Framework collapse upon solvent removal during activation remains a challenge for metal-organic frameworks (MOFs) and a better understanding of the underlying phenomena is needed. In this study, we simulated MOF activation processes for a range of solvents in IRMOF frameworks. Framing activation as a gas desorption problem, we used TMMC to estimate the transition energy of activation (ΔU ‡ act), revealing differences between good and poor activation solvents and thereby identifying 315 mechanisms for framework collapse. We identified highly contrasting desorption mechanisms between the two groups: good activation solvents behave similarly to a classical gas i.e. adsorbing in each pore space approximately uniformly, whereas poor activation solvents form strong mesophases in the pore, resulting in a concentration of stresses across a small number of metal-linker bonds and hence leading to framework collapse. This new analysis framework allows to identify the activation 320 pathway of a specific MOF-solvent pair, accelerating the development of suitable activation protocols.