Isosteric Substitution Enables Rational Design of Two‐Dimensional Energetic Crystals

ABSTRACT Two‐dimensional (2D) energetic crystals dissipate mechanical insult via interlayer slip, yet their molecular design space remains narrow. We introduce a functional group isosterism substitution strategy that expands the prevailing “NH _2– C–C–NO ₂ ” motif to the aminofurazan unit, thereby enlarging accessible chemistries for 2D architectures. From an initial pool of 2832 candidates generated by database mining and high‐throughput enumeration, a tiered screening process incorporating virtual assessment and cross‐scale stability evaluation was employed. This process narrowed the focus to two high‐priority targets ( 3 and 12 ), which were subsequently synthesized and structurally confirmed to exhibit the desired layer crystal packing. Both synthesized materials demonstrate a highly desirable combination of high thermal stability, low mechanical sensitivity, and robust detonation performance. Most significantly, 12 achieves a superior balance by exceeding TATB in detonation velocity, detonation temperature, and heat of detonation while retaining comparable insensitivity, highlighting the strategy's capacity to balance energy and safety. The results close the computation‐experiment loop for 2D energetic crystals discovery and establish aminofurazan as a versatile energetic building block. More broadly, the strategy is generalizable to additional isosteres, such as aminotriazole derivatives, providing a principled blueprint for co‐optimizing energy and safety in next‐generation low‐sensitivity energetic materials.