Multicomponent Supramolecular Assemblies of ... - ACS Publications

Oct 1, 2018 - Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain. §. Departament de Química ...
0 downloads 0 Views 2MB Size
Subscriber access provided by Kaohsiung Medical University

Article

Multicomponent Supramolecular Assemblies of Melamine and #-hydroxycarboxylic Acids: Understanding the Hydrogen Bonding Patterns and Their Physicochemical Consequences Alfonso Castineiras, Isabel Garcia-Santos, Josefa María González-Pérez, Antonio Bauza, Jan K. Zar#ba, Juan Niclós-Gutiérrez, Rocio Torres, Esther Vilchez, and Antonio Frontera Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01035 • Publication Date (Web): 01 Oct 2018 Downloaded from http://pubs.acs.org on October 4, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Multicomponent Supramolecular Assemblies of Melamine and αhydroxycarboxylic Acids: Understanding the Hydrogen Bonding Patterns and Their Physicochemical Consequences Alfonso Castiñeiras1∗, Isabel García-Santos1, Josefa María González-Pérez2, Antonio Bauzá3, Jan K. Zaręba4, Juan Niclós-Gutiérrez2, Rocío Torres1, Esther Vílchez2 and Antonio Frontera3 1

Department of Inorganic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain 2 Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain 3 Departament de Química, Universitat de les Illes Balears, Crta. de Valldemossa km 7.5, 07122 Palma /Baleares), Spain. 4 Advanced Materials Engineering and Modelling Group, Wroclaw University of Science and Technology, Wyb. Wyspiańskiego 27, 50370, Wrocław, Poland. ABSTRACT. The reaction of 1,3,5-triazine-2,4,6-triamine (melamine, me) with alphahydroxycarboxylic acids, namely, glycolic acid (H2ga), and mandelic acid (H2ma), provided three ionic multicomponent crystal structures (MCSs) of composition: [(Hme+) (Hga−)]·1/2H2O (I), [(Hme+) (Hma−)]·dioxane·2H2O (II) and [(Hme+) (Hma−)]·(me)·DMSO·3H2O (III). Those MCSs revealed the typical prospensity of “me”, and particularly of its monoprotonated form (Hme+), to form supramolecular aggregates such as linear and crinkled tapes and molecular ribbons. The energetic landscape of those assemblies has been explored with the use of density functional theory calculations of various models of Hme+ and “me” hydrogen-bonded aggregates. The stabilization energies of Hme+-based adducts are for the first time rationalized within the context of antielectrostatic hydrogen bonding concept. In addition, we discussed supramolecular arrangement of I-III in terms of synthon formation and explored structural peculiarities imparted by hydration and solvation. The salt-to-cocrystal continuum is analyzed based on structural analysis and physicochemical properties such as vibrational characteristics, thermal stability, and solubility. Finally, the analysis of dnorm-mapped Hirshfeld Surfaces of melamine at different protonation states allowed to establish strongly characteristic protonation-dependent features of those surfaces, which peculiar features are reflected in associated Fingerprint Plots (FPs). By comparison with literature precendents, we have found that our findings on FP plots of “me”, Hme+ species are indeed general.

*

Prof. Dr. Dr. h. c. Alfonso Castiñeiras Universidad de Santiago de Compostela Departamento de Química Inorgánica Campus Universitario sur E-15782 Santiago de Compostela (Spain) Tlf.: +34 881 814 951 Fax: +34 881 815 090 e-mail address: [email protected] URL: http://www.usc.es/giqimo ORCID ID: https://orcid.org/0000-0002-5070-5936

1 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Multicomponent Supramolecular Assemblies of Melamine and α-hydroxycarboxylic Acids: Understanding the Hydrogen Bonding Patterns and Their Physicochemical Consequences Alfonso Castiñeiras1∗, Isabel García-Santos1, Josefa María González-Pérez2, Antonio Bauzá3, Jan K. Zaręba4, Juan Niclós-Gutiérrez2, Rocío Torres1, Esther Vílchez2 and Antonio Frontera3

1

Department of Inorganic Chemistry, Faculty of Pharmacy, University of Santiago de

Compostela, 15782 Santiago de Compostela, Spain 2

Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada,

18071 Granada, Spain 3

Departament de Química, Universitat de les Illes Balears, Crta. de Valldemossa km

7.5, 07122 Palma /Baleares), Spain. E-mail: [email protected] 4

Advanced Materials Engineering and Modelling Group, Wroclaw University of

Science and Technology, Wyb. Wyspiańskiego 27, 50370, Wrocław, Poland. E-mail: [email protected]

ABSTRACT A greater understanding of structure-property relationships is crucial for development of multicomponent crystal structures (MCSs) based on acid-base compounds. In particular, one of the most interesting aspects of such compounds, yet to some extent unpredictable, is the salt-to-cocrystal continuum especially in strongly hydrogen-bonded systems. The reaction of 1,3,5-triazine-2,4,6-triamine (melamine, me) with alphahydroxycarboxylic acids, namely, glycolic acid (H2ga), and mandelic acid (H2ma), provided three complex ionic MCSs of composition: [(Hme+) (Hga−)]·1/2H2O (I), *

Prof. Dr. Dr. h. c. Alfonso Castiñeiras Universidad de Santiago de Compostela Departamento de Química Inorgánica Campus Universitario sur E-15782 Santiago de Compostela (Spain) Tlf.: +34 881 814 951 Fax: +34 881 815 090 e-mail address: [email protected] URL: http://www.usc.es/giqimo ORCID ID: https://orcid.org/0000-0002-5070-5936

2 ACS Paragon Plus Environment

Page 2 of 39

Page 3 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

[(Hme+) (Hma−)]·diox·2H2O (II) and [(Hme+) (Hma−)]·(me)·DMSO·3H2O (III). Those MCSs revealed the typical prospensity of me, and particularly of its monoprotonated form (Hme+), to form supramolecular aggregates such as linear and crinkled tapes and molecular ribbons. The energetic landscape of those assemblies has been explored with the use of density functional theory calculations of various models of Hme+ and me hydrogen-bonded aggregates. The stabilization energies of Hme+based adducts are for the first time rationalized within the context of antielectrostatic hydrogen bonding concept. In addition, we discussed supramolecular arrangement of IIII in terms of synthon formation and explored structural peculiarities imparted by hydration and solvation. The salt-to-cocrystal continuum is analyzed based on structural analysis and physicochemical properties such as vibrational characteristics, thermal stability, and solubility. Finally, the analysis of dnorm-mapped Hirshfeld Surfaces of melamine at different protonation states allowed to establish strongly characteristic protonation-dependent features of those surfaces, which peculiar features are reflected in associated Fingerprint Plots (FPs). By comparison with literature precendents, we have found that our findings on FP plots of me, Hme+ species are indeed general.

3 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

INTRODUCTION

Multicomponent crystal structures (MCSs) can be defined as crystals that contain two or more different residues in their crystal lattice.1-5 The design of MCSs provides a means to alter the physico-chemical properties of crystals without modifying the chemical properties of the molecule of interest, constituting any of these residues. This is an important current issue for the fields of crystalline engineering and pharmaceutical science, especially with regard to active pharmaceutical ingredients (APIs).6-11 In this context, in December 2011 the United States Food and Drug Administration (FDA), published a draft guide on the subject of regulatory classification of pharmaceutical cocrystals, creating three separate categories of them: cocrystals, polymorphs and salts.12 However, more recently it has been considered that these classifications are ignoring the current scientific and patent literature, since aforementioned categories cannot be mutually exclusive – in fact they are very often overlapped. Indeed, MCSs inherently interweave with one another (e.g. cocrystal can incorporate both free compound and its (de)protonated form - salt), and in addition they can exhibit polymorphism. Accordingly, there have been suggested three regulatory classes in which cocrystals and salts belong to the same regulatory class.13 Another approach to resolve the ambiguity connected with inconsistent classification for MCSs was proposed by Grothe et al.14 This classification system, developed upon in-depth analysis of the MCSs deposited in the Cambridge Structural Database (CSD), proposes that MCSs can be divided into seven subclasses: true solvates, true salts, true co-crystals and those that arise from the overlap between them, that is, solvates of salts, solvates of cocrystals, salts of cocrystals, and finally - solvates of cocrystal salts; worth stressing is that the seven proposed subclasses are indeed relevant in terms of frequency of their occurence. Apart from building up of the comprehensive classification systems, the understanding of non-covalent interactions in molecular crystals is very significant for the design of novel materials with tailored structures and properties.15 The term non-covalent can be applied to numerous intermolecular interactions including electrostatic interactions (ionion, ion-dipole and dipole-dipole interactions), hydrogen bonding, halogen bonding, π-π stacking and Van der Waals forces16 as well as the other interactions, referred to as “unconventional”. The utilization of these interactions for rational design of crystal structures requires an understanding of their supramolecular capabilities, distance and 4 ACS Paragon Plus Environment

Page 4 of 39

Page 5 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

directionality. Specifically, hydrogen bonding has been called the master-key of molecular recognition, since is the most reliable interaction in the toolkit of the crystal engineering, and is both strong and directional with regard to thermodynamic stability and geometrical preferences. In a milieu in which most of the interactions are weak and non-directional, strong and well directed interactions can have powerful impact on the establishment of a final crystal structure.17 With this in mind, a large number of crystal and cocrystal structures have been evaluated over recent decades and a series of frequently recurring hydrogen-bond motifs (referred to as synthons) has been identified. Supramolecular synthons represent the fundamental building block of those systems, and the development in understanding of the scope and boundaries of the interactions responsible for formation of these synthons has also been reviewed in detail.18 Melamine (1,3,5-triazine-2,4,6-triamine, me) and some of its derivatives are interesting from a crystal engineering perspective due to its D3h symmetry imposed by the triazine core and the availability of several hydrogen bond donor and acceptor functionalities. Indeed, the prospensity for extended hydrogen-bonding has been reflected in structures of supramolecular aggregates, such as cyclic rosettes, linear and crinkled tapes and molecular strands and ribbons. The applicational aspect of those is the molecular recognition and organization via weak intermolecular interactions that could be used for the preparation of chemical nanostructures and artificial receptors for biological compounds.19 Melamine is an example of a compound containing complementary arrays of hydrogen bonding sites that forms a 2D network in the solid state. Protonation of its triazine ring decreases the number of the active sites bringing about a decrease in the dimensionality of the supramolecular arrangement20 as well as decreases the symmetry from D3h to Cv. Crystalline compounds containing partially protonated melaminium cations (Hme+, H2me2+) combined with different organic and inorganic counterions are widely reported in the literature; and most of these crystals contain only one melamine form, i.e. the neutral molecule, singly or doubly protonated melaminium cations, and there are very few works reporting the crystal structures comprising neutral and protonated melamine (me and Hme+) simultaneously.21 It was noted that in the molecular complexes of me with polyhydroxy carboxylic acids, the carboxyl and hydroxyl groups both participate in the extensive hydrogen bonding. This is because melamine is well suited for the formation of hydrogen-bonded networks within crystal and cocrystal structures since they contain three N-aromatic acceptor sites 5 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

and six amine donor N-H sites, while the two alpha-hydroxycarboxylic acids contain three O-acceptor sites and two donor O-H sites each. However, the collective influence of hydroxyl and carboxyl groups in the recognition with me has not been systematically evaluated so far.9 Thus, to address this gap in knowledge we have considered glycolic (H2ga) and mandelic (H2ma) acids as possible coformers of salts or co-crystals. Another challenge of crystalline engineering that seeks a solution is the prediction whether the target structure will be formed with proton transfer or not.20 It has been proposed that the deprotonation of an acid by a base is guided by its pKa values in the sense that the difference of pKa between both constituents is considered as a decisive factor for the formation of a salt or a cocrystal.22 In this context, in the present work we have prepared and analyzed three new molecular complexes of Hme+ with both α-hydroxycarboxylic acids and one of them is a new example of salt containing a neutral melamine and a singly protonated melaminium cation in the same crystal. We discuss these molecular complexes in terms of synthon formation, structural variations due to hydration or solvation, their physicochemical properties such as thermal stability and solubility, and finally, with respect to salt to cocrystal continuum. Furthermore, we have also analyzed the H-bonding complexes observed in the solid state X-ray structures of compounds I–II between Hme+ moieties as examples of antielectrostatic H-bonds. Previous theoretical studies have suggested the possibility of finding cation–cation or anion–anion hydrogen-bonded cluster minima in the absence of solvent.23,24 Remarkably, these minima are stable due to the existence of a dissociation barrier, although their overall binding energy is repulsive.25-27 The attraction between the groups involved in the HB interaction is responsible for the presence of such minima, which are kinetically stable.28,29 We have analyzed the existence of such minima in the anti-electrostatic Hme+···Hme+ complexes and the influence of the counter-anion on the binding energies.

EXPERIMENTAL SECTION

Materials and physical measurements All of the starting materials employed were commercially available and were used without further purification. Melting points were determined on a Büchi melting point 6 ACS Paragon Plus Environment

Page 6 of 39

Page 7 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

apparatus and are uncorrected. Elemental analyses for carbon, hydrogen and nitrogen were performed with a Fisons-Carlo Erba 1108 microanalyser. 1H NMR and 13C NMR spectra in DMSO-d6 were run on a Varian Mercury 300 instrument, using TMS as the internal reference. IR spectra were recorded as KBr pellets (4000–400 cm–1) on a Bruker IFS-66v spectrophotometer. TGA experiments were carried out on a SHIMADZU TGA-DTG-50H Analyzer of TA Instruments from room temperature to 700 °C in a flow of air (100 mL min–1) and series of FTIR spectra (20–30 per sample) of evolved gasses were recorded using a coupled FT-IR Nicolet Magma 550 spectrophotometer. Differential scanning calorimetry (DSC) was conducted on a DSC Q100 apparatus of TA Instruments. Accurately weighed samples (1–2 mg) were placed in hermetically sealed aluminium crucibles (40 µL) and scanned from 0 to 350 °C at a heating rate of 10 °C min–1 under a dry nitrogen atmosphere. Powder X-ray diffraction (PXRD) patterns were collected on a Philips PW1710 with a Cu-Kα radiation (1.5406 Å). The tube voltage and amperage were set at 40 kV and 30 mA respectively. Each sample was scanned between 2 and 50° 2θ with a step size of 0.02°. The instrument was calibrated using a silicon standard prior to measurements.

Synthesis of multicomponent crystals Compounds were prepared by co-crystallization via solvent-drop grinding: For each system, stoichiometric amounts of me with H2ga or H2ma in 1:1 molar ratios were prepared and thoroughly ground using an agate mortar and pestle for ca. 5-7 min in order to obtain the physical mixture. After the addition of several drops of the appropriate solvent (10 µL of solvent per 50 mg of co-crystal formers) the clear, nonsaturated solution was poured on a 5 mL vial and were left to evaporate slowly at ambient

conditions

until

[(Hme+)·(Hga−)]·1/2H2O

cocrystals (I),

formed.

The

single

[(Hme+)·(Hma−)]·diox·2H2O

crystals (II)

of and

[(Hme+)·(Hma−)]·(me)·DMSO·3H2O (III), suitable for X-ray diffraction studies were obtained in 1–2 days from DMF, diox:H2O (1:1, v/v) and DMSO:H2O (1:1, v/v) solutions, respectively. [(Hme+) (Hga−)]·1/2H2O (I). Glycolic acid (0.009 g, 0.12 mmol) and melamine (0.015 g, 0.12 mmol). DMF (1.5 mL). Colorless crystals were harvested after fourteen days. M. p. (°C): 227–228. Elemental analysis: Found: C, 28.61; H, 5.61; N, 39.97. Calculated (%) for C5H10N6O3.5: C, 28.57; H, 4.80; N, 39.99. IR (νmax/cm−1): 3371s, 3338s, 3185s, 7 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3126s, 2935m, 2840m, 2692w, 1725m, 1682s, 1601s, 1563m, 1507m, 1409m, 1365m, 1336m, 1299m, 1164m, 1105m 1066m, 781m, 715w, 621w. 1H NMR (DMSO-d6, ppm): 6.05 (s, 6H), 3.85 (s, 2H). 13C NMR (DMSO-d6, ppm): 174.1 (CO), 167.6 (CN), 63.7 (CH2). [(Hme+) (Hma−)]·diox·2H2O (II). D,L-mandelic acid (0.152 g, 0.9 mmol) and Melamine (0.126 g, 0.9 mmol), 12 mL of 1,4-dioxane:H2O (1:1, v/v). Colorless crystals were harvested after two days. M. p. (°C): 165-170. Elemental analysis: Found: C, 45.97; H, 5.66; N, 24.88. Calculated (%) for C26H40N12O10: C, 45.88; H, 5.92; N, 24.69. IR (νmax/cm−1): 3358s, 3150s, 1668s, 1579m, 1507m, 1405m, 1369m, 1251w, 1184w, 1116w, 1083w, 1058m, 933w, 869w, 784m, 696m. 1H NMR (DMSO-d6, ppm): 7.427.27(m, 5H), 6.18 (s, 6H), 4.96 (s, 1H), 3.89 (s, 16H, diox). 13C NMR (DMSO-d6, ppm): 174.9 (CO), 167.2 (CN), 128.5-127.0(ph), 72.9 (CH), 66.7 (CH2, diox). [(Hme+) (Hma−)]·(me)·DMSO·3H2O (III). D,L-mandelic acid (0.152 g, 0.9 mmol) and Melamine (0.126 g, 0.9 mmol), 3 mL of DMSO:H2O (1:1, v/v). Colorless crystals were harvested after one day. M. p. (°C): 180-190. Elemental analysis: Found: C, 37.61; H, 5.66; N, 32.25; S, 5.91. Calculated (%) for C16H32O6N12S: C, 36.92; H, 6.20; N, 32.29; S, 6.16. IR (νmax/cm−1): 3422s, 3388s, 3350s, 3188s, 3146s, 1668s, 1549s, 1511m, 1465m, 1396m, 1367m, 1180m, 1065m, 1056m, 1014m, 931w, 896w, 811w, 788w, 727w. 1H NMR (DMSO-d6, ppm): 7.41-7.26 (m, 5H), 6.04 (s, 13H), 4.96 (s, 1H), 2.54(s, 6H, DMSO). 13C NMR (DMSO-d6, ppm): 169.2 (CO), 168.5 (CN), 130.5-129.8 (ph), 72.8 (CH), 39.80 (CH3, DMSO).

X-ray Crystallography Diffraction data were obtained at 100(1) K using a Bruker X8 Kappa APEXII diffractometer from crystals mounted on glass fibers. Data were corrected for Lorentz and polarization effects and for absorption following multi-scan26 type. The structures were solved by direct methods,31 which revealed the positions of all non-hydrogen atoms. These were refined on F2 by a full-matrix least-squares procedure using anisotropic displacement parameters.31 Hydrogen atoms were located in the difference maps and the positions of O–H and N–H hydrogens were refined (others were included as riders); the isotropic displacement parameters of H atoms were constrained to 1.2 for C and 1.5 for O/N Ueq of the carrier atoms. Molecular graphics were generated with DIAMOND.32 The crystal data, experimental details and refinement results are summarized in Table 1. 8 ACS Paragon Plus Environment

Page 8 of 39

Page 9 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Table 1. Crystal data and structure refinement for the cocrystals [(Hme+)·(Hga)]·1/2H2O (I), [(Hme+)·(Hma−)]·diox·2H2O (II) and [(Hme+)·(Hma−)]·(me)·DMSO·3H2O (III). Compound Empirical formula Formula weight Temperature / K Wavelength / Å Crystal system Space group Unit cell dimensions a/Å b/Å c/Å α/º β/º γ/º Volume / Å–3 Z Calc. density / Mg/m3 Absorp. coefc. / mm–1 F(000) Crystal size θ range / º Limiting indices / h,k,l Refl. collect / unique Completeness θ / º (%) Absorp. correct. Max. /min. transm. Data / parameters Goodness-of-fit on F2 Final R indices R indices (all data) Largest dif. peak/hole

I C5H10N6O3.5 211.20 100 0.71073 Monoclinic P21/n

II C26H40N12O10 680.70 100 0.71073 Triclinic P 1

III C16H29N12O6S 517.57 100 0.71073 Monoclinic C2/c

3.7814(6) 20.932(3) 11.3379(15) 90 95.507(8) 90 893.3(2) 4 1.570

10.7464(14) 11.8610(15) 14.3418(18) 66.876(4) 78.040(4) 88.780(4) 1641.0(4) 2 1.378

12.2510(6) 24.5431(14) 16.4361(10) 90 96.159(3) 90 4913.4(5) 8 1.399

0.132

0.108

0.190

444 0.33×0.30×0.04 1.946–30.508 –4/5, –29/29, –16/16 20318/2731 (Rint = 0.053) 25.242 (99.9)

720 0.32×0.18×0.16 1.581−27.484 −13/13, −14/15, −18/18 28272/7503 (Rint = 0.043) 25.242 (99.9)

2184 0.70×0.15×0.08 1.866−28.282 −16/16, −32/32, −21/21 46470 6095 (Rint = 0.063) 25.242 (99.9)

SADABS 1.000/0.924 2731/181 1.048

SADABS 1.000/0.977 7503/433 1.070

SADABS 1.000/0.929 6095/326 1.049

R1 = 0.047, wR2 = 0.126 R1 = 0.070, wR2 = 0.141 0.819/–0.382

R1 = 0.048, wR2 = 0.114 R1 = 0.071, wR2 = 0.125 0.346/–0.354

R1 = 0.046, wR2 = 0.111 R1 = 0.067, wR2 = 0.122 0.920/–0.412

9 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Hirshfeld Surface Analysis The Hirshfeld Surface (HS) analysis relies on the assumption that the electron density within the crystal is partitioned into each molecule, so one is able to define the surfaces that encompass spaces occupied by those molecules in a crystal. Every point that builds up the HS surface can be defined by two distances: internal distance, di, which defines the distance between the nearest atom that is located inside the HS and HS itself, and external distance de, which per analogy describes distance from the nearest atom outside of the HS to the HS itself. Mathematical analysis of this data with the use of appropriate functions (dnorm, shape index, curvedness - see definitions of those functions in the seminal paper of Spackmann et al.33) allows to parametrize each point of the surface, providing essential information on interactions between molecules. To enable a visual recognition of the HS properties, a color scales are assigned to those parameters, so specific interactions, such as hydrogen bonding, are easily visible. The plot of di values in function of de values gives two-dimensional (2D) fingerprint plot, which is used as a graphical ‘summary’ of interaction distances that have an influence on the HS. For this reason, structure, symmetry, and shapes of 2D fingerprint plots are considered as footprint of all intermolecular contacts. In this work Hirshfeld surface and 2D fingerprint calculations were performed using the Crystal Explorer package ver. 3.1. Crystal structures were imported from CIF files. Hirshfeld surfaces were generated for complex molecules using very high resolution and mapped with the dnorm function. 2D fingerprint plots were prepared with the use of the same software.

Solubility determination The solubility was determined in triplicate for all co-crystals, and compared with that of melamine (S = 3.2 mg/mL). First, the absorbance values of melamine solutions in water milli-Q were recorded, Phosphate Buffer Solution 1.0 M, pH 7.4 (25 °C) and HCl 0.1N, using a spectrophotometer Agilent 8453 UV-Vis at a wavelength of 235 nm, at which the glycolic acid does not absorb, and the calibration line was built [Abs = 0.2731x (mg/100 mL) - 0.0716]. Next, 50 mg of melamine or co-crystal was dispersed in 1 mL of milli-Q water in Eppendorf tubes and left to stir for one week at room temperature. Subsequently, the samples were centrifuged at 12000 rpm for 45 min and the supernatant was removed, where 1 mL of the supersaturated melamine solution was 10 ACS Paragon Plus Environment

Page 10 of 39

Page 11 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

taken to 100 mL of milli-Q water, and 1 mL of co-crystallized supersaturated solution was taken to 500 mL of milli-Q water, proceeding to the subsequent measurement of its absorbance in the spectrophotometer. The same procedure has been followed to determine the solubility of co-crystals with mandelic acid as a conformer.

Theoretical Methods The PBE0-D3/def2-TZVP level of theory was used to compute the energies of the Hbonding interactions by means of the program TURBOMOLE version 7.0.34 For the theoretical analysis of the noncovalent interactions, we have fully optimized the complexes. The binding energies were computed applying the correction for the BSSE (basis set superposition error) by means of the counterpoise technique developed by the Boys–Bernardi.35 The AIMall calculation package36 was employed to analyze the interactions studied using the Bader’s "Atoms in molecules" (AIM) theory.37 The calculations for the wavefunction analysis have been carried out at the PBE0/def2TZVP level of theory using Gaussian-09 software.38

RESULTS AND DISCUSSION

General comments on synthesis. The three crystals were obtained from the crystallization of solutions prepared by reacting the melamine with glycolic or mandelic acids in a molar ratio 1:1. Although the X-ray diffraction data was taken at 100 K, solids handling has always been done at room temperature.

Figure 1. A perspective view showing the assymetrical unit and the atom-numbering scheme, of: (a) (Hme+) (Hga−)·1/2H2O, I; (b) (Hme+) (Hma−)·diox·2H2O, II; (c) (Hme+)(Hma−)·(me)·DMSO·3H2O, III. 11 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Structural description and supramolecular analysis Crystallographic data and refinement parameters of the structures of crystals are provided in Table 1. The geometrical parameters of hydrogen bonding are shown in Table S1 for I and Table S2 for II and III. The aromatic-aromatic stacking interactions geometrical details are given in Table S3 for II and III. The geometric parameters of glycolic acid and D,L-mandelic acid within structures I-III are comparable to those of free acids and therefore not be discussed here in detail.

Compound I crystallizes in the P21/n monoclinic space group. The asymmetric unit consists of a Hme+ melaminium cation, in general position, half a water molecule and two independent halves of glycolate monoanion (Figure 1a), connected by extensive intermolecular hydrogen bonding of the types N-H···N, O-H···O, and N-H···O. The packing is defined by planar chains of melaminium cations are arranged parallel to the [010] direction, with a double amine-pyridyl synthon of ring motif  (8) between the neighbouring inverted Hme+ units (Figure 2). The motif for the hydrogen-bonded assembly of two melaminium cations is observed in many other melamine or melaminium structures, as reported previously.39,40 A Hme+ cation can create two cyclic H-bonding motifs, described by  (8) graph set, that are utilized for H-bonding between the neighbouring Hme+ cations. Additionally, the different molecular chains are connected via glycolate ions with typical hydrogen bond motifs between anion and cation hydrogen atoms such as  (5) or  (6). In the structure, however, there is also a significant amount of H-bonding motifsthat form larger rings, e.g.  (12). Every oxygen atom is a H-bond acceptor for either two, or three NH functionalities. Besides, the crystallization water molecules participate in additional N−H···O and O−H···O interactions, forming amongst others, ring motifs  (8) and  (12) (Figure 2).

12 ACS Paragon Plus Environment

Page 12 of 39

Page 13 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Figure 2. A partial packing diagram for (I), showing one layer of the two-dimensional network, the intermolecular interactions and the supramolecular synthons. Hydrogen bonds are shown as orange dashed lines. The crystals of compound II belong to the triclinic space group P1. The asymmetric unit consists of two Hme+ cations, two D, L-mandelate monoanions, two water molecules, all in general positions, and two independent halves of 1,4-dioxane molecules, since the solvent molecules are located at special positions (Figure 1 b). In the crystal packing of II, the extensive hydrogen bond interactions are observed (Figure 3a). A close inspection of the structure reveals that there are four types of secondary building units. A one-dimensional [(Hme)+]∞ ribbon running along the aaxis, is formed by pairs of the almost linear N-H···N hydrogen bonds between two crystallographically independent Hme+ cations. Such 1D chains are featured by a N4involved  8 ring motif. On the other hand, an anionic [(Hma)−]2 dimer originating from two crystallographic independent mandelate anions is formed by a pair of strong hydrogen bonds O-H···O in an almost linear geometry (Figure 3a). Thus, an O4involved  10 ring motif can be identified.

13 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 3. (a) Crystal packing diagram for II showing the intermolecular interactions and the supramolecular synthons. (b) Portion of the packing diagram showing the interaction linking the cations and anions. (c) Detail of the interactions between [(Hme)+]∞ ribbons, [(Hma)−]2 dimers and water molecules. (d) Molecular packing diagram of hydrogen bond and π–π stacking interactions in II along the b-axis. Hydrogen bonds are shown as orange dashed lines.

Compound III crystallizes in the C2/c monoclinic space group. The asymmetric unit is formed by a neutral melamine molecule (me), a melaminium cation (Hme+), a monoanion D, L-mandelate (Hma-), a DMSO molecule and three crystallization water molecules (Figure 1c). Thus (II) is a new example of a compound containing both a neutral melamine molecule and single protonated melaminium cation. The melamine molecules are interconnected by pairs of almost lineal N-H···N hydrogen bonds forming 1D polymers, characterized by a  8 motif. Those chains contain both

me and Hme+ residues which alternate within the chain, which is running in the [100] direction (Figure 4a). Such ribbons are frequently observed in cocrystals of melamine.40 The me molecules and Hme+ cations form N-H···O bonds with the carboxylate groups of H2ma with  8 and  6 structural motifs. In addition, the  9 and  10 14 ACS Paragon Plus Environment

Page 14 of 39

Page 15 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

structural motifs are present due to the O-H···O bonds which form with a water molecule and between the molecules of H2ma, respectively (Figure 4b). Note that between the layers of melamine water molecules are intercalated that give rise to structural motifs  14 ,  10 and  8 . The DMSO molecules that occupy crystal lattice also participate in forming hydrogen bonds N-H···O with the melamine, with the  8 motif (Figure 4a). As a whole, these interactions generate an infinite 2D network along a axis (Figure 4c), with a zigzag or herringbone appearance on the bc plane, which results in a 2D network with base vector [101] (Figure 4d) and they are stacked along [010], where the centroid-centroid distance between the two types of melamine rings is 3.57 Å, indicating strong π−π interactions between the aromatic triazine rings of two contiguous chains (Figure 4d).

Figure 4. A partial molecular packing diagram of H-bonding interactions for III, indicating supramolecular synthons from different motifs. (b) Ribbons of melamine interconnected by hydrogen bonds parallel to the ac-plane. (c) Detail of the interactions between Hme+, Hma− and water molecules. (d) Network arrangement of III formed through intermolecular hydrogen bonding interactions. Hydrogen bonds are shown as orange dashed lines.

15 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Salt-Cocrystal Continuum The tendency of an acid to dissociate a proton and of a base to accept it can be estimated on the basis of their dissociation constants.41 In general, it is expected that the reaction of an acid with a base forms a salt if the ∆pKa (∆pKa = pKa of base - pKa of acid) is greater than 3, whereas a ∆pKa of approximately 0 leads to the formation of a cocrystal. However, when the value of ∆pKa is between 0 and 3, the formation of a salt or a cocrystal is hard to predict.42 The pKa values of me, H2ga and H2ma are 5.00, 3.83 and 3.41, respectively.43 Therefore the combination me-H2ga should preferably form salts and the me-H2ma one co-crystals. However, it should be kept in mind that a thorough study of 6465 crystalline complexes containing ionized (A−B+) and non-ionised (AB) acid-base pairs in the CSD, at 1 < ∆pKa < 2 values the occurrences of AB and A−B+ are practically equal.44

Figure 5. Primary supramolecular heterosynthon with a R_2^2(8) graph-set motif in the crystal structure of (a) II and (b) III.

The other parameters that govern the synthesis of cocrystals/salts driven by hydrogen bonds, are related to two-point supramolecular synthon ( (8) graph set) which is assembled through a charge assisted complementary hydrogen bond between carboxylic acid and aminopyridine moiety, resulting in a dimeric unit (Figure 5). When the cocrystal displays carboxylic groups involved in hydrogen bonding, a complementary method to verify the proton transfer (formation of a salt) or a cocrystal is based on examination of the differences in the lengths of the C-O bonds of the carboxyl group in the acid molecule, ∆DC-O. The difference between the two bonds less than 0.03 Å undoubtedly corresponds to a salt (deprotonation). On the other hand, if the bond length difference is greater than 0.08 Å, most likely a cocrystal structure is formed.45 In the structures presented here, the values of ∆DC-O are less than 0.03 Å or are very close to this value (compound I = 0.034 Å, compound II = 0.010/0.013 Å, compound III =

16 ACS Paragon Plus Environment

Page 16 of 39

Page 17 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

0.017 Å), which means that the C-O distances are practically symmetrical, as in the carboxylate anions, which additionally proves the formation of salts. A similar prediction is obtained if instead of considering the differences in the length of the C-O bond of the carboxyl group, the relationship between the two bond distances is taken into account. In a study to examine the balance between co-crystallization and proton transfer in a set of acid–base reactions for substituted pyridines with a series of carboxylic acids via intermolecular interactions in the solid state, a comparison of crystal data for salts and co-crystals shows that the average ratio of carbonyl C=O bond distance to C–OH bond distance in co-crystals is 1.08, whereas the ratio of C–O/C–O bond distance for the carboxylate anion is 1.02.46 In the compounds studied here, the ratio C-O/C-O bond distances are 1.014(3) (I), 1.014(2) (II) and 1.009(2) (III), confirming the assignment of salts to co-crystals for these compounds, as indicated in the analysis of the IR spectra (vide infra). In the same compounds, C–OH···Npy average hydrogen bond length for the cocrystals is 2.67 Å, whereas the average C–O−···H+–Npy bond length in the salts is 2.64 Å. The average C=O···HNR hydrogen bond length in co-crystals is 2.91 Å and C–O−···HNR is 2.81 Å. These trends are indeed expected, as the charge-assisted hydrogen bond is likely to be stronger than the neutral analogue.46 In the melamine compounds herein studied, only II and III have in their structure heterosynthons of ring motif  (8). In II, the parameters are 2.693-2.811 Å and 2.769-2.808 Å, respectively for both synthons, which are consistent with the values previously referenced for salts. In III, such parameters are 2.912-2.640 Å, which although they are inverted with respect to the reference data, also correspond to a salt at room temperature, thus confirming its stability of solution at ambient conditions. From the spectroscopic point of view, in SI we provided the detailed vibrational analysis of compounds I-III (see section “FT-IR analysis”). In short, distinct shifts of diagnostic frequencies (stretching C=O) strongly supports the salt nature of those systems. In the SI is also provided the analysis of thermal behavior of compounds I-III, probed by thermogravimetry and differential scanning calorimetry (section Thermal analysis).

Hirshfeld Surface Analysis In the recent time the analysis of Hirshfeld surfaces (HS)45 and 2D fingerprint plots47 has become highly useful method that allows to gain insight into crystal structures in

17 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

both, qualitative and quantitative manner.48-55 For analysis of highly hydrogen-bonded systems the best suited is mapping with dnorm function. According to generally accepted color-coding pattern, the red spots (referred also to as areas) are diagnostic of short contacts, predominantly strong hydrogen bonds, but also weak hydrogen bonds (such as C-H···O) can be identified, since the sum of di and de distances are much lower than the sum of van der Waals radii of the participating atoms. Owing to strongly hydrogen-bonded character of compounds I to III, we have started our analysis from inspection of dnorm–mapped HSs (Figure 6) drawn for Hme+ molecules (4 entries) and me (1 entry). A common feature of all of those surfaces is the presence of at least three red spots on each side of melamine species which stem from either O···H or N···H contacts. More specifically, the supramolecular synthon of the  (8) graph set, between Hme+ - Hme+ and Hme+ - me is responsible for two spots on HS on two sides each (H···N and N···H contacts only), within melamine-based supramolecular chains. Remaining amino group, which does not participate in  (8) motif, in each case forms H···O contacts, seen as two red spots at the corner of HS. In addition to that, for Hme+ species there is pronounced congestion of O-acceptors, mainly carboxylates, in the vicinity of protonated ring, which gives rise to large amount of H···O contacts (areas of their presence is are indicated in Figure 6 with the use of red dashed elipses). Molecule me (Figure 6c, to the right), by contrast, does not form so much H···O contacts with D, L-mandelate. Indeed, the lack of protonation (that is, the lack of charge-assisted hydrogen bonding) causes that HS of the me is completed with H···O contacts to water molecules.

18 ACS Paragon Plus Environment

Page 18 of 39

Page 19 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Figure 6. Semitransparent HS mapped with dnorm function for respective melamine species (Hme+, me) for (a) I, (b) II, and (c) III. Most important intermolecular interactions are indicated with arrows. Note that for II there are two crystallographically independent Hme+ molecules.

Next, we moved to the detailed analysis of properties of 2D fingerprint (FP) plots. FP plots summarize di, de contact distances to the HS, giving the opportunity to quantify the share of each of intermolecular interactions that contribute to the HS. Shapes of 2D FP plots proved to be indicative of certain molecular contacts, thus it is interesting, whether the FP plots of melamine moieties at different protonation states (me, Hme+) will reveal any characteristic features that may have diagnostic value. We suspect that protonation can possibly have strong influence on FP plots, since in the past we have identified that FP plots determined for aromatic phosphonic acid (-PO3H2) in the free form systematically differed from those engaged into acid-base adducts (monodeprotonated

19 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

phosphonic acid, -PO3H-), which subsequently lead to substantial variations in the percentage contributions of H···O and H···N contacts.56 With the above clue in hand, we have generated 2D FP plots for each melamine moiety in compounds I-III (Figure 7a-c). In the first place, we felt it is necessary to disentangle effects on the 2D FP plots that result from multicomponent structure of compounds I-

III from those stemming from changes of protonation state. A comparison of 2D FP plots derived from HSs of I-III in Figure 7a-c clearly shows their asymmetric shape across the diagonal in each case. This is because the melamine moiety that is inside HS contacts not only with symmetry-related melamine molecules, but also with solvents and carboxylic acids. Quite recently, we have evidenced that the 2D FP asymmetry is a peculiar feature of crystal structures consisting of more than one constituent. For example, the lack of diagonal symmetry was determined for crystal structures possessing two or more crystallographically independent molecules57 as well as in solvatomorphic systems.58 Undoubtedly, compounds I-III fall into both of the above categories, thus more precise information on the protonation effects can be extracted from the analysis of contact-decomposed FP plots.

Figure 7. 2D fingerprint plots for (a) Hme+ moiety within structure I, (a) Hme+ moieties within structure II, (c) me and Hme+ moieties within structure III 20 ACS Paragon Plus Environment

Page 20 of 39

Page 21 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

As seen in Figure 7, all FPs possess so-called “spikes”, pointing to the lower left side of each plot. Upper spike corresponds to the presence of the hydrogen bond donor sites that form N-H···N, and N-H···O interactions, as determined from contact-decomposed FP plots (Figs S1-S5 in the SI). Lower spike predominantly represents N-acceptor sites of N-H···N and O-H···N hydrogen bonds. Note that the upper (donor) spike, consists from two contributions (H···N and H···O ones) while lower (acceptor) spike represents H···N contacts only. Indeed, it can be seen that for all FP plots drawn for Hme+ upper spikes are comparatively broadened and extend up to di value of 0.65 Å, while in the case of me (Figure 7c) the upper spike is shorter and thinner (with minimal di value of 0.80 Å). Thus, we see that the protonation of melamine (me) to the melaminium cation (Hme+) has profound effect on FP plots, seen as size reduction of acceptor spike, and extension of donor spike. We rationalize those observations as follows. The protonation of triazine ring causes that an additional proton starts to be present inside the HS, which increases the number of donor sites of hydrogen bond interactions of melamine moiety (three NH2 groups and protonated N-aromatic site). As presented in the crystal structure description section, the additional proton in Hme+ cations always participate in extensive hydrogen bonding with O-acceptor sites (acid molecules, crystallization water and other solvent molecules such as DMSO or dioxane), while the engagement of me is much lower. An additional, yet obvious consequence is that the protonation subtracts one acceptor site of hydrogen bond interaction, which reduces three N-aromatic sites to two. In this manner the capability of me to serve as an acceptor of hydrogen bonds is diminished. To assess quantitatively the influence of protonation state on the percentage shares of respective molecular contacts, we have calculated contact contributions of the most important interactions: H···O, H···N, H···C, H···H (see Table 2, entries 1-3) for me and

Hme+ moieties in compounds I-III. From entries 1-3 it is evident that Hme+ interacts with surroundings to a bigger extent via N···H (28.0 – 29.6 %) than via O···H (15.4 – 22.4 %) contacts. Compound III comprises Hme+ and me simultaneously, thus constitutes a good model for direct comparisons of protonation states. Indeed, analysis of results for this compound shows that me molecule is affected by slightly more N···H contacts (32.8 %) than Hme+, but the contribution from O···H contacts is definitely lower (7.9%). This supports our hypothesis that me is much less likely to participate in hydrogen bonding with O-acceptor sites. 21 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 39

Table 2. The summary of percentage contributions of respective contacts to the HS for melamine compounds at different protonation states (me, Hme+, H2me2+). Entry

1

2

Compound /

Protonation

H···N

H···O /

H···C /

CSD refcode

state

/N···H

O···H

C···H

I

Hme+

28.0

22.4

4.8

29.4

Hme

+

29.6

19.2

7.7

36.5

This

Hme

+

27.3

20.4

5.7

35.5

work

32.8

7.9

6.2

43.3

This

28.7

15.4

6.3

41.0

work

II

3

III

me

Hme

+

me a

4

DIWLAX

5b

ROJGIH

6c

QASFAS

7d

AJOFUA

e

8

9

f g

10

OCAYOG GONREI MIWFOO

H···H

Ref. This work

31.9

12.1

4.1

37.7

Hme

+

28.4

18.5

4.6

33.6

Hme

+

27.2

18.4

6.7

33.5

30.4

12.4

5.5

40.2

26.3

18.9

7.3

38.1

29.8

11.0

7.9

35.8

28.6

16.4

6.4

35.1

H2me2+

16.3

37.8

9.6

23.3

61

H2me

2+

15.4

35.6

2.8

30.2

62

H2me

2+

16.8

51.3

4.5

9.9

63

H2me

2+

19.2

40.3

2.5

21.3

64

me Hme

+

me Hme

+

a

59

21

60

b

bis(Melaminium) naphthalene-1,5-disulfonate melamine pentahydrate, Melaminium melamine 2c d acetylbenzoate dihydrate, bis(Melamine) bis(melaminium) 1,5-naphthalenedisulfonate decahydrate, e Melamini-1,3-diium L-tartrate monohydrate, Melamini-1,3-diium bis(4-hydroxybenzenesulfonate) f g dihydrate, Melamini-1,3-diium dinitrate, Melamini-1,3-diium sulfate.

We wondered whether our observations can be translated to the other melamine-based systems; accordingly, we examined related literature precedents involving both Hme+ and me. To this end, we have calculated FP plots (Figs. S6-S8 in the SI) for selected examples found in the CSD database (entries 4-6 in the Table 2) as well as percentage contact contributions. An analysis of N···H and O···H contributions for Hme+ and me components (entries 4-6) clearly reflects the behavior noted above for compound III:

Hme+ always forms slightly less N···H contacts and approximately 50% more O···H contacts than me. Apart from that, note also that FP plots calculated for entries 4-6 (see SI) have exactly the same structural features as those for compound I-III. Thus, described here effects of melamine protonation on the shape of FP plots and on the shares of molecular contacts have a general character. 22 ACS Paragon Plus Environment

Page 23 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Although doubly protonated melamine moiety, H2me2+, is not present in compounds I-

III at all, we examined whether our understanding of FP plots of melamine species at different protonation states has even more universal character. To test this, we have calculated HS and corresponding FP plots for selected crystal structures comprising

H2me2+ (entries 7 – 10 in the Table 2). Indeed, the increase of protonation state up to H2me2+ causes that O···H contacts start to overweigh N···H ones by 100%, continuing observed trend. Moreover, FP plots of H2me2+ possess only donor spike, while the acceptor one practically disappears, imparting pronounced asymmetry (Figure S9 in the SI).

Powder X-ray diffraction analysis X-ray diffraction of crystalline powder (PXRD) is frequently used to demonstrate the formation of crystalline or co-crystal molecular complexes. As shown in Figure 8, the PXRD patterns of the three co-crystals were compared with those of conformers and are clearly different from those of melamine and pure alpha hydroxycarboxylic acids, containing new peaks different from the peaks of the starting compounds. In addition, a qualitative analysis of the phases carried out by comparing the diffractogram of each cocrystal with all known polymorphs of the respective conformers reveals the singularity of the co-crystal forms studied.

Figure 8. XRPD patterns of α-hydroxycarboxylic acid (red), melamine (green) and cocrystal (blue) in (a) [(Hme+) (Hga−)]·1/2H2O (I), (b) [(Hme+) (Hma−)]·diox·2H2O (II) and (c) [(Hme+) (Hma−)]·(me)·DMSO·3H2O (III).

23 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

To confirm the bulk purity of the samples, simulated and measured PXRD have been compared. In I, we found that the structures of the polycrystalline and mono-crystalline samples. The two diffractograms are closely similar, confirming that the bulk crystalline sample consists of a single phase. There seems to be a couple of uninterpretable peaks. This may be due to the loss of crystallization water molecules. In II, the structures of the polycrystalline and mono-crystalline samples do not entirely coincide (Figure S12 in the SI). This may be due to the loss of 1,4-dioxane molecules included in the monocrystalline structure (Figure S13 in the SI), which is confirmed by the agreement between the peaks of the experimental and simulated diffractograms of the cocrystals with only crystallization water. In this case, the mono and polycrystalline samples are isoestructural (Figure S14 in the SI). Sometimes the whole pattern is different due to phase transitions between single crystal data (measured at low temperatures) and powder data (measured at room temperature). Finally, regarding the good quality of the adjustment and the interpretation of all experimental peaks in III, it is concluded that the mono and polycrystalline samples are also isoestructural (Figure S15 in the SI).

Solubility studies The solubility of the salt cocrystals in a milli-Q water solution at 22 °C has been determined. Table 3 shows the values found together with those of the pure conformers. In salt cocrystals, the solubility is a complex parameter that depends on the enthalpy of fusion, temperature of the solvent, melting point of the solid, hydrogen bonding in the solid and solvent, and other polar and nonpolar interactions in the solvent and the solute.65 For the compounds studied, the dissolution profile reached in I is 20.5 mg/mL, in II of 10.1 mg/mL and in III of 9.8 mg/mL, which represents 5.7, 2.8 and 2.7 times the solubility of the pure melamine in distilled water (literature value 3.6 mg/mL), respectively. This change in solubility is the expected for cocrystals and salts.66,67 The solubility of a cocrystal is the sum of all the component species in solution that are in equilibrium with it. For this reason, the lower increase in the solubility of compounds II and III compared to that of compound I and with respect to the solubility of melamine, should undoubtedly be justified on the basis that they contain solvation molecules other than water in their packing.68

24 ACS Paragon Plus Environment

Page 24 of 39

Page 25 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Table 3. General details and solubility of the molecular complexes* Compound me H2ga H2ma I II III

pKa 5.00 3.83 3.41 -

∆pKa 1.17 1.59 1.59

Solvent of crystallization water water/diox water/DMSO

DC-O 0.034 0.010/0.013 0.017

Solubility 3.2 2.4 1.6 20.5 10.1 9.8

*∆pKa = pKa(BH+)-pKa(AH); DC-O = dCOO−-dC=O; mg/mL

Antielectrostatic hydrogen bonding – A theoretical Study Aggregates of ions of the same sign are counterintuitive in terms of energetics due to Coulombic repulsive interactions, although such aggregates have been described in the solid state.23-29,69 Theoretical calculations have shown that it is feasible to form stable hydrogen-bonded aggregates between charged molecules with the same sign, although they exhibit positive (energetically unfavorable) binding energies. The stability of such “anti-electrostatic” (AE) aggregates seems contradictory, notwithstanding the common view of the hydrogen bond as an attractive electrostatic interaction. Theoretical calculations have shown that in spite of the overall Coulombic repulsion, local electrostatic forces can be attractive in the hydrogen-bond region29 and they are able to maintain the formation of these aggregates. In the solid state of compounds I–III the Hme+ cations form infinite 1D supramolecular tapes or ribbons, as shown in Figure 9 and aforementioned in the section 3.2. They are governed by the formation of H-bonding networks that in compounds I and II can be classified as anti-electrostatic H-bonds (AEHB). In III a neutral me is intercalated between the Hme+ cations. Two different binding modes for the AEHB complexes can be observed. In compound I both NH2 groups located in ortho with respect to the formal positive charge act as H-bond donors to generate the 1D tape (see Figure 9a). In compound II, both NH2 groups that are located in ortho and para with respect to the positive charge participate as H-bond donors thus extending the tape (see Figure 9b). The binding mode in III is similar to I, however the H-bonding is not anti-electrostatic since neutral and charged melamine moieties are alternated.

25 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 9. Supramolecular 1D tapes found in the solid state of compounds I (2), II (b) and III (c). Distances in Å

The theoretical study is devoted to analyze and compare the neutral and AE hydrogen bonding interactions involving melamine. We have fully optimized the complexes 1–7 shown in Scheme 1 in order to investigate if AIHB complexes between protonated

Hme+ moieties are stable and how they compare with me···me and Hme+···me dimers with neutral ones, using both energetic and Bader’s AIM analysis. Moreover, we have also investigated the influence of the counter-anion by using formate as a model of the anion in the calculations.

26 ACS Paragon Plus Environment

Page 26 of 39

Page 27 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Scheme 1. Complexes 1–7 studied in this work. The optimized geometries and interaction energies along with the distribution of critical points and bond paths for complexes 1–4 are given in Figure 10. The me H-bonded dimer presents a moderately strong interaction energy of ∆E1 = –11.4 kcal/mol, indicating that each H-bond contributes N–H···N in 5.5 kcal/mol with an equilibrium distance of 1.96 Å. In case that one melamine moiety is protonated (complex 2, see Figure 10b) the interaction energy significantly strengthens (∆E2 = –16.0 kcal/mol) because of the higher acidity of the H atoms of the NH2 group belonging to Hme+ moiety. Moreover, this H-bond distance shortens to 1.63 Å and the other H-bond (NH2 donor group belongs to the neutral me) enlarges to 2.08 Å, see Figure 10b. Remarkably, for both binding modes computed for the Hme+···Hme+ dimers (complexes 3 and 4) we have found stationary points (local minima) that are 36.6 kcal/mol and 35.0 kcal/mol (for 3 and 4, respectively) higher in energy that the separate monomers, but kinetically stable. The equilibrium distances for these dimers are similar to those found in the X27 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ray structures. In, complex 4, in which the positive charges are more separated is 1.6 kcal/mol more stable. The distribution of critical points and bond path reveals that each dimer is characterized by the presence of two bond CPs and bond paths interconnecting the N and H atoms. Moreover, a ring critical point is also generated due to the formation of a supramolecular ring. The charge density at the bond critical points is a good measure of the strength of the interaction. It is interesting to note that the neutral complex 1 and the AEHB complex 3 present very similar values of ρ(r) at the bond critical points (values in italics in Figure 9). Therefore, in spite of the difference in binding energies, the strength of the H-bond is similar in both systems.

Figure 10. Optimized structures of complexes 1–4. Distribution of bond and ring critical points (green and yellow spheres, respectively) and bond paths are also indicated. The density at the bond critical points are given in italics (a.u.). Distances (Å) are given in blue.

Finally, we have also analyzed the effect of the counterion in the binding energies, as it is shown in Figure 11. For the Hme+···me dimer the interaction energy is significantly reduced to ∆E5 = –10.8 kcal/mol when the formate counter-ion is present. Interestingly, the presence of the counterion has a huge effect of the Hme+···Hme+ dimers (complexes 6 and 7), where the strong effect of the Coulombic repulsion is minimized by the presence of the H-bonded formate anions. In addition, the interaction energies are similar to that found for the neutral me···me dimer and also the equilibrium distances. The density values at the bond critical points are also similar to that shown in Figure 10 28 ACS Paragon Plus Environment

Page 28 of 39

Page 29 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

for the me···me complex 1, which is also an indication that the H-bond itself is not influenced by the cationic nature of the monomer. This strongly agrees with recent studies on AEHB in anionic species29 that demonstrated that the contribution of the hydrogen bond to the dissociation energy of the anion–anion H-bonded complex resembles that of the neutral complexes. All these results reveal that the ionic character of the molecules has no significant influence on the nature of the hydrogen bond.

Figure 11. Optimized structures of complexes 5–7. Distribution of bond and ring critical points (green and yellow spheres, respectively) and bond paths are also indicated. The density at the bond critical points are given in italics (a.u.). Distances (Å) are given in blue.

CONCLUSIONS Three novel salt cocrystals (I-III) based on melamine and glycolic or mandelic acid were prepared. This study demonstrates that hydrogen bond interactions between melamine and the other molecules can force melamine to crystallise in layers. In summary, three very intricate hydrogen bonded networks are observed in those compounds. The hydrogen bonds and electrostatic interactions of the partly deprotonated acids with the protonated and/or neutral melamine generate twodimensional layers of [(Hme+)·(Hga−)]·1/2H2O, a three-dimensional double-layer of [(Hme+)·(Hma−)]·diox·2H2O, +

and

a

zigzag

(herringbone)

double-layer

of



[(Hme )·(Hma )]·(me)·DMSO·3H2O, respectively. Furthermore, it has been shown that solvent inclusion is possible in melamine crystal structures and that it plays a very 29 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 39

important role in the formation of a layered arrangement of melamine molecules. Nevertheless, the influence of the counter-ion seems to be more important when strong N−H···O interactions are considered. Synthons involving  8 interactions are favourable for the formation of doubly hydrogen-bonded complexes but other synthons can be taken into account for the formation of cocrystals of these compounds as well. Results also show that the π–π stacking interactions between the 1,3,5-triazine rings contribute to their overall three-dimensional packing. The analysis of dnorm-mapped Hirshfeld Surfaces of melamine at different protonation states (me, Hme+) allowed to establish strongly characteristic protonation-dependent features of those surfaces, which are especially reflected in peculiar characteristics of associated Fingerprint Plots (FPs). Our findings on FP plots of me, Hme+ species have been general, as corroborated by the analysis of the literature precendents; our observations have been extended to

H2me2+ species. We have used theoretical DFT study to characterize the antielectrostatic H-bonds that are formed in compound I and II and we have shown that the nature of the H-bond is similar in neutral me···me and charged Hme+···Hme+ complexes.

ASSOCIATED CONTENT SUPPORTING INFORMATION Supporting information available: Additional figures of 2D fingerprint plots, analysis of FT-IR spectra, analysis of TGA/DSC results, and comparison of experimental and calculated PXRD patterns for the compounds.

Accession Codes The structures were deposited at the Cambridge Crystallographic Data Centre with CCDC Nos. 1011489 (I), 1580155 (III) and 1580156 (II). These data can be obtained free

of

charge

via

www.ccdc.cam.ac.uk/data_request/cif,

or

by

emailing

[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes 30 ACS Paragon Plus Environment

Page 31 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

The authors declare no competing financial interest.

AUTHOR INFORMATION Corresponding Author *A. Castiñeiras, e-mail address: [email protected], Tel.: +34 88181 4951; fax: +34 88181 5090.

ORCID Alfonso Castiñeiras: https://orcid.org/0000-0002-5070-5936 Isabel García-Santos: https://orcid.org/0000-0001-6779-0359 Antonio Bauzá: https://orcid.org/0000-0002-5793-781X Juan Niclós-Gutiérrez: https://orcid.org/0000-0002-8882-640X Antonio Frontera: https://orcid.org/0000-0001-7840-2139

ACKNOWLEDGEMENTS Financial support from the Network of Excellence “Metal Ions in Biological Systems” MetalBio CTQ15-71211-REDT (Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016). AB and AF thank the MINECO/AEI of Spain (projects CTQ2014-57393-C2-1-P and CTQ2017-85821-R, FEDER funds) for financial support. JKZ acknowledges financial support from the Faculty of Chemistry, Wrocław University of Science and Technology. JKZ is also supported by the Foundation for Polish Science (FNP).

31 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

REFERENCES (1)

de J. Velásquez-Hernández, M.; Torres-Huerta, A.; Martínez-Otero, D.;

Sánchez-González, E.; Hernández-Balderas, U.; Ibarra, I. A.; Jancik, V. Structural Modularity of Unique Multicomponent Hydrogen-Bonded Organic Frameworks Based on Organosilanetriols and Silanediols as Molecular Building Blocks. Cryst. Growth Des. 2018, DOI: 10.1021/acs.cgd.8b00030 (2)

Lombard, J.; Loots, L.; le Roex, T.; Haynes, D. A. Formation of multi-

component crystals with a series of pyridinium-carboxyacrylate zwitterions. CrystEngComm 2018, 20, 25-34. (3)

Stokes, S. P.; Seaton, C. C.; Eccles, K. S.; Maguire, A. R.; Lawrence, S. E.

Insight into the mechanism of formation of channel hydrates via templating. Cryst. Growth Des. 2014, 14, 1158-1166. (4)

Lemmerer, A.; Adsmond, D. A.; Esterhuysen, C.; Bernstein, J. Polymorphic co-

crystals from polymorphic co-crystal formers: Competition between carboxylic acid⋯pyridine and phenol⋯pyridine hydrogen bonds. Cryst. Growth Des. 2013, 13, 3935-3952. (5)

Das, B. Screening of multicomponent crystals of l-tryptophan with three isomers

of pyridinedicarboxylic acids. J. Cryst. Growth 2016, 447, 67-72. (6)

Tenorio Clavijo, J. C.; Guimarães, F. F.; Ellena, J.; Martins, F. T. Isostructurality

and the conformational role of the 2′,3′-moieties in the diversity of lamivudine crystal forms probed in halide salts. CrystEngComm 2015, 17, 5187-5194. (7)

Sinha, A. S.; Maguire, A. R.; Lawrence, S. E. Cocrystallization of nutraceuticals.

Cryst. Growth Des. 2015, 15, 984-1009. (8)

Martins, I. C. B.; Sardo, M.; Santos, S. M.; Fernandes, A.; Antunes, A.; André,

V.; Mafra, L.; Duarte, M. T. Packing Interactions and Physicochemical Properties of Novel Multicomponent Crystal Forms of the Anti-Inflammatory Azelaic Acid Studied by X-ray and Solid-State NMR. Cryst. Growth Des. 2016, 16, 154-166. (9)

Domingos, S.; Fernandes, A.; Duarte, M. T.; Piedade, M. F. M. New

Multicomponent Sulfadimethoxine Crystal Forms: Sulfonamides as Participants in Supramolecular Interactions. Cryst. Growth Des. 2016, 16, 1879-1892. (10)

Diniz, L. F.; Carvalho, P. S.; De Melo, C. C.; Ellena, J. Reducing the

Hygroscopicity of the Anti-Tuberculosis Drug (S,S)-Ethambutol Using Multicomponent Crystal Forms. Cryst. Growth Des. 2017, 17, 2622-2630.

32 ACS Paragon Plus Environment

Page 32 of 39

Page 33 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

(11)

Bolla, G.; Nangia, A. Multicomponent ternary cocrystals of the sulfonamide

group with pyridine-amides and lactams. Chem. Commun. 2015, 51, 15578-15581. (12)

Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals;

Food and Drug Administration: Silver Spring, MD, December 2011. (13)

Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.;

Choudhury A. R.; ... Zaworotko, M. J. Polymorphs, Salts, and Cocrystals: What’s in a Name?. Cryst. Growth Des. 2012, 12, 2147−2152. (14)

Grothe, E.; Meekes, H.; Vlieg, E.; ter Horst, J. H.; de Gelder, R. Solvates, Salts,

and Cocrystals: A Proposal for a Feasible Classification System. Cryst. Growth Des.

2016, 16, 3237−3243. (15)

Desiraju, G. R. Crystal Engineering: From Molecule to Crystal. J. Am. Chem.

Soc. 2013, 135, 9952−9967. (16)

Atkinson, I. M.; F. Lindoy, L. Intermolecular Interactions: The Guide of

Supramolecular Chemistry. In Self Assembly in Supramolecular Systems, RSC: Cambridge, UK, 2001; pp. 7-18. (17)

Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering. A Textbook,

World Scientific Publishing: Singapore, 2011; pp. 32-38. (18)

Merz, K.; Vasylyeva, V. Development and boundaries in the field of

supramolecular synthons. CrystEngComm. 2010, 12, 3989−4002. (19)

Zhang, X.-L.; Ye, B.-H.; Chen, X.-M. Infinite Water Chains Trapped in an

Organic Framework Constructed from Melamine with 1,5-Naphthalenedisulfonic Acid via Hydrogen Bonds. Cryst. Growth Des. 2005, 5, 1609-1616. (20)

SeethaLekshmi, S.; Guru Row, T. N. Propensity of formation of zipper

architecture vs. Lincoln log arrangement in solvated molecular complexes of melamine with hydroxybenzoic acids. CrystEngComm 2011, 13, 4886–4894. (21)

Perpétuo, G. J.; Janczak, J. Supramolecular architectures in crystals of melamine

and aromatic carboxylic acids. J. Mol. Struct. 2008, 891, 429–436. (22)

Sarma, B.; Nath, N. K.; Bhogala, B. R.; Nangia, A. The Role of π-Stacking in

the Composition of Phloroglucinol and Phenazine Cocrystals. Cryst. Growth Des. 2009, 9, 1546−1557. (23)

Kass, S. R. Zwitterion−Dianion Complexes and Anion−Anion Clusters with

Negative Dissociation Energies. J. Am. Chem. Soc. 2005, 127, 13098–13099.

33 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(24)

Page 34 of 39

Mata, I.; Alkorta, I.; Molins, E.; Espinosa, E. Electrostatics at the Origin of the

Stability

of

Phosphate-Phosphate

Complexes

Locked

by

Hydrogen

Bonds.

ChemPhysChem 2012, 13, 1421–1424. (25)

Mata, I.; Alkorta, I.; Molins, E.; Espinosa, E. Tracing environment effects that

influence the stability of anion–anion complexes: The case of phosphate–phosphate interactions. Chem. Phys. Lett. 2013, 555, 106–109. (26)

Weinhold, F.; Klein, R. A. Anti‐Electrostatic Hydrogen Bonds. Angew. Chem.

Int. Ed. 2014, 53, 11214–11217 (27)

Mata, I.; Alkorta, I.; Molins, E.; Espinosa, E. The Paradox of Hydrogen-Bonded

Anion–Anion Aggregates in Oxoanions: A Fundamental Electrostatic Problem Explained in Terms of Electrophilic···Nucleophilic Interactions. J. Phys. Chem. A 2015, 119, 183–194. (28)

Frenking, G.; Caramori, G. F. No need for a re-examination of the electrostatic

notation of the hydrogen bonding: a comment. Angew. Chem., Int. Ed. 2015, 54, 2596– 2599. (29)

Alkorta, I.; Mata, I.; Molins, E.; Espinosa, E. Charged versus Neutral Hydrogen-

Bonded Complexes: Is There a Difference in the Nature of the Hydrogen Bonds? Chem.–Eur. J. 2016, 22, 9226–9234. (30)

Sheldrick, G. M., SADABS, Program for Empirical Absorption Correction of

Area Detector Data. University of Göttingen, Germany, 2001. (31)

Sheldrick, G. M., Acta Crystallogr. Sect. A: Found. Adv. 2015, 71, 3–8.

(32)

Brandenburg, K.; Putz, H., Diamond, version 3.2, Crystal Impact GbR: Bonn,

Germany, 2009 (33)

Spackman, M. A.; Jayatilaka, D. Hirshfeld surface analysis. CrystEngComm

2009, 11, 19-32. (34)

Ahlrichs, R.; Bär, M.; Hacer, M.; Horn, H.; Kömel, C. Electronic structure

calculations on workstation computers: The program system turbomole. Chem. Phys. Lett. 1989, 162, 165–169. (35)

Boys, S. B.; Bernardi, F. The calculation of small molecular interactions by the

differences of separate total energies. Some procedures with reduced errors. Mol. Phys.

1970, 19, 553–566. (36)

AIMAll (Version 13.05.06), Todd A. Keith, TK Gristmill Software; Overland

Park, KS, USA, 2013.

34 ACS Paragon Plus Environment

Page 35 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

(37)

Bader, R. F. W. A quantum theory of molecular structure and its applications.

Chem. Rev. 1991, 91, 893–928. (38)

Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.

Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Jr. Montgomery, J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009. (39)

Froschauer, B.; Weil, M. Melaminium hydrogen malonate, Acta Crystallogr.

Sect. E: Cryst. Comm. 2012, 68, o2553-o2554. (40)

Du, Zi-Y.; Zhao, C.-C.; Zhou, Z.-G.; Wang, K.-J. Two intricate hydrogen-

bonded networks formed by m-sulfophenylphosphonic acid, melamine, and water molecules. J. Mol. Struct. 2013, 1035, 183-189. (41)

Childs, S. L.; Stahly, G. P.; Park, A. The Salt−Cocrystal Continuum:  The

Influence of Crystal Structure on Ionization State. Mol. Pharm. 2007, 4, 323–338. (42)

Bhogala, B. R.; Basavoju, S.; Nangia, A. Tape and layer structures in cocrystals

of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals. CrystEngComm 2005, 7, 551–562. (43)

Banerjee, S.; Bhanja, S. K.; Chattopadhyay, P. K. Quantum chemical predictions

of aqueous pKa values for OH groups of some a-hydroxycarboxylic acids based on ab initio and DFT calculations. Comput. Theor. Chem. 2018, 1125, 29–38 (44)

Cruz-Cabeza, A. J. Acid–base crystalline complexes and the pKa rule.

CrystEngComm 2012, 14, 6362−6365. (45)

Cerreia Vioglio, P.; Chierotti, M. R., Gobetto, R. Pharmaceutical aspects of salt

and cocrystal forms of APIs and characterization challenges. Adv. Drug Deliv. Rev.

2017, 117, 86–110.

35 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(46)

Aakeröy, C. B.; Rajbanshi, A.; Jane Li, Z.;. Desper, J. Mapping out the synthetic

landscape for re-crystallization, co-crystallization and salt formation. CrystEngComm

2010, 12, 4231–4239. (47)

McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Towards quantitative analysis

of intermolecular interactions with Hirshfeld surfaces. Chem. Commun. 2007, 37, 38143816. (48)

Pietrzak, A.; Modranka, J.; Wojciechowski, J.; Janecki, T.; Wolf, W. M.

Topology of Ladder Supramolecular Assemblies in Azahetorocyclic Phosphonates: A Structural and Computational Approach. Cryst. Growth Des. 2018, 18, 200-209. (49)

Chhetri, P. M.; Yang, X. K.; Chen, J. D. Solvent-Mediated Reversible Structural

Transformation of Mercury Iodide Coordination Polymers: Role of Halide Anions. Cryst. Growth Des. 2017, 17, 4801-4809. (50)

Hayati, P.; Suárez-García, S.; Gutiérrez, A.; Molina, D. R.; Morsali, A.;

Rezvani, A. R. Sonochemical synthesis of a novel nanoscale 1D lead(II) [Pb2(L)2(I)4]n coordination Polymer, survey of temperature, reaction time parameters. Ultrason. Sonochem. 2018, 42, 320-326. (51)

Hayati, P.; Gutiérrez, A. The role of non-covalent interactions on

supramolecular assembly of coordination compounds of mercury(II) based on substituted pyridine mixed ligands. A survey of different conditions on morphology of new flower and ribbon like submicro structures. Inorg. Chim. Acta 2018, 479, 83-96. (52)

Bulut, A.; Worle, M.; Zorlu, Y.; Kirpi, E.; Kurt, H.; Zubieta, J.; Grabowsky, S.;

Beckmann, J.; Yucesan, G. A potential Cu/V-organophosphonate platform for tailored void spaces via terpyridine mold casting. Acta Crystallogr. Sect. B: Struct. Sci. 2017, 73, 296-303. (53)

Banik, R.; Roy, S.; Kirillov, A. M.; Bauza, A.; Frontera, A.; Rodríguez-Diéguez,

A.; Salas, J. M.; Maniukiewicz, W.; Das, S. K.; Das, S. Two mixed-ligand cadmium(II) compounds bearing 5-nitrosopyrimidine and N-donor aromatic blocks: Self-assembly generation, structural and topological features, DFT studies, and Hirshfeld surface analysis. CrystEngComm 2016, 18, 5647-5657. (54)

Banik, R.; Roy, S.; Dlháň, Ľ.; Titiš, J.; Boča, R.; Kirillov, A. M.; Martin, A. D.;

Bauza, A.; Frontera, A.; Rodríguez-Diéguez, A.; Salas, J. M.; Das, S. Self-assembly synthesis, structure, topology, and magnetic properties of a mononuclear Fe(III)violurate derivative: A combined experimental and theoretical study. Dalton Trans.

2016, 45, 16166-16172. 36 ACS Paragon Plus Environment

Page 36 of 39

Page 37 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

(55)

Schütrumpf, A.; Bulut, A.; Hermer, N.; Zorlu, Y.; Kirpi, E.; Stock, N.;

Yazaydın, A. Ö.; Yücesan, G.; Beckmann, J. From Tetrahedral Tetraphosphonic Acids E[p-C6H4P(O)(OH)2]4 (E=C, Si) to Porous Cu- and Zn-MOFs with Large Surface Areas. ChemistrySelect 2017, 2, 3035-3038. (56)

Białek, M. J.; Zaręba, J. K.; Janczak, J.; Zoń, J. Chains, layers, channels, and

more: Supramolecular chemistry of potent diphosphonic tectons with tuned flexibility. the generation of pseudopolymorphs, polymorphs, and adducts. Cryst. Growth Des.

2013, 13, 4039-4050. (57)

Mahmoudi, G.; Zaręba, J. K.; Gurbanov, A. V.; Bauzá, A.; Zubkov, F. I.;

Kubicki, M.; Stilinović, V.; Kinzhybalo, V.; Frontera, A. Benzyl Dihydrazone versus Thiosemicarbazone Schiff Base: Effects on the Supramolecular Arrangement of Cobalt Thiocyanate Complexes and the Generation of CoN6 and CoN4S2 Coordination Spheres. Eur. J. Inorg. Chem. 2017, 4763-4772. (58)

Mahmoudi, G.; Khandar, A. A.; Zaręba, J. K.; Białek, M. J.; Gargari, M. S.;

Abedi, M.; Barandika, G.; Van Derveer, D.; Mague, J.; Masoumi, A. The role of hydrogen bonding on supramolecular assembly of the mercury coordination compounds and final structure influenced by solvent effect. Inorg. Chim. Acta 2015, 429, 1-14. (59)

Janczak, J.; Perpetuo, G. J. Three-dimensional hydrogen-bonded framework in

bis(melamin-1-ium)

naphthalene-1,5-disulfonate

melamine

pentahydrate.

Acta

Crystallogr. Sect. C: Struct. Chem. 2008, 64, o91-o94. (60)

Zhang, X.-L.; Ye, B.-H., Chen, X.-M. Infinite Water Chains Trapped in an

Organic Framework Constructed from Melamine with 1,5-Naphthalenedisulfonic Acid via Hydrogen Bonds. Cryst. Growth Des. 2005, 5, 1609-1616. (61)

Marchewka, M. K.; Baran, J.,. Pietraszko, A; Haznar, A.; Debrus, S.; Ratajczak,

H. Crystal structure, vibrational spectra and nonlinear optical properties of new melaminium salt: 2,4,6-triamino-1,3,5-triazin-1,3-ium tartrate monohydrate. Solid State Sci. 2003, 5, 509-518. (62)

Janczak, J.; Perpetuo, G. J. Melaminium bis(4-hydroxybenzene-sulfonate)

dihydrate. Acta Crystallogr. Sect. C: Struct. Chem. 2001, 57, 873-875. (63)

Vella-Zarb, L.; Braga, D.; Guy Orpen, A.; Baisch, U. The influence of hydrogen

bonding on the planar arrangement of melamine in crystal structures of its solvates, cocrystals and salts. CrystEngComm 2014, 16, 8147-8159. (64)

Heine, A.; Gloe, K.; Doert, T. A New Supramolecular Assembly Formed by

Melamine and Sulfuric Acid. Z. Anorg. Allg. Chem. 2008, 634, 452‐456. 37 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(65)

Lipert, M. P.; Rodríguez-Hornedo, N. Cocrystal Transition Points: Role of

Cocrystal Solubility, Drug Solubility, and Solubilizing Agents. Mol. Pharmaceutics

2015, 12, 3535−3546. (66)

Elder, D. P.; Holm, R.; Lopez de Diego, H. Use of pharmaceutical salts and

cocrystals to address the issue of poor solubility. Int. J. Pharm. 2013, 453, 88-100. (67)

Cavanagh, K. L.; Maheshwari, Ch.; Rodríguez-Hornedo, N. Understanding the

Differences Between Cocrystal and Salt Aqueous Solubilities. J. Pharm. Sci. 2018, 107, 113-120. (68)

Kuminek, G.; Cao, F.; de Oliveira da Rocha, A. B.; Gonçalves-Cardoso, S.;

Rodríguez-Hornedo, N. Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5. Adv. Drug Delivery Rev. 2016, 101, 143–166. (69)

Prohens, R.; Portell, A.; Font-Bardia, M.; Bauzá, A.; Frontera, A. H-Bonded

anion–anion complex trapped in a squaramido-based receptor. Chem. Commun. 2018, 54, 1841-1844

38 ACS Paragon Plus Environment

Page 38 of 39

Page 39 of 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

For Table of Contents Use Only Multicomponent Supramolecular Assemblies of Melamine and αhydroxycarboxylic Acids: Understanding the Hydrogen Bonding Patterns and Their Physicochemical Consequences

Alfonso Castiñeiras, Isabel García-Santos, Josefa María González-Perez, Antonio Bauzá, Jan K. Zaręba, Juan Niclós-Gutiérrez, Rocío Torres, Esther Vílchez and Antonio Frontera

Synopsis Cocrystallization studies on 1,3,5-Triazine-2,4,6-triamine with two α-hydroxycarboxylic acids as conformers have led to the formation of three new salt-cocrystals with the coformers glycolic and mandelic acids. Studies on supramolecular assembly in terms of synthon formation and its influence on stability and solubility, energetic landscape and stabilization energies using density functional theory calculations and analysis of Hirshfeld Surfaces were made.

39 ACS Paragon Plus Environment