1. Introduction

Chiral recognition is a fundamental process in chemistry and biology. Many biologically active molecules, including pharmaceuticals, agrochemicals, and natural products, often exist as pairs of enantiomers sharing identical chemical compositions but differing in their spatial configuration. Despite their structural similarity, these enantiomers can exhibit drastically different biological activities, pharmacokinetics, and toxicity profiles. As a result, the ability to selectively recognize, separate, or transform enantiomers has become a critical objective in modern chemistry, particularly in pharmaceutical manufacturing and analytical science.

Porous crystalline materials such as metal-organic frameworks (MOFs) and covalent organic frameworks have become promising candidates for chiral recognition and separation^[1]. Their highly ordered structures, tunable pore environments, and modular design enable precise incorporation of functional groups capable of interacting with guest molecules^[2]. Over the past decade, various strategies have been explored to construct chiral porous frameworks, such as employing enantiopure organic linkers, chiral metal centers, or post-synthetic modifications to introduce stereogenic units, yielding materials with demonstrated capabilities in enantioselective adsorption, separation, and catalysis. However, enantioselective recognition in most existing chiral porous materials relies on static stereogenic units, which often limits their adaptability to complex guest molecules^[3,4]. In many existing chiral porous materials, the mere presence of framework chirality is considered sufficient for enantiomer discrimination. This static approach stands in stark contrast to the dynamic recognition processes observed in biological systems. In enzymes and biological receptors, enantioselectivity emerges from a combination of inherent chirality and the binding pocket’s ability to dynamically reorganize upon guest approach. Such adaptive behavior allows multiple weak interactions, hydrogen bonding, π-π stacking, and electrostatic contacts to synergistically stabilize the preferred enantiomer.

Mimicking the adaptive recognition found in biological systems within crystalline porous materials remains elusive. Although incorporating amino-acid-derived linkers via direct synthesis is a conceptually appealing route, this approach is frequently compromised by low crystallinity, structural disorder, and synthetic incompatibilities associated with the steric and polar characteristics of amino acid side chains. Thus, establishing a general and reliable strategy to embed biologically inspired chiral functionalities into robust porous frameworks while fully retaining crystallinity and structural integrity is of great importance.

2. Adaptive Chiral Recognition in Amino-Acid-Functionalized MOFs

Gómez-Tenés and co-workers describe an elegant strategy for engineering adaptive chiral environments within a robust MOF via click-enabled postsynthetic grafting of amino-acid-derived fragments^[5]. Their approach utilizes a UiO-68 framework functionalized with tetrazine groups (UiO-68-TZDC), which serve as reactive sites for inverse-electron-demand Diels-Alder click reactions (Figure 1a,b,c). This chemistry enables efficient installation of functional molecules within the framework under mild conditions while preserving the crystallinity of the host structure.

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Figure 1. (a) Octahedral cavity of UiO-68-TZDC; (b) Synthesis of enantiopure amino acid dienophiles (top) and subsequent click functionalization of the framework (bottom), showing optical images of crystals before and after modification (scale bar = 2 μm); (c) Chemical structures of grafted fragments and SEM images of the functionalized crystals; (d) Representative low-energy configurations of (S)- and (R)-cetirizine within the peptide-functionalized frameworks; (e) Relative interaction energies between (S)- and (R)-stereoisomers of CTZ; (f, g) Most stable conformations of UiO-68-(L)-His with (S)-CTZ (f) and (R)-CTZ (g). Adapted with permission from reference^[5]. Copyright © 2026 American Chemical Society. SEM: scanning electron microscope; CTZ: cetirizine.

To introduce chiral recognition motifs, the authors synthesized silyl-enol-ether dienophiles derived from protected amino acids (e.g., alanine, phenylalanine, and histidine), which retain the stereogenic centers and distinctive side chains of the amino acids, capable of providing hydrogen-bonding or aromatic interactions (Figure 1d). These dienophiles undergo click reaction with the tetrazine linkers within the UiO-68-TZDC framework, ultimately generating pyridazine-linked peptidic fragments that line the internal pore surfaces.

Structural and spectroscopic characterization confirms efficient postsynthetic functionalization with full retention of MOF integrity: powder X-ray diffraction patterns remain intact, while gas adsorption reveals a pore volume reduction consistent with the presence of grafted fragments. The successful incorporation of chiral moieties is further corroborated by circular dichroism measurements, which exhibit clear chiroptical responses attributable to the homogeneous distribution of amino-acid-derived groups throughout the bulk crystals.

Evaluation of the materials’ chiral recognition ability using cetirizine as a model guest revealed a striking contrast: only the histidine-functionalized framework exhibited pronounced enantioselectivity, whereas the alanine- and phenylalanine-modified analogues showed minimal discrimination. This finding highlights that effective recognition in porous materials requires more than the mere presence of a stereogenic center; the chemical nature and positioning of functional groups are equally critical. Computational studies shed further light on the origin of this selectivity. Simulations reveal that the histidine-functionalized pores undergo local reorganization upon binding the preferred cetirizine enantiomer, forming an extended network of stabilizing interactions that includes hydrogen bonds and aromatic contacts (Figure 1e,f,g). This adaptive rearrangement creates a cooperative host-guest interaction environment reminiscent of the induced-fit mechanism observed in biological receptors. The favored enantiomer establishes a greater number of stabilizing noncovalent interactions than its counterpart, resulting in enhanced enantioselective adsorption. Despite these advances, the system remains limited in substrate scope and general applicability, highlighting opportunities for future efforts to expand the versatility and transferability of adaptive chiral recognition in porous frameworks.

3. Conclusion

This work extends beyond the demonstration of a new functional material, offering a broader design paradigm for chiral porous frameworks. It shows that moving beyond static stereochemistry toward adaptive pore environments, those capable of dynamic reorganization in response to guest binding, offers a powerful strategy for enhancing enantioselective recognition. Beyond the simple amino-acid-derived fragments used here, this click-enabled grafting strategy provides a versatile platform for installing biomimetic functionality into crystalline frameworks and holds exceptional promise for extension to more complex peptide sequences or multifunctional recognition motifs. By integrating robust reticular chemistry with biologically inspired molecular recognition, this work establishes a compelling strategy for designing porous materials that exhibit sophisticated and selective host–guest interactions. Although demonstrated in UiO-68, extending this click-functionalization strategy to other MOF platforms with compatible reactive handles will be important to assess its generality and broader applicability. These adaptive crystalline systems are poised to advance enantioselective separations, molecular sensing, and asymmetric catalysis, thereby helping to bridge the divide between synthetic porous solids and the dynamic recognition behavior inherent to biological systems.

Acknowledgements

We used DeepSeek to improve the readability and grammatical accuracy of the manuscript. No AI tools were used for data generation, analysis, or interpretation of results.

Authors contribution

Zhang W, Gong W: Conceptualization, writing-original draft, writing-review & editing.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the Young Scientists Fund (C Class) of the National Natural Science Foundation of China (Grant No. 22505155 to Wenqiang Zhang), the National Key R&D Program of China (Grant No. 2023YFA1507601 to Wei Gong), and the National Natural Science Foundation of China (Grant Nos. 52373213, 22301176 and 22205138 to Wei Gong).

Copyright

© The Author(s) 2026.