Spectroscopic and X-ray structural characterization of new organotin carboxylates and their in vitro antifungal activities

Accepted Manuscript Spectroscopic and X-ray structural characterization of new organotin carboxylates and their in vitro antifungal activities C.S. Rocha, B.P. de Morais, B.L. Rodrigues, C.L. Donnici, G.M. de Lima, J.D. Ardisson, J.A. Takahashi, R.S. Bitzer PII: DOI: Reference:

S0277-5387(16)30182-6 http://dx.doi.org/10.1016/j.poly.2016.05.031 POLY 12005

To appear in:

Polyhedron

Received Date: Accepted Date:

12 April 2016 12 May 2016

Please cite this article as: C.S. Rocha, B.P. de Morais, B.L. Rodrigues, C.L. Donnici, G.M. de Lima, J.D. Ardisson, J.A. Takahashi, R.S. Bitzer, Spectroscopic and X-ray structural characterization of new organotin carboxylates and their in vitro antifungal activities, Polyhedron (2016), doi: http://dx.doi.org/10.1016/j.poly.2016.05.031

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Spectroscopic and X-ray structural characterization of new organotin carboxylates and their in vitro antifungal activities C. S. Rocha1, B. P. de Morais1, B. L. Rodrigues1, C. L. Donnici1, G. M. de Lima*1, J. D. Ardisson2 , J. A. Takahashi2 and R. S. Bitzer3 1

Departamento de Química, Universidade Federal de Minas Gerais, UFMG, Avenida Antônio Carlos 6627, Belo Horizonte MG,

CEP 31270-901, Brazil. 2

Centro de Desenvolvimento em Tecnologia Nuclear, CDTN/CNEN, Avenida Antônio Carlos 6627, Belo Horizonte MG, CEP

31270-901, Brazil. 3

Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ, CEP 21941-909, Brazil

Abstract The reactions of SnR2Cl2 (R = Me, Bu or Ph) with sodium 4-phenylbutyrate, NaO2C(CH2)3Ph (NaOPhb), yielded three organotin carboxylates, namely [{(Me2SnOPhb)2O}2] (1), [Bu2Sn(OPhb)2] (2) and [{PhSn(O)OPhb}6] (3). Complexes (1) and (2) have been spectroscopically authenticated by FT-IR,

119

Sn Mössbauer, and 1H,

13

C{1H} and

119

Sn{1H} NMR techniques. In addition, the

crystallographic structures of (1) – (3) have been determined by X-ray diffraction measurements. Complex (1) displays two signals in the solution 119Sn NMR spectrum corresponding to the exo ( 176.3) and endocyclic ( -188.4) SnMe2 moieties, whereas (2) exhibits only one 119Sn resonance ( -148.1). The crystallographic characterization of (1) confirms the centrosymmetric tetranuclear stannoxane structure and the existence of the exo and endocyclic SnMe2 moieties in the both distorted trigonal bipyramidal and octahedral environment, respectively. Complex (2) crystallises as a monomer in which the Sn(IV) cation lies at the centre of a distorted octahedron. The bonding scheme in (3) outlines a hexanuclear drum-like structure comprising two six-membered (-Sn–O-)3 stannoxane rings. The supramolecular arrangements of (1) – (3) result from noncovalent interactions, namely Sn···O (1) and (2), C–H··· (1), and C–H···O (1) – (3). Finally, antifungal activities of all organotin derivatives have been screened against Candida albicans (ATCC 18804), Candida tropicalis (ATCC 750), Candida glabrata (ATCC 90030), Candida parapsilosis (ATCC 22019), Candida lusitaniae (CBS 6936), and Candida dubliniensis (clinical isolate 28). Complex (2) exhibited the best biocide activity amongst the three organotin products. Keywords: biological activity, organotin carboxylate, structural determination, drum-like structure.

*

Corresponding author: [email protected] (Prof. Geraldo M. de Lima) Tel.: +55 31 3409 5744; fax: +55 31 3409 5720.

1

1. Introduction Several metallic cations play important roles in industrial processes as catalysts, or in biological systems, either as part of essential biomolecules, or in the treatment of a number of diseases. The synthesis of the first organotin compound by Sir Edward Frankland dates back to 1849 [1,2]. Nonetheless, industrial applications for such class of organometallics, including those in the polyvinyl chloride (PVC) industry, only started to emerge a century after Frankland’s original work [3,4]. The vast field of applications of organotin(IV) compounds results from the Lewis acidity of the Sn(IV) centre, which can coordinate O-, N-, P- or S-donor ligands, thus adopting various coordination numbers [3,4]. These bonding and geometrical features seem to tune organotin(IV) biocide activities towards bacteria, fungi or tumour cell lines, which are likely to occur by inhibition of metabolic pathways through the coordination of Sn(IV) centres to key biomolecules [5,6]. Tributyltin oxide (TBTO) can be pointed out as the first organotin compound commercialised as biocide agent in anti-fouling paints for ships [4,7-9]. According to the literature, a number of research groups have found cause and effect relationships between TBTO and imposex problems, prompting many countries to ban its use in the shipping industry [4,10-13]. Despite the environmental and toxicological problems associated with the technological use of organotin compounds [4,14], they are among the most widely employed organometallic species and continue to surprise experts in the field of medicinal inorganic chemistry [3,15-17]. Much attention has been drawn to the preparation and characterization of organotin carboxylates [18-20] and to the study of their biological activities against tumour cells, fungi, bacteria, and other microorganisms [21-24]. Nowadays, resistance of microorganisms and toxicity are some of the major problems concerning the clinical use of drugs. Therefore, the search for new metal-containing antimicrobial agents, more bio-specific and less toxic to the host and to the environment, is particularly urgent. More research is still needed to achieve a reasonable understanding of the mechanisms of action of biologically active organotin(IV) compounds. A general pattern emerged lately correlates structural features and covalence of the SnRnLm groups or the nature of the ligands with the biological activities [25]. Alkyl and aryl tri-substituted organotin(IV) compounds generally display higher toxicity than di-substituted ones, and the mono-substituted complexes are still less effective [26]. However, the order of toxicity depends on the microorganism and varies from strain to strain [27]. In addition, inhibitory activity increases in the order Et < Bu < Ph, suggesting that the toxicity of organotin(IV) species relate closely to hydrophobicity and lipophilicity of organyl groups [25,28]. 2

Besides preparing new organotin complexes [29-32], investigating their potential applications [33] and screening their activity towards some microorganisms [34-38], we have been interested in the mechanisms of action of such complexes in biological media [5,6]. According to our previous studies, organotin(IV) dithiocarbamate or carboxylate complexes reduce ergosterol biosynthesis in C. albicans [5,6]. Special techniques used for morphological investigations, such as scanning electron microscopy (SEM) and transmission electron microscopy (TEM), have suggested that the organotin complexes act on the cell membrane, in view of the observed cytoplasmatic leakage and strong deterioration of the cell membrane [5,6]. We have recently reported in this journal a similar work dealing with the synthesis and structural characterization of organotin(IV) valproates [39]. In the present article we provide a full structural description of three new organotin(IV) carboxylates, namely [{(Me2SnOPhb)2O}2] (1), [Bu2Sn(OPhb)2] (2) and [{PhSn(O)OPhb}6] (3) (OPhb = 4-phenylbutyrate). In addition, antifungal activities of these complexes have been screened against Candida albicans (ATCC 18804), Candida tropicalis (ATCC 750), Candida glabrata (ATCC 90030), Candida parapsilosis (ATCC 22019), Candida lusitaniae (CBS 6936) as well as Candida dubliniensis (Clinic isolate 28).

2. Experimental

2.1. Chemistry

2.1.1. Materials and instruments All starting materials were purchased from Aldrich, Alfa Aesar, Fluka, Merck, Vetec or Synth and used as received. NMR spectra in solution were recorded at 200 MHz using a Bruker DPX-200 spectrometer equipped with an 89 mm wide-bore magnet. NMR spectra in the solid state were recorded at 400 MHz using a Bruker Advance III DPX-400 spectrometer also equipped with an 89 mm wide-bore magnet. 1H and SiMe4, while

119

13

C{1H} chemical shifts (/ppm) are reported relative to

Sn{1H} chemical shifts were determined relative to SnMe4. The infrared spectra

were recorded using samples pressed as KBr pellets on a Perkin-Elmer 238 FT-IR spectrometer over the range of 4000–400 cm-1. Carbon, hydrogen and nitrogen microanalyses were performed on a Perkin-Elmer PE-2400 CHN analyzer.

119

Sn Mössbauer spectra were recorded on standard

equipment at liquid N2 temperature using BaSnO 3 source kept at room temperature. Intensity data for X-ray diffraction studies were collected at 270(2) and 120(2) K on a Xcalibur, Atlas, Gemini diffractomer using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). Data collection, 3

reduction and cell refinement were performed using the CrysAlis RED program [40]. The structures were solved and refined employing SHELXS-97 and SHELXL-97, respectively [41]. Further details are given in Table II. All non-H atoms were anisotropically refined. The H atoms were refined with fixed individual displacement parameters [Uiso(H) = 1.2 Ueq(C)] using the SHELXL-97 riding model. Molecular graphics were generated by ORTEP-3 for Windows [42] and Mercury 3.8 [43].

2.1.2. Syntheses Synthesis of [{(Me2SnOPhb)2O}2] (1): To a round bottom flask (250 mL) charged with Na(OPhb) (1.00g, 5.37 mmol) in EtOH (100 mL) was added SnMe2Cl2 (0.60g, 2.73 mmol) dissolved in 20 mL of EtOH. After 5 h of reflux the reaction vessel was left to settle down, and NaCl was removed by filtration. The solvent was pumped off and the remaining oily material was recrystallised in a mixture of MeOH/C7H16 (3:1) yielding X-ray quality crystals of (1). Yield: 63%. Mp: 105 – 107 °C. IR (cm-1): 1564 ( as CO2-), 1414 ( s CO2 -), 524 ( Sn-O). 1H NMR(δ, CDCl3): 2.30 - 2.23 {t, O2CCH2CH2CH2Ph}, 2.02 – 1.88 {m, O2CCH2CH2CH2Ph}, 2.73 – 2.66 {m, O2CCH2CH2CH2Ph}, 7.37 – 7.22 {m, O2CCH2CH2CH2Ph}, 0.84 {2J(119Sn-1H) = 87.3 Hz} {s, Sn(CH3)2};

13

C NMR(δ,

CDCl3): 179.9 {O2CCH2CH2CH2Ph}, 35.7 {O2CCH2CH2CH2Ph}, 27.4 {O2CCH2CH2CH2Ph}, 34.4 {O2CCH2CH2CH2Ph}, 141.8 - 126.3 {O2CCH2CH2CH2Ph}, 9.1 {1J(119/117Sn-13C) = 802/767 Hz}{Sn(CH3)2} and 6.6 {1J(119/117Sn-13C) = 758/722 Hz} {Sn(CH3)2}. 119Sn NMR (δ, CDCl3) -176.3, -188.4 {1J(119Sn-13C) = 802/758 Hz} {2J(119Sn-117Sn) = 102/97 Hz}. 119SnMössbauer: (mm s-1) 1.18;  (mm s-1) 3.57. Elemental analysis for C13H20O2Sn (MW 319.96 g mol-1) found(calc): C 45.16 (45.05); H 5.33 (5.36). Synthesis of [Bu2Sn(OPhb)2] (2): Prepared and recrystallised in a similar manner using Na(OPhb), (2.00g 10.7 mmol) and SnBu2Cl2 (1.68 g, 5.5 mmol). Yield: 35 %. Mp: 55 – 58 °C. IR (cm-1): 1575 m ( as CO2-), 1414 ( s CO2-), 630 ( Sn-O).

1

H NMR(δ, CDCl3): 2.34 - 2.27 {t,

O2CCH2CH2CH2Ph}, 1.96 – 1.82 {m, O2CCH2CH2CH2Ph}, 2.61 – 2.54 {m, O2CCH2CH2CH2Ph}, 7.22 – 7.06 {m, O2CCH2CH2CH2Ph}, 1.58 – 1.25 {m, Sn(CH2CH2CH2CH3)3}, 0.85 - 0.78 {t, Sn(CH2CH2CH2CH3)3};

13

C

NMR(δ,

CDCl3):

183.9

{O2CCH2CH2CH2Ph},

35.4

{O2CCH2CH2CH2Ph}, 27.2 {O2CCH2CH2CH2Ph}, 33.6 {O2CCH2CH2CH2Ph}, 141.5 - 126.0 {O2CCH2CH2CH2Ph}, 25.1 {1J(119/117Sn-13C) = 583/557 Hz}{Sn(CH2CH2CH2CH3)2}, 26.8 {Sn(CH2CH2CH2CH3)2}, 26.4 {Sn(CH2CH2CH2CH3)3}, 13.7 {Sn(CH2CH2CH2CH3)3}.

119

Sn

NMR(δ, CDCl3) -148.1 {1J(119Sn-13C) = 583 Hz}. 119Sn Mössbauer:  (mm s-1) 1.43,  (mm s-1) 3.57.

4

Elemental analysis for C22H38O2Sn (MW 559.31 g mol-1) found(calc) C 60.17 (60.12); H 7.15 (7.20). Synthesis of [{PhSn(O)OPhb}6] (3): Compound (3) crystallises in low yield from the reaction of SnPh2Cl2 and Na(OPhb). The reaction proceeds by using SnPh2Cl2 (0.96 g, 2.79 mmol) and Na(OPhb) (1.00 g, 5.37 mmol). X-ray quality crystals were obtained from the slow evaporation of ethanol solution of products of the reaction. Yield < 10 %. Mp > 330 °C(d). Elemental analysis for C84H120O18Sn6 (MW = 2129.91 g mol-1): found(calc) C 48.16 (47.37); H 5.62 (5.68); Sn 33.44 (33.46).

2.2. Biological tests The in vitro biocide activity of the starting materials and of complexes (1) - (3) were screened against Candida albicans (ATCC 18804), Candida tropicalis (ATCC 750), Candida glabrata (ATCC 90030), Candida parapsilosis (ATCC 22019), Candida lusitaniae (CBS 6936) and Candida dubliniensis (Clinic isolate 28), according to the Gupta and Zacchino method [44]. Fungal strains were grown in Sabouraud Dextrose Broth (SDB) and then incubated for 24 hours at 37°C. The concentration of the microorganisms was kept in the range of 1-2 x 108 cfu mL-1 (determined by the McFarland scale, cfu = colony forming unit), by spectrophotometric method. Different DMSO solutions of the complexes, starting materials and of nystatin and miconazole nitrate were prepared with concentration of 12.5 g mL-1. The MIC50 values were determined using an ELISA (BioTek) tray reader at a fixed wavelength of 490 nm.

3. Results and discussion

3.1. Chemistry The complexes [{(Me2SnOPhb)2O}2] (1), [Bu2Sn(OPhb)2] (2) and [{PhSn(O)OPhb}6] (3) were obtained according to Scheme 1, following the reactions of sodium 4-phenylbutyrate (NaOPhb) with SnR2Cl2 (R = Me, Bu or Ph) in ethanol. All products were isolated as analytically pure colourless and crystalline solids, as confirmed by satisfactory melting points and C and H elemental analyses. The melting points (Mp) of (1) - (3) were found in the range 105 - 107oC (1), 55 - 58oC (2) and (3) decomposed near 330oC. The stannoxane (1) was produced by hydrolysis in ethanol of the intermediate [Me2Sn(OPhb)2] during the process of recrystallization. The reaction of SnPh2Cl2 with NaOPhb, in turn, produced a mixture of [Ph3Sn(OPhb)] and complex (3). Even 5

though the literature reports that the cleavage of the Sn - Ph linkage occurs only in the presence of strong acids [45,46], we have again managed to isolate a organotin(IV) carboxylate with a drumlike structure, that resulted directly from a reaction of SnPh2Cl2 with Na(OPhb) [39]. This sort of compound is known as early as 1922 [47], however its chemical formation is attributed to the loss of benzene effected by the hydrolysis of the diphenyltin carboxylate. In the reaction of SnPh2Cl2 with NaOPhb carried out in this work we expected the production of [Ph2Sn(OPhb)2]. The resulting material was left to crystallise in ethanol from which crystals of (3) were isolated as minor product. Surprisingly, the 1H,

13

C and

119

Sn NMR study of the remaining solution revealed the presence of

b

[Ph3Sn(OPh )] as another organotin product. These results lead us to propose that in this work the hexagonal prismane in fact originates from a self-redistribution reaction of [Ph2Sn(OPhb)2] into [Ph3Sn(OPhb)] (i) and [PhSn(OPhb)3] (ii). Species such as (ii) hydrolysis further rendering the drum-like stannoxane [48].

3.2. Infrared results From the point of view of infrared spectroscopy, the symmetric and asymmetric COO stretching modes are important to analyse the Sn-carboxyl coordination. These vibrations are normally observed as strong bands in the infrared (ir) spectra of organotin carboxylate complexes. The COO- = (as – s) value constitutes an interesting means to determine whether the Sn-carboxyl coordination is bidentate (COO- < 200 cm-1) or monodentate (COO- > 200 cm-1) [49-51]. The ir spectrum of Na(OPhb) revealed a bidentate coordination in view of the following vibrational frequencies: as = 1575 cm-1 ; s = 1414 cm-1 (COO- = 161 cm-1). The symmetric and asymmetric stretching frequency assigned to the carboxylate group was observed in the infrared spectra of (1) and (2), [as = 1638 and 1564 cm-1, s = 1414 and 1380 cm-1 (1); as = 1582 cm-1, s = 1412 cm-1 (2)]. For complex (1) it was possible to observe two bands for each symmetric and asymmetric COO vibration, due to the presence of the exo and endocyclic SnMe2 moieties. The values of COO- are as follows: 224 and 184 cm-1, (1), and 170 cm-1, (2), respectively, [36,52] corroborating the carboxylate group acting as a bridging ligand in complex (2) and in the endocyclic SnMe2 fragment in (1), and as monodentate in the exocyclic part of this stannoxane, as confirmed by the Xray crystallographic experiments. Other important bands, corresponding to the Sn - O stretching mode, were observed in the region 640 - 508 cm-1. 3.3. NMR results 6

Complexes (1) and (2) have been characterized by 1H, 13C and

119

Sn NMR experiments in

solution, revealing chemical and magnetic features (Scheme 2). The hydrogen resonances obtained for (1) and (2) agree with the structures obtained by X-ray crystallography (Section 3.5) and with the literature [39,53]. The 1H signals of the methyl groups of (1) were observed at  0.84 with 2

J(119Sn-1H) = 87.3 Hz, Table I.

The main interest in the

13

C NMR spectra in this work concerns the resonances of the

carboxylate groups and R moieties, as well as the

119

Sn -

13

C coupling constants. The

13

C signals

corresponding to the endo and exocyclic Sn(CH3)2 fragments in [{(Me2SnOPhb)2O}2] (1) were detected at  9.1 and  6.6. For each signal, the following observed: 1J(119/117Sn-13C) = 802/767 and 758/722 Hz. The

119

119

Sn-13C coupling constants were

Sn-13C couplings detected in the

13

C

spectrum of [Bu2Sn(OPhb)2] (2) was 1J(119/117Sn-13C) = 583/557 Hz. 119

Sn{1H}

NMR

measurements

of

complexes

[{(Me2SnOPhb)2O}2]

(1)

and

[Bu2Sn(OPhb)2] (2) were performed in solution. Complex (1) displayed two tin resonances with the respective Sn - C couplings at  -176.3 {1J(119Sn-13C) = 802 Hz} and -188.4 {1J(119Sn-13C) = 758 Hz} assigned to the exo and endocyclic SnMe2 fragments present in the stannoxane molecule. A single signal was obtained at -148.1 {1J(119Sn-13C) = 584.6 Hz } for complex (2). Studies of 1H, 119

13

C and

Sn NMR were decisive to determine the path of the synthesis of complex (3). Complex (3) itself

was not soluble enough to produce good NMR signals, but the experiments carried out with the mother liquor, from which it crystallises, revealed the presence of [Ph3Sn(OPhb)]. The area in the 1

H NMR spectrum corresponding to H(2), H(3), H(4) and the aromatic hydrogens integrates as

2:2:2:20, which is not compatible with either [Ph2Sn(OPhb)2] or [{PhSn(O)OPhb}6] (3) but with [Ph3Sn(OPhb)]. In addition, the

119

Sn NMR resonance was observed in the same position as that

b

obtained for [Ph3Sn(OPh )], freshly prepared for comparison from the reaction of SnPh3Cl and NaOPhb,  -113.7 {1J(119Sn-13C) = 648 Hz}. The literature suggests that 1J and 2J are very sensitive to variations in the coordination environment. Empirical equations express mathematical relationships between the C - Sn - C angle, and 1J(119Sn-13C) for organotin complexes [54-56]: |1J(119Sn-13C)| = 11.4() – 875 for methyl-possessing derivatives

eq. 1 7

|1J(119Sn-13C)| = [(15.56±0.84)() – (1160±101)] for phenyl-containing derivatives

eq. 2

|1J(119Sn-13C)| = [(9.99±0.73)() – (746±100)] for butyl-containing complexes

eq. 3.

The chemical shifts and coupling constants analyses in solution generally depends on the knowledge of the structure, obtained in the solid state either from powder X-ray diffraction study or from crystallographic data. Therefore the interpretation of NMR results in solution from solid state data is subject to uncertainties produced from solvation or from dynamic effects. From equations 1 - 3 the C - Sn - C angle can be indirectly determined, with reasonable accuracy, by measuring J coupling parameters in solution. The average of the C - Sn - C angles obtained by the 1

J(119Sn-13C) couplings were: 147.1o and 143.2o for complex (1) and 133.1o for (2). The values

observed in the X-ray experiments were 145.3(2)o for both exo and endocyclic SnR2 moiety in complex (1) and 139.0(1)o for (2). The angles obtained for complexes (1) and (2), in the solid state, are very close to those identified by

119

Sn NMR experiments in solution, suggesting that the

structures of both complexes in solution and solid state are similar. 3.4. 119Sn-Mössbauer spectroscopic results This study was only performed for complexes (1) and (2). The structure and the corresponding

119

Sn parameters of the organotin precursors used in this work are as follows:

[SnMe2Cl2] {distorted tetrahedron,  = 1.54 mm s-1 and  = 3.55 mm s-1}, [57]; [SnBu2Cl2] { = 1.63 mm s-1 and  = 3.45 mm s-1} [58]. Upon complexation we have observed the following parameters for complexes (1) and (2): [{(Me2SnOPhb)2O}2] (1),  = 1.18 mm s-1 and  = 3.36 mm s-1; [Bu2Sn(OPhb)2] (2)  = 1.43 mm s-1 and  = 3.57 mm s-1. Despite the presence of both endo and exocyclic SnMe2 fragments, which are chemically and magnetically different, their geometric arrangements are similar. Therefore the

119

Sn Mössbauer spectroscopic experiments were not

sensitive enough to display such restrained structural variations. The X-ray crystallographic determination of (1) revealed that the chemical surroundings at the Sn atom changes from a deformed tetrahedron to a mixture of a distorted trigonal bipyramidal and octahedral arrangements. The decrease in the isomer shift from 1.54 mm s -1 in SnMe2Cl2 to 1.18 mm s-1 in (1) is a consequence of the re-hybridization from sp3 to sp3d/sp3d2, revealing a decrease in s contribution to the frontiers molecular orbitals. The same tendency is observed for complex (2), since  varies from 1.63 mm s-1 in SnBu2Cl2 to 1.43 mm s-1 in (2) because of the same re-arrangement of orbitals. The 8

symmetry of charge in complex (1) and (2) differs a little from the starting organotin halides as revealed by the small variation in the quadrupolar splitting.

3.5. X-ray crystallographic results Crystallographic authentication turns to be of extreme relevance in the study of new therapeutically active substances, since it can disclose similarities or differences between structures in solution or in the solid state. As observed for other biologically active molecules the structureactivity relationship (SAR) is of vital importance to understand the biological interactions of drugs with cells or microorganisms. The literature reports that organotin carboxylates can adopt several crystallographic arrangements [59]. Crystal data and refinement parameters for complexes (1) - (3) are listed in Table II.

Complex (1) displays the known ladder-type structure with terminal and bridging carboxylates, which are less usual [39]. It crystallises in the monoclinic C2/c space group, and the X-ray crystallographic study, Fig. 1, reveals that the centrosymmetric dimmer exhibits an inversion centre located at the interior of the four-membered Sn2O2 distorted ring. There are two crystallographically distinct tin centres in the structure, Sn(1) and Sn(2), outlining the exo and endocyclic SnR2 fragments, respectively. The exocyclic tin atom, Sn(1), locates at the centre of a distorted

, surrounded by two carbon atoms at the equatorial

position and three oxygen atoms, one in the apical coordination and the other two located at the equatorial positions. The exocyclic ring in (1) is formed by the following bond distances: Sn(1) O(4) = 2.187(3) Å, Sn(1) - O(1) = 2.199(3) Å, Sn(1) - O(3) = 2.036(3) Å (axial coordination), Sn(1) - C(21) = 2.089(4) Å and Sn(1) - C(22) = 2.091(4) Å, Table III. The longer Sn - O bonds, with O(1) and O(4), originate from both monodentate and bidentate coordinations of the carboxylate group, while the shorter contact involves an oxide anion, O(3). The O1 - Sn1 - O4 axial angle, 170.8(1)o, is more narrow than 180o and the mean value of the equatorial angles is 120o, as expected for a trigonal bipyramid. Each endocyclic Sn(2) atom in (1) lies at the centre of a highly distorted octahedron, sketched by the asymmetric coordination of bridging oxygen atoms and the carbon atoms of the methyl groups. The axial bonds are: Sn(2) - O(3) = 2.123(3) Å and Sn(2) - O(2) = 2.299(4) Å. The O(2) - Sn(2) - O(3) angle, 165.5(1)o, is narrower than 180o, the expected angle of the axial position of an octahedron. The corners of the equatorial position are occupied by C(23), C(24), O(2) and O(3`). The bond distances are Sn(2) - C(23) = 2.101(4) Å, Sn(2) - C(24) = 2.106(5) 9

Å, Sn(2) - O(2) = 2.556(3) Å and Sn(2) - O(3`) = 2.042(2) Å. The mean value of the angles at the equatorial positions, 93.5o, is a little bit wider than 90o.

In a recent work we found the coordination of the SnBu 2 to the valproate ligand very similar with that of the SnMe2 moiety [39] in view of the formation of the stannoxane derivative for both complexes. The X-ray crystallographic experiment revealed a completely different crystallographic arrangement of complex (2) in comparison with (1), since the corresponding stannoxane is not formed during the reaction. Complex (2) crystallises in the monoclinic system with space group C 2/c and Z = 4. The chemical environment at the hexacoordinated Sn(IV) centre outlines either a distorted octahedral or a distorted trapezoidal geometry, sketched by the two butyl groups and the asymmetric coordination of the carboxylates, Fig. 2. The axial positions are occupied by two identical oxygen atoms with two longer Sn - O bonds, Sn - O(1) = 2.519(1) Å. The O(1) - Sn - O(1) angle, 171.23(6)o, is more narrow than the expected angle, 180o, for the proposed geometries. The two shorter Sn - O bonds, Sn - O(1) = 2.125(1) Å, draw the two corners of the equatorial plane. The trans butyl groups are located at the remaining corners of the equatorial positions, Sn - C(14) = 2.114(2) Å. The angles at this plane are C(14) - Sn - C(14) = 139.0(1)o, C(14) - Sn - O(2) = 108.7(6)o, O(2) - Sn - O(2) = 78.9(6)o and C(14) - Sn - O`(2) = 102.7(6)o.

Complex (3) crystallises in the triclinic system with space group P-1 (Z=1). The staggered drum-like framework comprises the association of two six-membered (-Sn–O-)3 stannoxane rings, outlining the top and bottom faces of the drum, which exhibit a synclinal (gauche) conformation (dihedral angle = 60 degrees). Its sides are shaped by six distorted square faces, described by bridging Sn - oxide interactions, joining together the neighbouring stannoxane hexamers. Each face is covered by bidentate carboxylate ligands, bridging diagonal tin atoms and sustaining the integrity of the aggregate, assembling a mill wheel with zigzag blades, Figs 3 and 4.

The asymmetric unit of (3) is formed by one stannoxane hexamer, [SnPh{OPhb)2}O]3, comprising half of the molecule. Each half relates to the other by symmetry, in view of an inversion centre present at the centre of the drum-like arrangement. The Sn(IV) cations are chemically and magnetically equivalent and each of them are coordinated to three different groups: phenyl ring, 10

carboxylate anion, and one oxygen (oxide). A pseudooctahedral geometry is observed at each Sn(IV) atom, where one of the axial coordination is occupied by the Ph ring. The deformation arises from distorted angles and asymmetric bonding scheme. For instance, the Ph - Sn - O angle deviates a little from 180o, locating between 178.4(1) – 180.0(2)o (oxygen trans to Ph). In addition, the Ph Sn - O angles (oxide cis to Ph), found in the range 102.1(1)o to 104.1(1)o, are wider than those Ph Sn - O angles (carboxylate oxygen cis to Ph), varying from 88.5(1)o – 92.4(1)o. The two alternated stannoxane rings (-Sn–O-)3 adopt a double envelop chair-like conformation, with folding angles ranging from 17.1 to 24.9 degrees, Fig. 5. It is also observed in these rings the distance between the planes defined by the tin atoms, Sn(1 `) - Sn(2) - Sn(3) and Sn(1) - Sn(2`) - Sn(3`), 2.992

Å is

further apart in comparison with the separation of the planes shaped by the oxygen atoms, O(1) O(2`) - O(3`) and O(1`) - O(2) - O(3`), 2.515 Å. These distances are much longer than those found in the valproate analogue [39]. Despite the Sn(IV) cations are asymmetrically coordinated by the O atoms, two different groups of Sn - O bonds are clearly observed in the structure. The Sn-O bonds connecting the metal cations to the carboxylate ligand, in the range of 2.138 (3) - 2.162 (3) Å, are longer than the other Sn - O bonds, detected between 2.076 (3) - 2.108 (3) Å.

It is also observed

a symmetric coordination of the 4-phenylbutanoic group to the Sn(IV) cations in view of the small difference in the C - O bond lengths of the carboxylic moiety [1.249(5) – 1.270(5) Å].

As observed in the literature, organotin cage and cluster patterns can be displayed as hexagonal prismanes (drum-like structure), cubanes and ladders [60]. It has been demonstrated that the presence of other donor atoms, S, N or O in the ligand structure, can lead to other less common geometries [61].

3.6. Intermolecular interactions and supramolecular synthons The supramolecular structures of (1) – (3) result from noncovalent interactions, Table IV. These contacts were recognized by Mercury 3.8 (sum of van der Waals radii plus 0.1 Å) [43] and confirmed by Hirshfeld surface analysis [62-66]. Figure A1 (Appendix A) shows the Hirshfeld surfaces for complexes (1) (top), (2) (middle) and (3) (bottom) mapped with dnorm. These maps were generated by CrystalExplorer 3.1 [67]. In general, red spots on dnorm maps indicate relevant noncovalent close contacts [62]. Based on this unbiased analysis and on more relaxed geometric criteria [68-70], we claim that the weak D–H···A hydrogen bonds summarized in Table IV are

11

attractive and directional rather than mere van der Waals isotropic contacts. In Table IV, each motif must be counted twice due to crystal symmetries.

According to Table IV, the tetranuclear complex (1) displays a 1-D chain formed by secondary Sn1···O5i interactions [symmetry code: (i) –x,–y,–z] along the diagonal of the ab-plane, Fig. 6. These Sn···O contacts involve monodentate carboxylate groups and exhibit Sn···O distances (3.083 Å) much shorter than the sum of Sn and O van der Waals radii (3.70 Å) [71]. Adjacent Sn···O 1-D networks are interconnected along the [010] direction by C–H···π interactions involving the C15-C20 rings, Fig. 6. These nonclassical hydrogen bonds are readily translated into small red spots on the dnorm map for (1), Fig. A1 (label B). They form 1-D chains parallel to the baxis and exhibit high degree of linearity (D–H···A, 167o), Table IV. Together, all of these 1-D networks of (1) establish a 2-D supramolecular arrangement comprising Sn···O based layers intercalated by hydrophobic groups, whose Sn···Sn distances between parallel layers amount to 7.60 Å, Fig. 6.

In the supramolecular arrangement of (2), each metal centre is bifurcated owing to two Sn···O secondary interactions, Fig. 7. According to Table IV, the Sn1···O2ii contacts [symmetry code: (ii) x,1+y,z] observed for (2) are longer than the Sn1···O5i interactions of (1) and occur at the limit of Sn and O van der Waals radii [64]. Both the Sn1···O2ii and C9–H9B···O1iii supramolecular synthons [symmetry code: (iii) x,–1+y,z] define a 1-D arrangement parallel to the baxis, Fig. 7. The nonclassical C9–H9B···O1iii hydrogen bond defines a C(4) motif and involves sp3-like carbon atom, Table IV. Though at the limit of the van der Waals radii [64], the C2– H2···O1iv contact [symmetry code: (iv) ½–x,–½+y,½–z] displays high linearity (D–H···A angle > 150o), Table IV, and should not be neglected [4]. It provides a 1-D chain along the [001] direction, Fig. 7). In the crystal packing of 2, the O1 atom shows a bifurcated hydrogen-bond acceptor scheme.

The molecular structure of 3 is favoured by intramolecular C–H···O contacts, as shown in Table IV. Furthermore, chain and ring-type motifs dictate the supramolecular architecture of (3). Accordingly, 1-D chains parallel to the [100] direction are formed by C–H···O and C–H···π 12

interactions, Table VI, Fig. 8 and A2 (Appendix A). These weak hydrogen bonds exhibit acceptable geometric parameters [63]. Moreover, the C12–H12B···O9v and C13–H13B···Cg(4)v interactions [symmetry code: (v) –1+x,y,z] provide chain motifs along the a-axis, whereas the C41–H41···O4vi contact [symmetry code: (vi) 1–x,1–y,1–z] establish R22(14) motifs.

As illustrated in Figure A1, intermolecular contacts described in Table IV have been recognized on the Hirshfeld surfaces for (1) – (3) mapped with dnorm as red to white spots. Moreover, two-dimensional fingerprint (di,de) plots [64,66,67] for the diorganotin complexes have been used to evaluate individual noncovalent contributions to the Hirshfeld surfaces, Fig. 9. As depicted in Figure 9, the isotropic H···H van der Waals contacts largely contribute to the Hirshfeld surface areas for (1) – (3). In addition, the H···C/C···H contacts, referred to as C–H···π interactions, have a greater contribution to the Hirshfeld surface area for (3), whereas the H···O/O···H close contacts have a greater contribution to complex (2). Remarkably, C···C interactions, associated with π–π stacking, do not contribute to the Hirshfeld surface areas. Finally, the contribution of the Sn···O/O···Sn contacts amounts to only 2.8% for (1) and (2) and to 3.8% for (3). 3.7. Biocide assay results The biological activity of organotin complex depends on a series of properties such as lipophilicity/hydrophilicity that balances the transport of the compound across the cell membranes, or the affinity between the organotin fragments and the target site. Lipophilicity seems to be an important and critical physical property that affects the bioavailability of organotin complexes and depends of the nature and the number of the organic group attached to the tin centre. So, there is a close connection between structural properties of organotin complexes and their biological activities. The biocide assays in this work are reported in terms of inhibitory concentrations, IC50. A pre-screening against C. albicans, C. tropicalis, C. glabrata, C. parapsilosis, C. lusitaniae and C. dubliniensis has been performed with complexes (1) - (3) in a concentration of 250 μg mL -1, according to the literature [72]. Complexes (1) - (2) displayed 50% inhibition growth of the microorganisms in concentrations smaller or equal to 250 μg mL -1 and (3) produced no significant effect

in

growth

of

the

investigated

colonies.

Complexes

[{(Me2SnOPhb)2O}2]

(1),

[Bu2Sn(OPhb)2O}2] (2) displayed greater antifungal activities than the starting materials, the organotin halides, Me2SnCl2 and Bu2SnCl2, or than NaOPhb and HOPhb, however less effective 13

than the control drugs, nystatin and miconazole nitrate, Table V. Nevertheless, a synergic effect can observe resulted from the bonding of organotin fragments with -OPhb group.

It is well established that the biological activity of related compounds depends upon the (i) structure, (ii) the type and (iii) number of organic groups attached to the organotin moiety. It is not surprising that a butyltin containing complex, (2) is more active, since studies have suggested that toxicity of organotin complexes correlates with total molecule surface (TSA) and hence n-propyl, nbutyl, n-pentyl, etc, should be more toxic for microorganisms than ethyl, methyltin based complexes. It seems that in this case the biological activity might occur by an intracellular mechanism by transport through cell membrane, as pointed out by us previously [5, 6, 30, 35]. Therefore the order of biological activity suggests a close correlation between activity and lipophilicity.

4. Conclusions In this work we report the preparation of three new organotin carboxylates, [{(Me2SnOPhb)2O}2] (1), [Bu2Sn(OPhb)2] (2) and [{PhSn(O)OPhb}6] (3), from the chemical reactions of SnR2Cl2 (R = Me, Bu or Ph) with sodium 4-phenylbutyrate, NaO2C(CH2)3Ph (NaOPhb). The crystallographic structures of (1) – (3) were authenticated in terms of X-ray diffraction measurements. Complex (1) was confirmed as a centrosymmetric tetranuclear stannoxane with exo and endocyclic SnMe2 moieties, in the both distorted trigonal bipyramidal and octahedral environment, respectively, as suggested by the

119

Sn NMR experiments. Complex (2)

was expected to be a stannoxane as well, in view of other results obtained in our group or found in the literature, however it was isolated as a monomer in which the Sn(IV) cation lies at the centre of a distorted octahedron. The reaction of SnPh2Cl2 with NaOPhb, produced a mixture of complex (3) and [Ph3Sn(OPhb)], identified by 1H, 13C and 119Sn NMR studies. Complex (3) resulted from a selfredistribution reaction of [Ph2Sn(OPhb)2] into [Ph3Sn(OPhb)] (i) and [PhSn(OPhb)3] (ii), and the latter complex hydrolyses producing the hexagonal prismane. The 3D structural analyses of complexes (1) – (3) show that the supramolecular arrangements result from noncovalent interactions, namely Sn···O (1) and (2), C–H··· (1), and C–H···O (1) – (3). Finally, we have observed that complex (2) exhibited the best biocide activity amongst the three organotin products 14

towards Candida albicans (ATCC 18804), Candida tropicalis (ATCC 750), Candida glabrata (ATCC 90030), Candida parapsilosis (ATCC 22019), Candida lusitaniae (CBS 6936), and Candida dubliniensis (clinical isolate 28), however less effective than the control drugs nystatin or fluconazole nitrate.

5. Supplementary data Crystallographic data are available on request at Cambridge Crystallographic Data Centre on quoting the deposition numbers CCDC 1472228, (1), 1472227, (2), and 1472229 (3).

6. Acknowledgements This work was supported by CNPq, CAPES and FAPEMIG - Brazil.

15

7. References [1] E. Frankland, Liebigs Ann. Chem. 71 (1849) 171. [2] E. Frankland, J. Chem. Soc. 2 (1850) 267. [3] M. Gielen, Coord. Chem. Rev. 151 (1996) 41. [4] A.C.A. Sousa, M.R. Pastorinho, S. Takahashi, S. Tanabe, Environ. Chem. Lett. 12 (2014) 117. [5] F.T. Vieira, D.C. Menezes, G.M. de Lima, J.L. Wardell, M.E. Cortes, G.A.B. Silva, A. VilasBoas, J.R.S. Maia, Appl. Organomet. Chem. 22 (2008) 433. [6] D.C. Menezes, F.T. Vieira, G.M. de Lima, J.L. Wardell, M.E. Cortes, M.P. Ferreira, M.A. Soares, A.V. Boas, Appl. Organomet. Chem. 22 (2008) 221. [7] C.J. Evans, R. Hill, J. Oil Colour Chem. Assoc. 64 (1998) 215. [8] D. Liu, R.J. Maguire, Y.L. Lau, G.J. Pacepavicius, H. Okamaru, I. Aoyama, Water Res. 31 (1997) 2363. [9] N. Voulvoulis, M.D. Scrimshaw, J.N. Lester, Appl. Organomet. Chem. 13 (1999) 135. [10] R.J. Maguire, Water Qual. Res. J. Can. 26 (1991) 43. [11] K. Frent, Crit. Rev. Toxicol. 26 (1996) 1. [12] J. White, J.M. Tobin, J.J. Cooney, Can. J. Microbiol. 45 (1999) 541. [13] M. Hoch, Appl. Geochem. 16 (2001) 719. [14] K.E. Appel, Drug Metab. Rev. 36 (2004) 763. [15] M. Sirajuddin, S. Ali, V. Mckee, M. Sohail, H. Pasha, Eur. J. Med. Chem. 84 (2014) 343. [16] F. Arjmand, M. Muddassir, I. Yousuf, J. Photochem. Photobiol., B 136 (2014) 62. [17] M. Yousefi, M. Safari, M.B. Torbati, A. Amanzadeh, J. Struct. Chem. 55 (2014) 101. [18] H. Tlahuext, R. Reyes-Martinez, G. Vargas-Pineda, M. Lopez-Cardoso, H. Hopfl, J. Organomet. Chem. 696 (2011) 693. [19] A. Husain, S.A.A. Nami, K.S. Siddiqi, J. Mol. Struct. 970 (2010) 117. [20] J.P. Fuentes-Martinez, I. Toledo-Martinez, P. Roman-Bravo, P.G.Y. Garcia, C. GodoyAlcantar, M. Lopez-Cardoso, H. Morales-Rojas, Polyhedron 28 (2009) 3953. [21] A. Normah, K.N. Farahana, B. Ester, H. Asmah, N. Rajab, A.A. Halim, Res. J. Chem. Environ. 15 (2011) 544. [22] R. Singh, N.K. Kaushik, Spectrochim. Acta, Part A 71 (2008) 669. [23] E. Santacruz-Juarez, J. Cruz-Huerta, I.F. Hernandez-Ahuactzi, R. Reyes-Martinez, H. Tlahuext, H. Morales-Rojas, H. Hopfl, Inorg. Chem. 47 (2008) 9804. [24] S. Shahzadi, S. Ali, M. Fettouhi, J. Chem. Crystallogr. 38 (2008) 273.

16

[25] G. Yenişehirli, N.A. Ӧztaş, E. Şahin, M. Çelebier, N. Ancın, S.G. Ӧztaş, Heteroat. Chem. 21 (2010) 373. [26] T.S.B. Baul, Appl. Organomet. Chem. 22 (2008) 195. [27] J.S. White, J.M. Tobin, J.J. Coney, Can. J. Microbiol. 45 (1999) 541. [28] J.J. Cooney, S. Wuertz, J. Ind. Microbiol. 4 (1989) 375. [29] Takahashi, J.D. Ardisson, Appl. Organomet. Chem. 29 (2015) 305. [30] I.P. Ferreira, G.M. de Lima, E.B. Paniago, W.R. Rocha, J.A. Takahashi, C.B. Pinheiro, J.D. Ardisson, Polyhedron 79 (2014) 161. [31] G.M. de Lima, D.C. Menezes, J.A.F. dos Santos, J.L. Wardell, C.A.L. Filgueiras, S.M.S.V. Wardell, A.F.C. Alcantara, N.L. Speziali, J. Coord. Chem. 65 (2012) 559. [32] L.C. Dias, M.M.M. Rubinger, J.P. Barolli, J.D. Ardisson, I.C. Mendes, G.M. de Lima, L. Zambolim, M.R.L. Oliveira, Polyhedron 47 (2012) 30. [33] D.C. Menezes, G.M. de Lima, A.O. Porto, M.P. Ferreira, J.D. Ardisson, R.A. Silva, Main Group Met. Chem. 30 (2007) 49. [34] D.C. Menezes, G.M. de Lima, G.S. de Oliveira, A.V. Boas, A.M.A. Nascimento, F.T. Vieira, Main Group Met. Chem. 31 (2008) 21. [35] I.P.Ferreira, G.M. de Lima, E.B. Paniago, W.R. Rocha, J.A. Takahashi, C.B. Pinheiro, J.D. Ardisson, Eur. J. Med. Chem. 58 (2012) 493. [36] I.P. Ferreira, G.M. de Lima, E.B. Paniago, J.A. Takahashi, K. Krambrock, C.B. Pinheiro, J.L. Wardell, L.C. Visentin, J. Mol. Struct. 1048 (2013) 357. [37] I.P. Ferreira, G.M. de Lima, E.B. Paniago, J.A. Takahashi, C.B. Pinheiro, Inorg. Chim. Acta 423 (2014) 443. [38] I.P. Ferreira, G.M. de Lima, E.B. Paniago, J.A. Takahashi, C.B. Pinheiro, J. Coord. Chem. 67 (2014) 1097. [39] B.P. de Morais, G.M. de Lima, C.B. Pinheiro, R.A. Burrow, D.F. Back, R.A.S. San Gil, D.C. Menezes, J.D. Ardisson, Polyhedron 102 (2015) 244. [40] G.M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr. 64 (2008) 112. [41] G.M. Sheldrick,. SHELXL-97. Program for Crystal Structure Refinement, University of Göttingen, Germany, (1997). [42] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565. [43] C.F. Macrae, P.R. Edgington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor, M.J. van de Streek, J. Appl. Crystallogr.,39 (2006) 453.

17

[44] A.S. Zacchino, M.P. Gupta, Manual de técnicas in vitro para la detección de compuestos antifúngicos, Corpus Editorial y Distribuidora, Rosario, 2007. [45] R.K. Ingham, Chem. Rev. 60 (1960) 459. [46] J. Beckmann, M. Henn, K. Jurschat, M. Schürmann, Organometallics 21 (2002) 192. [47] H. Lambourne, J. Chem. Soc., 121 (1922) 2533. [48] R. R. Holmes, Acc. Chem. Res., 22 (1989) 190. [49] M. Nath, S. Pokharia, X. Song, G. Eng, M. Gielen, M. Kemmer, M. Biesemans, R. Willem, D. de Vos, Appl. Organomet. Chem. 17 (2003) 305. [50] M.A. Abdellah, S.K. Hadjikakou, N. Hadjiliadis, M. Kubicki, T. Bakas, N. Kourkoumelis, Y.V. Simos, S. Karkabounas, M.M.Barsan, I.S. Butler, Bioinorg. Chem. Appl. (2009) 542979. [51] B.P. Morais, G.M. de Lima, D.C. Menezes, C.B. Pinheiro, J.A. Takahashi, J.D. Ardisson, R.A.S.S. Gil, J. Mol. Struct. 1079 (2015) 246. [52] G.B. Deacon, R.J. Phillips, Coord. Chem. Rev. 33 (1980) 227. [53] C.S. Parulekar, V.K. Jin, T. Kesavadas, E.R.T. Tiekink, J. Organomet. Chem. 387 (1990) 163. [54] J. Holecek, M. Nadvornik, K. Handlir, A. Lycka, J. Organomet. Chem. 315 (1986) 299. [55] T.P. Lockhart, W.F. Manders, J.J. Zuckerman, J. Am. Chem. Soc. 107 (1985) 4546. [56] T.P. Lockhart, W.F. Manders, J. Am. Chem. Soc. 109 (1987) 7015. [57] A.G. Davies, H.J. Milledge, D.C. Puxley and P.J. Smith, J. Chem. Soc. A,(1970) 2862. [58] P.J. Smith, Organomet. Chem. Rev. A 5 (1970) 373. [59] V. Chandrasekhar, K. Gopal, P. Sasikumar, R. Thirumoorthi, Coord. Chem. Rev. 249 (2005) 1745. [60] C.L. Ma, S.L. Zhang, Z.S. Hu, R.F.Zhang, J. Coord. Chem. 65 (2012) 2569. [61] J.H. Zhang, R.F. Zhang, C.L. Ma, D.Q. Wang, H. Z. Wang, Polyhedron 30 (2011) 624. [62] M.A. Spackman, P.G. Byrom, Chem. Phys. Lett. 267 (1997) 215. [63] M.A. Spackman, J.J. McKinnon, CrystEngComm 4 (2002) 378. [64] J.J. McKinnon, M.A. Spackman, A.S. Mitchell, Acta Crystallogr., Sect. B: Struct. Sci. 60 (2004) 627. [65] J.J. McKinnon, D. Jayatilaka, M.A. Spackman, Chem. Commun. 3814 (2007) 3816. [66] M.A. Spackman, D. Jayatilaka, CrystEngComm 11 (2009) 19. [67] S.K. Wolff, D.J. Grimwood, J.J. McKinnon, M.J. Turner, D. Jayatilaka, M.A. Spackman, CrystalExplorer (Version 3.1), University of Western Australia, 2012. [68] R. Taylor, O. Kennard, J. Am. Chem. Soc. 104 (1982) 5063. [69] T. Steiner, G.R. Desiraju, Chem. Commun. (1998) 891. 18

[70] T. Steiner, Angew. Chem. Int. Ed. 41 (2002) 48. [71] A. Bondi, J. Phys. Chem. 68 (1964) 441. [72] J.J. Cooney and S. Wuertz, J. Industrial Microbiol and Biotechnol., 4 (2005) 375. [73] M.C. Etter, Acc. Chem. Res., 23 (1990) 120. [74] M.C. Etter, J.C. MacDonald, J. Bernstein, Acta Crystallogr., Sect. B: Struct. Sci., 46 (1990) 256.

19

Captions for Tables, Schemes and Figures

Scheme 1 - Preparation of complexes (1) - (3). Scheme 2 - Atom numbering scheme for the NMR chemical shift (/ppm) assignments. Figure 1 - Molecular structure of [{(Me2SnOPhb)2O}2] (1). Ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Figure 2 - Molecular structure of [Bu2Sn(OPhb)2] (2). Ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Figure 3 - Molecular structure of [{PhSn(O)OPhb}6] (3) - view 1. Ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Figure 4 - Molecular structure of [{PhSn(O)OPhb}6] (3) - view 2. Ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Figure 5 - Molecular structure of [{PhSn(O)OPhb}6] (3) - view 3. Ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Figure 6 - Packing diagram of (1) along the c-axis showing the two-dimensional supramolecular arrangement parallel to the ab-plane. Symmetry code: (i) –x,–y,–z. Figure 7 - Packing diagram of (2). Symmetry codes: (ii) x,1+y,z; (iv) ½–x,–½+y,½–z. Figure 8 - Packing diagram of (3) displaying a 1-D chain formed along the a-axis. Hydrogen atoms are omitted for clarity. Figure 9 - Percentage contributions of atom-type/atom-type close contacts to the Hirshfeld surface area for (1) – (3).

Table I - NMR data for complexes (1) - (3). Table II – Crystal data and refinement parameters for (1) - (3). Table III - Selected bond lengths (Å) and angles (o) for complexes (1) - (3). Table IV - Noncovalent interactions and supramolecular synthons for organotin compounds with pba (4-phenylbutanoic acid).a,b

11

Scheme 1

12

Scheme 2

13

Figure 1

14

Figure 2

15

Figure 3

16

Figure 4

17

Figure 5

18

Figure 6

19

Figure 7

20

Figure 8

21

Figure 9

22

Table I Assignment

[{(Me2SnOPhb)2O}2] (1)

[Bu2Sn(OPhb)2] (2)

H(2)

2.30-2.23 (t, 8H, 3J=7.3 Hz)

2.34-2.27 (t, 4H, 3J=7.4 Hz)

H(3)

2.02-1.88 (qt, 8H, 3J=7.4 Hz)

1.96-1.82 (qt, 4H, 3J=7.4 Hz)

3

H(4)

2.73-2.66 (t, 8H, J=7.5 Hz)

2.61-2.54 (t, 4H, 3J=7.5 Hz)

H(6) - H(10)

7.37-7.22(m, 20H)

7.22-7.06 (m, 10H)

H

0.84 (s, 24H, 2J=87.3 Hz)

1.58-1.56 (m, 12H)

3

H

2.30-2.23 (t, 8H, J=7.3 Hz)

1.38-1.25 (m, 12H)

H

2.02-1.88 (qt, 8H, 3J=7.4 Hz)

1.58-1.56 (m, 12H)

3

H

2.73-2.66 (t, 8H, J=7.5 Hz)

0.85-0.78 (t, 6H)

C(1)

179.9

183.9

C(2)

35.7

35.4

C(3)

27.4

27.2

C(4)

34.4

33.6

C(5)

141.8

141.5

C(6)

128.6

128.6

C(7)

128.5

128.5

C(8)

126.0

126.0

C(9)

128.5

128.5

C(10)

128.6 1

128.6 1

C

9.1 ( J=802/767), 6.6 ( J=758/722)

25.1 {1J=583/557}

C

-

26.8

C

-

26.4

C

-

13.7

11

Table II (1)

(2)

(3)

Empirical formula

C48H68O10Sn4

C28H40O4Sn

C96H96O18Sn6

Formula weight

1279.86

559.31

2249.99

Temperature, K

219.9

250

200.00(14)

Wavelength, Å

0.71073

0.71073

0.71073

Crystal system

Monoclinic

Monoclinic

Triclinic

Space group

C 2/c

C 2/c

P-1

a, Å

21.4749(6)

28.6361(6)

10.1485(3)

b, Å

7.5998(2)

5.0996(11)

14.9265(7)

c, Å

32.8447(12)

19.1889(5)

15.5415(7)

, °

90.00

90.00

77.209(4)

, °

99.801(3)

93.044(2)

73.190(3)

, °

90.00

90.00

86.438(3)

Volume, Å

5282.2(3)

2798.3(6)

2197.72(16)

Z

4

4

1

Calculated density, Mg m

1.609

1.328

1.700

Absorption coefficient, mm-1

1.920

0.942

1.748

F(000)

2544.0

1160

1116.0

Crystal size, mm

0.36 x 0.13 x 0.08

0.36 × 0.12 × 0.08

0.24 x 0.07 x 0.04

Theta range of data coll., °

1.92-30

2.13-32.88

2.10-29.42

Limiting indices

-28≤h≥ 26

-43≤h≥ 42

-12≤h≥ 14

-10≤k≥10

-7≤k≥7

-20≤k≥20

-45≤l≥45

-29≤l≥29

-20≤l≥21

Reflections collected

43103

50860

22654

Independent reflections

6826[R(int) = 0.0448]

5034 [R(int) = 0.0429]

10449[R(int) = 0.0387]

Reflections obs. (> 2 sigma)

5561

4299

8426

Completeness

99.95 %

99.94%

99.96%

Refinement method

FMLSQ on F2

FMLSQ on F2

FMLSQ on F2

Data/restrains/parameters

6826/ 0 / 357

5034 / 0 / 151

10449 / 0 / 541

Goodness-of-fit on F2

1.276

1.120

0.999

Final R indices [I>2(I)]

R1 = 0.0420,

R1 = 0.0307,

R1 = 0.0425,

wR2 = 0.0726

wR2 = 0.0651

wR2 = 0.1075

R1 = 0.0581,

R1 = 0.0398,

R1 = 0.0585,

wR2 =0.0726

wR2 = 0.0688

wR2 = 0.1196

1.532 and -0.719

0.551 and -0.40

2.696 and -2.008

3

-3

R indices (all data)

Largest diff. peak and hole, e.Å-3 





11

Table III Compound

Selected bond lengths (Å)

Selected angles (°)

[{(Me2SnOPhb)2O}2] (1)

Sn(1)-C(21) Sn(1)-C(22) Sn(1)-O(1) Sn(1)-O(3) Sn(1)-O(4) Sn(2)-O(2) Sn(2)-O(3) Sn(2)-O(3) Sn(2)-O(4) Sn(2)-C(23) Sn(2)-C(24)

2.089(4) 2.091(4) 2.199(3) 2.036(3) 2.187(3) 2.299(4) 2.042(2) 2.123(3) 2.556(3) 2.101(4) 2.106(5)

C(21)-Sn(1)-C(22) O(3)-Sn(1)-O(4) O(3)-Sn(1)-C(21) O(4)-Sn(1)-O(1) O(4)-Sn(2)-C(24) O(3)-Sn(2)-C(24) O(3)-Sn(2)-C(23) O(4)-Sn(2)-C(23) O(3)-Sn(2)-O(2)

145.3(2) 106.4(2) 108.3(2) 166.8(1) 80.9(2) 107.2(2) 100.3(2) 107.2(2) 165.5(1)

[Bu2Sn(OPhb)2] (2)

Sn(1)-C(14) Sn(1)-O(2) Sn(1)-O(1)

2.114(2) 2.125(1) 2.519(1)

C(14)-Sn(1)-C(14) O(2)-Sn(1)-O(1) O(2)-Sn(1)-O(1) O(2)-Sn(1)-O(2) O(1)-Sn(1)-O(1)

139.0(1) 55.2(4) 55.2(4) 78.9(6) 171.2(6)

[{PhSn(O)OPhb}6] (3)

Sn(1)-C(42) Sn(1)-O(1) Sn(1)-O(3) Sn(1)-O(5) Sn(1)-O(6) Sn(1)-O(7) Sn(2)-O(4) Sn(2)-O(5) Sn(2)-O(6) Sn(2)-O(7) Sn(2)-O(8) Sn(2)-C(48) Sn(3)-C(31) Sn(3)-O(2) Sn(3)-O(5) Sn(3)-O(6) Sn(3)-O(7) Sn(3)-O(9)

2.122(4) 2.161(3) 2.144(3) 2.080(3) 2.108(3) 2.086(3) 2.138(3) 2.100(3) 2.076(3) 2.078(3) 2.138(3) 2.114(4) 2.116(4) 2.162(3) 2.078(3) 2.083(3) 2.108(3) 2.162(3)

O(5)-Sn(1)-O(7) O(5)-Sn(1)-O(6) O(3)-Sn(1)-O(1) O(5)-Sn(1)-O(1) O(6)-Sn(1)-C(42) O(6)-Sn(2)-O(7) O(6)-Sn(2)-O(4) O(4)-Sn(2)-O(8) O(7)-Sn(2)-O(8) O(5)-Sn(2)-C(48) O(6)-Sn(3)-O(2) O(9)-Sn(3)-O(2) O(5)-Sn(3)-O(9) O(6)-Sn(3)-O(5) O(7)-Sn(3)-C(31)

102.5(1) 77.7(1) 77.0(1) 160.7(1) 180.0(2) 105.3(1) 85.3(1) 78.8(1) 86.9(1) 177.2(1) 87.6(1) 77.7(1) 89.1(1) 101.4(1) 178.4(1)

12

Table IV Complexes 1

2

Type

Sn···O Sn···O/Å Sn···O–C/o 1-D network along the diagonal of the ab-plane Sn1···O5i 3.083 169 D–H···A D–H/Å H···A/Å 1-D network parallel to the b-axis C12–H12B···Cg(1)ii 0.97 2.79 Sn···O Sn···O/Å 1-D network parallel to the b-axis Sn1···O2ii 3.712 D–H···A D–H/Å 1-D network parallel to the b-axis C9–H9B···O1iii 0.97 1-D network parallel to the a-axis C2–H2···O1iv 0.93

Sn···O–C/o

Gad(r) D···A/Å 3.743

D–H···A/o 167

A Gad(r)

2 x C(5)

Sn···O–Sn/o

dnorm B

Gad(r) -

dnorm

139 H···A/Å

119

2.44

3.320

151

2 x C(4)

C

2.78

3.696

168

2 x C(9)

D

D···A/Å

D–H···A/o

D–H···A D–H/Å H···A/Å D···A/Å D–H···A/o 1-D network parallel to the a-axis C12–H12B···O9v 0.97 2.61 3.427 142 C41–H41···O4vi 0.93 2.58 3.323 137 C13–H13B···Cg(4)v 0.97 2.84 3.650 141 intramolecular C(7)–H(7A)···O(1) 0.97 2.60 3.160 117 C(32)–H(32)···O(2) 0.93 2.60 3.094 114 C(41)–H(41)···O(3) 0.93 2.61 3.142 117 a Symmetry codes: (i) –x,–y,–z; (ii) x,1+y,z; (iii) x,–1+y,z; (iv) ½–x,–½+y,½–z; (v) –1+x,y,z; (vi) 1–x,1–y,1–z. 3

b

Hirshfeld surfacee dnorm

Motifc,d

Geometric parameters

Gad(r)

dnorm

Gad(r)

dnorm

2 x C(8) 2 x R22(14) 2 x C(9)

E F G

2 x S(6) 2 x S(5) 2 x S(5)

-

Cg(J) stands for centroid (center-of-gravity) of the jth ring. For 1: J =1, C15-C20. For 3: J = 1, C1-C6; J = 2, C15-C20; J = 3, C21-C26; J = 4, C31-C36; J =

5, C37-C42; J = 6, C43-C48. c

A motif is defined by only one type of hydrogen-bond pattern and can be encoded by Etter’s graph-set assignment Gad(r) [73, 74].

d

In the graph-set assignment of C–H···π interactions, the r value (pattern degree) corresponds to the number of atoms in the repeating unit from hydrogen to

the first carbon atom of the acceptor ring Cg(J), regarding the shortest pathway. e

Hirshfeld surfaces for 1 and 2 mapped with dnorm are depicted in Figure A1. The labels A–G refer to regions of the mapped surfaces which represent a given

noncovalent contact.

13

Table V

[Bu2Sn(OPhb)2] (2)

C. albicans 15.79 ± 1.33

C. tropicalis 50.25 ± 3.80

IC50/ mol L-1 C. parapsilosis C. glabrata 17.69 ± 0.81 99.88 ± 15.90

[{(Me2SnOPhb)2O}2] (1)

97.67 ± 1.05

>48.83 ± 0.87

>97.66 ± 0.28

>97.66 ± 1.05

>97.66 ± 1.02

>97.66 ± 1.10

<1342.80 ± 0.81

<1342.80 ± 1.33

<335.70 ± 2.62

<671.40 ± 0.06

<761.30 ± 1.12

<761.30 ± 2.38

<380.8 ± 1.64

>380.7 ± 2.45

Complexes

NaOPh HOPh

b

b

SnMe2Cl2

<671.40 ± 1.87 <380.70 ± 1.18 -

>761.30 ± 0.91 -

-

C. dubliniensis 35.45 ± 1.79

C. lusitaniae 35.42 ± 2.09

-

-

<1138.00 ± 3.62

-

-

40.75 ± 3.16

SnBu2Cl2

70.13 ± 2.34

168.7 ± 35.4

14.49 ± 0.354

Nystatin

2.77 ± 0.20

2.74 ± 0.05

2.59 ± 0.13

0.56 ± 0.01

4.13 ± 0.08

2.93 ± 0.06

Miconazole nitrate

7.70 ± 0.37

5.05± 0.43

0.0066 ± 0.0019

26.94 ± 1.43

2.744 ± 0.080

2.80 ± 0.13

11

Graphical abstract

The new complexes: [{(Me2SnOPhb)2O}2] (1), [Bu2Sn(OPhb)2] (2) and [{PhSn(O)OPhb}6] (3), (R = Me, Bu or Ph and -OPhb = -O2C(CH2)3Ph (NaOPhb), have been crystallographically authenticated. Complex (1) displays a stannoxane structure, (2) crystallises as a monomer and (3) outlines a hexanuclear drumlike structure comprising two six-membered (-Sn–O-)3 stannoxane rings.

11

12