On-surface synthesis has developed into a modern method to fabricate low-dimensional molecular nanostructures with atomic precision. It impresses the chemistry community mostly via its simplicity, selectivity, and programmability during the synthesis. However, an insufficient mechanistic understanding of on-surface reactions and the discriminations in methodologies block it out from the conventional cognition of reaction and catalysis, which inhibits the extensive implication of on-surface synthesis. In this Perspective, we summarize the empirical paradigms of conceptually appealing programmability in on-surface synthesis. We endeavor to deliver the message that the impressive programmability is related to chemical heterogeneity which can also be coded at the molecular level and deciphered by the catalytic surfaces in varying chemical environments as specific chemical selectivity. With the assistance of structure-sensitive techniques, it is possible to recognize the chemical heterogeneity on surfaces to provide insight into the programmable on-surface construction of molecular nanoarchitectures and to reshape the correlation between the mechanistic understanding in on-surface synthesis and conventional chemistry.

On-surface synthesis of phenylenes is a promising strategy to form extended πconjugated frameworks but normally lacks selectivity in achieving uniform products. Herein we demonstrate that the debromination reaction of 2,3-dibromophenazine (DBPZ) on Au(111) and Ag(111) surfaces can vary significantly considering the involvement of metal−organic hybrids (MOHs). On Au(111), [2 + 2] and [2 + 2 + 2] cycloadditions facilitate instantaneously upon the debromination occurring, while on Ag(111), several MOHs have been observed under sequential thermal annealing, leading to finally the uniform [2 + 2] cycloaddition product exclusively. By means of scanning tunneling microscopy (STM) and bond-resolved atomic force microscopy (BR-AFM), we have unambiguously depicted the chemical structure of related reaction intermediates and unraveled the undocumented role of hierarchical evolution of MOHs in steering the chemical selectivity.