NiII-SnIV cocrystals.

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DOI: 10.1039/C6DT03118H

Susanta Hazra,a,* Ricardo Meyrelles,a Adilia Januário Charmier,a,b Patrícia Rijo,c,d M. Fátima C. Guedes da Silvaa,* and Armando J. L. Pombeiroa,*

a Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049–001 Lisbon, Portugal. E-mail: [email protected]; [email protected] and [email protected] b

ULHT, Universidade Lusófona, Campo Grande 376, Lisbon, 1749–024, Portugal

c Center for Research in Biosciences and Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias,1749–024 Lisboa, Portugal d

Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649–003 Lisboa, Portugal

†Electronic Supplementary Information (ESI) available. Schemes S1 and S2. Tables S1 and S2. Figs. S1–S4. CCDC 1497747–1497750 for 1–4, respectively, contain the supplementary crystallographic data for this paper. For ESI and crystallographic data in CIF or other electronic format see the internet at www.rsc.org. These CIF data can also be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

1

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Published on 12 October 2016. Downloaded by Cornell University Library on 14/10/2016 21:37:10.

N–H···O and N–H···Cl Supported 1D Chains of Heterobimetallic CuII/NiII– SnIV Cocrystals†

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DOI: 10.1039/C6DT03118H

Abstract The Schiff base H2L1 [N,N-ethylenebis(3-methoxysalicylaldimine)] or H2L2 [N,Nethylenebis(3-ethoxysalicylaldimine)] was reacted with MCl2·xH2O and SnCl4·5H2O to afford L2 (2); M = Ni, L = L1 (3), L = L2 (4); ED = 1,2-ethylenediamine], whose structures were established by single crystal X-ray analyses. Each structure includes different entities, viz. a mononuclear [CuL]/[NiL] neutral complex (coformer), a hexachlorostannate dianion [SnCl6]2–, a 1,2-ethylenediammonium dication (H2ED2+) and, only in 2 and 4, a methanol molecule. Based on the work by Grothe et al. (Cryst. Growth Des., 2016, 16, 3237–3243), compounds 1 and 3 are cocrystal salts, 2 and 4 are cocrystal salt solvates. The ionic pairs (H2ED)2+·[SnCl6]2– in 1–4 are encapsulated by the Cu- or Ni-complexes, and stabilized by N–H···O and one N–H···Cl bond interactions leading to infinite 1D chains. The antimicrobial studies of 1–4 against yeasts (C. albicans and S. cerevisiae) and Gram-positive (S. aureus and E. faecalis) and -negative bacteria (P. aeruginosa and E. coli) indicate that the Ni2Sn systems (3 and 4) are more active than the analogous Cu2Sn ones (1 and 2).

Introduction Heterometallic compounds1 have a growing significance in modern synthetic chemistry for their diverse solid state structures2 and varieties of magnetic3,4 and catalytic1b,c,5 properties. Based on the number of different metal ions, they can be heterobi-,2–5 heterotri-5d,e,6 or heterotetrametallic7 compounds. The most abundant group is the heterobimetallic one which can be divided into several classes such as 3d-s, 3d-3d, 3d-p, 3d-f etc.2–5 The coordination chemistry of heterobimetallic 3d-3d systems is richer than all others while the second position is occupied by 3d-4f block compounds which are getting much interest for the slow magnetic relaxation.4 However, the 3d-p block compounds, being one of the less investigated heterometallic systems, could also be rather interesting for their versatile solid state structures. For example, the limited number of reported 3d–Sn systems8,9 has a considerable variety of structures (cocrystals, saltcocrystals and salts), which encourages us to synthesize new heterometallic 3d-Sn systems. Crystal engineering, defined by Desiraju10 as "the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in the 2



the supramolecular heterobimetallic systems (H2ED)2+·2[ML]·[SnCl6]2– [M = Cu, L = L1 (1), L =

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design of new solids with desired physical and chemical properties", mainly relies on noncovalent interactions (e.g., H-bonding, π···π interactions etc.) to achieve a targeted compound. For example, multicomponent crystals, which are important for pharmaceuticals,11 engineering, particularly in organic chemistry. Until recently, multicomponent crystals14–17 could be divided into three major types: a) salts14,15- assembly of two ionic species, b) cocrystals14,16formed by two or more neutral species, and c) solvates14b- as a combination of a solvent molecule and a coformer. Seven other subclasses, which include cocrystal solvate, cocrystal salt and cocrystal salt solvate, are also defined by Grothe et al.14b These species are well known for organic chemistry and recently getting attention in inorganic chemistry as well.14–17 Lately, through a Cambridge Structural Database consultation, a wider seven-membered classification method for multicomponent crystals was proposed,14b based on the type of species in the crystals, which resolves the problem of overlapping classes in the aforementioned classification. Some of us have reported the structural diversity of heterobimetallic CuII–SnII/IV systems obtained from the reactions of the mononuclear complex [CuL1(H2O)] or [CuL2(H2O)] with dichlorodiorganotin(IV) compounds [H2L1 = N,N-ethylenebis(3-methoxysalicylaldimine) and H2L2 = N,N-ethylenebis(3-ethoxysalicylaldimine)].9c The majority of them are stabilized by several non-covalent interactions (O–H···O / N–H···O / N–H···Cl / Cu···Cl / ···),9c and the variety in their crystal structures inspired us to extend this type of non-covalent interactions rich chemistry. We anticipate that using inorganic tin(IV) salts (SnCl4·5H2O), instead of organotin(IV) ones,9c and applying a different synthetic technique (such as the self-assembly reaction of the pro-ligand with metal salts, Scheme S1, Electronic Supplementary Information) might produce structures with relevance for crystal engineering and supramolecular chemistry. Accordingly, we have reacted the Schiff base H2L1 or H2L2 with CuCl2·2H2O or NiCl2·6H2O and SnCl4·5H2O and successfully isolated the supramolecular heterobimetallic 3d–SnIV systems (H2ED)2+·2[CuL1]·[SnCl6]2–

(1),

(H2ED)2+·2[CuL2]·[SnCl6]2–·2MeOH

(2),

(H2ED)2+·2[NiL1]·[SnCl6]2– (3) and (H2ED)2+·2[NiL2]·[SnCl6]2–·2MeOH (4) (ED = 1,2ethylenediamine) (Scheme 1), with compounds 1 and 3 being cocrystal salts, and 2 and 4 cocrystal salt solvates, according to the most recent classification.14b Schiff base metal complexes are also becoming important for their considerable antifungal, antibacterial and antitumor activities.18,19 A number of studies showed their effective 3



nonlinear optical materials,12 and charge-transfer solids,13 can be designed applying crystal

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and selective antimicrobial activity against bacteria, fungi and virus.18 To our knowledge, heterometallic 3d–SnII/IV systems have never been tested for such biological studies. In the present work, the new supramolecular heterobimetallic systems 1–4 and the corresponding Schiff test followed by a comparative study of minimum inhibitory concentration (MIC) and minimum bactericidal concentration tests (MBC) methods.19 The antibacterial activities were tested against the Candida albicans and S. cerevisiae yeasts, as well as against the Gram-positive (S. aureus and E. faecalis) and -negative (P. aeruginosa and E. coli) bacteria.

Results and discussion Synthesis and characterization The

Schiff

base

N,N-ethylenebis(3-methoxysalicylaldimine)

(H2L1)

or

N,N-

ethylenebis(3-ethoxysalicylaldimine) (H2L2) (Scheme 1) was synthesized by condensing the 3methoxy- or 3-ethoxysalicylaldehyde with 1,2-ethelenediamine (2:1) in methanol following published procedures.9c,20 The compounds were characterized by IR and NMR techniques, the obtained data matching the reported ones.2i,j,9c,20 The self-assembly reactions of H2L1 or H2L2 with MCl2·xH2O and SnCl4·5H2O in methanol under open atmosphere and room temperature (Scheme 1) produce the supramolecular heterobimetallic systems (H2ED)2+·2[ML]·[SnCl6]2– [M = Cu, L = L1 (1), L = L2 (2); M = Ni, L = L1 (3), L = L2 (4); ED = 1,2-ethylenediamine; 2 and 4 also with methanol of crystallization]. Compounds 1–4 were initially isolated in 30–35% yields (based on the amount of SnCl4·5H2O) when the Schiff bases (H2L1 or H2L2) and the metal salts (MCl2·xH2O) and SnCl4 were mixed in 1:1:1 ratio. But their yields increase to 51–59% with a lower amount of tin(IV) salt (2:2:1). A fractional amount of the Schiff base is hydrolyzed in the self-assembly reaction (Scheme S1, ESI) medium to generate the 1,2-ethylenediammonium cation (H2ED2+),9c which can account for the lower yields obtained for 1–4. Several attempts to prepare the compounds 1–4 by simply mixing the pro-ligand, the metal salts (CuII/NiII and SnIV) and 1,2-ethylenediammine dihydrochloride (ED.2HCl) were not successful.

4



bases H2L1 and H2L2 were screened for antibacterial activity using a disk diffusion susceptibility

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The IR spectra of 1–4 exhibit a medium intense absorption band in the 1633–1644 cm–1 range due to ν(C=N). They were also characterized by elemental analyses and single crystal X-

Scheme 1 Synthesis of 1–4. R = Me (H2L1), M = Cu and x = 2 for 1; R = Et (H2L2), M = Cu and x = 2 for 2; R = Me (H2L1), M = Ni and x = 6 for 3; R = Et (H2L2), M = Ni and x = 6 for 4.

Description of crystal structures Idealized ball and stick representations of the crystal structures of the supramolecular heterobimetallic systems 1–4 are depicted in Fig. 1. Selected geometric values are included in Table 1. Single crystal X-ray diffraction analysis reveals that the pairs of compounds 1 and 3, and 2 and 4 are isostructural, the former pair include three components cocrystal salts, and the latter four components cocrystal salt solvates.9c,14,17 Their unit cells comprise two copper or 5



ray diffraction studies.

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nickel coformers, one hexachlorostannate dianion [SnCl6]2–, one 1,2-ethylenediammonium dication H2ED2+ {(H3NCH2CH2NH3)2+} and, only in 2 and 4, two methanol molecules. Both the copper and the nickel cations present slightly distorted square-planar N2O2 roughly octahedral with quadratic elongations of 1.00 and angle variances of (3.89º)2, (0.78º)2, (2.82º)2 and (0.65º)2 for 1–4, respectively.21b The salicylaldimine ligands are not planar being more distorted in 1 and 3 than in 2 and 4, as indicated by the angles between the least square planes of their phenyl rings (ca. 19º in the former pair and 5–8º in the latter; Table 1). Therefore, although deviations are not severe, compounds 1 and 3 are the ones with least planar L ligands and less ideal coordination geometries. Moreover, while the methoxide groups in 1 and 3 are in the planes of the attached aromatic rings, the ethoxides in 2 and 4, are highly twisted from the global plane of the ligand, as evidenced by the CarOCethoxoCethoxo torsion angles (absolute values) in the 74 – 86º range. The MNimine and MOphenoxo bonds for 1 and 2 are longer than those in 3 and 4 (Table 1), thus following the trend of the ionic radii of the copper and nickel dications (0.73 and 0.69 Å, respectively). In every [SnCl6]2+ entity the Sn–Cl bonds differ by 0.042 – 0.093 Å, with the longest one being involved in N–H···Cl contacts and the medium one in Cu/Ni···Cl interactions. Several features of the compounds of this study are comparable with those of previously reported compounds of general formula (H2ED)2+·2[CuL]·[(R1)2SnCl4]2– [L = L1 or L2; R1 = Me, Et, n-Bu and Ph],9c which are cocrystal salts or cocrystal salt solvates containing tetrachlorodiorganostannate dianions instead of hexachlorostannate.

1

2 6



geometries [4 values of 0.14 (1), 0.08 (2), 0.10 (3) and 0.07 (4)],21a while the SnIV cations are

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3

4

Fig. 1 Idealized ball and stick presentations of the crystal structures of 1–4. Symmetry: i) 1–x,1– y,1–z (for 1–3) and 1–x,1–y,–z (for 4).

Table 1 Comparison of some selected bond distances (Å) and angles (º) in complexes 1–4 1 2 In the Schiff base ligand 1.268(7) 1.276(4) 1.272(7) 1.277(4)

3

4

1.273(8) 1.289(8)

1.276(4) 1.283(4)

19.17

19.08

5.11

Surrounding the metal centres 1.937(5) 1.938(2) 1.937(4) 1.941(2) 1.907(3) 1.9115(19) 1.907(4) 1.915(2) 3.407 3.454 2.367(2) 2.4086(8) 2.4359(19) 2.4266(7) 2.4509(17) 2.4555(7) 173.11(19) 174.95(9) 167.80(18) 173.14(9) 125.50 144.57

1.851(5) 1.842(5) 1.862(4) 1.871(4) 3.682 2.3805(19) 2.4075(19) 2.4736(15) 173.7(2) 172.7(2) 121.51

1.853(2) 1.856(2) 1.8666(17) 1.8736(18) 3.589 2.4129(7) 2.4195(6) 2.4546(6) 176.70(8) 176.69(8) 141.84

3.911

4.087

3.757

3.840

displacement of M from N2O2 basal plane

0.049

0.015

0.008

0.001

Displacement of Nammonium from l.s. plane of ligand O4 cavity

0.143

0.619

0.211

0.745

C=N  between the l.s. planes of the aromatic rings MNimine MOphenoxo M····Cl SnCl  NimineMOphenoxo  M···ClSn Intermolecular M···M (minimum)

8.49

7



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The coformers and the ionic species in 1–4 are interlinked through strong N–H···O and one N–H···Cl hydrogen bonds (Fig. 1 and Table S1, ESI). Two of the H-atoms of each ammonium group are oriented in such a way that they form bifurcated N–H···O bonds with the three component assembly (Fig. 2), while the remaining ammonium H-atoms interact with the chloride centers of the hexachlorostannate anion giving rise to an infinite 1D chain of (H2ED)2+ and [SnCl6]2– species (Fig. 3). Such contacts involving the diammonium entities result in a supramolecular 1D chain (Fig. 4) which, together with the non-covalent Cu or Ni···Cl interactions leads to the encapsulation of the ionic species in neutral Cu- or Ni-metalloligand pockets (Fig. 5). The structural analysis of the reported22 (H2ED)2+·[SnCl6]2– compound indicates that its non-covalent based supramolecular structural arrangement prevails upon encapsulation, as found in the present study. A representation of the encapsulation is shown in Fig. S1 (ESI) for better understanding.

Fig. 2 N–H···O supported supramolecular dimer in 1–4. M = Cu (in 1 and 2) and Ni (in 3 and 4) while R = Me (1 and 3) and Et (2 and 4).

Fig. 3 N–H···Cl supported one dimensional chain of the ionic pair (H2ED)2+·[SnCl6]2– in 1–4.

8



phenoxo and the methoxo (or ethoxo) oxygen atoms of the Cu or Ni complex moiety to form a

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Fig. 4 One dimensional supramolecular associates in 1–4, supported by N–H···O and N–H···Cl hydrogen bonds and Cu/Ni···Cl weak interactions. M = Cu (in 1 and 2) and Ni (in 3 and 4) while R = Me (1 and 3) and Et (2 and 4). For their isolated 1D chains, see Fig. S2 (ESI).

Fig. 5 Encapsulation of the ionic pair (H2ED)2+·[SnCl6]2– 1D chain (Fig. 3) by the neutral [ML] complexes in 1–4. M = Cu (in 1 and 2) and Ni (in 3 and 4) while R = Me (in 1 and 3) and Et (in 2 and 4). Methanol molecules in 2 and 4 are omitted for clarity. For separate encapsulated figures of 1–4, see Fig. S3 (ESI).

Comparison with related compounds It is worth mentioning that several Schiff bases2,20,23–25 (H2L, Scheme S2, ESI) having single23 or double24 compartments were utilized to synthesize several types of heterometallic systems

including

a

few

heterometallic

nickel(II)/cobalt(III)/zinc(II)/oxovanadium(IV)–

tin(II)/tin(IV) ones.9 We have recently reported a few heterobimetallic copper(II)–tin(II/IV) 9



DOI: 10.1039/C6DT03118H

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DOI: 10.1039/C6DT03118H

systems (Table 2, Scheme S2, ESI),9c derived from two of such pro-ligands, H2L1 and H2L2 (Scheme 1). The crystal structures of three oxovanadium(IV)–tin(IV)9b and two nickel(II)– tin(IV)9a derived from H2L1 are also known. However, three other nickel(II)–tin(IV) derivatives9a H2L1, which were not structurally characterized, were synthesized from the reactions of [SnCl4] and [NiL1] using the metalloligand strategy6e,9 (Scheme S2) in acetonitrile or chloroform solution. Interestingly, those compounds9a are supposed to be two components cocrystals with a neutral [SnCl4] and one neutral [NiL1] moieties in contrast to our isolated compounds 3 and 4 which are three components salt cocrystals containing an ethylenediammonium dication (H2ED)2+, two mononuclear [NiL1] units and a hexachlorostannate dianion [SnCl6]2–. Using a different solvent (methanol) and a comparatively simplified (self-assembly) reaction procedure, which facilitate the dissociation of the pro-ligand to produce the ethylenediammonium cation, could be the reason behind the isolation of a different type of compounds in our cases. Searches made on the Cambridge Structural Database (CSD)25 reveal that the second cavity of a mononuclear [ML] complex can interact with a hydronium (H3O+),24h an ammonium (NH4+)24i,j or a diammonium moiety of alkylenediammonium cation (e.g., H2ED2+).24d Hence, a supramolecular [ML]·(H2ED)2+·[ML] assembly,24d as shown in Fig. 2, is known but the stabilization (Figs. 3–5) of a 1D chain of the (H2ED)2+·[SnCl6]2– adduct by mononuclear [ML] units as observed in 1–4 has never been reported. However, related types of interactions and stabilization (Fig. S4, ESI) of the (H2ED)2+·[(R1)2SnCl4]2– adduct were observed in the heterometallic cocrystal salts or cocrystals salt solvates (H2ED)2+·2[CuL]·[(R1)2SnCl4]2– (L = L1, R1 = Me, Et, n-Bu and Ph; L = L2, R1 = Ph; excluding the solvent of crystallization) reported by us.9c Despite being closely similar ligands (H2L1 and H2L2), their metal derivatives (homo- or heterometallic) are notably different in several cases.2a,9c In contrast, we have not observed any type of diversity in the current study, and even with different metal combinations (Cu in 1 and 2 vs Ni in 3 and 4), we obtained similar salt cocrystals 1–4. Interestingly, the structural diversity, shown by these two ligands in presence organotin(IV) salts,9c is not revealed while an inorganic tin(II/IV) salt (SnCl4 or SnCl2) is used either in the metalloligand9c or in the self-assembly reaction strategy (Scheme S1).

10



([SnCl4]·[NiL1]·H2O; 2[SnCl4]·[NiL1]·H2O and [SnCl4]·[Sn(OH)Cl3]·[NiL1]·H2O, Table 2) of

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Schiff Base

H2L1

H2L2

Compounds [Me2SnCl2]·[NiL ]·H2O 2[Me2SnCl2]·[NiL1]·H2O [Ph2SnCl2]·[NiL1]·H2O [(n-Bu)SnCl3]·[NiL1]·H2O [SnCl4]·[NiL1]·H2O 2[SnCl4]·[NiL1]·H2O [SnCl4]· [Sn(OH)Cl3]·[NiL1]·H2O [Me2SnCl2(H2O)]·[NiL1]·CHCl3 [Ph2SnCl2(H2O)]·[NiL1] [Ph2SnCl2(H2O)]· [(VO)L1(Ph2SnCl2)]·CH2Cl2 [(V=O)L1(Ph3SnCl)]·CH3CN [{V=O(H2O)}L1{Ph3SnCl}] (H2ED)2+·2[CuL1]·[SnMe2Cl4]2– (H2ED)2+·2[CuL1]·[SnEt2Cl4]2–·0.5H2O (H2ED)2+·2[CuL1]·[Sn(n-Bu)2Cl4]2– (H2ED)2+·2[CuL1]·[SnPh2Cl4]2– (H2ED)2+·2[CuL1]·[SnPh2Cl4]2–·2MeOH [CuL1SnCl]+·[SnCl3]– (H2ED)2+·2[CuL1]·[SnCl6]2– (H2ED)2+·2[NiL1]·[SnCl6]2– [CuL2]2·[SnMe2Cl2(H2O)2]·0.2H2O [CuL2]·[Sn(n-Bu)2Cl2(H2O)] (H2ED)2+·2[CuL2]·[SnPh2Cl4]2– [CuL2SnCl]+·[SnCl3]– (H2ED)2+·2[CuL2]·[SnCl6]2–·2MeOH (H2ED)2+·2[NiL2]·[SnCl6]2–·2MeOH 1

References 9a 9a 9a 9a 9a 9a 9a 9a 9a 9b 9b 9b 9c 9c 9c 9c 9c 9c This work This work 9c 9c 9c 9c This work This work

Antimicrobial studies Compounds 1–4 were screened for their antimicrobial activity by the well diffusion assay.18,19 The aim of this preliminary test was to identify the antimicrobial compounds comparing with the corresponding positive controls. The antimicrobial activity was evaluated against a large panel of microorganisms: Gram-positive and -negative bacteria and yeasts (Table 3). This primary test allowed to select the antimicrobial compounds for further evaluation of their minimum inhibitory concentrations (MICs) and minimum bactericidal concentration (MBC) values (or minimum fungicidal concentration – MFC) by the microdilution method 11


Table 2 List of heterometallic 3d-SnII/IV systems derived from H2L1 and H2L2

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(Table 4). All compounds (1–4), as well as the Schiff bases (H2L1 and H2L2) and the metal salts (SnCl4·5H2O, CuCl2·2H2O and NiCl2·6H2O), are active against the yeast Candida albicans while both the pro-ligands and all the metal salts inhibited the growth of the other yeast tested S. of inhibition zone against E. faecalis and S. aureus, respectively) as well as the Gram negative bacteria, P. aeruginosa (9 mm of inhibition zone), while NiCl2·6H2O only showed low inhibitory growth (7 mm of inhibition zone) against the Gram positive bacteria, S. aureus. Although some copper complexes are cited as antimicrobial agents, in this study the systems 1 and 2 did not show antimicrobial properties against the microorganisms tested.19e Considering the systems 1– 4, only the nickel(II) derivatives 3 and 4 were active against the microrganisms tested, what is in agreement with other described nickel complexes.19e,f Complex 3 showed positive results (8–14 mm of inhibition zone) against the Gram positive bacteria (E. faecalis and S. aureus) while derivative 4 was active against the Gram positive and the Gram negative bacteria tested (6–12 mm of inhibition zone; Table 3).

Table 3 Antimicrobial activity of the compounds obtained by the well diffusion method18d against Gram-negative and Gram-positive bacteria and yeasts strains (in mm) S. aureus Compound

E. faecalis

P. aeruginosa E. coli Zone of Inhibition / mm

na na H2L1 na 15 2 na na H2L 6 10 na na na na SnCl4·5H2O na CuCl2·2H2O 14 13 9 na na na NiCl2·6H2O 7 na na na na 1 na na na na 2 na na 14 8 3 10 6 6 12 4 Positive 35 / 16 / VAN 35 / NOR Control 18/ VAN NOR na – not active; VAN – Vancomycin; NOR – Norfloxacin; AMPH – Amphotericin B.

C. albicans

S. cerevisiae

33 26 6 20 20 15 23 18 15

26 22 6 9 12 na na na na

17 / AMPH

17 / AMPH

Considering the positive and promising results obtained by the well diffusion test screening (Table 3), the selected antimicrobial compounds were evaluated by the microdilution method and the MIC and MBC values were estimated (Table 4). All the tested compounds showed a low antimicrobial activity (156 to >5000 µg/mL) compared to the respective positive 12



cerevisiae. CuCl2·6H2O inhibited the growth of the Gram positive bacteria tested (13 and 14 mm

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controls (5000 nt >5000

156.2 312.5 nt nt

2500 2500 nt nt

312.5 312.5 625 315.5

1250 2500 1250 1250

625 312.5 312.5 156.2

2500 2500 2500 625

625 nt nt >5000 >5000 7.82 VAN

2500 nt nt 2500 2500 nt

nt nt nt 5000 nt

nt

nt – not tested; VAN – Vancomycin; NOR – Norfloxacin; AMPH – Amphotericin B.

On account of the promising antimicrobial studies performed in this study, further works on nickel complexes should be accomplished to obtain new approaches to improve antimicrobial chemotherapy and thus contribute to tackling antimicrobial resistance and discover novel antimicrobial agents.

Conclusions Two Schiff bases were used to synthesize four new supramolecular heterobimetallic 3d– SnIV systems (H2ED)2+·2[CuL1]·[SnCl6]2– (1), (H2ED)2+·2[CuL2]·[SnCl6]2–·2MeOH (2), (H2ED)2+·2[NiL1]·[SnCl6]2– (3) and (H2ED)2+·2[NiL2]·[SnCl6]2–·2MeOH (4) (ED = 1,2ethylenediamine). Single crystal X-ray diffraction analyses revealed that 1 and 3 are cocrystal salts, 2 and 4 are cocrystal salt solvates. An interesting outcome of the current investigation is the 13



no more than four times the MIC value, there is an evidence of bactericidal properties for all the

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entrapping of 1D chains of ionic pairs of (H2ED)2+·[SnCl6]2– by the coformer units in 1–4. Although several (ammonium)·[SnCl6]2– adducts can be found in the literature, a heterometallic system as the ones of this work was not yet known. tin(II)9c (SnCl2) or tin(IV) salt (SnCl4), instead of a organotin(IV) one,9c is used in either the metalloligand9c or in the self-assembly reaction mixtures. The antimicrobial studies showed that ligands, metal salts and all the systems 1–4 inhibit the growth of the yeast Candida albicans and the Ni2Sn systems (3 and 4) are more active than the analogous Cu2Sn ones (1 and 2). Moreover, 3 and 4 showed some similar antibacterial activity against the Gram positive bacteria (S. aureus and E. faecalis). Only 4 exhibits antimicrobial activity against all the tested bacteria strains and the yeast Candida albicans. This type of supramolecular heterobimetallic 3d–SnIV systems has been tested for the first time in antibacterial studies. In summary, a simple protocol for the synthesis of a series of supramolecular heterobimetallic CuII/NiII–SnIV systems, stabilized by non-covalent interactions (N–H···O / N– H···Cl / O–H···Cl / M···Cl), is presented. These compounds are of significance in crystal engineering and supramolecular chemistry, contributing to understand the stability of multicomponents inorganic compounds. Similar reactions towards the synthesis of other heterometallic cocrystals are underway.

Experimental section Materials and physical methods All the reagents and solvents were purchased from commercial sources and used as received. Methanol used in all the syntheses was analytical reagent grade. The Schiff base H2L1 or H2L2 was synthesized by condensing 3-methoxy- or 3-ethoxysalicylaldehyde with 1,2ethylendiamine following reported procedures.9c,20 NMR spectra of H2L1 and H2L2 were obtained on a Bruker 400 MHz spectrometer using tetramethylsilane [Si(CH3)4] as internal reference. FT-IR spectra of Schiff bases H2L1 and H2L2 and their metal complex derivatives 1–4 were recorded in the region 400–4000 cm–1 on a Bruker Vertex 70 spectrophotometer with 14



Another observation is the disappearance of the structural diversity while an inorganic

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samples as KBr disks; abbreviations: s = strong, m = medium, and w = weak. Elemental analyses

Syntheses Compounds 2 and 4 are prepared following the similar procedures used to prepare 1 and 3, respectively. (H2ED)2+·2[CuL1]·[SnCl6]2– (1). To a methanol suspension (15 mL) of H2L1 (0.082 g, 0.25 mmol) was added a methanol solution (2 mL) of CuCl2·2H2O (0.043 g, 0.25 mmol). To the resulted green solution a methanol solution (3 mL) of SnCl4·5H2O (0.044 g, 0.13 mmol) was added dropwise to obtain a brown solution which was kept at room temperature for slow evaporation. Within 1 d, the formed dark brown crystals, suitable for X-ray diffraction analysis, were collected by filtration and washed with cold methanol. Yield: 0.090 g (59%). Anal. calcd (%) for C38H46Cl6N6O8Cu2Sn (1173.33): C 38.90, H 3.95, N 7.16; found: C 38.99, H 4.89, N 7.22. FT-IR (cm–1, KBr): ν(C=N), 1638s. (H2ED)2+·2[CuL2]·[SnCl6]2–·2MeOH (2). Yield: 0.089 g (53%). Anal. calcd (%) for C44H62Cl6N6O10Cu2Sn (1293.51): C 40.86, H 4.83, N 6.50; found: C 40.72, H 4.87, N 6.46. FTIR (cm–1, KBr): ν(C=N), 1644s. (H2ED)2+·2[NiL1]·[SnCl6]2– (3). To an acetone suspension (15 mL) of H2L1 (0.082 g, 0.25 mmol) was added a methanol solution (5 mL) of NiCl2·6H2O (0.060 g, 0.25 mmol). To the resulted red solution a methanol solution (5 mL) of SnCl4·5H2O (0.088 g, 0.13 mmol) was added dropwise to obtain a brown solution which was kept at room temperature for slow evaporation. After 1 d, the formed dark brown crystals, suitable for X-ray diffraction analysis, were collected by filtration and washed with cold methanol. Yield: 0.086 g (57%). Anal. calcd (%) for C38H46Cl6N6O8Ni2Sn (1163.62): C 39.22, H 3.98, N 7.22; found: C 39.11, H 3.94, N 7.19. FT-IR (cm–1, KBr): ν(C=N), 1633s. (H2ED)2+·2[NiL2]·[SnCl6]2–·2MeOH (4). Yield: 0.085 g (51%). Anal. calcd (%) for C44H62Cl6N6O10Cu2Sn (1283.81): C 41.16, H 4.87, N 6.55; found: C 41.02, H 4.82, N 6.49. FTIR (cm–1, KBr): ν(C=N), 1639s. 15



were performed by the Microanalytical Service of the Instituto Superior Técnico.

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DOI: 10.1039/C6DT03118H

Crystal structure determination X-ray quality crystals of 1–4 were immersed in cryo-oil, mounted in a Nylon loop and measured at 298 (for 1 and 3) or 150 K (for 2 and 4). Intensity data were collected using a radiation. Cell parameters were obtained with Bruker SMART26a software and refined with Bruker SAINT26a on all the observed reflections. Absorption corrections were made by the multiscan method (SADABS).26a Structures were solved by direct methods by using the SHELXS2014 package26b and refined with SHELXL-2014/7.26b Calculations were performed using the WinGX System-Version 2014.1.26c The hydrogen atoms attached to carbon atoms were inserted at geometrically calculated positions and included in the refinement using the riding-model approximation, while those attached to nitrogen (in 1–4) or to oxygen atoms (in 2 and 4) were located in a difference Fourier synthesis and were included in the corresponding final refinements. The DFIX commands were applied to restrain the N–H (0.89 Å in 1–4) and O–H (0.84 Å in 2 and 4) contacts while the DANG commands were used to fix the geometry around hydroxyl group (-OH) of the methanol molecules in 2 and 4. Least square refinements with anisotropic thermal motion parameters for all the non-hydrogen atoms and isotropic ones for the remaining atoms were employed. Crystallographic data are summarized in Table S2.

Antimicrobial studies Microorganisms The antimicrobial activity was evaluated against four bacterial species obtained from the American Type Culture Collection (ATCC), namely Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and two yeasts strains Candida albicans ATCC 10231 and Saccharomyces cerevisiae ATCC 9763.

Well diffusion test18d The well diffusion assay was used to screen the compounds for their antimicrobial activity against Gram-positive and -negative bacteria and yeasts. At first, the solution of each 16



Bruker APEX II SMART CCD diffractometer with graphite monochromated Mo-Kα (λ 0.71073)

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compound (1–4) was prepared in DMSO, with 1 mg/mL concentration. Stock solutions of the reference antibiotics (vancomycin, norfloxacin and nystatin for Gram-positive, Gram-negative and yeasts, respectively) with same concentration (1 mg/mL) were also prepared in DMSO. In inoculated with 0.1 mL of bacterial suspension matching a 0.5 McFarland standard solution and uniformly spread on the medium surface using a sterile swab. Wells of approximately 5 mm in diameter were made in the medium with a sterile glass Pasteur pipette and 50 μL of each compound were added into each well. Plates were incubated at 37 °C for 24 h. The antimicrobial activity was evaluated by measuring the diameter (mm) of the inhibition zone formed around the wells and compared to controls.19b

Determination of minimum inhibitory concentrations (MICs) Antimicrobial activity was also determined using the microplate broth microdilution method.19c Under aseptic conditions, 100 μL of liquid Mueller-Hilton medium (or Sabouraud for yeasts) was distributed in each well of a 96-well plate. At the beginning, to the well of each row was added 100 μL of each stock solution of the compounds, with the positive or negative control at a 1 mg/mL concentration. Using a multichannel micropipette, a successive dilution was made to 1:2 proportions between each row of wells (19.5–5000 μg/mL range). Finally, 10 μL of microbial suspension were added to all wells and plates were covered and incubated at 37 °C for 24 h. The microbial growth was measured with an absorbance microplate reader (Thermo Scientific Multiskan FC, Loughborough, UK) set to 620 nm. Assays were carried out in triplicate for each tested microorganism.19c

Minimum bactericidal/fungicidal concentration (MBCs/MFCs) To determine the Minimum Bactericidal Concentration (MBC) and Minimum Fungicidal Concentration (MFC) for each set of wells in the MIC determination, a loopful of broth was collected from those wells which did not show any growth and inoculated on sterile MuellerHilton medium broth (for bacteria) or Sabouraud (for yeasts) by streaking. Plates inoculated with 17



aseptic conditions, Petri dishes containing 20 mL of solid Mueller-Hinton culture medium were

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bacteria and yeasts were incubated at 37 ºC for 24 h. After incubation, the lowest concentration

Acknowledgements Financial supports from the Fundação para a Ciência e a Tecnologia (FCT), Portugal, for fellowship (SFRH/BPD/78264/2011) to S.H. and for the UID/QUI/00100/2013 project are gratefully acknowledged.

References 1

(a) H. Li, Z.‐J. Yao, D. Liu and G.‐X. Jin, Coord. Chem. Rev., 2015, 293–294, 139–157; (b) W.‐H. Zhang, Q. Liu and J.‐P. Lang, Coord. Chem. Rev., 2015, 293–294, 187–210; (c) P. Buchwalter, J. Rosé and P. Braunstein, Chem. Rev., 2015, 115, 28–126; (d) S. Sculfort and P. Braunstein, Chem. Soc. Rev., 2011, 40, 2741–2760; (e) G. Marinescu, M. Andruh, F. Lloret and M. Julve, Coord. Chem. Rev., 2011, 255, 161–185; (f) E. J. L. McInnes, G. A. Timco, G. F. S. Whitehead and R. E. P. Winpenny, Angew. Chem., Int. Ed., 2015, 54, 14244–14269; (g) M. Andruh, Dalton Trans., 2015, 44, 16633–16653.

2

(a) A. Jana and S. Mohanta, CrystEngComm, 2014, 16, 5494–5515; (b) A. S. Dinca, S. Shova, A. E. Ion, C. Maxim, F. Lloret, M. Julve and M. Andruh, Dalton Trans., 2015, 44, 7148–7151; (c) G. Marinescu, C. Maxim, R. Clérac and M. Andruh, Inorg. Chem., 2015, 54, 5621–5623; (d) S. Hazra, R. Koner, M. Nayak, H. A. Sparkes, J. A. K. Howard and S. Mohanta, Cryst. Growth Des., 2009, 9, 3603–3608; (e) S. Hazra, S. Sasmal, M. Nayak, H. A. Sparkes, J. A. K. Howard and S. Mohanta, CrystEngComm, 2010, 12, 470–477; (f) V. A. Milway, F. Tuna, A. R. Farrell, L. E. Sharp, S. Parsons and M. Murrie, Angew. Chem., Int. Ed., 2013, 125, 2003–2006.

3

(a) J.‐Z. Qiu, L.‐F. Wang, Y.‐C. Chen, Z.‐M. Zhang, Q.‐W. Li and M.‐L. Tong, Chem. Eur. J., 2016, 22, 802–808; (b) S. A. Magee, S. Sproules, A.‐L. Barra, G. A. Timco, N. F. Chilton, D. Collison, R. E. P. Winpenny and E. J. L. McInnes, Angew. Chem., Int. Ed., 2014, 53, 5310–5313; (c) K. Liu, W. Shi and P. Cheng, Coord. Chem. Rev., 2015, 289–290, 74–122; (d) S. Hazra, S. Bhattacharya, M. K. Singh, L. Carrella, E. Rentschler, T. Weyhermueller, G. Rajaraman and S. Mohanta, Inorg. Chem., 2013, 52, 12881–12892; (e) X.‐L. Li, F.‐Y. Min, C. Wang, S.‐Y. Lin, Z. Liu and J. Tang, Inorg. Chem., 2015, 54, 4337–4344; (f) E. N. Chygorin, V. N. Kokozay, I. V. Omelchenko, O. V. Shishkin, J. Titiš, R. Boča and D. S. Nesterov, Dalton Trans., 2015, 44, 10918–10922; (g) D. S. Nesterov, V. N. Kokozay, B. W. Skelton, J. Jezierska and A. Ozarowski, Dalton Trans., 2007, 558–564.

18



was noted as MBC (for bacteria) or MFC (for yeasts) at which no visible growth was observed.

Page 19 of 21


4

(a) S. Hazra, J. Titiš, D. Valigura, R. Boča and S. Mohanta, Dalton Trans., 2016, 45, 7510–7520; (b) M. Gregson, N. F. Chilton, A.‐M. Ariciu, F. Tuna, I. F. Crowe, W. Lewis, A. J. Blake, D. Collison, E. J. L. McInnes, R. E. P. Winpenny and S. T. Liddle, Chem. Sci., 2016, 7, 155–165; (c) J. Goura, J. Brambleby, P. Goddard and V. Chandrasekhar, Chem. Eur. J., 2015, 21, 4926–4930; (d) S. K. Langley, C. Le, L. Ungur, B. Moubaraki, B. F. Abrahams, L. F. Chibotaru and K. S. Murray, Inorg. Chem., 2015, 54, 3631–3642.

5

(a) P. Braunstein and J. Rosé, Heterometallic Clusters in Catalysis in Metal Clusters in Chemistry, P. Braunstein, L. A. Oro and P. R. Raithby (eds), Wiley‐VCH Verlag GmbH, Weinheim, Germany, 1999; (b) J. Li, J. Yang, Y.‐Y. Liu and J.‐F. Ma, Chem. Eur. J., 2015, 21, 4413–4421; (c) J. A. Mata, F. E. Hahn and E. Peris, Chem. Sci., 2014, 5, 1723–1732; (d) D. S. Nesterov, V. N. Kokozay, V. V. Dyakonenko, O. V. Shishkin, J. Jezierska, A. Ozarowski, A. M. Kirillov, M. N. Kopylovich and A. J. L. Pombeiro, Chem. Commun., 2006, 4605–4607; (e) D. S. Nesterov, V. N. Kokozay, J. Jezierska, O. V. Pavlyuk, R. Boča and A. J. L. Pombeiro, Inorg. Chem., 2011, 50, 4401–4411; (f) D. S. Nesterov, E. N. Chygorin, V. N. Kokozay, V. V. Bon, R. Boča, Y. N. Kozlov, L. S. Shul’pina, J. Jezierska, A. Ozarowski, A. J. L. Pombeiro and G. B. Shul’pin, Inorg. Chem., 2012, 51, 9110–9122.

6

(a) M, Andruh, R. Clerac, D. Visinescu, M.‐G. Alexandru, A. M. Madalan, C. Mathonier and I.‐R. Jeon, Dalton Trans., 2016, 45, 7642–7649; (b) D. Visinescu, M.‐G. Alexandru, A. M. Madalan, C. Pichon, C. Duhayon, J.‐P. Sutter and M. Andruh, Dalton Trans., 2015, 44, 16713–16727; (c) H.‐H. Wang, J. Yang, Y.‐Y. Liu, S. Song and J.‐F. Ma, Cryst. Growth Des., 2015, 15, 4986–4992; (d) M.‐G. Alexandru, D. Visinescu, M. Andruh, N. Marino, D. Armentano, J. Cano, F. Lloret and M. Julve, Chem. ‐Eur. J., 2015, 21, 5429–5446; (e) L. Wang, W. Yang, F.‐Y. Yi, H. Wang, Z. Xie, J. Tang and Z.‐M. Sun, Chem. Commun., 2013, 49, 7911–7913; (f) D. S. Nesterov, C. Graiff, A. Tiripicchio and A. J. L. Pombeiro, CrystEngComm, 2011, 13, 5348–5353.

7

N. Bridonneau, L.‐M. Chamoreau, P. P. Lainé, W. Wernsdorfer and V. Marvaud, Chem. Commun., 2013, 49, 9476–9478.

8

(a) J. Hilbert, C. Nather and W. Bensch, Inorg. Chem., 2014, 53, 5619–5630; (b) J. P. Euner and S. Dehnen, Chem. Commun., 2014, 50, 11385–11388; (c) E. Wachtler, R. Gericke, L. Zhechkov, T. Heine, T. Langer, B. Gerke, R. Pottgen and J. Wagler, Chem. Commun., 2014, 50, 5382–5384; (d) C. P. Sindlinger, S. Wei, H. Schubert and L. Wesemann, Angew. Chem., Int. Ed., 2015, 54, 4087– 4091.

9

(a) D. Cunningham, J. F. Gallagher, T. Higgins, P. McArdle, J. McGinley and M. O'Gara, J. Chem. Soc., Dalton Trans., 1993, 2183–2190; (b) B. Cashin, D. Cunningham, P. Daly, P. McArdle, M. Munroe and N. N. Chonchubhair, Inorg. Chem., 2002, 41, 773–782; (c) S. Hazra, P. Chakraborty and S. Mohanta, Cryst. Growth Des., 2016, 16, 3777–3790; (d) D. Cunningham, J. F. Gallagher, T. Higgins, P. McArdle and D. Sheerin, Chem. Commun., 1991, 432–433; (e) D. Agustin, G. Rima, H. Gornitzka and J. Barrau, Inorg. Chem., 2000, 39, 5492–5495; (f) D. Agustin, G. Rima, H. Gornitzka and J. Barrau, Eur. J. Inorg. Chem., 2000, 693–702.

19



DOI: 10.1039/C6DT03118H

Dalton Transactions


10

(a) G. R. Desiraju, Crystal Engineering: The Design of Organic Solids in Materials Science Monographs 54, Elsevier, Amsterdam, 1989; (b) The Crystal as a Supramolecular Entity, G. R. Desiraju (ed.) in Perspectives in Supramolecular Chemistry 2, Wiley, Chichester, 1996.

11

(a) J. W. Steed, Trends in Pharmaco. Sci., 2013, 34, 185–193; (b) Ö. Almarsson and M. J. Zaworotko, Chem. Commun., 2004, 1889–1896; (c) P. Sanphui, M. Kumar Mishra, U. Ramamurty and G. R. Desiraju, Mol. Pharmaceutics, 2015, 12, 889–897; (d) H. D. Clarke, M. B. Hickey, B. Moulton, J. A. Perman, M. L. Peterson, Ł. Wojtas, Ö. Almarsson and M. J. Zaworotko, Cryst. Growth Des., 2012, 12, 4194–4201.

12

(a) M. Morimoto and M. Irie, J. Am. Chem. Soc., 2010, 132, 14172–14178; (b) D. Yan and D. G. Evans, Mater. Horiz., 2014, 1, 46–57; (c) D. Yan, H. Yang, Q. Meng, H. Lin and M. Wei, Adv. Funct. Mater., 2014, 24, 587–594.

13

(a) A. A. Sagade, K. V. Rao, S. J. George, A. Datta and G. U. Kulkarni, Chem. Commun., 2013, 49, 5847–5849; (b) T. Ono, M. Sugimoto and Y. Hisaeda, J. Am. Chem. Soc., 2015, 137, 9519–9522.

14

(a) J. Wouters and L. Quéré (Eds), Pharmaceutical Salts and Co‐crystals, 2011, RSC Publishing; (b) E. Grothe, H. Meekes, E. Vlieg, J. H. ter Horst and R. de Gelder, Cryst. Growth Des., 2016, 16, 3237–3243.

15

(a) P. K. Goswami, R. Thaimattam and A. Ramanan, Cryst. Growth Des., 2016, 16, 1268–1281; (b) M. K. C. Mannava, K. Suresh and A. Nangia, Cryst. Growth Des., 2016, 16, 1591–1598.

16

(a) E. Sangtani, S. K. Sahu, S. H. Thorat, R. L. Gawade, K. K. Jha, P. Munshi and R. G. Gonnade, Cryst. Growth Des., 2015, 15, 5858–5872; (b) S. Tothadi, P. Sanphui and G. R. Desiraju, Cryst. Growth Des., 2014, 14, 5293–5302; (c) P. Sanphui, V. K. Devi, D. Clara, N. Malviya, S. Ganguly and G. R. Desiraju, Mol. Pharmaceutics, 2015, 12, 1615–1622.

17

(a) H. G. Brittain, Cryst. Growth Des., 2011, 11, 2500–2509; (b) S. Cherukuvada, G. Bolla, K. Sikligar and A. Nangia, Cryst. Growth Des., 2013, 13, 1551–1557; (c) R. Chadha, A. Saini, S. Khullar, D. S. Jain, S. K. Mandal and T. N. G. Row, Cryst. Growth Des., 2013, 13, 858–870; (d) F. Grifasi, M. R. Chierotti, K. Gaglioti, R. Gobetto, L. Maini, D. Braga, E. Dichiarante and M. Curzi, Cryst. Growth Des., 2015, 15, 1939−1948.

18

(a) M. R. Karekal, V. Biradar and M. B. H. Mathada, Bioinorg. Chem. Appl., 2013, 2013, 1–16; (b) E. Pahontu, V. Fala, A. Gulea, D. Poirier, V. Tapcov and T. Rosu, Molecules, 2013, 18, 8812–8836; (c) Y.‐F. Chen, L. Wei, J.‐L. Bai, H. Zhou, Q.‐M. Huang, J.‐B. Li and Z.‐Q. Pan, J. Coord. Chem., 2011, 64, 1153–1164; (d) S. Magaldi, S. Mata‐Essayag, C. H. de Capriles, C. Perez, M. T. Colella, C. Olaizola and Y. Ontiveros, Int. J. Infect. Dis., 2004, 8, 39–45.

19

(a) M. Balouiri, M. Sadiki and S. K. Ibnsouda, J. Pharm. Anal., 2016, 6, 71–79; (b) P. Rijo, D. Matias, A. S. Fernandes, M. F. Simões, M. Nicolai and C. P. Reis, Polymers, 2014, 6, 479–490; (c) P. A. Wayne, Performance standards for antimicrobial susceptibility testing: Twenty Fifth International Supplement M100‐S25., Clinical and Laboratory Standards Institute, 2015; (d) J. A. 20



DOI: 10.1039/C6DT03118H

Page 21 of 21


DOI: 10.1039/C6DT03118H

20

(a) J. R. Zamian, E. R. Dockal, G. Castellano and G. Oliva, Polyhedron, 1995, 14, 2411–2418; (b) I. Correia, J. C. Pessoa, M. T. Duarte, M. F. M. da Piedade, T. Jackush, T. Kiss, M. M. C. A. Castro, C. C. F. G. Geraldes and F. Avecilla, Eur. J. Inorg. Chem., 2005, 732–744; (c) M. R. Bermejo, M. I. Fernández, E. Gómez‐Fórneas, A. González‐Noya, M. Maneiro, R. Pedrido and M. J. Rodríguez, Eur. J. Inorg. Chem., 2007, 3789–3797; (d) D. Cunningham, K. Gilligan, M. Hannon, C. Kelly, P. McArdle and A. O’Malley, Organometallics, 2004, 23, 984–994.

21

(a) L. Yang, D. R. Powell and R. P. Houser, Dalton Trans., 2007, 955–964; (b) K. Robinson, G. V. Gibbs and P. H. Ribbe, Science, 1971, 172, 567–570.

22

W. Abriel, Acta Crystallogr., 1986, B42, 449–453.

23

(a) S. Mondal, S. Mandal, L. Carrella, A. Jana, M. Fleck, A. Köhn, E. Rentschler and S. Mohanta, Inorg. Chem., 2015, 54, 117–131; (b) G. Gonzalez‐Riopedre, M. R. Bermejo, M. I. Fernandez‐ Garcia, A. M. Gonzalez‐Noya, R. Pedrido, M. J. Rodriguez‐Douton and M. Maneiro, Inorg. Chem., 2015, 54, 2512–2521; (c) A. I. Nguyen, R. G. Hadt, E. I. Solomon and T. D. Tilley, Chem. Sci., 2014, 5, 2874–2878; (d) D. Zhang, Y. Bian, J. Qin, P. Wang and X. Chen, Dalton Trans., 2014, 43, 945– 949.

24

(a) J. Rouquette, J.‐M. Thibaud, R. A. S. Ferreira, L. D. Carlos, B. Donnadieu, V. Vieru, L. F. Chibotaru, L. Konczewicz, J. Haines, Y. Guari and J. Larionova, Angew. Chem., Int. Ed., 2015, 54, 2236 –2240; (b) M. Cametti, M. Nissinen, A. D. Cort, K. Rissanen and L. Mandolini, Inorg. Chem., 2006, 45, 6099–6101; (c) N. Bridonneau, G. Gontard and V. Marvaud, Dalton Trans., 2015, 44, 5170–5178; (d) M. Nayak, S. Sarkar, P. Lemoine, S. Sasmal, R. Koner, H. A. Sparkes, J. A. K. Howard and S. Mohanta, Eur. J. Inorg. Chem., 2010, 744–752; (e) A. Jana, S. Majumder, L. Carrella, M. Nayak, T. Weyhermueller, S. Dutta, D. Schollmeyer, E. Rentschler, R. Koner and S. Mohanta, Inorg. Chem., 2010, 49, 9012–9025 ; (f) S. Bhattacharya, A. Jana and S. Mohanta, CrystEngComm, 2013, 15, 10374–10382 ; (g) S. Hazra, R. Koner, M. Nayak, H. A. Sparkes, J. A. K. Howard, S. Dutta and S. Mohanta, Eur. J. Inorg. Chem., 2009, 4887–4894; (h) A. Jana, T. Weyhermüller and S. Mohanta, CrystEngComm, 2013, 15, 4099–4106; (i) A. Cucos, A. Ursu, A. M. Madalan, C. Duhayon, J.‐P. Sutter and M. Andruh, CrystEngComm, 2011, 13, 3756–3766; (j) S. Sarkar and S. Mohanta, RSC Adv., 2011, 1, 640–650.

25

F. H. Allen, Acta Crystallogr., 2002, B58, 380–388.

26

(a) APEX2, SMART, SAINT & SADABS, Bruker, AXS Inc. Madison, Wisconsin, USA, 2012; (b) G. M. Sheldrick, Acta Crystallogr., 2015, C71, 3–8; (c) L. J. Farrugia, J. Appl. Crystallogr., 2012, 45, 849– 854.

21



Lemire, J. J. Harrison and R. J. Turner, Nat. Rev. Microbiol., 2013, 11, 371–384; (e) H. Arslan, N. Duran, G. Borekci, C. K. Ozer and C. Akbay, Molecules, 2009, 14, 519–527; (f) D. C. Onwudiwe, A. C. Ekennia and E. Hosten, J. Coord. Chem., 2016, 69, 2454–2468.

Cocrystals and alloys of nitazoxanide: enhanced pharmacokinetics.

Generation of 1:1 Carbamazepine:Nicotinamide cocrystals by spray drying.

Continuous engineering of nano-cocrystals for medical and energetic applications.

Aniline-phenol recognition: from solution through supramolecular synthons to cocrystals.

Improving lithium therapeutics by crystal engineering of novel ionic cocrystals.

Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics.

Pharmaceutical cocrystals of diflunisal and diclofenac with theophylline.

Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development.

Non linear optical analyses of hexamine: phenol cocrystals based on hydrogen bonding: a comparative study.

4-Aminobenzoic Acid.

How cocrystals of weakly basic drugs and acidic coformers might modulate solubility and stability.

Can the Formation of Pharmaceutical Cocrystals Be Computationally Predicted? 2. Crystal Structure Prediction.

donor-acceptor-donor synthon.

Energetic-Energetic Cocrystals of Diacetone Diperoxide (DADP): Dramatic and Divergent Sensitivity Modifications via Cocrystallization.

Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt.

Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion.

Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5.

Cocrystals of the antibiotic trimethoprim with glutarimide and 3,3-dimethylglutarimide held together by three hydrogen bonds.

Simultaneous formation and micronization of pharmaceutical cocrystals by rapid expansion of supercritical solutions (RESS).

Cocrystals of nicotinamide and (R)-mandelic acid in many ratios with anomalous formation properties.

Nuclear quadrupole resonance investigation of hydrogen bonding in some cocrystals of 2,3,5,6-tetramethylpyrazine and carboxylic acids.

Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt.

Molecular structure investigation of organic cocrystals of 1,10-phenanthroline-5,6-dione with aryloxyacetic acid: a combined experimental and theoretical study.

Mechanochemical synthesis of bumetanide-4-aminobenzoic acid molecular cocrystals: a facile and green approach to drug optimization.