Synthesis and characterization of hybrid Anderson hexamolybdoaluminates(III) functionalized with indometacin or cinnamic acid

A post-functionalization protocol was used for the synthesis of two new tris-hybrid Al-centred Anderson-type polyoxomolybdates with indometacin or cinnamic acid.


Introduction
Polyoxometalates (POMs), an exceptional class of metaloxide clusters with various compositions, exhibit an oxygenrich surface with strong coordination potential (Pope, 1983). They have attracted much attention owing to their unique catalytic (Wang & Yang, 2015), redox , magnetic (Clemente-Juan et al., 2012) and bioactive properties (Bijelic & Rompel, 2015Molitor et al., 2017;Fu et al., 2015;Bijelic et al., 2018a,b) and constitute promising building blocks for advanced materials. Recently, increasing effort has been devoted to the introduction of organic and metal-organic units into the metal oxide frameworks in order to functionalize POM materials (Dolbecq et al., 2010). Among the various synthetic strategies for the organic functionalization of POMs, alkoxylation has gained much attention due to the diversity and tunability of alkoxyl ligands, especially when using the disk-shaped Anderson-type anions [X n+ H m -M 6 O 24 ] (12-n-m)-(M = Mo 6+ and W 6+ ; X = heteroatom, e.g. Te 6+ and I 7+ for A-type with m = 0, or Al 3+ and Ni 2+ for B-type with m = 6), with a wide spectrum of central heteroatoms (Blazevic & Rompel, 2016;Zhang et al., 2018). In particular, after Hasenknopf et al. (2002) had pioneered and established the synthesis of tris-derivatives of Anderson polyoxomolybdates (POMos), this archetype has been widely used as starting materials for the attachment of various tris [tris(hydroxymethyl)methane]-based organic ligands [RC(CH 2 OH) 3 , denoted R-Tris]. If the R group itself is reactive (-NH 2 , -CH 2 OH etc.), post-functionalization with a variety of organic mol-ecules, including ligands containing aromatic units  or alkyl chains (Rosnes et al., 2013) via imine, amide or ester-bond formation, is possible. The resulting hybrid materials were used in supramolecular self-assembly (Macdonell et al., 2015) or for the formation of metal-organic frameworks (MOFs; Li et al., 2016). Major application fields are bio-inorganic (Yvon et al., 2014), nano-structured (Song et al., 2009), energy storage (Ji et al., 2015), optical (Boulmier et al., 2018) and photochemical (Schaming et al., 2010) materials.

IR spectroscopy
Both compounds were identified by IR measurements on a Bruker Vertex70 IR Spectrometer equipped with a singlereflection diamond-ATR (attenuated total reflectance) unit in the range 4000-300 cm À1 .

1 H NMR
NMR spectra were recorded on a Bruker FT-NMR Avance III 500 MHz instrument at 500.32 ( 1 H) MHz in CD 3 CN at ambient temperature. Chemical shifts were referenced relative to the solvent signal for 1 H nucleus.

Elemental analysis
The determination of C/H/N/O/Cl was carried out using an 'EA 1108 CHNS-O' elemental analyzer by Carlo Erba Instruments at the Mikroanalytisches Laboratorium, University of Vienna.

MIC determination
Minimum inhibitory concentrations (MICs) were determined by the broth microdilution method according to guidelines of the Clinical Laboratory Standards Institute (Wikler, 2009). Double dilutions of tested compounds in 96well microtiter plates were prepared in the concentration range 1-256 mg ml À1 . M. catarrhalis (ATCC 23246) was grown on Columbia agar with 5% defibrinated sheep blood. Inocula were prepared by the direct colony suspension method and plates were inoculated with 5 Â 10 À4 CFU per well. Results were determined by visual inspection after 20-22 h of incubation at 310 K in ambient air. Testing was performed by the standard broth microdilution method with azithromycin Computer programs: APEX2 (Bruker, 2013), SAINT (Bruker, 2013), SHELXS97 (Sheldrick, 2008), SHELXL2018 (Sheldrick, 2015) and OLEX2 (Dolomanov et al., 2009).

Results and discussion
AlMo 6 -NH-Cin and AlMo 6 -NH-Indo were prepared via postfunctionalization by pre-forming the hybrid cluster AlMo 6 -NH 2 which was modified by amidation reactions (Fig. 1). The fact that single-side grafted anions were obtained supports an earlier theory claiming that the aqueous solvent is a key factor for the formation of single-sided Anderson derivatives (Wu et al., 2011;Blazevic et al., 2015;Gumerova et al., 2016).
X-ray crystallographic analysis shows that the asymmetric units in AlMo 6 -NH-Cin and AlMo 6 -NH-Indo consist of the hybrid Anderson anion, three TBA counter-cations, solvent molecules and, in the case of AlMo 6 -NH-Cin, one molecule of quinoline as a by-product from EEDQ decomposition. The structural analysis revealed that both compounds crystallize in the orthorhombic space group Pbca. AlMo 6 -NH-Cin and AlMo 6 -NH-Indo both show the characteristic Anderson-type structure, with a central {AlO 6 } octahedron surrounded by six edge-shared {MoO 6 } octahedra that form a planar array of distorted octahedra (Fig. 1 Table 2 and are in good agreement with other tris-functionalized Anderson POMos (Wu et al., 2011;Al-Sayed et al., 2015;Blazevic et al., 2015).
The crystal packing of AlMo 6 -NH-Cin can be described as alternate layers of POMo anions and TBA counter-cations, which are repeated along the c axis (Fig. 2). The orientations of the hybrid polyanions along the c and b axes also alternate with an angle of approximately 85 between the planes of the inorganic Anderson 'disks' (Fig. 2a). The attached ligands are turned towards each other along the bc plane. The distances between the inorganic POMo skeletons along the a axis are around 9.5 Å , and around 14 Å along the b axis. All four lattice water molecules are situated in front of the undecorated side of the anion and form strong intermolecular hydrogen bonds with 3 -O-H fragments, with short distances in the region 1.85-1.94 Å .

Figure 2
The crystal packing of AlMo 6 -NH-Cin, viewed along (a) the c axis and (b) the a axis. The TBA counter-cations and the solvent molecules have been omitted for clarity. Colour code: {MoO 6 } octahedra orange and {AlO 6 } octahedra yellow, with C atoms black, N blue, H grey and O red. Table 2 Selected bond lengths (Å ) in AlMo 6 -NH-Cin and AlMo 6 -NH-Indo. The crystal packing of AlMo 6 -NH-Indo is similar to that of AlMo 6 -NH-Cin and can be described as alternate layers of POMo anions and TBA counter-cations, which are repeated along the a axis (Fig. 3). The orientation of the hybrid polyanions along the c and b axes is the same, with the grafted sides turned in different directions (Fig. 3b). The distances between inorganic POMos along the a axis are around 12 Å , around 11 Å along the b axis and approximately 5 Å along the c axis. Six of nine lattice water molecules are situated in front of the unfunctionalized side and form strong intermolecular hydrogen bonds with 3 -O-H fragments and O t atoms, with distances in the range 1.86-2.08 Å . The crystallographic refinement results for both AlMo 6 -NH-Cin and AlMo 6 -NH-Indo suggest nointeractions between the aromatic ring and the C C double bond based on geometry and separation.
The IR spectra of AlMo 6 -NH-Cin and AlMo 6 -NH-Indo ( Fig. 4) are typical for Anderson-type POMos and the characteristic peaks of the core structure are all in agreement with the peaks observed in the spectrum of Na 3 (H 2 O) 6 [Al(OH) 6 -Mo 6 O 18 ]Á2H 2 O (Shivaiah & Das, 2005). The stretching vibrations of the terminal Mo O units appear at 939 cm À1 , whereas the peaks in the region from 300 to 920 cm À1 correspond to the antisymmetric and symmetric deformation vibrations of the Mo-O-Mo and Mo-O-Al bridging fragments. The peaks appearing in the region 1030-1125 cm À1 could be assigned to C-O stretching vibrations, indicating the successful grafting of the tris ligands.
The antibacterial activities of AlMo 6 -NH-Cin and AlMo 6 -NH-Indo against the Gram-negative human mucosal pathogen Moraxella catarrhalis (Karalus & Campagnari, 2000) were investigated by determination of the minimum inhibitory concentration (MIC). AlMo 6 -NH-Cin shows a higher activity, with MIC values of 32 mg ml À1 , while AlMo 6 -NH-Indo shows an MIC value of 256 mg ml À1 . The MIC values for both compounds are much higher than for the clinically applied  The crystal packing of AlMo 6 -NH-Indo, viewed along (a) the a axis and (b) the b axis. The TBA counter-cations and the solvent molecules have been omitted for clarity. Colour code: {MoO 6 } octahedra orange and {AlO 6 } octahedra yellow, with C atoms black, N blue, H grey and O red.

Figure 4
The IR spectra of AlMo 6 -NH-Cin and AlMo 6 -NH-Indo in the region from 4000 to 300 cm À1 . drug azithromycin, which has an MIC value of 0.06 mg ml À1 . Taking into account that AlMo 6 -NH-Cin and AlMo 6 -NH-Indo have the same inorganic POMo part, counter-cations and net charge, it can be assumed that their antibacterial activities differs only due to the organic ligands attached. It is known that cinnamic acid and its derivatives exhibit antimicrobial activity against pathogenic and spoilage bacteria (Sova, 2012), indometacin in its turn, as a nonsteroidal anti-inflammatory drug (Lucas, 2016), showed bacteriostatic activity against Helicobacter pylori (Shirin et al., 2006), whereas pure inorganic Ni-and Te-centred Anderson-type POMos and POTs are inactive (MIC > 256 mg ml À1 ) against M. catarrhalis . Thereby, the activity of AlMo 6 -NH-Cin is caused by the synergistic effect of AlMo 6 and cinnamic acid, which is not the case for AlMo 6 -NH-Indo. The preliminary results obtained here show that not only does the activity of the attached ligand play a role, but also synergism with POMs strongly influences the properties of the hybrid compounds.