Rational synthesis of elusive organic–inorganic hybrid metal-oxo clusters: formation and post-functionalization of hexavanadates

Abstract

Paving the way towards new functional materials relies increasingly on the challenging task of forming organic–inorganic hybrid compounds. In that regard, discrete atomically-precise metal-oxo nanoclusters have received increasing attention due to the wide range of organic moieties that can be grafted onto them through functionalization reactions. The Lindqvist hexavanadate family of clusters, such as [V₆O₁₃{(OCH₂)₃C-R}₂]²⁻ (V₆-R), is particularly interesting due to the magnetic, redox, and catalytic properties of these clusters. However, compared to other metal-oxo cluster types, V₆-R clusters have been less extensively explored, which is mainly due to poorly understood synthetic challenges and the limited number of viable post-functionalization strategies. In this work, we present an in-depth investigation of the factors that influence the formation of hybrid hexavanadates (V₆-R HPOMs) and leverage this knowledge to develop [V₆O₁₃{(OCH₂)₃CNHCOCH₂Cl}₂]²⁻ (V₆-Cl) as a new and tunable platform for the facile formation of discrete hybrid structures based on metal-oxo clusters in relatively high yields. Moreover, we showcase the versatility of the V₆-Cl platform through its post-functionalization via nucleophilic substitution with various carboxylic acids of differing complexity and with functionalities that are relevant in multiple disciplines, such as supramolecular chemistry and biochemistry. Hence, V₆-Cl was shown to be a straightforward and versatile starting point for the formation of functional supramolecular structures or other hybrid materials, thereby enabling their exploration in various fields.

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Introduction

Over time, the ability to synthesize increasingly complex chemical structures has begun to blur the line between organic and inorganic materials. The formation of organic–inorganic hybrid materials that synergistically combine the properties of both organic and inorganic components has attracted attention especially for the development of functional materials.¹ Therefore, in recent years, metal-oxo clusters have emerged as valuable building-blocks for the formation of a variety of discrete organic–inorganic hybrid structures. Of the multiple possible hybrid structures, hybrid polyoxometalates (HPOMs) have particularly garnered significant interest due to their applications in catalysis, materials science, energy storage, medicine, and supramolecular chemistry.^2–8 HPOMs are a subclass of a diverse family of discrete anionic metal-oxo clusters, commonly known as polyoxometalates (POMs), that can be covalently grafted with a wide range of organic molecules through the replacement of a metal centre by organophosphorus, organosilicon, organogermanium or organotin species or through replacement of the oxo ligands by alkoxides or amines.^2,9 Such functionalization of metal-oxo clusters with various moieties has already proven beneficial, for example, in enhancing their catalytic activity and efficiency.^10–12 Additionally, organic derivatization has been recently demonstrated as a valuable strategy for addressing important challenges in renewable energy and energy storage.^13,14 Moreover, these hybrid clusters can be regarded as analogues for MO_x hybrid materials such as Metal Organic Frameworks (MOFs) and functionalized metal oxide nanoparticles or surfaces, due to similarities in their structure and electronic delocalization.¹⁵ In fact, several MOFs based on HPOM building units have been reported showing the close connection between such hybrid frameworks and HPOMs.^16–19 However, the discrete atomically-precise structures of HPOMs and their solubility in many different solvents make them easier to study, thereby providing insights about metal-oxo based materials in general. Therefore, the synthetic challenges faced in the formation of MO_x hybrid materials are more easily tackled at the scale of HPOMs. Hence, the synthesis of more complex novel HPOMs is likely to drive progress in many different fields.

Although hybrid metal-oxo clusters have been attracting increasing attention in recent years, the factors that influence their formation in solution are still not well understood. As a result, there is a rather limited selection of HPOMs that can be easily functionalized with various organic moieties. This is particularly the case for the Lindqvist hexavanadate HPOMs, such as [V₆O₁₃{(OCH₂)₃C-R}₂]²⁻ (V₆-R), which due to their interesting chemical and redox properties have been investigated in several fields including catalysis,^10,15 memory devices,²⁰ energy conversion/storage,²¹ supramolecular self-assembly and host–guest chemistry, among others.^22,23 Moreover, these hexavanadate HPOMs have a great structural versatility, since they can be mono-, bis-, tris- or tetra-functionalized with triol ligands, depending on the composition and oxidation state of the metal centres.²⁴ However, despite V₆-R HPOMs being one of the first examples of HPOMs to be reported,²⁵ their synthesis and post-functionalization remain significantly less explored compared to other metal-oxo cluster types.^24,27,28 The relatively limited literature available on V₆-R HPOMs is likely due to the poor yields often obtained during their synthesis and the scarce number of V₆-R HPOMs that can be easily derivatized with a wide range of organic species. Hence, elucidating the formation mechanism of such clusters is essential to address the issues typically encountered during their synthesis.

In general, the synthesis of metal-oxo hybrids with complex organic moieties attached onto the inorganic core is often achieved by starting from a relatively simple building unit with a reactive terminal group that can then be modified through a post-functionalization reaction.²⁷ Therefore, [V₆O₁₃{(OCH₂)₃CCH₂OH}₂]²⁻ (V₆-OH), which can be easily obtained from decavanadate ([H₃V₁₀O₂₈]³⁻; V₁₀) and pentaerythritol ((HOCH₂)₃CCH₂OH),^29,30 is typically used for forming more complex V₆-R HPOMs with various organic moieties through esterification reactions with carboxylic acids and acid anhydrides, but it is not reactive towards many substrates (Scheme 1).^31,32 Alternatively, [V₆O₁₃{(OCH₂)₃CNH₂}₂]²⁻ (V₆-NH₂) can be used as a post-functionalization platform with a more reactive amine terminal group. However, its synthesis from V₁₀ and tris(hydroxymethyl)aminomethane ((HOCH₂)₃CNH₂; Tris-NH₂) typically results in very low yields (Scheme 1),^22,33,34 in contrast to other metal-oxo clusters that have been successfully functionalized with Tris-NH₂.^26,35 Due to this limitation, pre-functionalization of Tris-NH₂ is sometimes used for the direct formation of V₆-R HPOMs, but this also often results in relatively low yields.²⁸ Consequently, there is a need for post-functionalization platforms that can be employed to incorporate various organic functionalities onto V₆-R HPOMs in high yields, thereby driving the formation of new hybrid materials and expanding their potential applications. To achieve this goal, a deeper understanding of the factors that affect the synthesis and modification of these hybrid metal-oxo clusters is still necessary. Hence, by investigating the key factors in the synthesis of V₆-R HPOMs, a novel post-functionalization platform was developed. Moreover, this new HPOM was functionalized with multiple carboxylic acids of varying complexity to demonstrate the versatility of this platform in making the formation of hybrid polyoxovanadates more accessible compared to existing platforms.

Scheme 1 Synthesis of hexavanadate post-functionalization platforms starting from V₁₀ and triol ligands with reactive terminal groups.

Results and discussion

The low yields often obtained in the synthesis of V₆-R HPOMs are typically attributed to the ease of reduction of the V⁵⁺ centres.^22,33,34 However, to the extent of our knowledge, this has not been experimentally confirmed. Nevertheless, previously reported literature procedures suggest that the solvent and the nature of the functional groups on the triol ligand have a significant influence on the outcome of the reaction.^34,36,37 For example, literature reports show that V₆-OH can be easily synthesized in acetonitrile (ACN) and water while V₆-NH₂ can only be obtained directly in dimethylacetamide (DMA) and even in DMA the yield is typically less than 10% unless protecting groups are used.^{22,29,30,33,34} Therefore, in order to understand what happens in solution during the synthesis of V₆-R HPOMs, we set out to study the reactions between V₁₀ and different triol ligands by multinuclear NMR, IR and UV-vis-NIR spectroscopy as well as ESI-MS. Furthermore, the reaction of V₁₀ with (HOCH₂)₃CNHCOCH₂Cl (Tris-Cl) was investigated in detail, since this triol ligand can be easily synthesized in high yields at the gram-scale and its highly electrophilic chloroacetamide functionality can be exploited for nucleophilic substitution. As a result, the Tris-Cl ligand can be leveraged for post-functionalization with a wide variety of carboxylic acids, amines and thiols, as has been previously demonstrated by our group with other hybrid metal-oxo clusters.^38–40 Moreover, the high electrophilicity of the chloroacetamide carbon, and the S_N2 mechanism favoured under polar aprotic conditions, allow for easier substitution reactions with relatively bulky or less nucleophilic substrates than with V₆-OH and its derivatives. Additionally, the insights gained from following the reaction of V₁₀ with various triol ligands were used to optimize the procedure for the synthesis of TBA₂[V₆O₁₃{(OCH₂)₃CNHCOCH₂Cl}₂] (V₆-Cl) as a novel post-functionalization platform formed from Tris-Cl and V₁₀ (Scheme 1).

Elucidating the impact of ligand functionalities

Following changes in the speciation of reaction mixtures of V₁₀ in the absence or in the presence of three triol ligands by multinuclear NMR, IR, UV-vis-NIR and ESI-MS gave distinct results depending on the triol ligand: (HOCH₂)₃CCH₃ (Tris-CH₃), Tris-NH₂, or Tris-Cl. This demonstrates the important role of the ligands and the nature of their terminal group as critical factors in determining the outcome of the reaction (Scheme 2). Although Tris-CH₃ and Tris-NH₂ have very similar structures, simply switching the methyl group for an amine had a major effect on the speciation of vanadates in solution. With Tris-CH₃, the desired hexavanadate structure, [V₆O₁₃{(OCH₂)₃CCH₃}₂]²⁻ (V₆-CH₃), was observed to gradually form over time from the appearance of characteristic peaks in NMR and ESI-MS spectra while the peaks due to V₁₀ disappeared (Fig. S1, S3, S14 and Table S6†).^29,41 In contrast, when V₁₀ was reacted with Tris-NH₂ several peaks appeared in the ⁵¹V NMR spectrum within 0.5 h of heating (Fig. S1†), indicating that multiple vanadate species formed, with the main species being [V₁₂O₃₂]⁴⁻ (V₁₂) and [V₁₃O₃₄]³⁻ (V₁₃).^42,43

Scheme 2 Speciation of V₁₀ in ACN after heating at 80 °C for 0–24 h: (a) alone or with (b) Tris-CH₃, (c) Tris-NH₂ or (d) Tris-Cl.

The formation of V₁₂ and V₁₃ in the presence of Tris-NH₂ may be due to the poor solubility of Tris-NH₂ in ACN (Table S2†), especially in comparison with Tris-CH₃, since the conversion of V₁₀ into V₁₂ and V₁₃ was also observed when V₁₀ was heated at 80 °C on its own in ACN (Scheme 2 and Fig. S1, S2†). Furthermore, V₁₂ eventually became the main species in solution based on ⁵¹V NMR (Fig. S1†) and on negative mode ESI-MS (Fig. S14 and Table S5†). Similarly, the IR spectrum of V₁₀ alone after heating gave rise to characteristic peaks of V₁₂ between 1200 and 400 cm⁻¹ that were also observed after heating with Tris-NH₂ (Fig. S11†).⁴³ Therefore, it is likely that in the reaction with Tris-NH₂, only a small amount of the triol was present in solution at any given time, which reacted with V₁₀ to form other vanadate species that gave rise to several peaks around 5 ppm in the ¹H NMR spectrum (Fig. S4†) along with additional peaks in the ⁵¹V NMR spectrum. These are likely caused by Tris-NH₂ reacting with V₁₀ through both the –OH and –NH₂ groups, since reacting with just the –OH groups would result in the formation of the desired hexavanadate as observed for Tris-CH₃. In addition, over time, the peaks observed by ⁵¹V NMR gradually disappeared, except for a peak at −498 ppm, which may correspond to V₆-NH₂. However, this peak is relatively weak. Therefore, together with the IR and ESI-MS spectra (Fig. S14 and Table S7†), this suggests that V₆-NH₂ is only present in low concentration after 120 h.

In contrast, the reaction of V₁₀ with Tris-Cl did not give rise to observable peaks (Fig. S1†) corresponding to V₁₂ and V₁₃ in the ⁵¹V NMR spectra, which may be due to the higher solubility of Tris-Cl in ACN with respect to Tris-NH₂ (Table S2†). Instead, two broad peaks were observed to appear at −228 and −294 ppm in the ⁵¹V NMR spectrum of the reaction mixture (Fig. S1†), which correspond to V environments that are more deshielded than expected for fully oxidized vanadates with oxo or alkoxo ligands.⁴⁴ Hence, these new peaks may be due to paramagnetic shifting of V⁵⁺ centres in mixed valence vanadates or due to coordination of the ligand to V⁵⁺ centres through nitrogen.⁴⁴ Furthermore, as with Tris-NH₂, the reactions of vanadate species with the Tris-Cl ligand resulted in the gradual disappearance of most peaks observed by ⁵¹V NMR except for two weak peaks: one at −364 ppm, belonging to VO₂Cl₂⁻ formed through the decomposition of Tris-Cl, and another at around −498 ppm, likely due to V₆-Cl present in low concentration (Fig. S1†).⁴⁴ Likewise, the presence of V₆-Cl in low concentration together with side-products after 120 h could be observed by ¹H NMR (Fig. S5†). These changes observed by NMR can be attributed to reduction of V⁵⁺ centres to form mixed valence species.

The formation of mixed valence vanadates in the presence of Tris-NH₂ or Tris-Cl is confirmed by the observed change in colour of the solutions over time from orange/yellow (typical of V⁵⁺) to dark green, which is indicative of the reduction of some V⁵⁺ centres to form a mixture of V⁵⁺ and V⁴⁺.^16,45 This was confirmed by the appearance of a characteristic peak in the absorbance spectrum at around 900 nm due to an Intervalence Charge Transfer (IVCT) between V⁴⁺ and V⁵⁺ (Fig. 1 and Tables S3, S4†). Since the appearance of this IVCT broad peak is not as noticeable for V₁₀ alone or in the presence of Tris-CH₃ (Fig. 1 and S10†), the reduction of V⁵⁺ is most likely due to N–H⋯O–V interactions. Such N–H⋯O–V interactions have indeed been recently reported in crystal structures of V₁₀ with Tris-NH₂.⁴⁵ Furthermore, a similar reduction process has been proposed to result in the photoinduced reduction of alkylammonium salts of molybdates and is likely responsible for the reduction of NH₄VO₃ by the NH₄⁺ counterion during its thermal decomposition.^46–48

Fig. 1 UV-vis-NIR absorbance spectra of V₁₀ with (a) Tris-CH₃, (b) Tris-NH₂, or (c) Tris-Cl after 0 h at room temperature (r.t.) and after 0.5, 24, and 120 h at 80 °C, with the broad IVCT peak shown in the insert.

Reduction of V⁵⁺ may take place through the transfer of the N–H proton onto the oxo ligands of V₁₀ or other vanadates that may form in solution.³⁴ This likely occurs through a similar process to the formation of mixed valence or fully reduced V₆-R HPOMs with protonated μ₂-O ligands in the presence of hydrazine derivatives and organic acids, which has been reported to involve a proton-coupled electron transfer (PCET).^15,29,34,49 However, since the structure of the side-products could not be identified, the exact nature of the reduction mechanism could not be unambiguously determined. Nevertheless, it can be concluded that the main product for the reaction of Tris-Cl and Tris-NH₂ with V₁₀ in ACN is not the desired V₆-R HPOMs because of side-reactions giving rise to reduced vanadate species. This is evidenced by ESI-MS and IR spectroscopy (Fig. S11, S12, S14 and Tables S7, S8†), which after 120 h at 80 °C mainly showed peaks that did not correspond to the desired hexavanadates. Moreover, this indicates that the yield of V₆-R HPOMs depends highly on how the speciation of vanadates is affected by the ligand's availability in solution and the reactivity of its functional groups.

Investigating the role of the solvent

Since DMA has also been previously reported as a solvent in optimized procedures,^36,37 in this work the impact of the solvent on the formation of V₆-Cl was investigated further. In doing so, the use of DMA as the solvent for the synthesis of V₆-Cl was determined to be crucial for obtaining the product in relatively high yields, since the attempted synthesis in ACN or in water, following the typical procedures used for the formation of hexavanadates, resulted in many side products, which hindered the isolation of V₆-Cl.^29,30 The differences in the reaction of V₁₀ with Tris-Cl in ACN vs. in DMA can be seen from the ¹H and ⁵¹V NMR spectra of aliquots obtained over 20 h, which showed more intense peaks corresponding to V₆-Cl when the reaction was conducted in DMA (Fig. 2 and S7†). This means that the formation of V₆-Cl is more favourable in DMA, which may be in part due to the higher solubility of Tris-Cl in this solvent (Table S2†). Furthermore, when V₁₀ is heated at 80 °C in DMA without any triol ligands, the speciation is quite different from that in ACN (Fig. S6†). While the V₁₂ structure is highly favoured in ACN, V₁₃ is the main species in DMA along with multiple other vanadate species of lower nuclearity, ranging from V₁ to V₅, which gradually disappear over time.⁴⁴ This suggests that the vanadate structures are more labile and prone to interconversion in DMA than in ACN, generating a dynamic library of interconverting vanadate building blocks, which may also facilitate the formation of hexavanadates in DMA.

Fig. 2 (a) Synthesis of V₆-Cl from V₁₀ and Tris-Cl along with the corresponding ¹H NMR spectra of aliquots of the reaction mixture after heating at 80 °C for 0 and 20 h in (b) DMA or (c) ACN. All spectra were acquired for solutions in ACN-d₃ of the precipitate formed by addition of excess of diethyl ether to the aliquot.

It was also observed that changing the solvent had an impact on the ability of V⁵⁺ centres to be reduced. The cyclic voltammogram (CV) of V₆-Cl in either ACN or DMA (Fig. 3(a)) shows a similar reversible reduction/oxidation wave due to the V⁵⁺/V⁴⁺ redox couple in both solvents, but the half-wave potential (E_1/2) is more negative in DMA compared to in ACN: −1.01 and −0.80 V vs. Fc/Fc⁺, respectively.⁵⁰ Similarly, V₆-CH₃ gives rise to reversible reduction/oxidation waves with E_1/2 of −1.07 and −0.92 V vs. Fc/Fc⁺ in DMA and in ACN, respectively (Fig. S18†). Hence, the reduction of V⁵⁺ occurs more easily in ACN. This solvent-induced shift in E_1/2 is likely due to the higher Lewis acidity of ACN, as reflected by the Gutmann acceptor number of ACN (18.9) being higher than that of DMA (13.6).⁵¹ Furthermore, these results are in agreement with the previously reported trend in the redox potential of tungstate POMs in different solvents.^52,53 However, the solvent-induced shift in E_1/2 is greater for V₆-Cl (215 mV) than for V₆-CH₃ (150 mV), which may be linked to the N–H⋯O–V interactions observed in the crystal structure obtained by crystallization in ACN (Fig. 3(c)) since protonation of oxo ligands in the vanadate clusters has been shown to result in shifts towards lower potentials.²⁹ In contrast, the crystal structure of a similar V₆-R HPOM with an amide group obtained by Bamba et al. in DMA shows that DMA forms H-bonding interactions between its C=O group and the –NH group of the ligand, thereby preventing N–H⋯O–V interactions from occurring.⁵⁴ Therefore, reduction of V⁵⁺ induced by transfer of the proton from the ligand is less likely to occur in DMA than in ACN, making it overall a more suitable solvent.

Fig. 3 (a) CV of 0.5 mM V₆-Cl in ACN vs. in DMA with 0.1 M TBA-PF₆ as the electrolyte (100 mV s⁻¹). (b) Structural representation of V₆-Cl viewed along the crystallographic b axis and (c) crystal packing of V₆-Cl into a 1D H-bond network (H-bond distances shown as dashed grey lines). The counter ions were omitted from the structural representations for clarity. Hydrogen in white, carbon in brown, nitrogen in light blue, oxygen in red, chlorine in green and vanadium in orange.

Isolation and characterisation of V₆-Cl

Through optimization of the synthesis and purification procedures based on the insights obtained by following the reactions of the triols, it was possible to obtain V₆-Cl directly from V₁₀ and Tris-Cl in relatively high yield after reacting in DMA at 80 °C under an argon atmosphere for 5 days. However, despite the synthesis of V₆-Cl being more successful in DMA than in ACN, some side reactions resulting in the reduction of V⁵⁺ do still occur, as evidenced by the observed colour change of the solution. This is due to the formation of a mixture of the desired fully oxidized V₆-Cl and mixed valence V₆-Cl. Nevertheless, through the removal of DMA by rotary evaporation and the addition of a minimal amount of ACN, the mixed valence species were preferentially dissolved, forming a green solution, and the pure fully oxidized V₆-Cl could be separated by centrifugation as an orange crystalline solid. Furthermore, the mixed valence V₆-Cl in the green supernatant was successfully oxidized into the desired fully oxidized V₆-Cl by the addition of 35 wt% H₂O₂. Additionally, washing with water as well as re-precipitation with ACN/Et₂O and MeOH/Et₂O allowed for further purification of the re-oxidized sample as described in the SI. Moreover, through this re-oxidation and purification procedure the yield was increased to 61%.

The composition of V₆-Cl in high purity in the combination of the first fully oxidized sample and the re-oxidized sample was confirmed by ESI-MS, NMR, IR, and elemental analysis (Fig. 4). ESI-MS gave a peak at m/z = 1145.8 in negative mode, corresponding to V₆-Cl with only one TBA counter cation ([V₆-Cl + TBA]⁻; calcd. m/z = 1145.3) while in positive mode it gave a peak at m/z = 1630.1 that can be attributed to the POM with three TBA counter ions ([V₆-Cl + 3TBA]⁺; calcd. m/z = 1630.2). Furthermore, ¹H NMR showed a downfield shift from 3.57 ppm for Tris-Cl to 5.11 ppm for V₆-Cl, corresponding to the –CH₂O– group of the triol ligand becoming grafted onto the V₆ POM core, while ⁵¹V NMR gave a single peak at −494 ppm that is characteristic of trans-functionalized hexavanadates.^34,54 Furthermore, the peaks in the IR spectrum in the range 700–1000 cm⁻¹ are characteristic of ν V=O and ν V–O–V vibrations of the V₆ POM core, while the peaks at 1114 and 1063 cm⁻¹ due to ν C-O vibrations confirm the successful attachment of the triol ligands.^30,55 The exact structure of V₆-Cl was further confirmed by single crystal X-ray diffraction (SC-XRD). V₆-Cl crystallized in the triclinic space group P̄1 with half of one POM and one TBA cation in the asymmetric unit. The obtained crystal structure (Fig. 3(b)) shows a classical Lindqvist structure composed of six edge sharing {VO₆} octahedra in an octahedral arrangement. Moreover, two Tris-Cl moieties are attached on opposite faces of the V₆ POM core via three double-bridged oxygens (μ₂-O) each. In addition, V₆-Cl was observed to form a 1D H-bond network due to H-bonding interactions between the –NH group of the amide and a terminal oxygen of the V₆ POM core with N⋯O distances of 2.91 Å (Fig. 3(c)). Overall, the crystal structure together with the complementary spectroscopic techniques unambiguously confirm the formation of this novel post-functionalization platform.

Fig. 4 (a) ¹H NMR spectrum of V₆-Cl in DMSO-d₆ as well as (b) negative mode and (c) positive mode ESI-MS spectra of V₆-Cl in ACN.

Post-functionalization of V₆-Cl

The potential of V₆-Cl as a valuable post-functionalization platform was evaluated via nucleophilic substitution reactions with different carboxylic acids: valeric acid, phenylacetic acid, adamantanecarboxylic acid, and biotin (Scheme 3). These carboxylic acids were selected to showcase the applicability of this post-functionalization strategy to yield compounds with widely different functionalities. Furthermore, functionalities that are of interest in supramolecular chemistry were chosen since HPOMs have been shown to produce new dynamic supramolecular structures that often result in enhanced properties.⁸ Consequently, four novel V₆-R HPOMs were synthesized from V₆-Cl and the aforementioned carboxylic acids: TBA₂[V₆O₁₃{(OCH₂)₃CNHCOCH₂-R}₂] where R = –OOC(CH₂)₃CH₃ (V₆-Val), –OOCCH₂C₆H₅ (V₆-Ph), –OOCC₁₀H₁₅ (V₆-Ad), and –OOCC₉H₁₅N₂OS (V₆-Biot).

Scheme 3 Post-functionalization of V₆-Clvia nucleophilic substitution with valeric acid, phenylacetic acid, adamantanecarboxylic acid, and biotin to form V₆-Val, V₆-Ph, V₆-Ad, and V₆-Biot (top to bottom).

The nucleophilic substitution reactions were performed by mixing V₆-Cl with tetrabutylammonium iodide (TBA-I), a carboxylic acid and a base in dry DMA for 2–5 h at 80 °C. Either Na₂CO₃ or tetrabutylammonium hydroxide (TBA-OH) were used as the base and both successfully promoted the nucleophilic substitution reaction. Na₂CO₃ was found to be more suitable for post-functionalization of V₆-Cl since hydrolysis of the ester bond after post-functionalization was observed by ESI-MS if the solution was left stirring for too long when using TBA-OH (Fig. S15–S17†). As a result, the yield and the purity of the product were generally higher with Na₂CO₃ than with TBA-OH. For example, the synthesis of V₆-Ad gave a yield of 42% with TBA-OH while with Na₂CO₃ the yield was 50%. Nevertheless, when using Na₂CO₃, a small amount of the Na salt of the HPOM or mixed salts were sometimes obtained, but these could be easily converted back to the desired TBA salt by the addition of excess tetrabutylammonium bromide (TBA-Br). Hence, once the reaction conditions were optimized, post-functionalization of V₆-Cl resulted in yields of around 50% or higher overall.

It is worth noting that the post-functionalization of V₆-Cl with all selected carboxylic acids was possible despite their differences in steric hindrance and functionality. However, the nature of the organic species being used can have an impact on the outcome of the reaction. This was especially noticeable during the synthesis of V₆-Ph since the solution turned green due to the formation of mixed valence V₆-Ph. Hence, in order to obtain the desired fully oxidized V₆-Ph, an additional oxidation step with H₂O₂ was required. The higher propensity of V₆-Ph towards reduction over the other V₆-R HPOMs reported in this study is likely due to the ability of the aromatic ring to transfer electrons to the POM.⁵⁶ Additionally, reduction of the V₆ core may be favoured by the stabilising electron-withdrawing inductive effect of the aromatic group.^50,57 This resulted in a slightly lower yield for V₆-Ph compared to other V₆-R HPOMs. In contrast, V₆-Biot was successfully obtained in relatively high yield, even when using TBA-OH as the base. This is significant because the attempted post-functionalization of V₆-OH with biotin via esterification – using N,N′-dicyclohexylcarbodiimide (DCC) as the coupling agent and 4-dimethylaminopyridine (DMAP) to promote the reaction – was unsuccessful, and the previously reported esterification with stearic acid only gave a relatively low yield (10%).³¹ This shows the limitations of V₆-OH as a post-functionalization platform. Furthermore, modifications of the platform to improve its reactivity, such as the incorporation of an alkyne terminal group that has been reported to allow for the attachment of biotin in high yields via Huisgen 1,3-cycloaddition, are often not as straightforward as the single-step synthesis of Tris-Cl.^55,58 Therefore, this highlights the versatility and accessibility of V₆-Cl for the derivatization of hexavanadates with a wide range of different species to obtain new V₆-R HPOMs in reasonable yields.

Successful post-functionalization of V₆-Cl to form and isolate V₆-Val, V₆-Ph, V₆-Ad, and V₆-Biot was confirmed by ¹H NMR (Fig. S8†) from the disappearance of the peak at around 12 ppm due to the –COOH environment and a downfield shift in the chemical shift of the –COCH₂– group from 4 ppm to around 4.45 ppm due to the chloro (–Cl) functionality being substituted by the carboxylate (–OOC–). The chemical shift and integration of the other peaks in the spectra of each compound were also consistent with the attachment of the carboxylate moieties to both tripodal anchors on the V₆ HPOM (Fig. S8 and S9†). Furthermore, ⁵¹V NMR (Fig. S8†) showed that the V₆ POM core structure remained intact after the post-functionalization, giving rise to a single peak at around −495 ppm for all compounds. This was further confirmed from the characteristic peaks at around 700–1000 cm⁻¹ in the IR spectra of the compounds due to ν V=O and ν V–O–V vibrations (Fig. S13†). Negative ion mode ESI-MS also showed peaks corresponding to the molecular ions of the POM alone (M²⁻) or with one TBA counter cation ([M + TBA]⁻) for each compound. Peaks in positive ion mode due to the POM with extra TBA counter cations ([M + 3TBA]⁺) were also observed for the POMs with molecular weights within the measurement range. Moreover, the crystal structure of V₆-Val (Fig. 5), obtained from crystals formed by slow evaporation of a solution of V₆-Val in CHCl₃, matched that of V₆-Cl with Cl replaced by the carboxylate. However, unlike V₆-Cl, V₆-Val crystallized in the monoclinic P2₁/c space group. Yet, V₆-Val also formed a 1-D H-bond network due to H-bonding interactions between the –NH group of the amide bond and a terminal oxygen of the hexavanadate POM core with N⋯O distances of 2.88 Å (Fig. 5(b)). Furthermore, aside from having two TBA molecules per hexavanadate unit as expected, two chloroform molecules per hexavanadate unit were also present in the unit cell (Fig. 5(a)). Overall, this confirms the successful post-functionalization of V₆-Cl with carboxylic acids.

Fig. 5 (a) Structural representation of V₆-Val showcasing the relative position of the CHCl₃ and TBA molecules with respect to V₆-Val in the crystal structure (two of each per hexavanadate unit that are symmetrically equivalent). (b) Crystal packing of V₆-Val into a 1D H-bond network (H-bond distances shown as dashed grey lines) viewed along the crystallographic b axis without showing the TBA counter ions and CHCl₃ for clarity. Hydrogen in white, carbon in brown, nitrogen in light blue, oxygen in red, chlorine in green and vanadium in orange.

Conclusions

In this work, an in-depth investigation of the factors that affect the synthesis of hexavanadates was leveraged to develop V₆-Cl as a novel post-functionalization platform. The study showed that the low yields often observed in the synthesis of hexavanadates are linked to the solution properties of the ligand and the reactivity of its functional groups, both of which affect the speciation of vanadates in solution. In general, the formation of a suitable post-functionalization platform requires a ligand with a reactive terminal group, however this may also cause undesired side reactions. Overall, the key factors influencing the synthesis of hybrid hexavanadate clusters were determined to be: (i) the reactivity of the terminal group of the organic ligand with respect to vanadate species in solution, (ii) the solubility of the organic ligand, (iii) the interactions of the solvent with the ligand, which can prevent side reactions, and (iv) the Lewis acidity of the solvent, which affects the ease of reduction of V⁵⁺. Controlling these factors was shown to be crucial for the facile, one-step synthesis of V₆-Cl in relatively high yields from a decavanadate cluster and Tris-Cl, using DMA as the solvent. We also showed that V₆-Cl could be easily post-functionalized with a wide range of carboxylic acids that differ significantly in composition and complexity. The formation of such (bio)organic hybrids with biomolecules, such as biotin, in particular may have potential for the development of antitumor, antiviral, anticancer and anti-amyloid agents,^7,59–62 while adamantane derivatives could be used for drug carrier systems in combination with cyclodextrin, among many other possible applications.^{23,61,63–67} Furthermore, this post-functionalization strategy can be extended to functionalization with other organic moieties or even other inorganic clusters, resulting in novel hybrid metal-oxo clusters for potential use in catalysis, medicine and molecular magnetism.^{8,10,23,68–70} Hence, through the successful synthesis of V₆-Cl as a novel, accessible, and versatile starting point for the formation of various hybrid structures the range of potential applications of polyoxovanadates can be expanded.

Data availability

Crystallographic data for compounds V₆-Cl and V₆-Val has been deposited at The Cambridge Crystallographic Data Centre (CCDC) and allocated the deposition numbers CCDC 2217991 and 2217992, respectively. All other data supporting the results discussed in this work is available within the paper and its ESI.†

Author contributions

D. E. S. M. and G. K. performed the synthesis and characterisation of all compounds with the assistance of M. A. M. K. V. H. solved the crystal structures. T. N. P.-V. and M. A. M. helped with the design and interpretation of the experiments. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank KU Leuven and the Research Foundation Flanders (FWO) for funding. D. E. S. M. (1183021N), G. K. (1185522N) and M. A. M. (1279721N) thank the FWO for PhD and post-doctoral fellowships.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2217991 and 2217992. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc00038a

‡ Authors contributed equally to this work.

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