Anion-Binding Properties of Short Linear Homopeptides.

A comprehensive thermodynamic and structural study of the complexation affinities of tetra (L1), penta (L2), and hexaphenylalanine (L3) linear peptides towards several inorganic anions in acetonitrile (MeCN) and N,N-dimethylformamide (DMF) was carried out. The influence of the chain length on the complexation thermodynamics and structural changes upon anion binding are particularly addressed here. The complexation processes were characterized by means of spectrofluorimetric, 1H NMR, microcalorimetric, and circular dichroism spectroscopy titrations. The results indicate that all three peptides formed complexes of 1:1 stoichiometry with chloride, bromide, hydrogen sulfate, dihydrogen phosphate (DHP), and nitrate anions in acetonitrile and DMF. In the case of hydrogen sulfate and DHP, anion complexes of higher stoichiometries were observed as well, namely those with 1:2 and 2:1 (peptide:anion) complexes. Anion-induced peptide backbone structural changes were studied by molecular dynamic simulations. The anions interacted with backbone amide protons and one of the N-terminal amine protons through hydrogen bonding. Due to the anion binding, the main chain of the studied peptides changed its conformation from elongated to quasi-cyclic in all 1:1 complexes. The accomplishment of such a conformation is especially important for cyclopeptide synthesis in the head-to-tail macrocyclization step, since it is most suitable for ring closure. In addition, the studied peptides can act as versatile ionophores, facilitating transmembrane anion transport.

Enhancing the Cation-Binding Ability of Fluorescent Calixarene Derivatives: Structural, Thermodynamic, and Computational Studies.

Novel fluorescent calix[4]arene derivatives L1 and L2 were synthesized by introducing phenanthridine moieties at the lower calixarene rim, whereby phenanthridine groups served as fluorescent probes and for cation coordination. To enhance the cation-binding ability of the ligands, besides phenanthridines, tertiary-amide or ester functionalities were also introduced in the cation-binding site. Complexation of the prepared compounds with alkali metal cations in acetonitrile (MeCN), methanol (MeOH), ethanol (EtOH), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) was investigated at 25 °C experimentally (UV spectrophotometry, fluorimetry, microcalorimetry, and in the solid state by X-ray crystallography) and by means of computational techniques (classical molecular dynamics and DFT calculations). The thermodynamic parameters (equilibrium constants and derived standard reaction Gibbs energies, reaction enthalpies, and entropies) of the corresponding reactions were determined. The tertiary-amide-based compound L1 was found to have a much higher affinity toward cations compared to ester derivative L2, whereby the stabilities of the ML1+ and ML2+ complexes were quite solvent-dependent. The stability decreased in the solvent order: MeCN ≫ EtOH > MeOH > DMF > DMSO, which could be explained by taking into account the differences in the solvation of the ligands as well as free and complexed alkali metal cations in the solvents used. The obtained thermodynamic quantities were thoroughly discussed regarding the structural characteristics of the studied compounds, as well as the solvation abilities of the solvents examined. Molecular and crystal structures of acetonitrile and water solvates of L1 and its sodium complex were determined by single-crystal X-ray diffraction. The results of computational studies provided additional insight into the L1 and L2 complexation properties and structures of the ligands and their cation complexes.

Utilization of a kinetic isotope effect to decrease decomposition of ceftriaxone in a mixture of D2O/H2O.

The discovery of cephalosporin and demonstration of its improved stability in aqueous solution, as well as enhanced in vitro activity against penicillin-resistant organisms, were major breakthroughs in the development of ß-lactam antibiotics. Although cephalosporins are more stable with respect to hydrolytic degradation than penicillins, they still experience a variety of chemical transformations. The present study offers an insight into the rates and mechanisms of ceftriaxone degradation at the therapeutic concentration in water, a mixture of water and deuterium oxide, and deuterium oxide itself at the neutral pH. Specific ceftriaxone degradation products were observed in aged samples (including a previously unreported dimer-type species), and by comparing the degradation rates in H2O and D2O, the observation of a kinetic isotope effect provided some valuable insight as to the nature of the initial ceftriaxone degradation. The effect of protium to deuterium isotope change on the degradation kinetics of ceftriaxone was evaluated using the method of initial rates based on HPLC analysis as well as by quantitative 1H NMR spectroscopy. Moreover, computational analysis was utilized to get a molecular insight into chemical processes governing the ceftriaxone degradation and to rationalize the stabilizing effect of replacing H2O with D2O.

Anion-Sensing Properties of Cyclopentaphenylalanine.

Cyclic pentaphenylalanine was studied as an efficient anion sensor for halides, thiocyanate and oxoanions in acetonitrile and methanol. Stability constants of the corresponding complexes were determined by means of fluorimetric, spectrophotometric, 1H NMR, and microcalorimetric titrations. A detailed structural overview of receptor-anion complexes was obtained by classical molecular dynamics (MD) simulations. The results of 1H NMR and MD studies indicated that the bound anions were coordinated by the amide groups of cyclopeptide, as expected. Circular dichroism (CD) titrations were also carried out in acetonitrile. To the best of our knowledge, this is the first example of the detection of anion binding by cyclopeptide using CD spectroscopy. The CD spectra were calculated from the structures obtained by MD simulations and were qualitatively in agreement with the experimental data. The stoichiometry of almost all complexes was 1:1 (receptor:anion), except for dihydrogen phosphate where the binding of dihydrogen phosphate dimer was observed in acetonitrile. The affinity of the cyclopeptide receptor was correlated with the structure of anion coordination sphere, as well as with the solvation properties of the examined solvents.

The Role of Triazole and Glucose Moieties in Alkali Metal Cation Complexation by Lower-Rim Tertiary-Amide Calix[4]arene Derivatives.

The binding of alkali metal cations with two tertiary-amide lower-rim calix[4]arenes was studied in methanol, N,N-dimethylformamide, and acetonitrile in order to explore the role of triazole and glucose functionalities in the coordination reactions. The standard thermodynamic complexation parameters were determined microcalorimetrically and spectrophotometrically. On the basis of receptor dissolution enthalpies and the literature data, the enthalpies for transfer of reactants and products between the solvents were calculated. The solvent inclusion within a calixarene hydrophobic basket was explored by means of 1H NMR spectroscopy. Classical molecular dynamics of the calixarene ligands and their complexes were carried out as well. The affinity of receptors for cations in methanol and N,N-dimethylformamide was quite similar, irrespective of whether they contained glucose subunits or not. This indicated that sugar moieties did not participate or influence the cation binding. All studied reactions were enthalpically controlled. The peak affinity of receptors for sodium cation was noticed in all complexation media. The complex stabilities were the highest in acetonitrile, followed by methanol and N,N-dimethylformamide. The solubilities of receptors were greatly affected by the presence of sugar subunits. The medium effect on the affinities of calixarene derivatives towards cations was thoroughly discussed regarding the structural properties and solvation abilities of the investigated solvents.

Chloride-Assisted Peptide Macrocyclization.

The role of the Cl- anion as a templating agent for the synthesis of cyclopeptides was assessed through the preparation of three new homocyclolysines and other six cyclic peptides by head-to-tail lactamization. Isolated yields of products obtained by chloride-templating approach were considerably higher than those gained by a cation-promoted procedure, whereby, in some cases, only the anion-assisted synthesis yielded the desired cyclopeptides.

Protonation and Anion Binding Properties of Aromatic Bis-Urea Derivatives-Comprehending the Proton Transfer.

A series of aromatic bis-urea derivatives was prepared and their proton dissociation, as well as anion binding properties in DMSO were investigated. To this end, UV/Vis and 1 H NMR spectroscopies and computational methods were employed. The synthesized molecules differed in the relative position of the urea moieties (ortho- and meta-derivatives) and in the functional groups (-H, -CH3 , -OCH3 , -NO2 ) in the para-position of the pendant phenyl groups. Remarkably high acidities of the compounds (logK1 H ≈14), were ascribed primarily to the stabilizing effect of the aromatic subunits. Quantum chemical calculations corroborated the conclusions drawn from experimental data and provided information from the structural point of view. Knowledge regarding protonation properties proved to be essential for reliable quantitative determination of anion binding affinities. Studied receptors were selective for acetate and dihydrogen phosphate among several anions. Formation of their complexes of 1:1 and 1:2 (ligand/anion) stoichiometries was quantitatively characterized. Proton transfer was taken into account in the course of data analysis, which was especially important in the case of AcO- . ortho-Receptors were proven to be more efficient acetate binders, achieving coordination with all four NH groups. The meta-analogues preferred dihydrogen phosphate, which acted as both hydrogen bond donor and acceptor. Cooperative binding was detected in the case of 1:2 H2 PO4 - complexes, which was assigned to formation of interanionic hydrogen bonds.

Quantum Chemical Calculations of Monomer-Dimer Equilibria of Aromatic C-Nitroso Compounds.

Monomer-dimer equilibria of nitrosobenzene and 2-nitrosopyridine in gas phase and solution were studied by range of quantum chemical methods in an attempt to find the level of theory suitable for modeling dimerization reactions of aromatic C-nitroso compounds in general. The best agreement with the experimental standard reaction Gibbs energies was obtained with a combination of double-hybrid density functionals B2PLYP-D3, PBE0DH, and DSD-PBEB86, and basis sets of triple-ζ quality. Of all other tested functionals, global hybrid PBE0 behaved equally well, and proved to be more than adequate for at least preliminary work. Other tested methods either produced inferior results (MP2, MP4(SDQ), CCSD, G4(MP2), CBS-QBS, CBS-APNO), or were too demanding for practical use (CCSD(T)). Analysis of computationally obtained thermodynamic data reveal intricate details of these reactions. Both E- and Z-dimers have several different conformers, which all have different solvation energies. While in the gas phase the nitrosobenzene E-dimer is more stable that its Z-form, in chloroform, the Z-form is more stable. Gas-phase dimerization entropies are large and negative, so these reactions are strongly temperature dependent. In some cases, like with 2-nitrosopyridines, entropy and enthalpy terms essentially cancel each other out, allowing structural and media effects to significantly influence dimerization equilibria.

Neutral glycoconjugated amide-based calix[4]arenes: complexation of alkali metal cations in water.

Cation complexation in water presents a unique challenge in calixarene chemistry, mostly due to the fact that a vast majority of calixarene-based cation receptors is not soluble in water or their solubility has been achieved by introducing functionalities capable of (de)protonation. Such an approach inevitably involves the presence of counterions which compete with target cations for the calixarene binding site, and also rather often requires the use of ion-containing buffer solutions in order to control the pH. Herein we devised a new strategy towards the solution of this problem, based on introducing carbohydrate units at the lower or upper rim of calix[4]arenes which comprise efficient cation binding sites. In this context, we prepared neutral, water-soluble receptors with secondary or tertiary amide coordinating groups, and studied their complexation with alkali metal cations in aqueous and methanol (for the comparison purpose) solutions. Complexation thermodynamics was quantitatively characterized by UV spectrometry and isothermal titration calorimetry, revealing that one of the prepared tertiary amide derivatives is capable of remarkably efficient (log K ≈ 5) and selective binding of sodium cations among alkali metal cations in water. Given the ease of the synthetic procedure used, and thus the variety of accessible analogues, this study can serve as a platform for the development of reagents for diverse purposes in aqueous media.

A comprehensive study of the complexation of alkali metal cations by lower rim calix[4]arene amide derivatives.

The complexation of alkali metal cations by lower rim N,N-dihexylacetamide (L1) and newly synthesized N-hexyl-N-methylacetamide (L2) calix[4]arene tertiary-amide derivatives was thoroughly studied at 25 °C in acetonitrile (MeCN), benzonitrile (PhCN), and methanol (MeOH) by means of direct and competitive microcalorimetric titrations, and UV and 1H NMR spectroscopies. In addition, by measuring the ligands' solubilities, the solution (transfer) Gibbs energies of the ligands and their alkali metal complexes were obtained. The inclusion of solvent molecules in the free and complexed calixarene hydrophobic cavities was also investigated. Computational (classical molecular dynamics) investigations of the studied systems were also carried out. The obtained results were compared with those previously obtained by studying the complexation ability of an N-hexylacetamidecalix[4]arene secondary-amide derivative (L3). The stability constants of 1 : 1 complexes were determined in all solvents used (the values obtained by different methods being in excellent agreement), as were the corresponding complexation enthalpies and entropies. Almost all of the examined reactions were enthalpically controlled. The most striking exceptions were reactions of Li+ with both ligands in methanol, for which the entropic contribution to the reaction Gibbs energy was substantial due the entropically favourable desolvation of the smallest lithium cation. The thermodynamic stabilities of the complexes were quite solvent dependent (the stability decreased in the solvent order: MeCN > PhCN ≫ MeOH), which could be accounted for by considering the differences in the solvation of the ligand and free and complexed alkali metal cations in the solvents used. Comparison of the stability constants of the ligand L1 and L2 complexes clearly revealed that the higher electron-donating ability of the hexyl with respect to the methyl group is of considerable importance in determining the equilibria of the complexation reactions. Additionally, the quite strong influence of intramolecular hydrogen bond formation in compound L3 (not present in ligands L1 and L2) and that of the inclusion of solvent molecules in the calixarene hydrophobic cone were shown to be of great importance in determining the thermodynamic stability of the calixarene-cation complexes. The experimental results were fully supported by those obtained by MD simulations.

Solvation Effect on Complexation of Alkali Metal Cations by a Calix[4]arene Ketone Derivative.

The medium effect on the complexation of alkali metal cations with a calix[4]arene ketone derivative (L) was systematically examined in methanol, ethanol, N-methylformamide, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. In all solvents the binding of Na+ cation by L was rather efficient, whereas the complexation of other alkali metal cations was observed only in methanol and acetonitrile. Complexation reactions were enthalpically controlled, while ligand dissolution was endothermic in all cases. A notable influence of the solvent on NaL+ complex stability could be mainly attributed to the differences in complexation entropies. The higher NaL+ stability in comparison to complexes with other alkali metal cations in acetonitrile was predominantly due to a more favorable complexation enthalpy. The 1H NMR investigations revealed a relatively low affinity of the calixarene sodium complex for inclusion of the solvent molecule in the calixarene hydrophobic cavity, with the exception of acetonitrile. Differences in complex stabilities in the explored solvents, apart from N,N-dimethylformamide and acetonitrile, could be mostly explained by taking into account solely the cation and complex solvation. A considerable solvent effect on the complexation equilibria was proven to be due to an interesting interplay between the transfer enthalpies and entropies of the reactants and the complexes formed.

Dehydroacetic Acid Derivatives Bearing Amide or Urea Moieties as Effective Anion Receptors.

Derivatives of dehydroacetic acid comprising amide or urea subunits have been synthesized and their anion-binding properties investigated. Among a series of halides and oxyanions, the studied compounds selectively bind acetate and dihydrogen phosphate in acetonitrile and dimethyl sulfoxide. The corresponding complexation processes were characterized by means of 1 H NMR titrations, which revealed a 1:1 complex stoichiometry in most cases, with the exception of dihydrogen phosphate, which formed 2:1 (anion/ligand) complexes in acetonitrile. The complex stability constants were determined and are discussed with respect to the structural properties of the receptors, the hydrogen-bond-forming potential of the anions, and the characteristics of the solvents used. Based on the spectroscopic data and results of Monte Carlo simulations, the amide or urea groups were affirmed as the primary binding sites in all cases. The results of the computational methods indicate that an array of both inter- and intramolecular hydrogen bonds can form in the studied systems, and these were shown to play an important role in defining the overall stability of the complexes. Solubility measurements were carried out in both solvents and the thermodynamics of transfer from acetonitrile to dimethyl sulfoxide were characterized on a quantitative level. This has afforded a detailed insight into the impact of the medium on the complexation reactions.

Simultaneous quantitative determination of paracetamol and tramadol in tablet formulation using UV spectrophotometry and chemometric methods.

The UV spectrophotometric methods for simultaneous quantitative determination of paracetamol and tramadol in paracetamol-tramadol tablets were developed. The spectrophotometric data obtained were processed by means of partial least squares (PLS) and genetic algorithm coupled with PLS (GA-PLS) methods in order to determine the content of active substances in the tablets. The results gained by chemometric processing of the spectroscopic data were statistically compared with those obtained by means of validated ultra-high performance liquid chromatographic (UHPLC) method. The accuracy and precision of data obtained by the developed chemometric models were verified by analysing the synthetic mixture of drugs, and by calculating recovery as well as relative standard error (RSE). A statistically good agreement was found between the amounts of paracetamol determined using PLS and GA-PLS algorithms, and that obtained by UHPLC analysis, whereas for tramadol GA-PLS results were proven to be more reliable compared to those of PLS. The simplest and the most accurate and precise models were constructed by using the PLS method for paracetamol (mean recovery 99.5%, RSE 0.89%) and the GA-PLS method for tramadol (mean recovery 99.4%, RSE 1.69%).

Thermodynamic study of dihydrogen phosphate dimerisation and complexation with novel urea- and thiourea-based receptors.

Complexation of dihydrogen phosphate by novel thiourea and urea receptors in acetonitrile and dimethyl sulfoxide was studied in detail by an integrated approach by using several methods (isothermal titration calorimetry, ESI-MS, and (1)H NMR and UV spectroscopy). Thermodynamic investigations into H2PO4(-) dimerisation, which is a process that has been frequently recognised, but rarely quantitatively described, were carried out as well. The corresponding equilibrium was taken into account in the anion-binding studies, which enabled reliable determination of the complexation thermodynamic quantities. In both solvents the thiourea derivatives exhibited considerably higher binding affinities with respect to those containing the urea moiety. In acetonitrile, 1:1 and 2:1 (anion/receptor) complexes formed, whereas in dimethyl sulfoxide only the significantly less stable complexes of 1:1 stoichiometry were detected. The solvent effects on the thermodynamic parameters of dihydrogen phosphate dimerisation and complexation reactions are discussed.

Supramolecular stabilization of metastable tautomers in solution and the solid state.

This work presents a successful application of a recently reported supramolecular strategy for stabilization of metastable tautomers in cocrystals to monocomponent, non-heterocyclic, tautomeric solids. Quantum-chemical computations and solution studies show that the investigated Schiff base molecule, derived from 3-methoxysalicylaldehyde and 2-amino-3-hydroxypyridine (ap), is far more stable as the enol tautomer. In the solid state, however, in all three obtained polymorphic forms it exists solely as the keto tautomer, in each case stabilized by an unexpected hydrogen-bonding pattern. Computations have shown that hydrogen bonding of the investigated Schiff base with suitable molecules shifts the tautomeric equilibrium to the less stable keto form. The extremes to which supramolecular stabilization can lead are demonstrated by the two polymorphs of molecular complexes of the Schiff base with ap. The molecules of both constituents of molecular complexes are present as metastable tautomers (keto anion and protonated pyridine, respectively), which stabilize each other through a very strong hydrogen bond. All the obtained solid forms proved stable in various solid-state and solvent-mediated methods used to establish their relative thermodynamic stabilities and possible interconversion conditions.

The effect of specific solvent-solute interactions on complexation of alkali-metal cations by a lower-rim calix[4]arene amide derivative.

Complexation of alkali-metal cations with calix[4]arene secondary-amide derivative, 5,11,17,23-tetra(tert-butyl)-25,26,27,28-tetra(N-hexylcarbamoylmethoxy)calix[4]arene (L), in benzonitrile (PhCN) and methanol (MeOH) was studied by means of microcalorimetry, UV and NMR spectroscopies, and in the solid state by X-ray crystallography. The inclusion of solvent molecules (including acetonitrile, MeCN) in the calixarene hydrophobic cavity was also investigated. The classical molecular dynamics (MD) simulations of the systems studied were carried out. By combining the results obtained using the mentioned experimental and computational techniques, an attempt was made to get an as detailed insight into the complexation reactions as possible. The thermodynamic parameters, that is, equilibrium constants, reaction Gibbs energies, enthalpies, and entropies, of the investigated processes were determined and discussed. The stability constants of the 1:1 (metal:ligand) complexes measured by different methods were in very good agreement. Solution Gibbs energies of the ligand and its complexes with Na(+) and K(+) in methanol and acetonitrile were determined. It was established that from the thermodynamic point of view, apart from cation solvation, the most important reason for the huge difference in the stability of these complexes in the two solvents lay in the fact that the transfer of complex species from MeOH to MeCN was quite favorable. That could be at least partly explained by a more exergonic inclusion of the solvent molecule in the complexed calixarene cone in MeCN as compared to MeOH, which was supported by MD simulations. Molecular and crystal structures of the lithium cation complex of L with the benzonitrile molecule bound in the hydrophobic calixarene cavity were determined by single-crystal X-ray diffraction. As far as we are aware, for the first time the alkali-metal cation was found to be coordinated by the solvent nitrile group in a calixarene adduct. According to the results of MD simulations, the probability of such orientation of the benzonitrile molecule included in the ligand cone was by far the largest in the case of LiL(+) complex. Because of the favorable PhCN-Li(+) interaction, L was proven to have the highest affinity toward the lithium ion in benzonitrile, which was not the case in the other solvents examined (in acetonitrile, sodium complex was the most stable, whereas in methanol, complexation of lithium was not even observed). That could serve as a remarkable example showing the importance of specific solvent-solute interactions in determining the equilibrium in solution.

Revision of iron(III)-citrate speciation in aqueous solution. Voltammetric and spectrophotometric studies.

A detailed study of iron (III)-citrate speciation in aqueous solution (θ=25°C, I(c)=0.7 mol L(-1)) was carried out by voltammetric and UV-vis spectrophotometric measurements and the obtained data were used for reconciled characterization of iron (III)-citrate complexes. Four different redox processes were registered in the voltammograms: at 0.1 V (pH=5.5) which corresponded to the reduction of iron(III)-monocitrate species (Fe:cit=1:1), at about -0.1 V (pH=5.5) that was related to the reduction of FeL(2)(5-), FeL(2)H(4-) and FeL(2)H(2)(3-) complexes, at -0.28 V (pH=5.5) which corresponded to the reduction of polynuclear iron(III)-citrate complex(es), and at -0.4V (pH=7.5) which was probably a consequence of Fe(cit)(2)(OH)(x) species reduction. Reversible redox process at -0.1 V allowed for the determination of iron(III)-citrate species and their stability constants by analyzing E(p) vs. pH and E(p) vs. [L(4-)] dependence. The UV-vis spectra recorded at varied pH revealed four different spectrally active species: FeLH (logß=25.69), FeL(2)H(2)(3-) (log ß=48.06), FeL(2)H(4-) (log ß=44.60), and FeL(2)(5-) (log ß=38.85). The stability constants obtained by spectrophotometry were in agreement with those determined electrochemically. The UV-vis spectra recorded at various citrate concentrations (pH=2.0) supported the results of spectrophotometric-potentiometric titration.

An Integrated approach (thermodynamic, structural, and computational) to the study of complexation of alkali-metal cations by a lower-rim calix[4]arene amide derivative in acetonitrile.

The calix[4]arene secondary-amide derivative L was synthesized, and its complexation with alkali-metal cations in acetonitrile (MeCN) was studied by means of spectrophotometric, NMR, conductometric, and microcalorimetric titrations at 25 °C. The stability constants of the 1:1 (metal/ligand) complexes determined by different methods were in excellent agreement. For the complexation of M(+) (M = Li, Na, K) with L, both enthalpic and entropic contributions were favorable, with their values and mutual relations being quite strongly dependent on the cation. The enthalpic and overall stability was the largest in the case of the sodium complex. Molecular and crystal structures of free L, its methanol and MeCN solvates, the sodium complex, and its MeCN solvate were determined by single-crystal X-ray diffraction. The inclusion of a MeCN molecule in the calixarene hydrophobic cavity was observed both in solution and in the solid state. This specific interaction was found to be stronger in the case of metal complexes compared to the free ligand because of the better preorganization of the hydrophobic cone to accept the solvent molecule. Density functional theory calculations showed that the flattened cone conformation (C(2) point group) of L was generally more favorable than the square cone conformation (C(4) point group). In the complex with Na(+), L was in square cone conformation, whereas in its adduct with MeCN, the conformation was slightly distorted from the full symmetry. These conformations were in agreement with those observed in the solid state. The classical molecular dynamics simulations indicated that the MeCN molecule enters the L hydrophobic cavity of both the free ligand and its alkali-metal complexes. The inclusion of MeCN in the cone of free L was accompanied by the conformational change from C(2) to C(4) symmetry. As in solution studies, in the case of ML(+) complexes, an allosteric effect was observed: the ligand was already in the appropriate square cone conformation to bind the solvent molecule, allowing it to more easily and faster enter the calixarene cavity.

Desmotropy, polymorphism, and solid-state proton transfer: four solid forms of an aromatic o-hydroxy Schiff base.

The Schiff base derived from salicylaldehyde and 2-amino-3-hydroxypyridine affords a diversity of solid forms, two polymorphic pairs of the enol-imino (D1 a and D1 b) and keto-amino (D2 a and D2 b) desmotropes. The isolated phases, identified by IR spectroscopy, X-ray crystallography, and (13)C cross-polarization/magnetic angle spinning (CP/MAS) NMR spectroscopy, display essentially planar molecular conformations characterized by strong intramolecular hydrogen bonds of the O-H⋅⋅⋅N (D1) or N-H⋅⋅⋅O (D2) type. A change in the position of the proton within this O⋅⋅⋅H⋅⋅⋅N system is accompanied by substantially different molecular conformations and, subsequently, by divergent supramolecular architectures. The appearance and interconversion conditions for each of the four phases have been established on the basis of a number of solution and solvent-free experiments, and evaluated against the results of computational studies. Solid phases readily convert into the most stable form (D1 a) upon exposure to methanol vapor, heating, or by mechanical treatment, and these transformations are accompanied by a change in the color of the sample. The course of thermally induced transformations has been monitored in detail by means of temperature-resolved powder X-ray diffraction and infrared spectroscopy. Upon dissolution, all forms equilibrate immediately, as confirmed by NMR and UV/Vis spectroscopy in several solvents, with the equilibrium shifted far towards the enol tautomer. This study reveals the significance of peripheral groups in the stabilization of metastable tautomers in the solid state.