Amine-linked Covalent Organic Frameworks as a Powerful Platform for Post-Synthetic Modification: Structure Interconversion and Combined Linkage- and Pore-Wall-Modification

Covalent organic frameworks have emerged as a powerful synthetic platform for installing and interconverting dedicated molecular functions on a crystalline polymeric backbone with atomic precision. Here, we present a novel strategy to directly access amine-linked covalent organic frameworks, which serve as a scaffold enabling pore-wall modification and linkage-interconversion by new synthetic methods based on Leuckart-Wallach reduction with formic acid and ammonium formate. Frameworks connected entirely by secondary amine linkages, mixed amine/imine bonds, and partially formylated amine linkages are obtained in a single step from imine-linked frameworks, or directly from corresponding linkers in a one-pot crystallisation-reduction approach. The new, 2D amine-linked covalent organic frameworks, rPI-3-COF, rTTI-COF, and rPy1P-COF, are obtained with high crystallinity and large surface areas. Secondary amines, installed as reactive-sites on the pore wall, enable further post-synthetic functionalisation to access tailored covalent organic frameworks, with increased hydrolytic stability, as potential heterogeneous catalysts.


Introduction
In recent years, covalent organic frameworks (COFs) have emerged as a versatile class of crystalline porous polymers, which have been pushing the frontiers of single-site heterogeneous catalysis ever since. The unique combination of ordered and tuneable pore structures, with high surface areas and versatile (opto-)electronic properties, offers great opportunities beyond gas storage and separation, including sensing, electrochemical energy storage, optoelectronics, and heterogeneous (photo-)catalysis. 1, 2, 3,4 Imine-linked COFs constitute the most widely studied subclass of COFs owing to their wide synthetic scope and facile building block synthesis. The dichotomy of dynamic covalent chemistry in COF synthesis implies that while reversible bond formation is critical for crystallisation, the reversibility of imine bond formation also causes its limited stability against hydrolysis. To address this issue, several post-synthetic locking strategies have been developed in the past, e.g. converting labile imine-linked COFs into stable benzothiazole-, 5, 6 amide-, 7 or quinoline-linked frameworks. 4,8,9,10,11,12,13 Although these methods significantly increase the material's hydrolytic stability, most do not activate, but rather deactivate potential reactivity of the linkages for further pore-wall modification. To achieve the latter, reactive centres have to be installed into the linker moieties, which are often incompatible with synthesis conditions. This incompatibility requires an additional pore-wall activation step, e.g. reduction of nitro groups to amines, 14 or deprotection of ethers to alcohols. 15 In essence, a typical synthetic route would consist of at least four sequential steps, including a) framework crystallisation, b) linkage transformation, c) pore-wall activation and d) pore-wall functionalisation to obtain both stable and decorated frameworks. Being faced with varying conversion yields and loss of material between each step, innovative synthetic methods condensing these transformations into fewer steps, or even a single synthetic step, are highly desirable.
As a solution to the challenges discussed, we here demonstrate amine-linked covalent organic frameworks as a powerful platform for facile pore-wall modification and linkage-interconversion enabled by new synthetic methods based on Leuckart-Wallach 16,17 reduction with formic acid and ammonium formate. By fine-tuning the reaction conditions, frameworks connected entirely by secondary amine linkages, mixed amine/imine bonds, and partially formylated amine-linkages are accessible in a single step from imine-linked frameworks, or directly from the corresponding linkers in an one-pot crystallisation-reduction approach. We thus present a novel strategy enabling direct access to amine-linked covalent organic frameworks. In addition, we reveal correlations between topologically equivalent disordered and crystalline frameworks which are not accessible by typical X-ray powder diffraction (XRPD) analysis, using pair distribution function (PDF) analysis, solid-state nuclear magnetic resonance spectroscopy (ssNMR) and quantum-chemical calculations. These findings enable us to identify unique pH-dependent amorphisation pathways and hence expand our fundamental understanding of amine-linked covalent organic frameworks as an important, yet underexplored class of heterogeneous catalysts.

Previous Strategies and Drawbacks
During our studies, we found that a reduction of imine-linkages would both increase the hydrolytic stability of the framework and introduce secondary amine-linkages as reactive centres for further functionalisation of the pore-wall. This transformation, familiar from small organic molecules as well as molecular cages, is usually achieved using borohydride-based reducing agents, such as sodium borohydride or sodium cyanoborohydride. 18,19,20 Borohydride-based reduction has successfully been used for robust and rigid 3D systems, while 2D frameworks have only been obtained with diminished crystallinity and low surface areas at best. 11,15,21 While highly reactive, reactions with sodium borohydride, in particular, suffer from limited selectivity and low functional group tolerance. 5,22 With these shortcomings in mind, we sought an alternative, mild reduction procedure affording crystalline and porous amine-linked covalent organic frameworks. To this end, we identified the Leuckart-Wallach reduction with formic acid, reported for small organic molecules by R. Leuckart in 1885 and further developed by O.
Structural analysis of rPI-3-COF via XRPD reveals high crystallinity (Supplementary Table S3 To demonstrate the general applicability of this protocol, we applied it to two additional imine COFs with larger pores, different linker composition and pore geometry.  Table S1, S2).

One-pot procedure: Reductive crystallisation
When comparing the conditions needed for the synthesis of the imine framework and the following reduction, acids and the same solvent mixture are used in both cases, and only the amount and type of acid changes. Thus, we expected formic acid could act as a catalyst for both the formation and reduction of the framework, condensing the individual steps into a single one-pot crystallisation-reduction approach.
Indeed, with 21 equiv. of formic acid in a 2:1 mixture of mesitylene:1,4-dioxane at 120°C for 72 h, a crystalline sample of rPI3-COF was obtained directly from its corresponding aldehyde and amine building blocks (Supplementary Fig. S15). Compared to its two-step analogue, it was obtained in a different, spherical morphology ( Supplementary Fig. S82). As visible from broadened signals in the 13 C ssNMR and FT-IR spectra ( Supplementary Fig. S7, S48), this sample is structurally less well-defined with a major impact on the resulting porosity (BET area of 174 m 2 g -1 , Supplementary Fig. S76).
During our studies, we noticed a significant impact of the reaction temperature on the obtained product. While formic acid catalyses the imine condensation both at high (120°C) and already at low (60°C) temperature, the subsequent reduction is fast only at elevated temperature ( Supplementary Fig. S16). As such, the one-pot protocol can be used to thermally switch between the reversible synthesis of an imine-linked COF at low temperature or the irreversible "locking" of the framework structure by simultaneous reduction to the amine-linked COF using otherwise identical reaction conditions. We expect this unique property to be key for the adaptation to other covalent organic frameworks. Besides this "thermo-switchability" it highlights formic acid as a versatile, yet underexplored catalyst for the synthesis of imine-linked COFs at reduced temperature.

Reductive formylation: Combined reduction and protection
Solid ammonium formate as a green, less toxic, and less corrosive alternative to formic acid was also effective for the reduction of imine bonds under solvent-free conditions.
Reacting a salt-melt of ammonium formate and PI-3-COF for 3 h at 170°C in a closed vessel afforded a product with broadened secondary amine vibrations at vN-H = 3370 cm -1 and carbonyl stretching modes at vC=O = 1669 cm -1 in the FT-IR spectrum ( Supplementary   Fig. S6). An additional signal at 162.8 ppm in the 13 C ssNMR spectrum, referring to an N-formyl-carbon ( Supplementary Fig. S42, S45), shows that besides the reduction, a subsequent N-formylation resulted in a partially formylated, reduced PI-3 framework (pfrPI-3-COF). Comparison of FT-IR and ssNMR spectra excludes a degradation of the chemical connectivity. The XRPD pattern shows substantial reduction in the long-range order reminiscent of an amorphous solid, although a small feature corresponding to the 100 peak further suggests that the intralayer connectivity is maintained ( Supplementary   Fig. S17). When reacting pf rPI-3-COF with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dichloromethane, the secondary amine linkages are oxidised back to the imine linkages, affording re-oxidized, partially formylated reduced PI-3-COF (opfrPI-3-COF). 15 Remarkably, after this treatment sharp signals in the XRPD pattern similar to the parent PI-3 framework become visible ( Supplementary Fig. S11, S17. The feasibility of this amorphous-to-crystalline conversion suggests a significant topological and structural similarity of the reduced, amorphous COF to the crystalline compound, and led us to further investigate the correlations between crystalline and non-crystalline amine-linked frameworks.

Crystalline vs. Disordered
During our screenings to find optimal reduction conditions for the imine-linked frameworks, we noticed that a large excess of formic acid can decrease the crystallinity of the product, suggesting a profound role of protonation on the layer structure. Using 59.5 equiv. of formic acid with PI-3-COF under the same conditions as above leads to a practically X-ray amorphous structure with slightly broadened but otherwise essentially identical signals as rPI-3-COF in the FT-IR and ssNMR spectra ( Supplementary Fig. S5,   S47). SEM and TEM did not show any morphological changes of the particles ( Supplementary Fig. S81, S91).  To elucidate conformational changes in the structure of PI-3-COF upon reduction, quantum-chemical calculations on PBE0-D3/def2-TZVP level of theory were performed to obtain optimised structures for model compounds. 31,32,33,34 The surface plot for combined rotations around dihedral angles U and Z in molecular models PI-3 M and rPI-3 M (Supplementary Fig. S97-S99) shows increased flexibility for the amine-linked molecular model, apparent from a broad range of low energy conformations (Fig. 2a-c).
Although interlayer steric repulsion in the amine framework is increased due to additional benzylic protons (C-10, Fig. 1c) that align perpendicular to the 2D surface, reduced 1,4-repulsion between protons at C-9 and C-10 causes  Fig. S47), whereas in the actual, well-ordered rPI-3-COF structure, a narrow statistical distribution of dihedral angles indicates a preferred conformation and thus a fairly sharp signal for this carbon (C-7). A protonation-dependent broad distribution in the disordered rPI-3-COF causes this signal to broaden and, ultimately, to vanish, however without disrupting the overall connectivity of the layer.
To determine the local and intermediate length-scale structure modifications due to conformation induced disordering, we performed pair distribution function (PDF) analysis on X-ray total scattering synchrotron data. Notably, high similarity in the reduced total scattering patterns (Fig. 2d) from ~5-20 Å -1 and peak positions up to approximately 7 Å in the PDFs of all samples evidence intact, imine or amine bonded layer connectivity in the disordered state. The PDFs of PI-3-COF and rPI-3-COF (Fig. 2e) show distinct medium-and long-range ordered structuring, consisting of two primary oscillations due to the ordering of the stacked layers (higher frequency), and porous channels (lower frequency). The structural correlations are more strongly damped for disordered rPI-3-COF and pfrPI-3-COF, becoming relatively flat around 12 Å. This indicates that the spatial relationships of atoms in stacked layers and across porous channels are largely reduced, although as seen in the diffraction patterns, there are still weakly correlated motifs over at least a few layers or pore distances (Fig. 2e). Distinct differences could be visualised between crystalline and disordered structures by refinement of a 16-layer structure model to the PDFs for rPI-3-COF and disordered rPI-3-COF PDFs, with random translations allowed in a single direction (Fig. 2f, g). For the disordered sample, much larger translations were required to damp out the interlayer and ordered pore channel structure signals. It must be noted that these models may overpredict layer translations due to undersampling the number of layers. Furthermore, the interlayer correlations could also be damped by larger, and random torsions of the amine or phenyl bonds, as shown in quantum-chemical single-pore models. Average stacking offsets were estimated by refining models to the PDFs in the range of neighbouring layers, i.e., r < 6 Å, using PDFgui. 29,35 The values obtained are 1.0 Å (PI-3-COF), 1.2 Å (rPI-3-COF), 3.3 Å (disordered rPI-3-COF), and 3.3 Å (pfrPI-3-COF). As visible from the disordered model, random layer translations drastically reduce pore accessibility and thus help to explain reduced BET surface areas for the disordered models. Besides frameworks containing only amine or imine-linkages, hybrid materials with varying imine/amine linkage content can also be obtained with our method by adjusting reaction time, and the amount of formic acid (Fig. 3a, Supplementary Fig. S1). As an example, partially reduced Py1P-COF (prPy1P-COF) was synthesized, showing distinct signals at 149.0 ppm (imine) and 146.4 ppm (amine) in the 13 C ssNMR spectrum for the aromatic carbon next to the nitrogen (approx. 42% amine sites, Supplementary Fig. S39).
The presence of N-formyl groups opens up further avenues for additional framework functionalisation. For instance, partially functionalised frameworks may be generated by reacting the partially formylated framework with an electrophile, since formyl groups act as protecting group for secondary amine sites. Partial functionalisation can avoid reduced pore accessibility and diffusion limitations, which is critical for example in catalysis. 36 In a more complex case, bi-functionalised frameworks may be synthesized in a subsequent step, after exposing previously protected amine sites. Deprotection of N-formyl groups in pfrPI-3-COF was achieved under acidic conditions (aqueous 1 M HCl, 120°C, 20 min), affording rPI-3-COF as evident from a vanishing formyl signal at 162.8 ppm in the 13 C ssNMR spectrum ( Supplementary Fig. S45), while acid chlorides or isocyanates have proven as strong and effective electrophiles to derivatise secondary amines in rTTI-COF ( Fig. 3b-c). Figure 4: Pathways leading to a set of amine-linked covalent organic frameworks as demonstrated with the PI-3 COF system.

Discussion
In summary, amine-linked frameworks were introduced as a hydrolytically stable and tailorable system for further post-synthetic modification, which can be accessed from imine-linked frameworks or directly from their corresponding amine and aldehyde building blocks (Fig. 4). In contrast to many earlier locking strategies, generating amide, benzoxazole or benzothiazole linked frameworks, our approach locks and simultaneously activates the connectivity of the framework for further functionalisation. 5,7,11,37 The introduced reduction methods using either formic acid or ammonium formate give access to a range of fully amine-linked, or intermediate amine/imine-linked crystalline frameworks with large surface areas, or topologically identical, disordered analogues with reduced pore-accessibility. Importantly, the degree of amine functionalisation can be rationally controlled by adjusting the amount of acid and reaction time. For the first time, we demonstrate amine-linked frameworks as a modular platform enabling the facile interconversion of chemically and structurally distinct frameworks, including reductionre-oxidation cycles, crystalline-to-disordered, and disordered-to-crystalline conversions.
Finally, we show that the obtained amine linkages readily react with electrophiles such as acid chlorides and isocyanates, opening new avenues to the facile post-synthetic functionalisation of COFs at the linkage site with a built-in protection-deprotection strategy and without the need for additional building block engineering. In essence, the demonstrated methods enable hitherto undiscovered functionalisation strategies that are widely applicable to all imine-linked covalent organic frameworks, the largest family of COFs to date.
The precipitate was collected via suction filtration and extracted with MeOH in a Soxhlet extractor for 12 h. Extraction with supercritical CO2 afforded rPI-3-COF (28.0 mg, 92%) as a yellow powder.
The precipitate was collected via suction filtration and extracted with MeOH in a Soxhlet extractor for 12 h. Extraction with supercritical CO2 afforded rTTI-COF (27.1 mg, 90%) as a yellow powder.
The precipitate was collected via suction filtration and extracted with MeOH in a Soxhlet extractor for 12 h. Extraction with supercritical CO2 afforded rPy1P-COF (14.2 mg, 94%) as an orange solid.