Insights into Functionalization of Metal-Organic Frameworks Using In Situ NMR Spectroscopy

Postsynthetic reactions of metal-organic frameworks (MOFs) are versatile tools for producing functional materials, but the methods of evaluating these reactions are cumbersome and destructive. Here we demonstrate and validate the use of in situ NMR spectroscopy of species in the liquid state to examine solvent-assisted ligand exchange (SALE) and postsynthetic modification (PSM) reactions of metal-organic frameworks. This technique allows functionalization to be monitored over time without decomposing the product for analysis, which simplifies reaction screening. In the case of SALE, both the added ligand and the ligand leaving the framework can be observed. We demonstrate this in situ method by examining SALE and PSM reactions of the robust zirconium MOF UiO-67 as well as SALE with the aluminum MOF DUT-5. In situ NMR spectroscopy provided insights into the reactions studied, and we expect that future studies using this method will permit the examination of a variety of MOF–solute reactions.

of UiO-67 with various solvents and chemicals 34 . Prior to monitoring SALE in UiO-67 using in situ 1 H NMR, we first considered some practical issues. In order to obtain quantitative information about dissolved species, it is essential to avoid relaxation-weighted NMR intensities; thus, the repetition delay was optimized prior to gathering reaction data. Further, in order to minimize the effect of mass transfer on reactions in the NMR tube, the MOF was ground before use. Finally, the multiphase SALE reaction can only be followed by in situ 1 H NMR if the exchanging linker is present in the liquid state, rather than adsorbed on or in the MOF. To test whether this was the case, we measured the room-temperature ex situ 1 H NMR spectrum of a solution of bpdc in deuterated dimethylsulfoxide (DMSO-d 6 ) with an internal standard, before and after the addition of 2 mg UiO-67-bpdc. The measured intensity of bpdc fell by ~9% after the MOF was added, indicating that only a small amount of linker was adsorbed under these conditions; even less adsorption is expected at the higher temperatures used in SALE (vide infra).
Having confirmed that bpdc is observed by ex situ 1 H NMR in the presence of UiO-67, we monitored SALE between UiO-67-bpdc and bpydc in real time using in situ 1 H NMR. In the following discussion, we do not distinguish the neutral and the singly and doubly deprotonated forms of the ligands; rather, we use the extension (sol) to indicate any form of the ligand that was initially present in solution, and (frame) to indicate any form of the linker that was initially present in the MOF. In each reaction, ground UiO-67-bpdc was combined with a solution of bpydc (sol) in an NMR tube to give a mixture with linker (frame) :linker (sol) in the range 0.5-1.5. The NMR tube was immediately inserted into the NMR probe, which had been preheated to 57 °C. In situ 1 H NMR spectra collected throughout the reaction showed the disappearance of bpydc (sol) as it was either adsorbed onto or incorporated into the MOF, concurrently with the appearance of bpdc (frame) in solution (Fig. 1). As the sample remained in the NMR spectrometer for the duration of the experiment, no standard solution was necessary. No peaks associated with acetic acid, the modulator used to prepare UiO-67-bpdc (see Supporting Information, section S3), were detected.
The rate of linker exchange between UiO-67-bpdc and bpydc (sol) depended strongly on solvent (Fig. 2) and was slowest in DMSO-d 6 . The reaction was slightly faster in a mixture of DMSO-d 6 and C 6 D 6 (37 mol% DMSO-d 6 ) than in DMSO-d 6 alone. This observation could be partially due to the comparably higher viscosity of DMSO-d 6 , which is estimated to permit linker diffusion at just over half the rate that is possible in the DMSO-d 6 /C 6 D 6 mixture (Supporting Information); however, DMSO-d 6 also clearly produces a lower reaction rate. This solvent cannot be omitted entirely as neither bpdc nor bpydc is soluble in C 6 D 6 . SALE between UiO-67-bpdc and bpydc (sol) was fastest in deuterated dimethylformamide, (DMF-d 7 ), and the reproducibility of the in situ 1 H NMR measurement was confirmed in this solvent (Fig. S5). In all cases, the disappearance of bpydc (sol) from solution in the presence of UiO-67-bpdc followed pseudo-first-order kinetics (Fig. S6).
Although the substitution of bpydc (sol) into UiO-67-bpdc was much faster in DMF-d 7 than in DMSO-d 6 , both reactions eventually reached a steady degree of exchange (40-45% under these conditions). This illustrates an important point for SALE; if sufficient time is provided, the extent of exchange can be determined by thermodynamic factors, i.e. the relative stability of the linkers in the MOF and in the solution. DMF-d 7 and DMSO-d 6 are both polar aprotic solvents, and thus it is reasonable that similar degrees of exchange are reached from the same starting point in both solvents. The degree of exchange could be different for other linker pairs and in other solvents, and in situ NMR offers a convenient method to examine the multiple sets of reaction conditions using  S7) demonstrated that the degree of exchange could be raised to 56% by raising the bpydc (sol) : bpdc (frame) ratio from 0.57 to 1.4. SALE can also be relevant in the construction of MOFs bearing catalytically active complexes; in fact, such MOFs can be produced via several routes. For example, iridium-containing MOFs have been synthesized directly using iridium complexes with ligands bearing carboxylate groups as linkers 35,36 , but have also been synthesized using a mixture of linkers 25,26 or via the postsynthetic modification of a MOF 36,37 . Martín-Matute, Zou, and co-workers have observed the undesired demetallation of Ir-containing MOFs (a side reaction that is easily detected by liquid-state 1 H NMR) under some reaction conditions 27 . We therefore investigated the exchange of bpdc (frame) in UiO-67-bpdc with [Cp*Ir(bpydc)(Cl)]Cl (we hereafter denote [Cp*Ir(bpydc)Cl] + , as well as its analogues that are singly and doubly deprotonated at the carboxylic acids, collectively as Ir-bpydc) in CD 3 OD (Fig. 3). We found that 6.4 and 5.6% of the bpdc (frame) were replaced with functionalized linker for starting linker (sol) :linker (frame) ratios of 0.82 and 0.41, respectively. No additional 1 H NMR peaks consistent with Cp*Ir-containing species were observed over the course of the 30-h reaction, which indicates that no demetallation occurred. Further, no exchange was observed between UiO-67-bpdc and Ir-bpydc (sol) in DMSO-d 6 or ethanol-d 6 .
In order to compare the results obtained from reactions performed in NMR tubes to the larger-scale methods conventionally used for SALE, we performed two types of ex situ experiments. First, the reaction of UiO-67-bpdc with bpydc (sol) in DMSO-d 6 was scaled up sevenfold and performed in vials. The mixture was stirred with magnetic bars. Aliquots were removed from the reaction mixture and analyzed by 1 H NMR spectroscopy (Fig. 4, filled symbols). The ex situ and in situ measurements produced very similar results. In two experiments scaled up to 50-60 mg MOF, UiO-67-bpdc was combined with bpydc (sol) in non-deuterated DMSO and DMF for 24.5 and 18 h, respectively. The products were filtered and washed with ethanol, and the resulting solids were examined using powder X-ray diffraction and N 2 sorption (Supporting Information, Figs S2 and S4) to confirm that the crystalline and porous structure of the MOF were retained. The solids were then examined using solid-state 1 H NMR spectroscopy (Supporting Information, Figs S9 and S10). The material exchanged in DMSO contained 41% bpydc, the same fraction calculated from the in situ experiment (Fig. 2, circles). In DMF, the product was 45 and 53% bpydc when observed ex situ and calculated from in situ data, respectively. The minor discrepancy between the values in and ex situ in DMF likely occurs because the 1 H NMR peaks for bpdc overlap with that for the aldehyde proton in DMF, complicating their integration. Thus overall, monitoring the reaction of UiO-67-bpdc with bpydc (sol) using in situ 1 H NMR proved a convenient method to obtain data that was consistent with observations made on larger scales.   Although SALE is most commonly performed with the aim of replacing a less-functionalized linker with a functionalized one, the converse reaction can also be examined using in situ 1 H NMR. However, we found the reaction of UiO-67-bpydc with bpdc (sol) in DMSO-d 6 to give varied results (Fig. S8), regardless of whether the reaction was performed in the NMR spectrometer or ex situ in vials. The mechanism of SALE is complex for at least some systems 16 , and it is clear that this reaction requires further study.
The stability of UiO-67 in solvent has been the subject of literature discussion 34,[38][39][40] , and the appearance of linker (frame) from UiO-67 in a solvent was therefore examined by soaking UiO-67-bpdc or UiO-67-bpydc (the same amounts as used for SALE, Figs 2 and 3) in DMSO-d 6 , DMF-d 7 , or D 3 COD at 57 °C and monitoring the in situ 1 H NMR spectra of the reaction (Fig. 5). Regardless of the starting MOF, only a small amount of linker (frame) was released into DMF-d 7 over the course of 4 h, in stark contrast to the rapid SALE observed in this solvent. The release of linker (frame) was also much slower in DMSO-d 6 when no linker (sol) was present. However, when 1 μL acetic acid was added to the mixture of UiO-67-bpydc in DMF-d 7 or DMSO-d 6 , bpydc (frame) began to appear in solution (Fig. S11). Thus this in situ 1 H NMR technique may also be of use in examining the formation of defects in MOFs, as defects can be introduced using solution-based chemistry 41 . Linker (frame) did appear in solution when UiO-67-bpdc was soaked in CD 3 OD at 57 °C (Fig. S12), even without added acid, indicating that defects can be introduced into this MOF using solvent if the solvent and temperature are chosen accordingly. In addition to SALE, the in situ 1 H NMR method described here should be useful for studying other reactions between MOFs and dissolved species, and we therefore examined the course of a PSM. Pyridinic N atoms in and pendant from MOF linkers have been alkylated using alkyl iodides [42][43][44] or sulfonates 45 . We therefore followed the reaction of UiO-67-bpydc with I(CH 2 ) 2 I in THF-d 8 at 55 °C (Fig. 6).
In this case, the growth of a 1 H NMR peak at a chemical shift of 5.3 ppm, which represents an -N + -CH 2moiety 46 , was monitored. Thus, a somewhat different strategy was used to follow this reaction than to study SALE (vide supra), in that the species monitored here was bound to the MOF. This particular species could be detected using liquid-state NMR because, as a pendant alkyl group, it has significant rotational freedom and hence is detectable. On the other hand, if the bifunctional I(CH 2 ) 2 I formed a bridge between the two pyrdinic N atoms in a bpydc linker, the resulting liquid-state 1 H NMR signal intensity would be expected to decay rapidly, resulting in a broad bump or a lack of signal. The intensity of the peak at 5.3 ppm was still increasing after 60 h when the sample was removed from the spectrometer. Only trace signals were observed in the aromatic region of the 1 H NMR spectra, which is further evidence that the alkylpyridinium moieties were bound in the MOF and that very little bpydc (frame) was released in THF at 55 °C, at least when I(CH 2 ) 2 I was present. After the in situ PSM, the sample was filtered and the resulting yellowish solid washed with non-deuterated THF. The UV-vis spectrum of the solid (Fig. S13) featured a broad absorbance centered at approximately 400 nm, which confirmed the presence of the alkylpyridinium moiety 43 .
To our knowledge, there are no reports of SALE in the aluminum MOF DUT-5-bpdc. Our in situ 1 H NMR method, which requires only 1-2 mg of MOF per trial, enabled us to straightforwardly assess the feasibility of this reaction under the conditions used for SALE in UiO-67. Hence, we monitored SALE to exchange bpydc (sol) with bpdc (frame) in DUT-5-bpdc. No reaction occurred in DMF-d 7 or DMSO-d 6 , although the modulator used in the preparation of DUT-5-bpdc, benzoic acid, was observed in solution. This conclusion was reached with a minimal use of material.

Conclusions
The presented studies of linker exchange and modification in MOFs demonstrate that in situ NMR is a versatile and straightforward tool to study the reactions of MOFs with solvents or dissolved species. Reaction conditions such as solvent, concentration and temperature are easily varied; thus, the method promises to greatly improve the efficiency with which conditions for MOF-solute reactions can be screened. We believe that this method could also be used to give valuable insights into defect formation and control as well as into postsynthetic modifications such as deprotection and insertion reactions. Detailed mechanistic investigations of other MOF-solution reactions using in situ 1 H NMR measurements are underway.
Experimental Section. In situ 1 H NMR spectroscopy. Proton ( 1 H) nuclear magnetic resonance (NMR) experiments were recorded on a 9.4 T ( 1 H Larmor frequency 400 MHz) Bruker Avance spectrometer equipped with a 5-mm double resonance broadband probe (BBI) optimized for 1 H detection. The repetition time was set to 10 s and the acquisition time was 1.5 s. A single pulse experiment with a radiofrequency pulse of between 30-80° was employed to record the NMR signal. The spectral width was 37.4 ppm and the signal was accumulated 32 times. The recorded signal was processed with Matlab (Mathworks) using own scripts. The number of moles of linkers in solution were normalised using the sum of the peak integrals of the linkers from the first recorded experiment and the known amount of linker (sol) . To account for the different linker (sol) :linker (frame) ratios, the moles of linker were normalized by the known moles of the linker (frame) .
For further experimental details, see Supplementary Information.

Data Availability
The datasets generated and analysed during the current study are available from the corresponding author on request. The data points in Figs 2-6 are obtained from the 1 H NMR spectra displayed in Figs S15-23 the Supplementary Information.