Hydrogen-bonded Dimers Research Articles

The structural pathway from its solvated molecular state to the solution crystallisation of the α- and β-polymorphic forms of para amino benzoic acid.

Para amino benzoic acid (PABA) has two well-characterised α- and β-polymorphic forms and, whilst both crystallise in the monoclinic space group P21/n, they have quite different crystal chemistry and crystallisability behaviour. Previous work has shown that the molecular conformation deformation energy in the crystalline state is higher for the β-form than for the α-form and that the lattice energy for the former converges more slowly than for the latter overall. This suggests that not only is there a higher barrier to crystallisation for the β-form but also that low solution supersaturations might be needed for it to preferentially nucleate. Additionally, solute cluster propensity and solute solvation energetic analysis highlight the importance of an aqueous solvation environment in inhibiting the α-form's strong OH⋯O carboxylic acid hydrogen bond (H-bond) dimer. Despite this, the detailed molecular-scale pathway from solvated molecules to 3D crystallographic structure still remains unclear, most notably regarding how the nucleation process is activated and how, as a result, this mediates the preferential formation of either of the two polymorphic forms. Molecular dynamics (MD) simulations coupled with FTIR studies and intermolecular synthon analysis address this issue through characterisation of the propensity of the incipient bulk synthons that are important in the crystallisation of the two polymorphic forms within the solution state. MD molecular trajectory analysis within crystallisation solutions reveals a greater propensity for OH⋯O synthons (both single H-bonds and homodimers) typical of the α-form and NH⋯O synthons found in both the α- and β-forms when compared to aqueous solution but much lower propensities for the β-form's "fingerprinting" OH⋯N and π-π stacking synthons. In contrast, data from the aqueous solution environment reveals a much greater propensity for the β-form's π-π interaction synthons. IR dilution studies in acetonitrile in the carbonyl region reveal the presence of two CO vibrational stretching bands, whose relative intensities vary as a function of solution dilution. These were assigned to the solvated PABA monomer and a COOH dimer of PABA. Similar data in ethanol shows a main CO stretching band with a shoulder peak suggesting a similar monomer vs. dimer speciation may exist in this solvent. The IR data is consistent with the organic solvent MD data, albeit the corresponding analysis for the aqueous solution was precluded due to the latter's strong OH vibrational mode which restricted validation in aqueous solutions.

Intermolecular noncovalent interactions with carbon in solution.

One of the most familiar carbon-centered noncovalent interactions (NCIs) involving an antibonding π*-orbital situated at the Bürgi-Dunitz angle from the electron donor, mostly lone pairs of electrons, is known as n → π* interactions, and if it involves a σ* orbital in a linear fashion, then it is known as the carbon bond. These NCIs can be intra- or inter-molecular and are usually weak in strength but have a paramount effect on the structure and function of small-molecular crystals and proteins. Surprisingly, the experimental evidence of such interactions in the solution phase is scarce. It is even difficult to determine the interaction energy in the solution. Using NMR spectroscopy aided with molecular dynamics (MD) simulation and high-level quantum mechanical calculations, herein we provide the experimental evidence of intermolecular carbon-centered NCIs in solution. The challenge was to find appropriate heterodimers that could sustain room temperature thermal energy and collisions from the solvent molecules. However, after several trial model compounds, the pyridine-N-oxide:dimethyltetracyanocyclopropane (PNO-DMTCCP) complex was found to be a good candidate for the investigation. NBO analyses show that the PNO:DMTCCP complex is stabilized mainly by intermolecular n → π* interaction when a weaker carbon bond gives extra stability to the complex. From the NMR study, it is observed that the NCIs between DMTCCP and PNO are enthalpy driven with an enthalpy change of -28.12 kJ mol-1 and dimerization energy of ∼-38 kJ mol-1 is comparable to the binding energies of a conventional hydrogen-bonded dimer. This study opens up a new strategy to investigate weak intermolecular interactions such as n → π* interaction and carbon bonds in the solution phase.

The self-assembly and pyridine regulation of a hydrogen-bonded dimeric building block formed by a low-symmetric aromatic carboxylic acid.

The supramolecular self-assembly behavior of a low-symmetric aromatic carboxylic acid molecule (H5BHB) and its co-assembly behavior with a series of pyridine molecules (BPD, BPDYB and TPDYB) were studied at the heptanoic acid/HOPG liquid-solid interface. Scanning tunneling microscopy (STM) observations revealed that H5BHB molecules tend to form dimeric building blocks which then assemble into a close-packed structure. BPD, BPDYB and TPDYB pyridine molecules were all able to form a stable two-component co-assembled structure with the H5BHB molecule, and in these co-assembled structures, the H5BHB molecule still takes the form of a dimer. It was found that the pyridine molecules were able to regulate the self-assembly structure of the H5BHB molecule, and the molecular arrangement of the co-assembly structures varies with the shape of the pyridine molecules. Based on the analysis of the STM results and density functional theory (DFT) calculations, the formation mechanism of the assembled structures was revealed.

On the anomalous homogeneity of hydrogen-disordered ice and its origin.

Pauling's successful estimation of the residual entropy of hydrogen-disordered ice was based on the homogeneity of the binding energy of individual water molecules in ice. However, it has not been explained why the binding energies are homogeneous although the pair interaction energy of hydrogen-bonded dimers distributes widely. Here, we provide a rationale for this phenomenon. The topological constraints imposed by the ice rules, in which water molecules form directed cyclic paths of hydrogen bonds, cancel out the variability of local interactions. We also show that the cancellation mechanism does not work due to some imperfect cyclic paths on the surface of ice. Such water molecules do not enjoy homogeneity in the bulk state and suffer from a wide spectrum in the binding energy.

Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment.

This study provides a significant contribution to the development of multiple hydrogen-bonded supramolecular nanocarrier systems by demonstrating that controlling the hydrogen bond strength within supramolecular polymers represents a crucial factor to tailor the drug delivery performance and enhance the effectiveness of cancer therapy. Herein, we successfully developed two kinds of poly(ethylene glycol)-based telechelic polymers Cy-PEG and UrCy-PEG having self-constituted double and quadruple hydrogen-bonding cytosine (Cy) and ureido-cytosine (UrCy) end-capped groups, respectively, which directly assemble into spherical nanogels with a number of interesting physical characteristics in aqueous solutions. The UrCy-PEG nanogels containing quadruple hydrogen-bonded UrCy dimers exhibited excellent long-term structural stability in a serum-containing biological medium, whereas the double hydrogen-bonded Cy moieties could not maintain the structural integrity of the Cy-PEG nanogels. More importantly, after the drug encapsulation process, a series of in vitro experiments clearly confirmed that drug-loaded UrCy-PEG nanogels induced selective apoptotic cell death in cancer cells without causing significant cytotoxicity to healthy cells, while drug-loaded Cy-PEG nanogels exerted nonselective cytotoxicity toward both cancer and normal cells, indicating that increasing the strength of hydrogen bonds in nanogels plays a key role in enhancing the selective cellular uptake and cytotoxicity of drugs and the subsequent induction of apoptosis in cancer cells.

Crystal structures of 6-nitro-quinazolin-4(3H)-one, 6-amino-quinazolin-4(3H)-one and 4-amino-quinazoline hemi-hydro-chloride dihydrate.

The title compounds, 6-nitro-quinazolin-4(3H)-one (C8H5N3O3; I), 6-amino-quinazolin-4(3H)-one (C8H7N3O; II) and 4-amino-quinazolin-1-ium chloride-4-amino-quinazoline-water (1/1/2), (C8H8N3 +·Cl-·C8H7N3·2H2O; III) were synthesized and their structures were determined by single-crystal X-ray analysis. In the crystals of I and II, the quinazoline mol-ecules form hydrogen-bonded dimers via N-H⋯O inter-actions. The dimers are connected by weak inter-molecular C-H⋯N and C-H⋯O hydrogen bonds, forming a layered structure in the case of I. In the crystal of II, N-H⋯N and C-H⋯O inter-actions link the dimers into a three-dimensional network structure. The asymmetric unit of III consists of two quinazoline mol-ecules, one of which is protonated, a chloride ion, and two water mol-ecules. The chloride anion and the water mol-ecules form hydrogen-bonded chains consisting of fused five-membered rings. The protonated and unprotonated quinazolin mol-ecules are linked to the chloride ions and water mol-ecules of the chain by their amino groups.

Speciation of Substituted Benzoic Acids in Solution: Evaluation of Spectroscopic and Computational Methods for the Identification of Associates and Their Role in Crystallization

Self-association of four benzoic acid derivatives 2-chloro-4-nitrobenzoic acid, 2-methyl-4-nitrobenzoic acid, 3-hydroxybenzoic acid, and 2,6-dimethoxybenzoic acid in solution was investigated using spectroscopic measurements (Fourier transform infrared and 1H and 13C NMR spectroscopy) and molecular simulation methods. Based on the formation of hydrogen bonds, solvents can be divided into two groups: apolar solvents or solvents with a low hydrogen bond acceptor propensity, in which the benzoic acid derivatives form hydrogen-bonded dimers, and solvents with hydrogen bond acceptor propensity β > 0.3, interacting with the carboxylic group of benzoic acid, thus screening its interaction in the formation of self-associates. The formation propensity and structure of self-associates stabilized by weak interactions, such as π···π stacking and CH3···π interactions, however, are determined by the substituents in the benzene ring. Despite all the studied compounds being polymorphic, in none of the cases, an unequivocal structural link between self-associates present in the solution and the crystal form was observed.

Novel urea/thiourea-betaine inclusion compounds consolidated by host-guest hydrogen bonds

Two new inclusion compounds, (CH3)3N+CH2 COO−·2(NH2)2CS (1) and (CH3)3N+ CH2COO−·2(NH2)2CO (2), have been prepared and characterized by X-ray crystallography. In the crystal structure of 1, the cationic moieties are trapped in the channel-like lattice with quasi-rectangular section constructed from the linkage of the carboxyl anionic moieties and thiourea ribbons formed by the centrosymmetric hydrogen-bonded thiourea dimers. In the honeycomb-like stereo host lattice of two that are built by urea molecules, each channel is parallel to the b axis, and every two cationic moieties lie in the same column but link different ribbons with host-guest hydrogen bonds.

Structural characterization of hydrogen bonding for antipyrine derivatives: Single-crystal X-ray diffraction and theoretical studies

Objectives. The paper is devoted to the crystal structure characterization of 5-methyl-2-phenyl4H-pyrazol-3-one (compound I) and 2-(4-chlorophenyl)-5-methyl-4H-pyrazol-3-one (compound II).Methods. Single-crystal X-ray diffraction studies and theoretical calculations: Density functional theory and quantum theory of atoms in molecules.Results. In the solid state, the crystal structure of compound I is characterized by the alternation of OH and NH tautomers connected via O–H---O and N–H---N hydrogen bonds. For compound II, the existence of chains built from the NH monomers via hydrogen bonding can be explained by the peculiarities of cooperative effects. In the framework of quantum theory of atoms in molecules, the following topological characteristics are calculated for all dimers: electron density, Laplacian of electron density, density of kinetic, potential, and total energy in the critical point of the intermolecular hydrogen bond. It is concluded that the hydrogen bond in dimers 1–4, 7 (compound I), and 8–11 (compound II) can be assigned to the intermediate (between covalent and dispersion types) interaction owing to hydrogen bond formation with the participation of electronegative oxygen- (and/or nitrogen-) atoms, whereas H-bond in dimers 5 and 6 (compound I) can be attributed to the dispersion one (no hydrogen bond formation or weak H-bond formation), and it represents the weak interaction, being in agreement with length for intermolecular hydrogen bond in dimers. The electron density and total energy density values demonstrate that the strongest intermolecular H-bonds take place in dimers 1 (OH---O), 4 (OH---O), 7 (OH---N), 8 (OH---O), 9 (NH---N), and 11 (OH---N). The results obtained for compounds I and II are compared with data for antipyrine (1,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazol-3-one; compound III)Conclusions. An important role of intermolecular hydrogen bonding in the crystal packing, molecule association and self-organization via dimer- or more extended species formation has been demonstrated.

Solid-state and solution-state self-association of dimethylarsinic acid: IR, NMR and theoretical study

The structure of dimethylarsinic acid (Me2AsOOH, DMA) in crystal and in solution in aprotic medium was studied by X-ray, spectroscopic (IR, NMR and Raman) and quantum chemical calculation (DFT) methods. Two polymorphs of DMA – hydrogen-bonded cyclic dimers or infinite chains – were obtained by growing crystals from protic and aprotic solvents. By comparison of the experimental data with the results of quantum-chemical calculations performed with periodic boundary conditions we propose ways how to distinguish two polymorphs using IR marker bands. The self-association of DMA in polar aprotic solution was studied by low-temperature NMR (T = 100 K, solvent CDF3/CDF2Cl mixture). By using H/D isotope effects on 1H NMR chemical shifts (appearing after a partial deuteration of DMA in the mobile proton sites) we were able to prove that in solution DMA forms cyclic dimers with two equivalent strong hydrogen bonds (in contrast, for example, to Me2POOH acid, which forms predominantly cyclic trimers). Based on the available IR spectra, the type of complexation does not change when the aprotic solvent is varied.

2-Chloro-3-nitro-5-(tri-fluoro-meth-yl)benzoic acid and -benzamide: structural characterization of two precursors for anti-tubercular benzo-thia-zinones.

8-Nitro-1,3-benzo-thia-zin-4-ones are a promising class of new anti-tubercular agents, two candidates of which, namely BTZ043 and PBTZ169 (INN: macozinone), have reached clinical trials. The crystal and mol-ecular structures of two synthetic precursors, 2-chloro-3-nitro-5-(tri-fluoro-meth-yl)benzoic acid, C8H3ClF3NO4 (1), and 2-chloro-3-nitro-5-(tri-fluoro-meth-yl)benzamide, C8H4ClF3N2O3 (2), are reported. In 1 and 2, the respective carb-oxy, carboxamide and the nitro groups are significantly twisted out of the plane of the benzene ring. In 1, the nitro group is oriented almost perpendicular to the benzene ring plane. In the crystal, 1 and 2 form O-H⋯O and N-H⋯O hydrogen-bonded dimers, respectively, which in 2 extend into primary amide tapes along the [101] direction. The tri-fluoro-methyl group in 2 exhibits rotational disorder with an occupancy ratio of 0.876 (3):0.124 (3).

A triorganotin(IV) cocrystal with pyridinic phosphoramide: crystal structure and DFT calculations

Herein, a two-component cocrystal [Ph3SnCl(4-PCAPh) 1] encompassing 4-PCAPh = N-isonicotinyl, N′,N″-bis(hexamethylenyl) phosphoric triamide and triphenyltin(IV) chloride in 1:1 stoichiometric ratio has been reported. Crystallographic information and theoretical calculations, mainly analysis based on the non-covalent interactions (NCI) visualization index, were pursued to generate a profound understanding of the structure-directing interactions in this cocrystal. Two crystallographically independent molecules are present for each component in the crystalline lattice, 1(A) and 1(B). Different conformational structures of 4-PCAPh primarily form centrosymmetric N–H⋯O hydrogen-bonded dimers in the crystal. Geometrical parameters around tin(IV) centers reveal that cocrystal components are interlinked through Sn⋯Npy semi-coordination. The formation of cocrystal and failure in achieving an adduct can be justified in terms of the steric bulk of phenyl groups along with π⋯π-stacking forces between components. The importance of non-covalent interactions in the stability of crystalline structure was elucidated by computing their binding energies using theoretical studies. QTAIM and NBO analyses data also justify the presence of two different Sn⋯N interactions, in agreement with crystal data and NCI-RDG analyses. The small HOMO–LUMO bandgap for Ph3SnCl(4-PCAPh) also signifies more reactivity for the cocrystal than 4-PCAPh.

Crystal structure from laboratory X-ray powder diffraction data, DFT-D calculations, Hirshfeld surface analysis, and energy frameworks of a new polymorph of 1-benzothiophene-2-carboxylic acid

Several benzothiophene-based compounds, including 1-benzothiophene-2-carboxylic acid, exhibit a wide variety of pharmacological activities. They have been extensively used to treat various types of diseases with high therapeutic effectiveness. In this contribution, the crystal structure of a new polymorph of 1-benzothiophene-2-carboxylic acid (BTCA) was determined from laboratory X-ray powder diffraction data with DASH, refined by the Rietveld method with TOPAS-Academic, and optimized using DFT-D calculations. The new form of 1-benzothiophene-2-carboxylic acid crystallizes in space group C2/c (No. 15) with a = 14.635(4), b = 5.8543(9), c = 19.347(3) Å, β = 103.95(1)°, V = 1608.8(6) Å3, and Z = 8. The structure is a complex 3D arrangement which can be described in terms of hydrogen-bonded dimers of BTCA molecules, joined by the acid–acid homosynthon, which interact through C–H⋯O hydrogen bonds to produce tapes further connected through head-to-tail π⋯π and edge-to-face C–H⋯π interactions. A comparison with a previously reported triclinic polymorph and with the related 1-benzofuran-2-carboxylic acid (BFCA) is also presented.

Glutathione Self-Assembles into a Shell of Hydrogen-Bonded Intermolecular Aggregates on "Naked" Silver Nanoparticles.

A detailed understanding of the molecular structure in nanoparticle ligand capping layers is crucial for their efficient incorporation into modern scientific and technological applications. Peptide ligands render the nanoparticles as biocompatible materials. Glutathione, a γ-ECG tripeptide, self-assembles into aggregates on the surface of ligand-free silver nanoparticles through intermolecular hydrogen bonding and forms a few nanometer-thick shells. Two-dimensional nonlinear infrared (2DIR) spectroscopy suggests that aggregates adopt a conformation resembling the β-sheet secondary structure. The shell thickness was evaluated with localized surface plasmon resonance spectroscopy and X-ray photoelectron spectroscopy. The amount of glutathione on the surface was obtained with spectrophotometry of a thiol-reactive probe. Our results suggest that the shell consists of ∼15 stacked molecular layers. These values correspond to the inter-sheet distances, which are significantly shorter than those in amyloid fibrils with relatively bulky side chains, but are comparable to glycine-rich silk fibrils, where the side chains are compact. The tight packing of the glutathione layers can be facilitated by hydrogen-bonded carboxylic acid dimers of glycine and the intermolecular salt bridges between the zwitterionic γ-glutamyl groups. The structure of the glutathione aggregates was studied by 2DIR spectroscopy of the amide-I vibrational modes using 13C isotope labeling of the cysteine carbonyl. Isotope dilution experiments revealed the coupling of modes forming vibrational excitons along the cysteine chain. The coupling along the γ-glutamyl exciton chain was estimated from these values. The obtained coupling strengths are slightly lower than those of native β-sheets, yet they appear large enough to point onto an ordered conformation of the peptides within the aggregate. Analysis of the excitons' anharmonicities and the strength of the transition dipole moments generally is in agreement with these observations.

Experimental and computational diagnosis of the fluxional nature of a benzene-1,3,5-tricarboxamide-based hydrogen-bonded dimer.

Precise characterization of the hydrogen bond network present in discrete self-assemblies of benzene-1,3,5-tricarboxamide monomers derived from amino-esters (ester BTAs) is crucial for the construction of elaborated functional co-assemblies. For all ester BTA dimeric structures previously reported, ester carbonyls in the side chain acted as hydrogen bond acceptors, yielding well-defined dimers stabilized by six hydrogen bonds. The ester BTA monomer derived from glycine (BTA Gly) shows a markedly different self-assembly behaviour. We report herein a combined experimental and computational investigation aimed at determining the nature of the dimeric species formed by BTA Gly. Two distinct dimeric structures were characterized by single-crystal X-ray diffraction measurements. Likewise, a range of spectroscopic and scattering techniques as well as molecular modelling were employed to diagnose the nature of dynamic dimeric structures in toluene. Our results unambiguously establish that both ester and amide carbonyls are involved in the hydrogen bond network of the discrete dimeric species formed by BTA Gly. The participation of roughly 4.5 ester carbonyls and 1.5 amide carbonyls per dimer as determined by FT-IR spectroscopy implies that several conformations coexist in solution. Moreover, NMR analysis and modelling data reveal rapid interconversion between these different conformers leading to a symmetric structure on the NMR timescale. Rapid hydrogen bond shuffling between conformers having three (three), two (four), one (five) and zero (six) amide carbonyl groups (ester carbonyl groups, respectively) as hydrogen bond acceptors is proposed to explain the magnetic equivalence of the amide N-H on the NMR timescale. When compared to other ester BTA derivatives in which only ester carbonyls act as hydrogen bond acceptors, the fluxional behaviour of the hydrogen-bonded dimers of BTA Gly likely originates from a larger range of energetically favorable conformations accessible through rotation of the BTA side chains.

Terahertz Spectroscopy and Molecular Modeling of Barbituric Acid

The well-resolved terahertz (THz) absorption spectrum of barbituric acid has been investigated using terahertz time-domain spectroscopy. Four distinct THz spectral features and two shoulder peaks were observed in the range of 10–124 cm–1. A complete analysis was performed with density functional theory, which provided an excellent agreement between solid-state simulation and experiment. The solid-state analysis indicates that the six experimental spectral features observed at low temperature consist of nine infrared-active vibrational modes. Further simulations based on hydrogen-bond isotopologues were performed to study the involvement of hydrogen bonds in the collective modes. A feature at 118.0 cm–1 mainly stems from the collective vibration of dimer hydrogen bonds (m) while features at 102.0 and 109.6 cm–1 primarily come from the collective vibrations of linear hydrogen bonds (n). The results may be useful for monitoring molecular reaction in industrial production according to the state of hydrogen bonds.

Rigid, biconical hydrogen-bonded dimers that strongly encapsulate cationic guests in solution and the solid state

The octol of a new rigid, tetraarylene-bridged cavitand was investigated for self-assembly behaviour in solution. 1H and DOSY NMR spectroscopic experiments show that the cavitand readily dimerizes through an unusual seam of interdigitated hydrogen-bonds that is resistant to disruption by polar co-solvents. The well-defined cavity encapsulates small cationic guests, but not their neutral counterparts, restricting the conformation of sequestered tetraethylammonium in solution and the solid state.

Lactic Acid Spectroscopy: Intra- and Intermolecular Interactions.

Lactic acid, a relevant molecule in biology and the environment, is an α-hydroxy acid with a high propensity to form hydrogen bonds, both internally and to other hydrogen-bond-accepting molecules. This work includes the novel recording of infrared spectra of gas-phase lactic acid using Fourier transform infrared spectroscopy, and the vibrational absorption features of lactic acid are assigned with the aid of computationally simulated vibrational spectra with anharmonic corrections. Theoretical chemistry methods are used to relate intramolecular hydrogen-bond strengths to the relative stability of lactic acid conformers. The formation of hydrogen-bonded lactic acid dimers and 1:1 water complexes is investigated by simulated vibrational spectra and calculated thermodynamic parameters for the lactic acid monomer and dimer and its water complex in the gas phase. The results of this study are discussed in the context of environmental chemistry with an emphasis on indoor environments.

Adaptive Chirality of an Achiral Cage: Chirality Transfer, Induction, and Circularly Polarized Luminescence through Aqueous Host–Guest Complexation

Chirality transfer, induction, and circularly polarized luminescence (CPL) using supramolecular hosts, such as macrocycles and cages, have been explored for wide-ranging applications in chiral reco...

Polymorph-Selective Role of Hydrogen Bonding and π–π Stacking in p-Aminobenzoic Acid Solutions

Understanding molecular self-association in solution is vital for uncovering polymorph-selective crystal nucleation pathways. In this paper, we combine solution NMR spectroscopy and molecular dynamics simulations to shed light on the structural and dynamical features of p-aminobenzoic acid (pABA) in solution, and on their role in pABA crystals nucleation. pABA is known to yield different crystal forms (α, and β) depending on solvent choice and supersaturation conditions. NMR reveals that dominant interactions stabilizing pABA oligomers are markedly solvent-dependent: in organic solvents, hydrogen bonds dominate, while water promotes π-πstacking. Despite this clear preference, both types of interactions contribute to the variety of self-associated species in all solvents considered. MD simulations support this observation and show that pABA oligomers are short-lived and display a fluxional character, therefore indicating that the growth unit involved in pABA crystallization is likely to be a single molecule. Nevertheless, we note that the interactions dominating in pABA oligomers are indicative of the polymorph obtained from precipitation. In water, at low pABA concentrations - conditions that are known to yield crystals of the β form - carboxylic-carboxylic hydrogen bonds are exclusively asymmetric. At higher pABA concentration conditions in which the crystallization is known to yield the α form - a small but statistically significant fraction of symmetric carboxylic-carboxylic hydrogen-bonded dimers is present. We interpret the presence of these interactions in solvated pABA oligomers as indicative of the fact that a simultaneous and complete desolvation of two carboxylic groups, necessary to form the symmetric hydrogen-bonded dimer typical of the α crystal form, is accessible, therefore directing the nucleation pathway toward the nucleation of α-pABA.