Bond-Energy-Guided Program Synthesis for Chemical Reaction Network Discovery

Abstract

Chemical Reaction Network (CRN) discovery is a time-consuming task that can be automated using program synthesis. However, the search space for realistic CRNs is large, making exhaustive search intractable. This paper investigates whether incorporating bond-breaking energy as a search heuristic can improve the efficiency of grammar-based CRN discovery. This paper proposes two heuristics: a maximum-bond-order heuristic and a more sophisticated delta-energy heuristic, which prioritise reactions with lower net energy change. Both are benchmarked against naive breadth-first search across an entire synthesis pipeline and the three individual stages, for seven Chemical Reaction Networks: water formation, methane combustion, photosynthesis, ethylene glycol formation, methyl acetate hydrolysis, an esterification reaction, and fermentation of glucose. Results show that both the Delta-Energy and Max-Bond heuristics consistently reduce the number of candidates explored and total runtime compared to BFS, with Delta-Energy generally outperforming the Max-Bond heuristic. However, neither heuristic guarantees improvement in all cases. These findings suggest that energy-guided search is a promising direction for scalable CRN discovery, with more accurate bond-energy estimation being a natural avenue for future work.