Flexible hydrogen-bonded organic frameworks (HOFs): opportunities and challenges

Flexible behavior is one of the most fascinating features of hydrogen-bonded organic frameworks (HOFs), which represent an emerging class of porous materials that are self-assembled via H-bonding between organic building units. Due to their unique flexibility, HOFs can undergo structural changes or transformations in response to various stimuli (physical or chemical). Taking advantage of this unique structural feature, flexible HOFs show potential in multifunctional applications such as gas storage/separation, molecular recognition, sensing, proton conductivity, biomedicine, etc. While some other flexible porous materials have been extensively studied, the dynamic behavior of HOFs remains relatively less explored. This perspective highlights the inherent flexible properties of HOFs, discusses their different flexible behaviors, including pore size/shape changes, interpenetration/stacking manner, H-bond breaking/reconstruction, and local dynamic behavior, and highlights their potential applications. We believe that this perspective will not only contribute to HOF chemistry and materials science, but will also facilitate the ongoing extensive research on dynamic porous materials.

H-bonds are a type of weak supramolecular interaction characterized by an attractive force between permanent dipoles, occurring between a hydrogen atom bonded to another atom via a covalent bond and another electronegative atom (X-H/Y).Typically, the atoms (X and Y) on both sides of the hydrogen atom involved in H-bonding are highly electronegative (e.g., N and O).It's worth noting that H-bonds can form both intermolecularly and intramolecularly.Although many arguments exist about H-bonds, their widespread presence and signicance in chemistry, materials science, and biology have been recognized.As shown in Fig. 1, some common H-bond motifs used for constructing HOFs include carboxyl dimer, guanidinium-sulfonate, pyrazole, benzimidazolone, amidinium-carboxylate, 2,4-diaminotriazine, 2,6-diaminopurine, etc.For these typical H-bonds, the bond lengths (X-H/Y, distance between X and Y) usually range from 2.5 to 3.2 Å, much longer than the 1.2-1.5 Å typically found in covalent bonds.Therefore, the exibility of H-bonding is one of its essential features in terms of strength and angle.
Open frameworks based on H-bonds have been reported as early as 1914, 23 and along with the development of single-crystal diffraction techniques, many related structures have been published since then.However, most of them have remained at the level of structural characterization; this may be due to the lack of in-depth understanding and effective activation methods in the early days, similar to the challenges faced in the early development of MOFs. 24In 2011, Chen et al. successfully achieved the activation of HOF-1, a compound that was reported more than a decade ago via a 2,4-diaminotriazine moiety, 25,26 using a solvent exchange strategy, demonstrating for the rst time the permanent porosity and exibility of this type of material.They also discovered its potential application in gas separation as the rst representative of a functional HOF. 27In the same period, Schröder et al. reported another example of a supramolecular organic framework (SOF-1) with permanent porosity, marking the official beginning of the era of rapid development of HOFs. 28][31][32][33][34] Much of the exibility of HOFs comes from the weak H-bonding strength and the wide range of H-bond angles (from 130°to 180°).In some cases, this angle even approaches 90°. 11Such a exibility of H-bonding will signicantly affect the structural diversity of HOFs.Functional modication of organic motifs is a very effective method to regulate the H-bonding patterns by using steric hindrance or planarity changes.6][37] Even for the same organic motifs, changing solvents/conditions could have a considerable impact on Hbonding patterns during crystallization (Fig. 2).For example, the rapid recrystallization of tris(4-carboxyphenyl)amine (TCA) in methanol can result in HOF-16 with free -COOH sites in the channel, whereas it can lead to HOF-11 in THF/hexane with an inert pore surface. 38The exibility in the self-assembly process has greatly increased the diversity of HOFs while posing challenges for targeted synthesis.In 2011, Cooper et al. demonstrated that the complicated assembly of porous cages can be precisely predicted by lattice energy calculations, which exhibited the application of "design by computational selection" for porous organic frameworks. 39Therefore, scientists have always remained hopeful of controlling the exible and complex self-assembly behavior and mastering effective strategies for targeting and constructing HOFs.Furthermore, the dynamic behaviors of HOFs in response to external stimuli are also quite attractive.This dynamic behavior can signicantly affect the properties of HOFs and even lead to many unpredictable results, which we will discuss in detail in this paper.Flexible HOFs have some obvious advantages: (1) more accessible exible behaviors.Generally, the bonding energy of H-bonds is 10-40 kJ mol −1 , much lower than the coordination bonds in MOFs (90-350 kJ mol −1 ) and the covalent bonds in COFs (300-600 kJ mol −1 ), making it easier for HOFs to exhibit a certain degree of structural exibility and diversity; 13 (2) better reproducibility.The reversibility of H-bonds allows us to reconnect broken H-bonding units under certain conditions, enabling the original HOFs to recover and regenerate; (3) compared to MOFs, HOFs lack metal ions (or have a lower proportion of metal ions), resulting in lower density; however they exhibit higher structural diversity than COFs, combining the different advantages of both.
In this perspective, we aim to provide a unique viewpoint on discussing exible HOFs.Rather than offering a comprehensive overview of all exible HOFs, we will focus on discussing the exible behaviors of some representative exible HOFs (Table 1) and their unique applications.Additionally, we will highlight the differences between exible HOFs and other porous materials such as MOFs and COFs.

Different types of flexible behaviors
The exibility of HOFs derives from the organic motifs as well as the weak bond strength and reversibility of the H-bond.We have so far obtained a lot of exible HOFs, although in many cases, the fragility of the crystals makes it challenging to identify the structural changes where the exible behavior occurs.Generally speaking, during the synthesis or in response to external stimuli, HOFs display four primary exible features: pore size/shape changes, interpenetration/stacking manner, H-bond breaking/ reconstruction, and local dynamic behavior (Fig. 3).
The process of pore expansion/contraction can be effectively characterized by in situ PXRD of the gas-loaded sample.In 2023, our group reported a exible-robust HOF (HOF-FJU-8) derived from 4,4 0 ,4 00 ,4 000 -(pyrrolo[3,2-b]pyrrole-1,2,4,5tetrayl)tetrabenzonitrile (DP-4CN) by employing a stickedlayer strategy. 43Based on the CO 2 sorption isotherm at 196 K, the activated HOF-FJU-8a exhibits a stepwise adsorption isotherm, suggesting its framework exibility and the existence of a gating effect.Furthermore, in situ PXRD of CO 2loaded HOF-FJU-8a at 196 K conrmed that with pressure increasing, Miller indices ( 102) shi slightly to the right, indicating a slight change in the structure.The pore-size distribution calculated from the CO 2 isotherm is also slightly larger than the calculated one based on the single crystal structure due to the pore space expansion during the third step of the adsorption process.
7][48] In 2021, Chi et al. reported the design and synthesis of a dynamic two-dimensional (2D) woven HOF. 48The researchers were able to emulate a weaving cra by interlocking 1D strands through H-bonding, resulting in a 2D molecular woven network.Thus, the dynamic nature of the woven structure allows for reversible structural deformations in response to different solvents, as well as large-scale elasticity switching.

Interpenetration/stacking manner
It has been established that interpenetration is a crucial structural characteristic of porous materials because it can increase structural stability, endow the framework with exibility, and allow for ne-tuning of the pore structure. 77,78Therefore, realizing a controlled interpenetration design in HOFs can enhance functional diversity.Similarly, the layer-stacked 2D HOFs can also exhibit exible behavior due to the relatively weak p-p interactions between layers, resulting in sliding.
2.2.1 Interpenetrated network.In 2021, our group reported a microporous HOF-FJU-1, which is composed of 3,3 0 ,6,6 0 -tetracyano-9,9 0 -bicarbazole via intermolecular H-bonding interactions. 52Each bicarbazole unit is linked to four adjacent bicarbazoles by four pairs of C-N/H-C H-bonds with distances of 3.431-3.536Å to form a dia topology (Fig. 6).HOF-FJU-1 exhibits a threefold-interpenetrated structure, with distinct offset p-p interactions along the a axis.The pore windows in the channels have a size of about 3.4 × 5.3 Å 2 , which is suitable for the separation of C 2 H 4 .This exible HOF exhibits a gateopening effect, where the opening pressure required for C 2 H 4 uptake varies with temperature.The in situ PXRD patterns of the CO 2 loaded sample at 195 K conrm the minor expansion of the pore window.Additionally, the interpenetrated network exhibits high stability even under various harsh conditions.]53 2.2.2 Layer network sliding.The exible behavior of 2D HOFs has also been observed in single-crystal structures.In 2022, our group reported an adaptive HOF, HOF-29, based on 4,4 0 ,4 00 ,4 000 -(porphyrin-5,10,15,20-tetrayl)tetrabenzonitrile (PTTBN). 57Each PTTBN unit is connected with four adjacent units via four pairs of intermolecular C-H/NC H-bonds, resulting in a 2D sql net.Different layers were packed in an AA stacking pattern through multiple H-bonding and p-p stacking interactions (Fig. 7a and b).HOF-29 exhibited a singlecrystal-to-single-crystal transformation from the as-synthesized AA stacking phase to another AB stacking phase aer adsorbing pX molecules by sliding the 2D layers and the local distortion of the ligand (Fig. 7c and d) realized the exclusive recognition of pX over mX, oX and EB.
In some other studies, the exibility of 2D HOFs has already been applied in the eld of gas separation. 56,58In 2023, Zhang et al. reported a CO 2 -selective HOF-FJU-88 from 2,4,6tri(1Hpyrazol-4-yl)pyridine (PYTPZ) building units. 58HOF-FJU-88 consists of a 2D H-bonded layer formed from PYTPZ molecules.Each layer is further connected by p-p interactions between pyridine and pyrazole groups.During the activation process, PXRD indicates a partial loss of crystallinity due to the sliding of the 2D layers.The CO 2 adsorption isotherm also exhibits a signicant gate-opening effect, demonstrating the dynamic framework nature of HOF-FJU-88.
Another typical example was reported in 2023 by Wu et al.HOF-NBDA(DMA) was constructed from 4 0 ,4 00 ,4 000 -nitrilotris([1,1 0biphenyl]-3,5-dicarboxylic acid) (H 6 NBDA). 67Each organic unit is  connected to three adjacent H 5 NBDA units through six sets of intermolecular H-bonds to form a 2D honeycomb-like layer.It is worth noting that there are two types of H-bonds in HOF-NBDA(DMA).As shown in Fig. 9, H-1 is the classic carboxyl dimer that forms a pair of parallel H-bonds.However, in H-2, one carboxyl group was deprotonated, and thus further connected to another DMA cation via a N-H/O H-bond to balance the charge, resulting in a relatively low symmetry of the monoclinic P 1 space group.However, upon activation, HOF-NBDA(DMA) transformed into another structure, HOF-NBDA.The single-crystal structure revealed that only H-1 type H-bonds remain; all the carboxyl groups are not deprotonated.The resulting HOF-NBDA exhibited a relatively high symmetry of the orthorhombic Fddd space group.
In 2023, Zhao et al. reported a very interesting study.Two different macrocyclic molecules, trimeric pyromellitic diimide (Tri-PMDI) and Tri-PMDI-Br, are synthesized and crystalized into two distinct structures (Fig. 10). 62In Tri-PMDI, H-bond interactions between the Ph-H and the O]C hold the molecules together and nally lead to the formation of PMC-Tri-PMDI (PMC, porous molecular crystals).For Tri-PMDI-Br, an unusual H-bond forms between C(sp 3 )-H from the cyclohexane and O]C, leading to the formation of HOF-Tri-PMDI-Br.The obtained HOF-Tri-PMDI-Br can simultaneously exhibit robustness and exibility.The structural exibility enables a reversible transformation between non-crystalline and crystalline phases by introducing or removing some specic solvent molecules, which act as a "key" to control the crystallinity.The single crystal structure of n-hexane@HOF-Tri-PMDI-Br has shown that n-hexane could easily go through the smaller pore of HOF-Tri-PMDI-Br and form H-bonds with cyclohexane linkages.Interestingly, only the solvent molecules with short chains, such as npentane and n-hexane, have the effect of crystallinity recovery.From this example, we can see the unexpected impact that a cleverly designed organic building block can have on the properties of a exible HOF.
Recently, Zhang et al. reported a multifunctional HOF (HOF-FJU-2) using a tetrabenzaldehyde molecule, 4,4 0 ,4 00 ,4 000 -(9Hcarbazole-1,3,6,8-tetrayl) tetrabenzaldehyde (CTBA), with a carbazole N-H binding site (Fig. 11). 66This D-p-A type molecule has been conrmed to be able to construct exible and/or exiblerobust HOFs for unprecedented functions.In this work, HOF-FJU-2 can be crystallized from different solvents.HOF-FJU-2 exhibits a 3D framework where CTBA molecules form p-stacking rod dimers.These dimers connect via H-bonds (C-H/O) and p-p interactions between aldehyde and carbazole groups, leading to the formation of larger p-stacking rod structures.The framework extends further through interactions between adjacent rod dimers, facilitated by C-H/O]C H-bonds.Interestingly, the  (d-f) gas adsorption isotherms for C 2 H 4 (orange) and C 2 H 6 (purple) at 298 K, 318 K and 333 K, respectively. 52Fig. 7 The AA stacking pattern of HOF-29 viewed perpendicularly (a) and side views (b); the AB stacking pattern of HOF-29IpX viewed perpendicularly (c) and side views (d). 57ctivation of HOF-FJU-2 will result in a single-crystal-to-singlecrystal (SCSC) transformation to a closed framework HOF-FJU-2a.However, when soaked in acetone or exposed to acetone vapor, the yellow HOF-FJU-2a crystals can be facilely transformed back into the white porous HOF-FJU-2, exhibiting exibility in structure.Unlike HOF-FJU-1, the H-bonds formed between the CTBA molecules are not in pairs like in HOF-FJU-1, thus further increasing the local exibility and leading to structural transformation during the activation process.However, the overall stronger intermolecular interactions still maintain the stability of HOF-FJU-2, allowing this exible HOF to exhibit related properties while maintaining crystallinity.

Local dynamic behavior
The concept of local dynamics highlights the local motions throughout the entire framework in contrast to the behavior of global dynamics.It has been well established that modifying dangling groups on organic ligands in MOFs can lead to exible behavior, even though the framework may not exhibit signicant exibility.The dangling groups can be small groups or complex interlocking supramolecular structures.Similarly, in HOFs, local exibility in the organic units can bring about signicant dynamic behavior, and this effect can either affect the properties or bring about a structural change.][73] In 2023, Chi et al. reported a exible HOF, 8PZ, with local dynamics for adaptive guest accommodation through incorporating so ethyl-ester chains. 728PZ was developed from a exible building block tetraethyl 4 0 ,4 000 ,4 00000 ,4 0000000 (ethene-1,1,2,2-tetrayl)tetrakis([1,1 0 -biphenyl]-4-carboxylate) (TPE-4PZ), which includes four identical so ethyl-ester chains.8PZ has been conrmed to have signicant local dynamics in response to solvents and temperature changes, especially the in-plane and out-of-plane motions of terminal carbon atoms, leading to an effective approach to regulating the pore sizes.In 2023, Little et al. reported a exible oxygen-bridged prismatic organic cage molecule, Cage-6-COOH, which has three pillars that exhibit rotational motion like a hinge in the solid state (Fig. 12). 73This organic building unit can form a series of exible HOFs by crystallizing in different solvents.CageHOF-2a was crystallized from the THF/CH 3 CN solution, and each Cage-6-COOH molecule was connected to six neighboring Cage-6-COOH molecules via H-bonds between directional carboxylic acid dimers with distances of 2.58-2.59Å.Although CageHOF-2a shows an acs topology, it is nonporous.Another CageHOF-2b was crystallized from ethanol with similar Hbonding patterns.However, in CageHOF-2b, the H-bond building units are not all planar, and the aromatic pillars have profoundly different orientations.CageHOF-2b exhibited good thermal stability and a BET surface area of 458 m 2 g −1 .Furthermore, another ve HOFs are found with different dihedral angles between the pillars varying from 90°to 157°.The exibility of Cage-6-COOH allows this molecule to rapidly transform from a low-crystallinity solid into CageHOF-2a and CageHOF-2b under mild conditions simply by using acetonitrile or ethanol vapor, respectively.This work highlights the potential of exible organic cage hinges in the design and synthesis of exible HOFs with tunable properties.

Diverse applications for flexible HOFs
Flexible HOFs stand out because of their inherent exibility, offering a wide range of potential applications.Although still    relatively short in development compared to exible MOFs and COFs, exible HOFs have demonstrated their unique advantages in gas storage/separation, molecular recognition, biomedicine, heterogeneous catalysis, chemical sensing, and other areas.Their outstanding exibility, along with the reversibility of H-bonding, allows them to be synthesized from a diverse range of building blocks, enabling mild synthetic reactions, excellent solution processability, easy repair, easy regeneration, and recyclability.

Gas storage/separation
The ability of exible HOFs to adjust their structure dynamically when facing changes in temperature, pressure, or guest molecule adsorption offers excellent potential for gas storage/ separation.8,60,64,66,67,[79][80][81][82][83][84][85][86][87][88][89] In addition, the recyclability of HOFs reduces the cost.The dynamic behavior of exible HOFs in gas adsorption makes the research more complex than that of other rigid porous materials.Therefore, many in situ characterization methods have been used in recent years to help us better understand this behavior.
Early in 2010, Schröder et al. reported the gas adsorption of SOF-1, which demonstrated impressive adsorption capabilities for CH 4 (106 cm 3 g −1 , 10 bar, and 195 K), C 2 H 2 (124 cm 3 g −1 , 1 bar, and 195 K), and CO 2 (69 cm 3 g −1 , 16 bar, and 298 K). 28 Most notably, the activated SOF-1a demonstrated a exible response to temperature increases from 77 K to 125 K, with a signicant increase in N 2 adsorption capacity, indicating a certain framework exibility.Such a exible behavior appears to be more pronounced in HOF-1 and is applied for the rst time in the eld of gas separation. 27As described above, HOF-1 exhibited a signicant gate-opening effect on C 2 H 2 .The adsorption isotherm of C 2 H 2 showed a sudden increase around 200 mmHg, with a nal adsorption capacity of 63.2 cm 3 g −1 (at 800 mmHg and 273 K).Meanwhile for C 2 H 4 it only adsorbed 8.3 cm 3 g −1 under the same conditions, thus leading to a highly selective adsorptive separation of C 2 H 2 and C 2 H 4 at ambient temperature.The subsequently reported HOF-5 also exhibits high porosity and CO 2 adsorption capacity.
Aer these early studies, a large number of exible HOFs have been reported for gas adsorption/separation.As mentioned above, HOF-FJU-1 showed a clear gate-opening effect due to the interpenetrated framework, and the experimental results showed that the adsorption capacity for C 2 H 4 was 47 cm 3 g −1 at 298 K and 1 bar, while for C 2 H 6 it was very   low. 52In addition, with the increase in temperature, the adsorption capacity for C 2 H 6 will further decrease.Breakthrough experiments conrmed the high selectivity of HOF-FJU-1 for C 2 H 4 with a purity of 99.1% at 333 K.It is worth mentioning that HOF-FJU-1 exhibits stability under various harsh conditions and can be easily processed into different forms for gas separation.Interestingly, theoretical simulation shows that neither C 2 H 4 nor C 2 H 6 molecules can diffuse into HOF-FJU-1 without considering the exibility of the framework, but the distribution of C 2 H 4 in the pore is clearly observed by single crystal X-ray diffraction, which fully demonstrates the key role of exibility in this adsorption process.However, in another study, instead of showing the same exibility towards smaller gas molecules (C 2 H 2 and CO 2 ), HOF-FJU-1 achieves the high sieving effect of C 2 H 2 /CO 2 . 54Therefore, such an interesting robust-exible HOF exhibited completely different adsorption behaviors with different adsorption guests, showing the remarkable versatility of exible HOFs.
The potential application of exible HOFs in gas adsorption/ separation is actually more widespread.The renewability of    55 HOFs, in particular, provides this material with a unique economic advantage.Their lower density, on the other hand, allows for a better balance of volumetric and gravimetric uptake, which is also an important aspect in this eld. 90Flexible HOFs, in general, can exhibit more unpredictable dynamic behaviors, allowing them to deal with some difficult separation systems and establish a new class of energy-saving and environmentally friendly physical adsorbents.

Molecular recognition
In molecular recognition applications, exible HOFs can precisely accommodate guest molecules within their pores through dynamic structural changes. 47,57,86,91This attribute enables selective binding and recognition of target molecules, which is crucial for sensors, drug delivery systems, and chemical sensing applications.By adjusting the framework's exibility, researchers can enhance the specicity and efficiency of molecular recognition processes, paving the way for advanced sensing technologies and targeted therapeutics.
Ward et al. have reported a series of host frameworks based on guanidinium cations and interchangeable organosulfonate anions, which exhibited impressive exible behaviors.In these compounds, the guanidinium molecules are connected to sulfonate via N-H/O-S H-bonds, forming a 2D quasihexagonal H-bonding network. 25,92Different types of organosulfonate molecules will further connect the layer, resulting in diverse structures.The exibility of the H-bonded network allows these compounds to adapt to changes in the steric requirements of guest molecules that occupy the channels.The typical example reported in 1997 described a case of HOF, (G) 2 (BPDS) based on guanidinium (G) and 4,4 0 -biphenyldisulfonate (BPDS). 25 (4) different H-bonding patterns in the guanidinium-sulfonate layer structure; (5) selection of "bilayer" versus "brick" stacking patterns.Guanidinium is capable of changing its pore structure to accommodate various monosubstituted benzene guests and disubstituted isomers, revealing host-guest interactions.
Another interesting recent study was reported in 2019.Chi et al. found an exceptionally exible HOF, 8 PN, which exhibited permanent porosity derived from 1,1,2,2-tetrakis(4 0 -nitro-[1,1 0biphenyl]-4 yl)ethane. 478 PN exhibits unprecedented exibility, allowing for the regulation of pore volume in HOFs through the control of molecular assembly and conformation.Nine different single crystals of 8 PN achieved a pore volume adjustment ranging from 89.4 Å 3 to 1816.0 Å 3 (Fig. 14).Moreover, the pore volume adjustment enables multimodal reversible structural transformations in response to various external stimuli, including guest molecules, temperature variations, and mechanical pressure changes.Flexible frameworks can accommodate guest molecules of different sizes, thereby yielding ve high-quality co-crystals, further indicating the potential application prospects of exible 8PN in adaptively regulating pore structures.
In 2023, Xue et al. reported a exible luminescent HOF for the separation of benzene and cyclohexane. 93The researchers designed and synthesized a nonplanar phenothiazine derivative with three cyano moieties (PTTCN) as the functional crystal (Fig. 15).Two different forms of PTTCN crystals, ax form and eq form, have different uorescence colors.The ax form crystals were found to selectively adsorb benzene through an SCSC transformation.However, the purity of the separated benzene from a benzene/cyclohexane equimolar mixture was relatively low at 79.6%.On the other hand, the eq form of PTTCN molecules co-assembled with benzene to construct an HOF (X-HOF-4) with S-type solvent channels and yellow-green uorescence.This exible HOF exhibited a strong preference for aromatic benzene over cyclohexane.The researchers discovered that the framework could release benzene to form a nonporous guest- free crystal under heating.This nonporous crystal could selectively reabsorb benzene from the benzene/cyclohexane mixture, allowing for the recovery of the original framework.The purity of the reabsorbed benzene reached approximately 96.5%.This work addressed the challenge of separating benzene and cyclohexane by designing a exible luminescent HOF with selective adsorption and release properties.

Sensing
HOFs have demonstrated signicant promise in the elds of multiple stimulus-response and intelligent optics because of their modular building units and exible frameworks.[96][97][98][99][100][101][102] A novel triaryl formamidine salt containing two isomers (BA-C and BA-N) was reported by Lin et al. 68 These two isomers can be recrystallized in different solvents to form two different HOFs, and it was found that the removal of acetone from the lattice of BA-C by grinding or heating could lead to the conversion of BA-C to BA-N, and in turn, exposing to acetone vapor or cooling at 77 K could lead to the conversion of BA-N to BA-C, thus realizing the reversibility of the conversion of BA-N and BA-C, and showing the exibility of these HOFs (Fig. 16).The exible behavior of this anionic HOF enables dynamic switching of multiple luminescence behaviors, including prompt uorescence, TADF, and phosphorescence.As a result, this HOF can be used for highly sensitive and specic sensing of acetone with an ultra-low detection limit of 66.74 ppm.
There are many similar examples of utilizing the exible behavior of HOFs to achieve ne-tuning of optical properties, such as the previously mentioned 8PZ, where so ethyl-ester chains bring adaptability to different guest molecules, and endow it with programmable temperature-dependent luminescence behaviors. 72In another case, Cong et al. reported a novel polycatenated HOF MEP-HOF, which is composed of uorenylidene-aza [1 6 ]cyclophane (FLAC). 63This HOF exhibits dynamic reversible transformation in crystallinity during guest removal/adsorption and also exhibits sensitive detection of nitrobenzene.In 2021, Xue et al. investigated the inuence of guest molecules on the photoluminescence and force-stimuli response of X-HOF-1. 102The research demonstrated that the mechanouorochromic HOF materials could be regenerated through recrystallization and adsorbing the guest and highlighted the potential of guest molecules in regulating the properties and functions of exible HOFs.

Biomedical applications
HOFs are a promising material for biomedical applications due to their excellent biocompatibility and low toxicity.One of the most signicant advantages of exible HOFs is their ability to adaptively accommodate a variety of guest molecules, enabling reversible guest encapsulation and controlled release in response to mild stimuli.][105][106] A very typical example of a drug carrier is PFC-1, which is a photoactive HOF for synergetic chemo-photodynamic therapy. 107Subsequently, much work has been reported in this eld, and exible HOFs act as carriers or shells to protect or transport biomedical molecules.In 2022, Ouyang et al. reported a case where by encapsulating cytochrome c (Cyt c), a hemecontaining enzyme, within HOF-101, they could create a biomimetic system that allowed for non-native biocatalytic activity (Fig. 17). 108The results of the experiment demonstrate that the H-bonded nano-biointerface between encapsulated Cyt c and the HOF cage induces Cyt c to alter its native conformation.This work demonstrates the synergistic relationship between Cyt c and HOFs in terms of structural exibility.
In recent years, more and more scientists have applied exible HOFs in the biomedical eld.In 2022, Qu et al. reported the development of a novel strategy for the encapsulation and transplantation of neural stem cells (NSCs) using a HOF as a protective shell (Fig. 18). 109The HOF-based cell protectors effectively shielded the NSCs from physical and chemical stressors.They were degradable under near-infrared II (NIR-II)  under humidied conditions. 114Although the exible behavior of HOFs in proton conduction is not always visible, the simplicity of processing and regeneration due to their exibility also benets this application.
In 2023, our group reported a 2D layered structure by constructing a donor-acceptor p-p stacked HOF (HOF-FJU-36) utilizing 1,1 0 -bis(3-carboxyphenylmethyl)-4,4 0 -bipyridine (H 2 L 2+ ) as the acceptor and 2,7-naphthalene disulfonate (NDS 2− ) as the donor. 112The presence of three water molecules in the channel, interconnecting the acids by H-bonding, forms a 3D framework.Continuous p-p interactions along the a-axis direction and smooth H-bonding chains along the b-axis direction provide pathways for electron and proton transport.Aer 405 nm illumination, the photogenerated radicals were able to give HOF-FJU-36 both switchable electron and proton conductivity due to   coupled electron-proton transfer.This work demonstrated that by rationally designing exible HOFs, the coupling of protonelectron transfer can be realized, resulting in controllable photoresponsive electronic and proton conductivity.

Other applications
Further research on exible HOFs remains ongoing, and their applications involve many areas that will not be detailed here, such as catalysis, 61,117-122 chiral separation, 123,124 etc.
In 2022, Liu et al. reported the synthesis and characterization of porphyrin-based HOFs (PFC-71, PFC-72, and PFC-73) for photocatalytic CO 2 reduction. 615,10,15,20-tetrakis(4carboxyphenyl)porphyrin] (TCPP) is applied to synthesize these HOFs with different metalized porphyrin centers.In the case of PFC-71, the porphyrin center is not metalized, whereas, in PFC-72, PFC-73-Ni, PFC-73-Cu, and PFC-73-Zn, the porphyrin center is metalized with different metal ions (Co, Ni, Cu, and Zn, respectively).This metallization of the porphyrin center leads to a larger electronegativity difference on the macrocycle backbone, causing increased polarizability and electron cloud distortion, resulting in the formation of stronger offset p-p interactions between adjacent interlamellar porphyrins.PFC-72 and PFC-73 exhibit higher stability compared to PFC-71.The undulated geometry of the metalized layers, along with the deeper interlayer penetrations and orientation of benzene rings orthogonal to the layer, increases the geometrical barrier for sliding and contributes to the higher stability of PFC-72 and PFC-73 (Fig. 19).The authors investigate the metallization process of the HOFs and its effect on the photocatalytic activity, demonstrating the potential of these HOFs as photocatalysts for CO 2 reduction.

Future directions for exible HOFs' applications
Over the last decade, research on exible HOFs has demonstrated great potential for diverse applications.In-depth research into the structure-function relationship has greatly improved the response of exible HOFs to a broader range of stimuli, particularly in biomedical applications.In recent years, there has been a lot of interest in the development of HOF membranes, and exible HOFs have the potential to expand the range of applications in this eld even further. 125In addition, researchers are improving the synthesis and processing technologies of exible HOFs in order to enable further application in industry.Overall, research in the future should concentrate on utilizing the unique features of exible HOFs to provide inventive solutions for a variety of practical applications.

Conclusions and outlook
In this perspective, we have summarized and analyzed the very common and interesting phenomenon of exibility in HOFs.We believe that exibility refers to the ability or range of deformability of the overall or local structure, i.e., the ability to undergo structural changes or deformations under certain stimuli without losing (or restoring) its crystallinity or function.This exibility allows HOFs to be adapted to different environments and applications.We should note that the exibility of HOFs differs notably from that of MOFs and COFs.First, the exibility of HOFs mainly comes from the exibility and reversibility of H-bonding.H-bonding is important for HOFs' exible behavior, and they can be distorted, broken, and reformed in response to external stimuli, which is a unique property of HOFs.MOFs, on the other hand, are typically exible due to their metal-organic coordination bonds between metal ions and organic ligands, which can undergo stretching or rotation to some extent, making MOFs exible to a limited degree.COFs are composed of organic molecules connected by covalent bonds that can be bent or twisted under external stresses, allowing them some deformability.The distinctive features of exible HOFs endow them with some special advantages, but they also pose challenges for their design and application.
Currently, the challenges of exible HOFs mainly focus on: (1) the complexity of structural design; (2) framework stability; (3) controlling H-bond dynamic behaviour.Designing exible HOFs requires precise control of the structure and arrangement of organic molecules to ensure that the framework can undergo reversible changes.However, exible HOFs usually have lower structural stability due to the exible and reversible nature of Hbonding, and thus, the relationship between exibility and stability needs to be balanced in the design.At the same time, it is essential to explore how to effectively control the kinetic behaviour of H-bonds to achieve the desired structure change and performance.
HOFs are still facing challenges and opportunities in their applications.Although typically HOFs are not as stable as MOFs and HOFs in terms of their structure rigidity and thus porosity, some HOFs can indeed be very stable even under highly acidic/ basic conditions and high temperatures, particularly when framework interpenetration and other weak interactions such as p/p and C-H/p can collaboratively reinforce the HOF framework.The simple recrystallization nature of most HOF materials can allow us to easily and straightforwardly regenerate HOF materials for their reusage, which will save the material costs for some of their applications, particularly in gas storage and separation, and catalysis.Apparently, HOFs are not as designable as MOFs and HOFs, so extensive exploration of different synthetic approaches is still necessary to discover some unique HOF materials for different applications.To make use of the framework exibility, we can execute more parameters through changing the temperatures and pressures to nely tune and maximize the gas separation and purication, targeting some functional HOF materials for gas separation/ purication even without our imagination.Because HOFs purely contain only organic species and can be reversibly dissociated/re-assembled, their compatibility with biological systems is expected to be better than that of MOFs and COFs.HOFs also do not have metal ion species, and this might be another advantage for HOFs for their biomedical applications.Given the fact that HOF structures can be easily stimulated even by some very weak external stimuli such as light and ultrasonic irradiation, HOFs are very promising materials for drug delivery and thus for the treatment of some challenging diseases.As fast development in MOF chemistry and materials science, HOF composite materials will be also developed in the near future for their broad applications.In conclusion, exible HOFs will provide us with the bright promise to design and construct many HOF materials for a variety of applications.We believe that some exible HOF materials might be eventually implemented in practical applications in energy and environmental science and biomedical applications in the future.

Fig. 2
Fig. 2 The flexibility of HOFs in (a) the self-assembly process and (b) response to external stimuli.

Fig. 3
Fig. 3 Representative modes of different types of flexible behaviors for flexible HOFs.

Fig. 5
Fig. 5 Illustration of the structural deformation of HOF-5 and the arrangement of CO 2 molecules in the pores. 45

Fig. 9
Fig. 9 (a) The structure of H 6 NBDA; (b and c) representation of the reorganization of H-bond dimers upon heating; (d) scheme of H 6 NBDA and the six-connected node; (e and f) the transformation of layered frameworks before and after heating.67

67
Fig. 9 (a) The structure of H 6 NBDA; (b and c) representation of the reorganization of H-bond dimers upon heating; (d) scheme of H 6 NBDA and the six-connected node; (e and f) the transformation of layered frameworks before and after heating.67

Fig. 12
Fig.12Schematic illustration of the dihedral angles of the pillar ring changes from 90°to 157°in Cage-6-COOH based structures.73

73
Fig.12Schematic illustration of the dihedral angles of the pillar ring changes from 90°to 157°in Cage-6-COOH based structures.73

Fig. 13 (
Fig. 13 (a) Single-crystal structure of ZJU-HOF-8 and the structural transformation with framework contraction upon activation; (b) N 2 adsorption of ZJU-HOF-8a at 77 K; (c) different gas adsorption at 296 K; (d) IAST selectivities of ZJU-HOF-8a at 296 K.55 Single-crystal diffraction results show that each BPDS molecule is connected to six G molecules via N-H/O-S H-bonding, resulting in a pillared structure.A variety of exible response forms are observed, including (1) N-H/O-S Hbonding rotations; (2) twisted C-C bonding in BPDS molecules; (3) rotations of the C-S bonding in the BPDS molecules;

Fig. 14 (
Fig. 14 (a) Packing model of 8PN-EA in the [010] direction, with the solvent-accessible void space; (b) single-crystal X-ray structures of eight 8 PN frameworks with varying void space; (c) S-shaped channel surface of 8PN-THF. 47

Fig. 15 (
Fig. 15 (a) Assembling of PTTCN molecules (left) to a 2D H-bonded framework with pores (middle), and intermolecular stacking in a 2 × 2 × 2 cell (right); (b) PXRD patterns; (c) schematic representation of the separation for benzene/cyclohexane. 93 Fig. 16 (a) Tautomerism of BA-N and BA-C; (b) images showing reversible switching between BA-N and BA-C (l ex = 365 nm), as well as LED light-emitting images before and after acetone fumigation; (c) histogram of the prompt emission peaks of BA-N following fumigation; (d) repeatability of luminescence color switching when stimulated with acetone vapor and heated. 68

3. 5
Proton conductivityHOFs are excellent candidates for proton conductors due to their intrinsic H-bonding networks.In general, the structural diversity of HOFs allows for the construction of a well-dened H-bonding network in the structure, either in the host framework or from guest molecules, which enables proton motion.A large number of studies have demonstrated the advantages of HOFs as a platform for proton conductors.[110][111][112][113][114][115][116]For example, in 2011, Kim et al. reported proton conductivity in organic molecular porous materials based on cucurbituril (CB) compounds. 115Among them, CB[6]$H 2 SO 4 exhibited the highest proton conductivities at 98% RH and 298 K with a value of 1.3 × 10 −3 S cm −1 , representing one of the pioneering studies that demonstrated the application of HOFs in this area.Another important study reported by Ghosh et al. described two porous HOFs, HOF-GS-10 and HOF-GS-11, based on arene sulfonates and guanidinium ions.The materials show high proton conduction values of 0.75 × 10 −2 S cm −1 and 1.8 × 10 −2 S cm −1

Fig. 18 A
Fig.18A schematic representation of the construction and removal of HOF shells on individual NSCs, as well as the process for remodeling impaired neural networks.109

Table 1
Selected representative flexible HOFs categorized into different flexible behaviors