通讯作者：Jonathan R. Nitschke论文DOI：10.1038/s41557-024-01708-5（点击文末「阅读原文」，直达链接）合成纳米笼可以根据特定客体调整腔体大小和形状，在化学纯化等各个领域都有潜在应用。一种灵活的拟立方金属有机笼现已被开发出来，它可以通过翻转笼面，动态地将空腔从初始体积的46% 扩大到 154%。本文背景主要围绕金属有机笼子（MOCs）在主客体化学中的应用，特别是它们在化学分离、催化、药物递送等领域的潜力。金属有机笼子通常具有非常规则的结构和高度的稳定性，能够为各种客体分子提供封闭的结合腔体，因此广泛应用于分子识别和气体吸附等领域。然而，传统的金属有机笼子大多由刚性结构单元组成，这些单元限制了笼子在结合不同大小、形状的客体时的适应能力。因此，如何设计具有更高适应性的金属有机笼子，以便其能够动态地调整腔体大小和形状来容纳不同种类的客体分子，一直是该领域中的一个挑战。这项研究的创新点在于提出了一种新的伪立方体金属有机笼子设计，采用了具有旋转单元的配体结构，使得笼子的面能够在“内向”（endo）和“外向”（exo）构型之间切换。具体来说，研究人员通过引入2,6-萘基臂的四胺配体单元，使得每个面能够根据客体分子的大小变化，调整其面的构型，从而动态地增大或缩小腔体体积。这一设计突破了传统笼子结构刚性限制，实现了笼子在保持结构稳定性的同时，能够容纳多种大小、形状的客体分子。该研究不仅展示了金属有机笼子在构象适应性方面的巨大潜力，还为提高金属有机笼子在分子识别和其他应用中的功能性提供了新的设计思路。通过这一创新，研究人员成功地表明，构象灵活的金属有机笼子能够根据不同客体的需求优化其空间适配性，显著提升其作为分子受体的多功能性，且可扩展至其他类型的金属有机笼子设计中。Fig. 1 | Preparation and characterization of cage 1.a, Synthesis of pseudo-cube 1 from tetramine subcomponent A. b,The two conformations of each face, as a result of the 2,6-naphthalyl rotational units. c, 1H NMR and 1H DOSY spectra of pseudo cube 1, revealing a diffusion coefficient of 3.34×10-10 m2·s-1 (400 MHz, 298 K, CD3CN).这项研究介绍了一种具有构象适应性的伪立方体金属有机笼子，能够根据不同客体分子的大小动态地调整腔体体积。这种伪立方体笼子由一个具有旋转结构单元的配体设计而成，配体的2,6-萘基臂能够在“内向”（endo）和“外向”（exo）构型之间切换，从而使笼子能够根据客体的需求改变其形状和大小。Fig. 2 | Single crystal structure of cage 1.a, Oblique view of the crystal structure of 1, showing the Molovol-calculated cavity in cyan and a cartoon representation of its all-endo conformation. b, Front view of the crystal structure, showing its all-endo conformation. Color codes: C = gray, N = blue, fac-Δ-Zn = yellow, fac-Λ-Zn = purple. Hydrogens, counterions and solvent molecules have been omitted for clarity.该笼子通过自组装反应合成，并在核磁共振（NMR）和高分辨质谱（ESI-HRMS）等技术下得到了确认。笼子的晶体结构显示其具有D3对称性，面采用了非平面构象，这种构象的切换是由于邻近的萘基之间的立体阻碍所导致的。在空腔未被任何客体分子占据时，笼子的面处于全“内向”构型，这种构型有助于最小化腔体体积。Fig. 3 | The range of guest molecules used in this study, all of which exhibited 1:1 binding with 1. The sphericity-corrected volumes of guests ranged from 178 to 599 Å3 (summarized in Supplementary Table 2), with larger guests flipping more faces of 1 from endo to exo during dynamically adaptive guest encapsulation. The all-endo structure here used for illustration is the single crystal X-ray diffraction structure of 1. The all-exo structure is a structure of B(p-Cl-C6H4)4Cl4-⊂1 optimized with GFN2-xTB, which gave six exo faces in the minimization. Colour codes: C = grey, blue (for endo faces), or orange (for exo faces), fac-Δ-Zn = yellow, fac-Λ-Zn = purple. The host hydrogen atoms in both conformations and the guest in the all-exo structure are omitted, and the vertices have been simplified, for clarity.通过一系列的实验，研究人员发现，笼子可以结合多种中性和阴离子客体分子，客体的体积范围从178 ų（例如金刚烷）到599 ų（例如四氯苯基硼酸盐）。其中，最小和最大客体之间的体积差异达到接近四倍，这与传统的灵活笼子相比，显示出其显著的适应性。Fig.4| 1D NOESY spectra of host-guest complexes, showing the host conformational changes upon guest binding. a, b Illustration of different naphthalene protons to show NOEs between guest molecules and host panels in endo vs exo configurations: When a small guest is bound in proximity to an endo panel, protons f, g and h will exhibit NOEs with the guest. Larger guests will show NOEs with protons i, j and k with an exo host panel. c,1H NMR spectrum and d, 1D selective gradient NOESY spectrum (irradiated as highlighted at 7.03-6.69 ppm) of B(p-Cl-C6H4)4Cl4-Ì1. e,1H NMR spectrum, and f, 1D selective gradient NOESY spectrum (irradiated at 2.08-2.00 ppm) of diamantaneÌ1.通过1H NMR和核Overhauser效应（NOESY）谱等技术，研究人员探讨了笼子在结合不同客体时的构象变化。较小的客体（如双金刚烷）使笼子面部分保持在“内向”构型而部分翻转到“外向”，而较大的客体（如四氯苯基硼酸盐）则促使笼子面转向“外向”构型，这表明笼子能够根据客体分子的大小变化自适应其结构。![]()
Fig.5|Mass spectrometry and NMR reveal how cage 1 increases its size in discrete increments upon binding progressively larger guests. a, Normalized mobilograms of ions corresponding to cage 1 with varying numbers of counterions. b, Stacked, normalized mobilograms, and c, Collisional cross section (CCS) values of the [1·(NTf2)11]5+ ion from cage 1 and its host-guest complexes, showing how larger guests lead to larger CCS values that cluster into tiers, which we infer to correspond to increasing numbers of exo cage faces. Guest volumes are corrected for sphericity. Data are presented as mean values ± standard deviation from the CCS values of ~1000-3000 distinct ion peaks, with details provided in Supplementary Table 3 and section 5.4 of the Supplementary Information. d, Solvodynamic diameter of cage 1 and its various host-guest complexes from 1H DOSY data. Data are presented as mean values ± standard deviation from the solvodynamic diameters, calculated from ~20-40 individual NMR signals with the Stokes-Einstein equation. For details please see Supplementary Table 4 and section 5.5 of the Supplementary Information.![]()
Fig. 6|Illustration of possible conformations of cage 1.a,Enumeration of the 10 possible states that cage 1 can adopt, with differing face conformations. A blue color and “0” denote endo faces, while orange and “1” represent exo faces. b, GFN2-xTB model of B(p-Cl-C6H4)4Cl4-Ì1, which minimized to give 6 exo faces (111111 in a above, ‘all-exo’ in b below). Color codes: C = grey or orange (guest), N = blue, fac-Δ-Zn = yellow orange, fac-Λ-Zn = purple, Cl = green, H = white. Hydrogen atoms of the cage are omitted for clarity. c, Illustration of the pathway for conversion between the all-endo to the all-exo conformation of 1, calculated with the GFN-FF potential and computational tools from the energy landscape framework (See Supplementary Video 1). The metal vertices are simplified for clarity. Blue, lime and orange denote endo, intermediate and exo states of the structure, respectively.总的来说，这项研究通过引入具有旋转单元的2,6-萘基臂的四胺配体，成功设计了一种新型的伪立方体金属有机笼子（笼1），它能够根据客体分子的大小和形状动态调整腔体体积。笼1从全“内向”构型开始，面板能够转换为“外向”构型，从而适应不同大小的客体分子。实验和计算结果表明，笼1可以通过面板构型的切换，形成不同的体积量化状态，导致形成不同的腔体体积。
这项研究为金属有机笼的设计提供了一种新的思路，通过引入可切换构型的面板，显著增强了笼在分子识别中的多功能性。这种构象灵活的设计不仅提高了笼的适应性，还扩展了其作为分子受体的应用潜力，可能对其他类型金属有机笼的设计也具有广泛的适用性。
本文通讯作者Jonathan R. Nitschke是于2001年博士毕业于加州大学伯克利分校T. Don Tilley课题组。2001年到2003年在法国斯特拉斯堡大学Jean-Marie Lehn组从事博士后研究。2003年开始在日内瓦大学任瑞士国家科学基金会助理教授，2007年开始在英国剑桥大学化学系任教，2014年，正式升为剑桥大学教授，主要研究方向为多重亚组分自组装（Subcomponent Self-Assembly）的金属有机分子笼及其主客体化学。
本文第一作者是剑桥大学化学系博士生Houyang Xu（徐厚扬），2017-2021年本科期间在中山大学朱克龙课题组从事研究，2021年起加入Nitschke课题组。
https://www.nature.com/articles/s41557-024-01708-5
