Explorer Amino acids as highly efficient modulators for single crystals of zirconium and hafnium metal–organic frameworks

The synthesis of zirconium and hafnium metal – organic frameworks (MOFs) often relies on coordination modulation – the addition of competing monotopic modulators to reaction mixtures – to reproducibly generate highly crystalline material. Typically, large excesses of monocarboxylic acids such as formic, acetic and benzoic acid are applied, but access to di ﬀ raction quality single crystals, particularly of UiO-66 topology MOFs, remains troublesome. Herein, we show that amino acids, in particular L -proline, are highly e ﬃ cient modulators of Zr and Hf MOFs of the UiO-66 series, with as little as four equivalents a ﬀ ording access to large, di ﬀ raction quality single crystals that are free of defects. Five crystal structures are reported, including MOFs which previously could not be characterised in this manner, with molecular dynamics simulations utilised to understand dynamic disorder. Additionally, a series of MOFs are characterised in depth, allowing a comparison of the thermal stabilities and porosities for Zr and Hf analogues. We also show that the protocol can be extended to microwave synthesis, and that modulating ability varies dramatically across a series of amino acids. Access to single crystals has facilitated our own in depth study of the mechanical properties of these MOFs, and we expect that our protocols will enable the discovery of new Zr and Hf MOFs as well as o ﬀ er new insights into their materials properties.


Introduction
Metal-organic frameworks (MOFs) are 3D hybrid materials that have received appreciable amounts of interest in recent years 1 as the almost innite combination of inorganic metal clusters and organic spacing ligands achievable allows highly specialised materials to be investigated for use in a wide range of applications including selective gas capture and sequestration, 2 drug delivery 3 and catalysis. 4 Some MOFs have been known to exhibit relatively low chemical and mechanical stabilities, but the use of zirconium, a strong Lewis acid that demonstrates a high affinity for oxygen, results in resilient MOFs as a result of the robust Zr-O bonds that tether the organic and inorganic moieties. 5 Many zirconium MOFs adopt the well-documented UiO-66 framework topology containing Zr 6 O 4 (OH) 4 secondary building units (SBUs) connected by 12 bridging dicarboxylate ligands, thereby expanding to form cubic framework structures containing large octahedral cages and smaller tetrahedral cages. 5b Incorporation of organic ligands that present different coordination environments, including tri-and tetra-topic ligands, into Zr MOFs leads to materials with alternative structures and topologies. 6 Functionalised ligands presenting greater chemical complexity, or bearing a functional group required for specic post-synthetic modication, have been incorporated in the anticipation of producing highly specialised materials. 6b,d,e,7 Hafnium displays similar chemical properties to zirconium; hafnium MOFs are isostructural with their zirconium analogues, where direct substitution of the Zr 6 SBUs by Hf 6 ones is observed. 8 There are fewer reports of hafnium MOFs in the literature, 6i,9 but they have shown great promise in medicinal applications, 10 as well as in catalysis 11 and CO 2 xation. 12 Coordination modulation 13 results in materials with enhanced crystallinity and has recently enabled the isolation of single crystals of zirconium and hafnium MOFs with the UiO-66 topology. 6b,d,e,7c,d,9b,14 This technique usually requires the addition of large excesses of small foreign materials directly to the MOF synthesis, with small monodentate organic compounds, such as acetic acid and benzoic acid, routinely employed. The precise role of the modulator during synthesis is not known, although it is believed that the crystallisation kinetics are altered, introducing reversibility to the system and ultimately resulting in products with improved crystallinity. 15 Preformation of Zr 6 O 4 (OH) 4 (RCO 2 ) 12 building blocks containing the monodentate modulators may also be responsible for the enhanced crystallinity of the resulting MOFs. 14b Under certain conditions, modulation can also promote defect formation, which is prevalent 9d,14f,16 in UiO-66 type MOFs of both Zr and Hf, and these defects can be exploited to confer the MOFs with enhanced gas uptake, 17 proton conduction, 18 mechanical 5f or catalytic 19 properties.
Recently the scope of modulators has been broadened and the role of hydrochloric acid in zirconium MOF synthesis has been investigated. HCl modulation was observed to increase the rate of product formation whilst providing access to otherwise inaccessible materials, therefore it has been postulated that HCl could perform numerous roles during synthesis, including conditioning the DMF solvent or assisting in the pre-formation of Zr 6 clusters. 16b,20 Despite these advances, reliable isolation of X-ray quality single crystals of UiO-66 topology Zr and Hf MOFs remains troublesome, and so we seek to extend the range of potential modulators for both bulk and single crystal syntheses of Zr and Hf MOFs.

Results and discussion
Herein, we fully investigate for the rst time the ability of amino acids to act as modulating agents in the directed synthesis of both zirconium and hafnium MOFs. Amino acids can be viewed as attractive modulating agents as they are readily available small biomolecules and the large diversity of side-chains within these compounds may potentially result in unprecedented modulating properties. We have investigated 21 a comprehensive range of ligands (L1-L8, Scheme 1) and report the inuence of seven amino acids on the crystallinity of the products obtained, which have the general formula [M 6 O 4 (OH) 4 L 6 ] n , where M ¼ Zr 4+ or Hf 4+ , and are referred to as M-L for simplicity. MOF syntheses were carried out to a general synthetic protocol (see ESI, Section S2 †). One equivalent each of MCl 4 and the chosen ligand were dissolved separately in reagent grade N,N-dimethylformamide (DMF), with ve equivalents of the amino acid and one equivalent of HCl added to the metal solution. The solutions were combined (the nal concentrations of metal and ligand being 45 mM), sonicated and heated for 24 h at 120 C. The resultant precipitates were thoroughly washed by DMF and methanol, and vacuum dried. 22 Powder X-ray diffraction (PXRD) analysis was used to determine the extent of formation and crystallinity of the MOFs in comparison to identical control samples with no amino acid added.
Our examination of this broad experimental parameter space showed dramatic improvements in crystallinity of the Zr MOFs of the longer linkers, L5-L8, when certain amino acids were used as modulators; the results for Zr-L5 ( Fig. 1) are representative of the longer linkers. The single crystal structure of Zr-L5 has been reported 9b previously, using 47 equivalents of acetic Scheme 1 Chemical structures of the dicarboxylate ligands, L1-L8, utilised in this study. Fig. 1 Stacked PXRD patterns of Zr-L5 synthesised with different amino acid modulators (five equivalents), compared with Zr-L5 synthesised with one equivalent of HCl only and the pattern predicted from the previously reported crystal structure. 9b An unknown crystalline impurity, marked by an asterisk, was occasionally found in balanine modulated samples. acid as modulator, and comparison of the PXRD patterns of the amino acid modulated syntheses with that predicted from the crystal structure conrm that Zr-L5 is formed cleanly, and that the smaller, more hydrophobic amino acids, in concert with HCl, signicantly enhance the crystallinity of the product in comparison to syntheses using HCl alone. 23 Across the Zr MOFs of L5-L8, L-proline stands out as the most effective modulator, with considerable improvements in the crystallinity of the MOFs (Fig. 2a). SEM images of materials synthesised according to the general synthetic procedure using ve equivalents of L-proline ( Fig. 2b and d) show Zr-L5 and Zr-L7 to form sheets of polycrystalline material, which has been observed previously 24 for Zr-L7, with intergrown crystals of around 5-10 mm for Zr-L5 and up to 50 mm for Zr-L7. In contrast, Zr-L6 and Zr-L8 tend to form discrete octahedral crystals ( Fig. 2c and e), around 10-20 mm in size for Zr-L6 (but with occasional larger crystals up to 60 mm) and 5-10 mm size for Zr-L8, which also forms some spherical polycrystalline assemblies (see ESI, Section S3 †).

Ross Forgan is a Royal Society
In contrast, the synthesis of Zr MOFs of L1-L4, all terephthalate-based linkers, did not show any appreciable benets when amino acid modulation was employed in comparison with samples prepared using HCl alone. The binding of monocarboxylic acids to the zirconium cluster in situ has been proposed to decelerate the rate of crystallisation, through establishing exchange equilibrium with the bridging organic ligands, 15 and so we are unable to account for this unusual, seemingly size-selective phenomenon.
The overwhelming performance exhibited by L-proline directed future modulation studies of zirconium MOFs. Considering our synthetic technique combines HCl and L-proline it was vital to investigate the modulation ability of L-proline in the presence/absence of HCl, considering the recent work detailing the advantages of addition of HCl to zirconium MOF syntheses. 16b,20 Zr-L6 (UiO-67) was used to demonstrate the effect of L-proline modulation (see ESI, Section S4 †). PXRD patterns (Fig. 3a) showed that while addition of one equivalent of HCl alone to solvothermal syntheses was capable of intermittently producing relatively crystalline material, 23 addition of ve equivalents of L-proline consistently produced better quality materials, and a synergistic effect appears to be present when both are incorporated into syntheses. Proline equivalency studies on Zr-L6 (see ESI Section S4 †) revealed that the addition of between 4 and 10 equivalents of L-proline to syntheses alongside HCl resulted in signicantly improved PXRD patterns (Fig. 3b). SEM images of the synthesised materials (Fig. 3c) showed that when two equivalents of L-proline are added to the synthesis, the Zr-L6 that forms is ill-dened with a globular morphology, while samples with between four and ten equivalents of L-proline added to syntheses resulted in well-dened octahedral crystals around 10-20 mm in size.
Examination of both PXRD patterns and SEM images suggest that four to ve equivalents of L-proline and one equivalent of HCl represent the most efficient modulating conditions. Syntheses can also be carried out under microwave heating, 25 with reduced synthesis times (see ESI, Section S5 †). Zr-L6 prepared in 1 h in a single mode microwave cavity, using ve equivalents of L-proline, showed comparable particle size, morphology and porosity to samples prepared by heating for 24 h in the oven.
Further optimisation of the L-proline/HCl modulated conditions allowed the synthesis (see ESI, Section S6 †) of single crystals of many of the MOFs (Fig. 4a-c). High quality single crystals of Zr-L6, approximately 60 mm in size, were synthesised solvothermally, at 120 C in DMF for 24 h, in the presence of 5 equivalents of L-proline and one equivalent of HCl, which is minimal when compared to the large excess of modulators commonly required for effective modulation. Until recently, Zr-L6 had only been isolated as a microcrystalline powder however, during the course of this study single crystals were reported by a number of different groups. Kaskel et al. by 30 equivalents of benzoic acid, 28 while Shar and Gutov reported a similar benzoic acid (30 equivalents) modulated route which included a subsequent "healing" step using additional L6. Our own determination of the crystal structure of Zr-L6 showed it to be very similar to those reported recently (Fig. 4d), with no evidence of defects or diffuse scattering observed. 29 Similarly, L-proline modulation yielded 50-100 mm single crystals of both Zr-L7 and Zr-L8, which have "bent" linkers. Zr-L7 was reported previously in 2012 by Behrens et al., with the use of 30 equivalents of benzoic acid as the modulator resulting in crystalline sheets rather than discrete single crystals, and weak diffraction combined with disorder meaning no crystal structure could be elucidated. 24 A recent catalytic study reported an acetic acid (525 equivalents) modulated synthesis of Zr-L7 that resulted in micron-sized particles. 30 Isolation of discrete octahedral single crystals of Zr-L7 and Zr-L8 was possible using four equivalents of L-proline and one equivalent of HCl in a solvothermal synthesis at 100 C for 48 h in DMF. During repeated syntheses, it was noted that order of addition was key to gaining large single crystals; addition of HCl to a pre-sonicated mixture of the other reagents provided optimal results.
Determination of the crystal structures of the closely related Zr-L7 and Zr-L8 MOFs revealed them to be isostructural (Fig. 4e). Despite the non-linearity of the "bent" azobenzene and stilbene linkers, L7 and L8, the resultant MOFs crystallise in the cubic Fm 3m space group, with the ligands disordered at their  interiors and exhibiting geometric frustration (Fig. 4f). The longer linkers result in larger unit cells; for Zr-L7, a ¼ 29.3248 (8) A and for Zr-L8, the larger value of a ¼ 29.8884(3)Å may be due to the longer length of the C]C bond compared to the N]N bond. 31 Indeed, the separation between the Zr 6 metal clusters, measured from analogous carboxylate oxygen atoms on an individual linker molecule, increases from 13.3104(2)Å in Zr-L7 to 13.5713(1)Å in Zr-L8, illustrating the increase in linker length. Molecular dynamics (MD) simulations were utilised to understand the nature of the disorder in the MOFs and also to elucidate the slight differences in unit cell values (see ESI, Section S7 †). We have previously used MD simulations to characterise the structural properties of Zr-L7 in a communication discussing its mechanical properties, 21 and so analogous calculations were carried out on Zr-L8. The simulations conrm that the increase in unit cell length from Zr-L7 to Zr-L8 is a consequence of moving from an azobenzene to a stilbene linker, and reveal that the geometrically frustrated ligands, L7 and L8, are accommodated in the structures by bowing out of the mirror plane, sitting above and below the plane with bowing angles as high as 10 (Fig. 4g, average value 5(3) , see ESI, Section S7 †). The average effect of this dynamic disorder process, wherein the linkers bend and ip between opposite sides of the mirror plane, is the frustrated linear arrangement as observed in the crystal structure.
The time-averaged structures generated by these simulations show a close correlation to the spatially-averaged disorder in the experimental crystal structures (Fig. 4h), suggesting that the exing of the ligand is responsible for the disorder, and atomic pair-distribution functions derived from the MD trajectory show that the ligand is indeed the most dynamic component of the structure (Fig. 4i). Finally, key bond distances within the Zr 6 clusters of Zr-L8 match closely to those of its solid-state structure and those calculated for UiO-66 (Zr-L1) by Lamberti et al.,16d validating the simulations. The disorder model applied to the structures of Zr-L7 and Zr-L8 is very representative of the bulk material; PXRD patterns predicted from the single crystal structures match the experimental patterns from bulk-synthesised samples closely (see ESI, Section S7 †).
Following effective amino acid modulation of the zirconium MOFs, we investigated the suitability of this technique for the synthesis of their hafnium analogues (see ESI, Section S8 †). We initially sought to investigate the effect of both HCl and L-proline inclusion during the synthesis of Hf-L6, analogous to the control experiments performed for Zr-L6 (Fig. 5a). Surprisingly, HCl alone proved to be an ineffective modulator for synthesis of Hf-L6, even in the quantities found to modulate the synthesis of Zr-L6 by Farha et al., 16b however L-proline is observed to greatly enhance crystallinity. As with Zr-L6, it was observed that a combination of one equivalent of HCl and ve equivalents of L-proline in the synthetic mixture leads to the greatest improvement in crystallinity of Hf-L6, yielding 10-20 mm octahedral crystals instead of amorphous material (Fig. 5b  and c). Subsequently, syntheses of Hf-MOFs of L1-L8 were attempted using HfCl 4 as a replacement for ZrCl 4 in the reaction mixture, and modulated by six different amino acids. 32 As with the zirconium analogues, the greatest enhancement in crystallinity from amino acid modulation is observed for the Hf MOFs of the longer linkers, L5-L8, although para-aminobenzoic acid seems to slightly improve the PXRD patterns of the Hf MOFs of the terephthalate ligands, L1-L4, when it is used as the modulator. For the longer linkers, the incorporation of smaller hydrophobic amino acids into MOF synthesis results in significantly improved crystallinity. L-Proline is again found to be the most effective modulator, although the synthesis of Hf-L8 seems to benet most from inclusion of L-tryptophan.
Single crystals of Hf-L6 suitable for X-ray diffraction were isolated from solvothermal syntheses in DMF at 120 C for 24 h with ve equivalents of L-proline and one equivalent of HCl as modulators (see ESI, Section S9 †). With small modications in the synthesis procedure, it was possible to isolate single crystals of Hf-L7, using three equivalents of L-proline and one of HCl as modulators in a solvothermal synthesis in DMF at 100 C for 48 h. Both MOFs are, as expected, isostructural to their zirconium analogues, with a comparison of some pertinent crystallographic details from the ve structures (Table 1) illustrating the similarities between the Zr and Hf analogues. We have as yet been unable to isolate single crystals of Hf-L8, likely due to the tendency to form spherical microcrystalline architectures when modulated by L-proline in a manner similar to Zr-L8 (see ESI, Section S8 †).
With a range of analogous Zr and Hf MOFs in hand, it was possible to examine their physical properties and similarities. Previous reports of the monocarboxylic acid modulation of Zr-L6 have described 6d, 16a,19,28 incorporation of acid modulators into the structure, postulated to be at defect or surface inclusion sites, and so 1 H NMR spectra of acid-digested samples of Zr and Hf MOFs of L5-L8 were examined for evidence of L-proline incorporation (see ESI, Section S10 †). Only Zr-L5 and Hf-L5 appeared to contain any appreciable quantities of L-proline or its breakdown products, which may be due to their smaller pore size than the other MOFs, although their incorporation at defects or as surface ligands cannot be ruled out. Thermogravimetric analysis (TGA) of the MOFs conrms that the Hf MOFs retain the thermal stability of their Zr analogues (see ESI, Section S11 †), while an additional mass loss event at 350-450 C for Zr-L5 and Hf-L5 is observed that can be ascribed to removal of incorporated L-proline, with a modulator content of 10% w/w calculated for the two analogous MOFs. Subtle changes in TGA proles are evident as the ligand is changed for both the Zr and Hf MOFs, indicating that the organic linker has a role to play in the thermal stability of the MOFs. N 2 adsorption isotherms (see ESI, Section S12 †) carried out at 77 K on the L-proline modulated materials show the high surface areas expected for highly crystalline MOFs (Fig. 6). In the case where the Zr MOFs have been reported previously, 9b,16b,24,30 the BET surface areas closely correlate to those previously measured; 1300 m 2 g À1 (Zr-L5), 2465 m 2 g À1 (Zr-L6), 2830 m 2 g À1 (Zr-L7) and 2950 m 2 g À1 (Zr-L8). The value for Zr-L5 is slightly lower than reported previously by Kaskel et al.
(1400 m 2 g À1 ) 9b which may be a consequence of the presence of L-proline, as indicated by 1 H NMR spectroscopy and TGA. Pore size distributions calculated using QSDFT show an increase in major pore diameter in concert with the increase in linker length. The Hf analogues show decreased gravimetric surface areas in line with the increased mass of Hf compared to Zr, however, the surface areas of Hf-L5 (810 m 2 g À1 ) and Hf-L8 (2020 m 2 g À1 ) are slightly lower than expected based on this mass increase. Interestingly, both of these MOFs display spherical microcrystalline aggregates under SEM imaging, whereas all other MOFs formed either discrete single crystals or lms, but the effect of morphology on accessible surface area has not been further investigated. The BET surface areas of Hf-L6 (1930 m 2 g À1 ) and Hf-L7 (2270 m 2 g À1 ) correlate closely to their corresponding Zr analogues.

Conclusions
To conclude, we report that amino acids, in concert with HCl, can effectively modulate the syntheses of zirconium and hafnium MOFs, enhancing crystallinity and ultimately resulting in the isolation of previously inaccessible MOFs, many as single crystals suitable for X-ray diffraction. Whilst a range of amino acids have been investigated, the greatest success has been achieved using L-proline, which is required in as little as four  (8) a Measured as the separation between opposite carboxylate oxygen atoms of one linker molecule. equivalentsa great reduction when compared with the large excess of modulator routinely required for single crystal synthesis (see ESI, Section S13 †)to offer unprecedented access to defect free single crystals of a number of UiO-66 topology MOFs of both Zr and Hf. 33 The ability to reliably synthesise Zr and Hf MOFs simply and efficiently has allowed us to compare the properties of the analogous materials. We have found that the change in metal has little effect on thermal stability, and N 2 adsorption isotherms show the MOFs have the high surface areas expected from materials of excellent crystallinity. Access to single crystals of Zr MOFs has already facilitated detailed investigations of their mechanical properties by high pressure single crystal X-ray diffraction and nanoindentation, 21 and also single-crystal to single-crystal post-synthetic modication. 14e We expect that adoption of amino acid modulated synthetic protocols, either solvothermally or microwave heated, will result in the improved synthesis of other Zr and Hf MOFs, and we are currently attempting to elucidate the mechanism of modulation while extending the protocol to MOFs linked by other metals.