• The application of isoreticular chemistry in MOF structure design, including microstructure design, pore size tailoring, secondary building unit modification, post-synthesis modification, and cooperative regulation are summarized and highlight. • The adsorption/separation function-oriented MOF structure design and high-throughput screening process are summarized. Based on isoreticular chemistry design and optimized high-performance MOF adsorbents and membranes, we are committed to exploring an energy-intensive and environmentally friendly alternative separation route, and strive to achieve efficient separation of hydrogen, carbon dioxide, natural gas, and petroleum-based platform compounds. Precise control of the pore size and environment of metal–organic framework (MOF) is a necessary condition for achieving high performance of gas adsorption and separation. After nearly two decades of development, the synthesis of MOF materials has gradually evolved from exploration and trial to precise-design, including function-oriented microstructure design and optimization, pore size tailoring, and secondary building unit (SBU) modification. The unique pore environments of MOF materials enable their advantages in gas adsorption and separation applications. In addition, the introduction of isoreticular chemistry within MOFs (with the same framework structure and different chemical components) provides opportunities for improving gas adsorption and separation performance. Isoreticular chemistry gives MOFs more functions to promote specific binding or sieving with gas molecules. Furthermore, MOF-based adsorbents and separation membranes exhibit superior separation performance in many industrial gas purification processes. In this review, we summarized and highlight the application of isoreticular chemistry in MOF structure design, including microstructure design, pore size tailoring, SBU modification, post-synthesis modification, and cooperative regulation. The gas adsorption and separation performances are improved through pore size and environment optimization. In addition, we also summarized the adsorption/separation function-oriented MOF structure design and high-throughput screening process. Based on isoreticular chemistry design and optimized high-performance MOF adsorbents and separation membranes, an energy-intensive and environmentally friendly alternative separation route is explored to achieve efficient separation of hydrogen, carbon dioxide, natural gas, and petroleum-based compounds. Finally, we provided an outlook based on prospect developments of isoreticular chemistry within MOFs for gas storage and separation.
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