In Situ Monitoring of Mechanochemical Covalent Organic Framework Formation Reveals Templating Effect of Liquid Additive
Covalent organic frameworks (COFs) have emerged as a new class of molecularly precise, porous functional materials characterized by a broad structural and chemical versatility, leading to a diverse range of applications. Despite the increasing popularity of COFs, fundamental aspects of their formation are poorly understood and profound experimental insights into their formation processes are still lacking.Here we use a combination of in situ X-ray powder diffraction and Raman spectroscopy to elucidate the reaction mechanism of mechanochemically synthesized imine COFs, leading to the observation of key reaction intermediates. Real-time monitoring provides experimental evidence of templating effects by the liquid additive for the subsequent pore formation and layer assembly. Moreover, the solid-state catalyst scandium triflate Sc(OTf)3 is revealed to be instrumental in directing the reaction kinetics and mechanism, resulting in products with crystallinity and porosity en par with solvothermally synthesized COFs. This work highlights the potential of mechanochemistry as a green synthetic route towards COF synthesis, and emphasizes the subtle interplay between choice of liquid additives, catalysts, and activation procedure.
Introduction<!>Results and discussion<!>Structure elucidation of reaction intermediates<!>Influence of Liquid Additives<!>Influence of Catalyst<!>Mechanochemical synthesis<!>Conclusion
<p>Covalent organic frameworks (COFs) are an emerging class of organic solids whose chemical and structural modularity enable remarkable features including a highly tunable, molecularly precise backbone, paired with porosity and crystallinity. [1,2] The reticular assembly of molecular building blocks with inherently different sizes, shapes, and flexibility into two-(2D) or three-dimensional (3D) frameworks of increasingly complex structures and topologies allows for the tailored design of functional materials with targeted properties. The so far proposed applications of COFs are many, including gas storage and separation, [3][4][5] heterogeneous catalysis, [6][7][8][9] waste water treatment, [10][11][12] fuel cells, [13,14] and sensing. [15][16][17] COFs are typically synthesized by solution methods, e.g. solvothermally, sonochemically, using microwave irradiation, or in continuous flow, [18] and more recently also by electron beam irradiation, [19] as well as by mechanochemistry. [20][21][22] Mechanochemistry, i.e. the application of mechanical agitation to conduct and sustain chemical and materials transformations, has recently been established as a cornerstone of green, sustainable solvent-free chemistry. [23][24][25] Mechanochemistry has successfully been applied to a wide range of reactions, including the formation of nanoparticles, [26] molecular cages, [27] small molecules, [28] cocrystals, [29,30] solid electrolytes, [31] coordination polymers, [32] as well as metal-organic frameworks (MOFs) [33] and COFs. [20][21][22] Mechanochemistry is not only highly efficient for the synthesis of new metastable solid phases, [33] but is also a superior technique to screen and explore the phase landscape for new polymorphs or novel materials. [34,35] Bulk mechanochemical reactions are usually performed by either direct grinding of reactants (neat grinding), or in the presence of grinding additives, as in liquid-assisted grinding (LAG). [36] Recently, mechanistic studies of mechanochemistry have been facilitated by the development of methods for in situ monitoring using synchrotron X-ray powder diffraction (XRPD), [37,38] Raman spectroscopy, [39,40] X-ray absorption spectroscopy, [41] solid-state nuclear magnetic resonance spectroscopy (ssNMR), [42] and/or thermal measurements. [43] This has enabled rapid progress in fundamental understanding of mechanochemical processes and the discovery of new materials. [44] Although COFs are well established, mechanistic and time-resolved formation studies are quite rare. While previous work has mostly focused on characterization, [45][46][47] post-synthetic modifications and transformations of COFs, [48][49][50] only a handful of reports so far have investigated the linkage formation, particle growth, and self-assembly process itself. [51,52] This previous work has been done either through solution-based studies (e.g. using turbidity), [53] in situ wide-angle X-ray diffraction, [54] and nuclear magnetic resonance (NMR) measurements, as well as theoretical investigations, [51,55] thus often lacking direct structural information during the COF formation.</p><p>Here we report the first real-time mechanistric study of mechanochemical COF formation using time-resolved in situ synchrotron XRPD and Raman spectroscopy. A library of four different 2D hexagonal imine COFs based on C2 and C3 linkers were chosen as model systems, with only one system (COF-LZU1) previously prepared mechanochemically. [20] The effects of liquid additive and catalyst on reaction kinetics and product formation were investigated, revealing pronounced effects on COF formation, both regarding the reaction kinetics and mechanism as well as crystallinity of the products. The time-resolved in situ experiments led to the observation of crystalline reaction intermediates, with direct evidence of templating effects by the liquid additive, highlighting the role and critical importance of solvent choice during COF synthesis.</p><!><p>Real-time in situ XRPD measurements were performed at the Powder Diffraction and Total Scattering beamline P02.1 at the Deutsches Elektronen-Synchrotron (DESY) using a modified Retsch MM400 ball mill operating at a milling frequency of 30 Hz. [37] The reactions were carried out in custommade 5 mL volume X-ray transparent poly(methyl methacrylate) (PMMA) milling jars, enabling direct, realtime monitoring of the mechanochemically formed COFs with a time resolution of 10 or 20 s. We used a combination of different C2 and C3 amine and aldehyde linkers, forming four different hexagonal imine COFs (Figure 1). Reactions were performed with one 7 mm diameter stainless steel ball (1.38 grams weight), using a 1,4-dioxane/mesitylene mixture (1:1 v/v) as a liquid additive, with either aqueous acetic acid (AcOH) or scandium(III) triflate (Sc(OTf)3) as a catalyst. The optimal reaction conditions were extensively screened prior to the beamtime by maximizing the measured diffraction intensities of the assynthesized COFs in laboratory XRPD measurements. This step was crucial to maximize the diffraction signal of the weakly scattering light-element based COFs during in situ monitoring with the given setup (Figure S6 in Electronic Supporting Information, ESI).  [56] In situ monitoring of COF formations</p><p>In situ monitoring of mechanochemical COF-LZU1 [9] formation was performed by milling paraphenylenediamine (pPDA) with 1,3,5-triformylbenzene (Tb) in the presence of a 1,4-dioxane/mesitylene mixture (1:1 v/v) using AcOH as catalyst with the ratio of liquid additive volume to reactant weight (ηparameter) [36] of 0.60 μL/mg. Unexpectedly, the formation of COF-LZU1 proceeded via a reaction intermediate (1), visible by the appearance of new Bragg reflections at 2.3, 2.4, 2.5, and 3.2 °2𝜃 (Figure 2a). This previously unknown phase was later identified and characterized by ex situ diffraction and spectroscopic techniques. The COF formation was readily followed by integrating the most intense COF and intermediate Bragg reflections. The intermediate formed immediately upon grinding, simultaneously with the loss of pPDA signal and only traces of Tb remaining after ca. 3 minutes. The (100) COF X-ray reflection appeared after ca. 3 mins, with an initial fast increase, reaching a slower transformation around ca. 15 min, exhibiting a typical sigmoidal reaction curve. [57] The reaction was found to be complete after ca. 25 min, coinciding with the disappearance of the diffraction signal of 1 (Figure 2b). Measured ex situ XRPD pattern show the formation of COF-LZU1 in accordance with previous reports (Figure S10). [9,58]  Next, the isoreticular TbBd-COF [59] was synthesized by milling benzidine (Bd), a similar diamine linker with an extended length of one phenyl group, with Tb. Mechanochemical formation of TbBd-COF was conducted using a 1,4-dioxane/mesitylene (1:1, v/v) mixture with 6 M AcOH as catalyst (η = 0.61 μL/mg). As for COF-LZU1, the COF formation proceeds via a reaction intermediate (2), with corresponding diffraction signals at 2.4, 2.6, 2.9, 3.0, 3.2 and 3.8 °2𝜃 (Figure 2b). The reaction was readily followed by integrating the most intense Bragg reflections of the intermediate and TbBd-COF. The diffraction signals of the reactants were barely visible after few minutes with the intermediate appearing after ca. 4 min. The COF formation was found to be significantly slower in comparison to COF-LZU1, with signals from the COF only starting to appear after an initial induction time of ca. 10 min and the diffraction signal of the intermediate visible up to 60 min of milling (Figure 2b,e). The measured ex situ XRPD patterns show the successful formation of TbBd-COF in accordance with previous reports (Figure S10). [59] The third COF in the series of C3-C2 linkers, IISERP-COF4, [60] was obtained by milling 2,4,6-tris(4aminophenyl)-1,3,5-triazine (TAT) with terephthaladehyde (BDA) in the presence of 1,4-dioxane/mesitylene (1:1 v/v) using 6 M AcOH as catalyst (η = 0.94 μL/mg) (Figure 2c). No reaction intermediate was observed in this case and the reaction was readily followed by integrating the most intense Bragg reflections of the reactants and the (100) X-ray reflection of the IISERP-COF4 product (Figures 2c and S9). Notably, the second most intense (110) X-ray reflection was also observed during in situ monitoring (Figure 2c). The formation of the COF starts after an induction period of approx. 10 min, with an initially steep growth rate, and is complete after 40 minutes of milling time. Full consumption of TAT was only achieved after around 60 minutes of milling time. Measured ex situ XRPD patterns show the formation of IISERP-COF4 in accordance with literature reports (Figure S10). [60] Next, we monitored the mechanochemical formation of N-COF [61] by milling the two C3 linkers TAT and Tb in a 1:1 ratio using a 1,4-dioxane/mesitylene (1:1 v/v) with 6 M AcOH as catalyst (η = 0.73 μL/mg) (Figure 2d). The reaction was readily followed by integrating the most intense Bragg reflections of the reactants and the (100) reflection of N-COF. There was no apparent evidence for a crystalline intermediate during the synthesis. The COF formation started after an induction period of ca. 4 minutes, with an initial fast formation rate in the first 20 minutes and subsequently a continuous growth regime (Figures 2d and S9). The reaction did not reach completion within the measured time frame of 80 minutes, visible by the remaining diffraction peaks of TAT linker. XRPD patterns measured ex situ confirm the formation of N-COF in accordance with previous reports (Figure S10). [61]</p><!><p>We attempted to separately synthesize and ex situ characterize the first reaction intermediate 1 using reaction conditions identical to those used for the in situ reaction of COF-LZU1. Subsequent analysis of the reaction mixture after 3 min of milling failed due to poor XRPD data quality and time-resolved XRPD measurements of the reaction mixture indicated that the mixture further polymerized into poorly crystalline COF-LZU1 over several hours (Figure S5). In situ Raman monitoring under similar reaction conditions indicated that the first reaction step constitutes an imine condensation reaction, visible by the appearance of the strong Raman band at 1623 cm -1 , assigned to the 𝜈 𝐶=𝑁 vibration (Figure S19). Further milling led to an increase in baseline of the Raman spectra, likely caused by fluorescence associated with the assembly of the conjugated 𝜋-system of COF-LZU1 (Figure S18). Since the diffraction signal of the Tb linker coexisted with intermediate 1 during the time-resolved in situ measurement of COF-LZU1 formation, we expected 1 to exhibit a molecular composition of pPDA and substoichiometric Tb. Therefore, a 1 to 3 ratio of Tb:pPDA was milled to prepare the suspected trimeric intermediate 1. Indeed, the crystal structure of 1 was successfully solved ab initio from ex situ XRPD analysis, revealing the condensation of the trimesaldehyde in the form of a solvate with the presence of 0.5 eq. of 1,4-dioxane per sum formula, which was further confirmed by liquid and solid-state NMR (ssNMR), Fourier-transform infrared (FT-IR) and high-resolution mass spectroscopy, as well as thermal gravimetric analysis measurements (TGA, see ESI). Intermediate 1 crystallizes in the triclinic space group 𝑃1 ̅ with one fully condensed trimer and half a 1,4dioxane in the asymmetric unit. The trimers form a layered hydrogen bonded network whereas two amines interacting with adjacent imines and the third amine forms a weak N-H•••𝜋 hydrogen bond (Figure 3a). This is in good agreement with the 15 N ssNMR spectrum, where two peaks for the three crystallographically inequivalent amine were observed (Figure S33). Adjacent hydrogen bonded layers possess an offset with respect to each other of approx. ½ of the repeating unit. Prominently, 1,4-dioxane is embedded between two condensed amine dimers forming rhombohedrally shaped cavities (Figure 3a). The intermediate can conceptually be "transformed" into the final COF-LZU1 by rotation and/or translation of the condensed imines within the hydrogend bonded layer, connected through the missing equivalent number of Tb linkers (Figure 4). In this process, 1,4-dioxane acts as a template for the subsequent pore formation during the COF-LZU1 assembly. The imine formation also occurred during neat grinding, i.e. milling without the addition of a liquid additive or catalyst, leading to the formation of a non-solvated imine trimer 1' (Scheme S1). Liquid and ssNMR spectra of the trimers were essentially the same except for the absence of the 1,4-dioxane signals in the non-solvated form (Figures S28-36). The crystal structure of the non-solvated trimer could not be determined, due to poor crystallinity in addition to the presence of potentially two polymorphs. 13 C and 15 N ssNMR spectra suggest that two phases with identical chemical connectivity but slightly different intermolecular arrangement are present (Figures S35, S36). These differences compared to the solvated intermediate suggest that 1,4-dioxane molecules act as structure-directing agents, with a profound influence on crystallinity. Different experimental conditions were screened for the synthesis of intermediate 2, which was observed during the in situ monitoring of TbBd-COF. Intermediate 2 only formed as the main phase by milling solely Bd in the presence of 1,4-dioxane. Different grinding additives lead to different phases; neat grinding or grinding with aqueous AcOH lead to a polymorphic transition of Bd, with the presence of an additional second (new) phase in case of AcOH, while 2 formed in reactions using 1,4-dioxane as a liquid additive (Figure S17). The formation of different crystalline phases or polymorphs using different liquid additives is a well-known phenomenon in organic mechanochemistry. [34] The crystal structure of 2 was ab initio determined from XRPD data, geometry optimized using periodic density functional theory (DFT) calculations, and characterized using liquid-ssNMR and FT-IR spectroscopy (see ESI). Intermediate 2 was found to be a 1,4-dioxane solvate of benzidine, which crystallizes in the monoclinic space group P21/c with both Bd and dioxane molecules lying on a crystallographic center of inversion. The crystal structure is composed of hydrogen-bonded zig-zag chains along the c-axis with alternating molecules of Bd and dioxane, forming amine -ether N-HO hydrogen bonds (dN-O = 3.02 Å). All adjacent chains have a slight offset to each other, introduced through the glide planes, which enables a weak N-H•••𝜋 interaction between neighbouring chains.</p><!><p>To further investigate the influence of liquid additive on COF formation and potential templating effects, additional ex situ milling experiments were performed by varying the LAG additive. Specifically, either pure mesitylene, 1,4-dioxane, or their mixture were used as additives while keeping 𝜂 constant (0.6 μL/mg). Notably, the LAG experiments with either mesitylene or 1,4-dioxane as a liquid additive led to the formation of COF-LZU1, as confirmed by XRPD measurements (Figure 5a). However, COF-LZU1 prepared with mesitylene as a liquid additive exhibited a significantly lower crystallinity compared to the materials prepared with 1,4-dioxane, lacking the stacking X-ray reflection (001) around 26 °2𝜃 (Figure 5a), indicating apparent stacking disorder. Morever, it possess a very broad diffraction signal around 21 °2𝜃, typical for materials with an amorphous content. These trends in crystallinity are in good agreement with porosity measurements, where the Brunauer-Emmett-Teller surface areas (SBET) for the materials synthesized with pure 1,4-dioxane (SBET = 880 m 2 g -1 ) or a mesitylene/dioxane mixture (SBET = 757 m 2 g -1 ) are significantly higher compared to that of the product made using pure mesitylene (SBET = 138 m 2 g -1 ) as the liquid additive (Figure 5b). The increased crystallinity and surface area in samples prepared in the presence of 1,4-dioxane are attributed to the formation of 1, where the 1,4-dioxane embedded in rhombohedrally shaped cavities can act as template for the COF pore formation. The pre-orientation of the layered hydrogen-bonded trimers facilitates the final condensation step and layer assembly through templating effects and consequently improves the overall crystallinity. Moreover, the displacement of layers prohibits strong 𝜋-𝜋 interactions between molecular building blocks. Strong irreversible 𝜋-𝜋 interactions in the early stage of COF formation have been identified to prohibit high crystallinity due to the implementation and lock-in of defects. [55,62] While templating effects have been proposed in previous theoretical work, [55] this is to the best of our knowledge the first experimental evidence of solvent templating during COF formation. Notably, our results also suggest that the liquid additive mixture could even be simplified to pure 1,4-dioxane, meaning that complex solvent mixtures are not always necessary for the synthesis of COFs, at least using mechanochemistry.</p><!><p>We further explored the influence of the catalyst on the reaction mechanism and kinetics. To this end, real-time in situ monitoring was extended to milling reactions in which aqueous AcOH was replaced by the solid Lewis acid Sc(OTf)3. Matsumoto et al. reported the use of metal triflates to promote the formation of imine COFs in solution, leading to a significant reduction of reaction time under milder reaction conditions. [63] In all reactions that were monitored in situ, 0.06 eq. Sc(OTf)3 were used with respect to the corresponding amine linkers. While the overall reaction pathway was mostly unaffected by the choice of catalyst, the reaction kinetics, as well as crystallinity of the final COFs were increased.</p><p>COF-LZU1 was the only investigated COF system where a crystalline intermediate was observed in the presence of Sc(OTf)3 as catalyst. The intermediate 1 formed immediately upon milling, with the diffraction signal of the targeted framework COF-LZU1 appearing after ca. one min (Figure 6a). The diffraction signal of 1 completely vanished within 12 min, i.e. in approximately half of the reaction time compared to the AcOH catalysed reaction (ca. 25 min). The intensity of the (100) Bragg reflection of COF-LZU1 increased throughout the entire experiment, even after the consumption of 1 (Figure 6b). The continuous increase in diffracted intensity might arise from a continued error correction by Sc(OTf)3, acting as an efficient transimination catalyst and resulting in overall improved crystallinity (Figure 6c). [64] The induction times for most other COF systems were significantly reduced, by a factor of two or more (Figures 6b and S9). The synthesis of BdTb-COF showed the most pronounced effect, both in reduction of induction time as well as in increase of product formation rate. The TbBd-COF formation started after an induction time of only ca. 3 min and was found to reach completion after ca. 30 minutes using Sc(OTf)3, while for AcOH the diffraction signal of COF only appeared after 30 min and still exhibited a weak scattering signal after 60 min with 2 remaining throughout the whole experiment. It is assumed that due to the rapid COF formation rate Bd is consumed before the solvate is formed and 2 was consequently not observed in the Sc(OTf)3 catalysed reaction. These findings demonstrate the unique interplay between thermodynamics and kinetics in COF formation and suggest that different reaction pathways may open up as a function of liquid and catalyst choice. Encouraged by our findings of the effects of Sc(OTf)3 on reaction kinetics and mechanism during COF formation we further explored its influence on mechanochemically snythesised COF properties. The direct comparison of separatly mechanochemically synthesized COFs using AcOH and Sc(OTf)3 as catalyst shows that not only the crystallinity was significantly improved using Sc(OTf)3 (Figure 6c), but also SBET was found to be generally larger (Figure 6d). TbBd-COF shows the most pronounced effect with an SBET increase of 475 %. These results are in good agreement with our in situ studies showing an increased COF formation rate. Interestingly, while previous mechanochemical COF syntheses report a significantly lower crystallinity and porosity (SBET < 300 m 2 g -1 ) compared to the respective solvothermal syntheses of the corresponding COF systems, [20][21][22] the herein presented results show partially the opposite (Table 1). Most notably, the porosity of milled IISERP-COF4 exceeds the solvothermally reported surface area by almost 40 %, independent of the catalyst choice. Also, the surface area of COF-LZU1 with Sc(OTf)3 was found to be almost 2.7 times higher (SBET = 1097 m 2 g -1 ) than most literature values obtained by classical solvothermal synthesis with SBET = 410 m 2 g -1 , [9] but still slightly lower than other synthetic strategies, where a SBET of approx. 1500 m 2 g -1 was reported (Table 1). [65,66] It is noteworthy, however, that the latter required much longer reaction times, up to 48-120 h, whereas the milling reaction was found to be complete within an hour. The increased SBET in comparison to previous mechanochemically prepared COFs are attributed to a milder activation process. Activation under harsher conditions, e.g. solvent exchange and heating under vacuum, are known to lead to a collapse of the framework pore structure through the action of capillary forces, and consequently to a reduction or loss of porosity. [67] This strongly depends on the polarity of the used solvent, as well as framework stability. [68] In contrast, scCO2 is considered as a rather mild activation method due to the absence of capillary forces and thus, the structural integrity is retained during the activation process. [67] Table 1: Pore sizes and comparison of surface areas of mechanochemically synthesized COFs with literature values of solvothermally synthesized pendants.</p><!><p>Reported values COF system Pore size [a] / nm SBET(AcOH) / m 2 g -1 SBET(Sc(OTf)3) / m 2 g -1 SBET / m 2 g -1 COF-LZU1 1.9 757 1097 410 [9] , 1500 [65,66] TbBd-COF 2.2 167 799 1948 [59] IISERP-COF4 3.2 871 981 716 [60] N-COF 1.5 929 996 1163 [61] [a] calculated by DFT.</p><p>Overall, Sc(OTf)3 shows advantages in terms of reaction times and measured surface areas in these examples and is consequently an interesting alternative to AcOH for mechanochemical COF chemistry. Fine-tuning of the reaction conditions as well as scCO2 activation enabled the mechanochemical preparation of COFs that are on an equal footing with solvothermally synthesized COFs, while retaining the benefits of significantly reduced reaction times, milder reaction conditions, and scalability.</p><!><p>In conclusion, we report the first in situ monitoring of mechanochemical COF formation, readily followed using real-time in situ XRPD. Our study provides the first direct experimental evidence of templating effects during COF assembly through a crystalline intermediate. Using 1,4-dioxane as a liquid additive let to the observation of reaction intermediates in the form of solvates during both COF-LZU1 and TbBd-COF synthesis. The intermediate for TbBd-COF is the result of a competing reaction, which can occur due to slow imine bond formation and is suppressed by using Sc(OTf)3 as a catalyst. In contrast, in the COF-LZU1 intermediate a solvated, hydrogen-bonded layered trimer is formed with 1,4-dioxane being embedded in rhombohedral cavities, acting as a template for the subsequent pore formation during COF assembly. The quasi layered structural arrangement in the solvate does not only inhibit initial 𝜋-𝜋 stacking during the early self-assembly process, an effect that is known to lower the overall crystallite size, [62] but also promotes the self-assembly of the 2D COF sheets. The formation of a discrete trimer could potentially be used for the rational design of mixed-linker COFs, as it has been previously done for mixed-metal MOFs. [69] Moreover, our study reveals pronounced effects of the catalyst choice -AcOH vs Sc(OTf)3 -on COF formation, both regarding reaction kinetics, mechanism and crystallinity of the product. Notably, a combination of Sc(OTf)3 as a catalyst and mild activation with supercritical CO2 results in COFs with surface areas that can even exceed those reported for solvothermally synthesized COFs, which generally require higher temperatures, longer reaction times, and the use of bulk-solvents.</p><p>Our results highlight the potential of mechanochemical synthesis not only as a material-efficient, green and potentially scalable synthetic route, but reveal the subtle interplay between liquid additives, catalyst choice, and activation procedure in the synthesis of COFs, which often follows standardized procedures owing to the lack of mechanistic insights. Utilizing the power of templated COF synthesis through the targeted formation of intermediates thus enables a more rational design of COFs by utilizing a toolbox of non-covalent interactions and directed self-assembly.</p>