energy landscape of the proton transfer process [1,2] This presentation will report on work investigating the relationships between changes in molecular and crystal structure on proton transfer processes in multi-component materials. Both experimental crystal growth and computational modelling have been used to study proton transfer in binary and ternary systems based on the carboxylic acid...pyridine hydrogen bond. Understanding the interplay between packing forces and proton transfer in controlling the observed photochromism in bipy/rac-mandelic acid system and how this can be used to design new material based on these concepts.

Proton location in acid⋯pyridine hydrogen bonds of multi-component crystals

Role of local crystal environment on proton location was modelled using DFT calculations. Alteration in the strength of the hydrogen bonding can convert a system from a salt to a co-crystal.

Polymorphic Co-crystals from Polymorphic Co-crystal Formers: Competition between Carboxylic Acid···Pyridine and Phenol···Pyridine Hydrogen Bonds

The recent literature has shown an increase in the number of co-crystals reported to be polymorphic, with at least 45 such systems identified thus far. The question of whether co-crystals, defined as any multicomponent neutral molecular complex that forms a crystalline solid, are inherently less prone to polymorphism than the individual components is shown to be untrue in four sets of polymorphic co-crystals. The co-crystal formers in this study, acridine, nicotinamide, 3-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, malonic acid, and pimelic acid, are all polymorphic in their unimolecular states and are shown to be dimorphic in the following combinations: (3-hydroxybenzoic acid)·(acridine) [1(I) and 1(II)], (2,4-dihydroxybenzoic acid)·(nicotinamide) [4(I) and 4(II)], (malonic acid)·(nicotinamide) [5(I) and 5(II)], and (pimelic acid)·(nicotinamide) [6(I) and 6(II)]. These co-crystals are assembled primarily using carboxylic acid and phenol hydrogen bond donors that hydrogen bond to pyridine N or amide carbonyl acceptors. Two different combinations of donors and acceptors are primarily responsible for the formation of polymorphs in 1 and 4, whereas conformational differences within the malonic and pimelic acid molecules lead to different packing arrangements using the same combination of hydrogen bonded interactions in 5 and 6. The 1:2 co-crystal of (3-hydroxybenzoic acid)·(acridine)2 (2) displays both the phenol O–H···N hydrogen bond observed in 1(I) and the carboxylic acid O–H···N hydrogen bond observed in 1(II). In addition, a methanol solvate of (2,4-dihydroxybenzoic acid)·(nicotinamide) (3) is reported. DFT calculations show that the carboxylic acid···pyridine hydrogen bond is strongest and one of co-crystallization’s most useful interactions.

Adventures in co-crystal land: high Z′, stoichiometric variations, polymorphism and phase transitions in the co-crystals of four liquid and solid cyclic carboxylic acids with the supramolecular reagent isonicotinamide

The supramolecular reagent isonicotinamide (isonico) was used to co-crystallize with three liquid carboxylic acids, cyclopropanecarboxylic acid (C3A), cyclobutanecarboxylic acid (C4A) and cyclopentanecarboxylic acid (C5A), and a solid carboxylic acid, cyclohexanecarboxylic acid (C6A). A total of six co-crystal structures resulted, which are an illustration of the co-crystal space observed in the ever-expanding research on co-crystallization of multiple molecular components. Co-crystal 1, (C3A)·(isonico), has a crystal structure with one of the highest reported Z′ values. 12 acid and 12 isonico molecules combine in the asymmetric unit to give a Z′ = 12, all forming 1-D ribbons. Co-crystals 2a and 2b, both having a formula of (C4A)2·(isonico), having, respectively, a Z′ of 1 and 2, illustrate both stoichiometric variation as well as polymorphism, resulting in different packing architectures. Co-crystals (C5A)·(isonico) 3 and (C6A)·(isonico) 4 have isostructural structures at low temperature, and both show phase transitions above room temperature. For (C6A)·(isonico), we determined the structure of both the low temperature phase, 4a, as well as a high temperature phase, 4b, by single crystal X-ray diffraction, and monitored the transition of 3 by variable temperature powder X-ray diffraction. In all of the compounds reported here, synthesized from two components that are not necessarily solids at ambient conditions and which we have called co-crystals, the primary hydrogen bonded interaction is the carboxylic acid⋯pyridine hydrogen bond.

Covalent assistance to supramolecular synthesis: modifying the drug functionality of the antituberculosis API isoniazidin situ during co-crystallization with GRAS and API compounds

The anti-tuberculosis molecule isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes and also allows for its biological activity to be improved and modified by a simple covalent reaction. The low temperature crystal structures of both isoniazid (1) and the related N′-(propan-2-ylidene)isonicotinohydrazide molecule (2), the latter known to be a more effective agent against Mycobacterium tuberculosis, are reported. In addition, these two molecules were then co-crystallized with the same three Generally Regarded As Safe (GRAS) molecules, succinic acid, 4-hydroxybenzoic acid and 2-hydroxybenzoic acid, to produce the following pharmaceutical co-crystals: (isonicotinic acid hydrazide)2·(succinic acid) 3, (N′-(propan-2-ylidene)isonicotinohydrazide)2·(succinic acid) 4, (isonicotinic acid hydrazide)·(4-hydroxybenzoic acid) 6, (N′-(propan-2-ylidene)isonicotinohydrazide)·(4-hydroxybenzoic acid) 7, (isonicotinic acid hydrazide)·(2-hydroxybenzoic acid) 8, and (N′-(propan-2-ylidene)isonicotinohydrazide)·(2-hydroxybenzoic acid) 9. In addition, a co-crystal using 2-butanone as a modifier is also reported, (N′-(butan-2-ylidene)isonicotinohydrazide)2·(succinic acid) 5. Drug–drug co-crystals were also made with the anti-HIV compound 2-chloro-4-nitrobenzoic acid: (isonicotinic acid hydrazide)·(2-chloro-4-nitrobenzoic acid) 10, and (N′-(propan-2-ylidene)isonicotinohydrazide)·(2-chloro-4-nitrobenzoic acid) 11. All the co-crystals use the carboxylic acid⋯pyridine hydrogen bond to connect the GRAS or drug molecule to the pyridine ring. In general, the co-crystals with the modified isoniazid feature the C(4) homosynthon, and those with the original isoniazid a variety of homo- and heterosynthons. By comparing the melting points of the co-crystals that use isoniazid and those that use the modified isoniazid, a reduction in melting point is observed.

Structures and conformational analysis of a 3 × 3 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides

A 3 × 3 isomer grid of N-(fluorophenyl)pyridinecarboxamides is reported and integrating crystal structure analyses, ab initio optimisation calculations (gas phase and solvated forms in CH2Cl2, H2O) and conformational analyses. The nine NxxF isomers (x = 4-, 3- or 2-substitution on N and F) are investigated and compared to determine and correlate factors underpinning (a) the roles of the F/N atom substituents on molecular conformation and overall supramolecular aggregation, (b) competition between intermolecular amide⋯amide (in NppF) or intra-/intermolecular amide⋯pyridine hydrogen bond formation and (c) structural and physico-chemical properties. Crystal structure analyses of the NxxF isomers reveal different primary aggregation processes as either N–H⋯N or N–H⋯OC and with NmpF forming an unusual cyclic N–H⋯N hydrogen bonded tetrameric assembly [as a R44(24) ring]. Compounds NpmF and NpoF are isomorphous and the latter is also disordered. Conformational analysis of the NxxF molecular structures from DFT calculations differs from the crystal structure results for several isomers and highlighting the co-operative effects of intra-/intermolecular interactions in the solid state.

Pharmaceutical Co-crystals with Isonicotinamide—Vitamin B3, Clofibric Acid, and Diclofenac—and Two Isonicotinamide Hydrates

The co-crystals of three industrially important pharmaceutical molecules, the Vitamin B group member nicotinamide (1), the antihyperlipidemic drug clofibric acid (2), and the nonsteroidal anti-inflammatory drug diclofenac (3), are synthesized with the co-crystal former isonicotinamide and characterized by thermal analysis and single crystal X-ray diffraction. Two dimorphic hydrates of isonicotinamide were obtained during the course of these experiments: hydrate 4 (form I) has been reported recently, and hydrate 5 (form II) is new. Both are monohydrates but differ in the number of independent molecules in the asymmetric unit, Z′ = 2 and 8, respectively. Form II is metastable compared to I and converts to form I in the solid state. In all three pharmaceutical co-crystals, it is the pyridine N atom of either the nicotinamide molecule in 1 or the N atom of the isonicotinamide molecule in 2 and 3 that is used in connecting the different molecules together, as a hydrogen bond acceptor from the amine of the isonicotinamide in 1 and the carboxylic acid protons in 2 and 3. The carboxylic acid···pyridine hydrogen bond is an often used supramolecular synthon. A survey of relevant structures in the Cambridge Structural Database of isonicotinamide and nicotinamide co-crystals is given for completeness, and the co-crystal former ability of isonicotinamide and nicotinamide was investigated by performing density functional theory calculations.

Structural Characterization of Zinc and Iron (II/III) Complexes of a Porphyrin Bearing Two Built-in Nitrogen Bases. An Example of High-Spin Diaqua-Iron(III) Bromo Complex

A bis-strapped porphyrin with two intramolecular nitrogen bases was synthesized, and its zinc(II), iron(II), and iron(III) complexes have been structurally characterized. Whereas the zinc(II) complex is square pyramidal five-coordinate and the iron(II) complex is six-coordinate despite a significant distortion of the macrocycle induced by the rigidity of the straps, the iron(III) complex exhibits a peculiar bis-aqua structure in which no intramolecular axial base is bound to the iron atom in the porphyrin. Furthermore, on one side, the bromide counteranion of the iron is bound inside the cycle formed by a strap and establishes a hydrogen bond with an axially bound water molecule. On the other side, a residual HBr molecule protonates one pyridine base leading to the formation of an intermolecular pyridinium-pyridine hydrogen bond. The large ionic radius of the high-spin iron(III) cation is accommodated in the macrocycle with no displacement of the metal out of the mean porphyrinic plane, with an average Fe-Np bond distance of 2.057 A, and the axial Fe-Ow(aqua) bond distance measured at 2.090 A. As a result, this high-spin iron(III) bis-aqua complex is only lightly distorted.

Design and stabilization of block copolymer micelles via phenol–pyridine hydrogen-bonding interactions

A new approach for the preparation of block copolymer micelles in non-selective solvent is introduced. Phenol–pyridine hydrogen-bonding interactions are used for the first time to prepare core–shell micelles in non-selective solvents using block copolymers and bifunctional low-molecular-weight hydrogen-bonding crosslinkers. Poly(styrene- b-4-vinylphenol)/Bis-pyridyl ethane and poly(styrene- b-4-vinylpyridine)/Bisphenol A were investigated as micelle formation due to phenol–pyridine hydrogen bond crosslinking. The influence of several factors such as temperature, concentration, solvent and pH in micellization–demicellization process was analyzed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic light scattering (DLS) and atomic force microscopy (AFM). This method opens new possibilities to the generation of block copolymer micelles in non-selective solvents.

Hierarchy of Supramolecular Synthons: Persistent Carboxylic Acid···Pyridine Hydrogen Bonds in Cocrystals That also Contain a Hydroxyl Moiety

A Cambridge Structural Database (CSD) analysis was conducted in order to evaluate the hierarchy of supramolecular heterosynthons that involve two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids and alcohols, in competitive environments. The study revealed that 34% of the 5690 molecular carboxylic acid entries and 26% of the 25 035 molecular alcohol entries form supramolecular homosynthons, whereas the remaining entries form supramolecular heterosynthons with other functional groups, in particular Narom, CONH2, C−O−C, C═O, and chloride anions. Further refinement of this raw data revealed the following: 98% occurrence of the COOH···Narom supramolecular heterosynthon in the 126 crystal structures that contain acid and pyridine moieties in the absence of other hydrogen bond donors or acceptors; and 78% occurrence of the OH···Narom supramolecular heterosynthon in 228 crystal structures that contain hydroxyl and pyridine moieties (excluding intramolec...

Hydrogen-Bonded Helices for Anion Binding and Separation

Herein we report the competitive crystallization of urea-functionalized hydrogen-bonded helical frameworks as a new approach to separating anions from aqueous mixtures. N,N′-Bis( m-pyridylurea) ( 1) containing orthogonal pyridine and urea hydrogen-bonding functionalities forms upon monoprotonation with 1 equiv of HX acids (X = Cl −, Br −, I −, NO 3 −, and ClO 4 −) an isomorphous series of crystalline hydrogen-bonded helices assembled by pyridinium···pyridine hydrogen bonds, with the urea functional groups binding the anions through chelate hydrogen bonding. The helices are further connected in the crystals by CH···X − and pyridinium···X − interactions, as well as π-stacking interactions. Competitive crystallization experiments and lattice energy calculations of the 1·HX crystals showed the solvation-based Hofmeister bias that typically dominates anion separation selectivities from water was attenuated, but not completely overturned. The observed selectivity is apparently a result of the relatively soft and unspecific hydrogen-bonding environment around the anions in the crystals, combined with the high flexibility of the helices, which expand or contract as necessary to accommodate each anion.

Synthesis and structural characteristics of lithocholate triads: steroid-type channels occupied by spacer fragments

Reported in this paper are the syntheses and X-ray investigations of C(2) symmetrical molecular A-B-A triads consisting of two steroid units (lithocholic acid or its methyl ester) joined together by linkers derived from bifunctional molecules such as terephthalic acid or N,N'-dicarboxypiperazine. Unlike their monomeric analogues, some of these compounds form inclusion complexes. All steroidal triads form crystals that are highly pseudo-centrosymmetric, in which the constituting molecules are held together either exclusively by van der Waals forces or form lattice inclusion complexes, with guest molecules hydrogen bonded to the host. The presence of carboxyl groups promotes the inclusion of pyridine molecules and the formation of the well known carboxylic acid...pyridine hydrogen bonds. Combined with pairwise face-to-face pi-stacking between pyridine rings, these hydrogen-bond interactions lead to the formation of extended supramolecular tapes, analogous to polymers. The co-crystals of pyridine and a lithocholic acid triad undergo a symmetry-lowering phase transition from a P1 cell with Z = 1 to a P1 cell with Z = 2. The two structures are virtually the same, the two independent molecules in the larger cell being related by pseudo-translation. Changes in the type of spacer between two methyl lithocholate units from planar aromatic (terephthalic acid) to highly puckered aliphatic six-membered ring (N,N'-dicarboxypiperazine) bring about inclusion properties and changes in side-chain conformation in a crystal. Although the efficient packing of these highly elongated molecules is hindered, as indicated by low values of crystal density, ranging from 1.16 to 1.19 g cm(-3), several very short C...O and H...H contacts are present in the crystals.

Effects of Hydrogen Bonding on the Ring Stretching Modes of Pyridine

The effects of hydrogen bonding on the ring stretching modes (both ring breathing and triangle) of pyridine are experimentally investigated using noisy light based coherent Raman scattering spectroscopy. Three systems, pyridine/formamide, pyridine/water, and pyridine/acetic acid, provide varying degrees of strength for the diluent-pyridine hydrogen bond complex. Formamide forms a relatively weaker hydrogen bond, while acetic acid essentially fully transfers a proton to pyridine. Both dilution studies and temperature studies are performed on the three systems. Together, these provide a broad context in which a very simple model for the electronic behavior of pyridine is formulated. This model is based on a molecular orbital picture and electrostatic arguments, and it well explains the observed experimental results. Additionally, a new mechanism for the line broadening of the ring breathing mode for the pyridine-water hydrogen bonded complex is proposed.

Molecular Complexes of Homologous Alkanedicarboxylic Acids with Isonicotinamide: X-ray Crystal Structures, Hydrogen Bond Synthons, and Melting Point Alternation

Crystallization of α,ω-alkanedicarboxylic acids (HOOC−(CH2)n-2−COOH, n = 2−6) with isonicotinamide (IN) is carried out in 1:2 and 1:1 stoichiometry. Five cocrystals of (diacid)·(IN)2 composition (diacid = oxalic acid, malonic acid, succinic acid, glutaric acid, and adipic acid) are characterized by X-ray diffraction at 153(2) K. Tapes of acid−pyridine O−H···N and amide−amide N−H···O hydrogen bond synthons stabilize these five crystal structures as predicted by the hierarchic model: the best donor (COOH) and best acceptor group (pyridine N) hydrogen bond as acid−pyridine and the second best donor−acceptor group (CONH2) aggregates as an amide dimer. Glutaric acid and adipic acid cocrystallize in 1:1 stoichiometry also, (diacid)·(IN), with acid−pyridine and acid−amide hydrogen bonds. Synthon energy calculations (ΔEsynthon, RHF/6-31G**) explain the observed hydrogen bond preferences in 1:2 (five examples) and 1:1 (two examples) cocrystals. The acid−pyridine hydrogen bond is favored over the acid−amide dimer ...

Solid State 15N NMR Study of Pyridine Adsorption on Clay Minerals

A solid state nuclear magnetic resonance (NMR) method is presented for spectroscopic adsorption studies of organic pollutant compounds on surfaces of powders under environmentally relevant hydration conditions. The applicability of the solid state NMR spectroscopy was investigated using pyridine as a model adsorbate and a clay mineral, hectorite, as an adsorbent. Solid state 15 N magic angle spinning (MAS) and cross-polarization (CP)/MAS NMR methods were used to study adsorption of [ 15 N]pyridine on fully hydrated and on dehydrated homoionic K-, Ca-, Mg-, and Al-hectorites. Powder X-ray diffraction (XRD) was used to determine the expansion of basal spacings and to confirm intercalation of pyridine into clay interlayers. With the exception of hydrated Al-hectorite, more intense signals were obtained with MAS than with CP/MAS, and cross-polarization was less efficient on dehydrated clay/pyridine samples than on hydrated ones, indicative of a higher mobility of pyridine in the interlayers of dehydrated clays compared to hydrated ones. Pyridine interacted primarily through hydrogen bonding to the interlayer water on the hydrated hectorites. On the dehydrated K-hectorite (d 001 = 10.7 A before pyridine adsorption), pyridine solvated the interlayers. Dehydrated Ca-and Mg-hectorites (d 001 = 12.9 and 12.8 A, respectively, before pyridine adsorption) retained one layer of hydration water to which pyridine hydrogen bonds. Intercalation of pyridine was facilitated by the presence of water, the extreme case being Al-hectorite where almost no intercalation was observed without water. Spinning sidebands were only observed for the pyridine resonance between -90 and -94 ppm. This anisotropic species is assigned to the pyridine keying into the ditrigonal hole, hydrogen bonded to the proton of structural OH. The results clearly show that 15 N NMR of an adsorbed N-containing organic compound is a powerful tool for identifying and distinguishing various surface complexes and adducts on hydrated mineral surfaces.