This study highlights the e icacy of a simple but streamlined workflow for the rapid screening of 1,2,4,5-tetrazine reactivity with trans-cyclooctene. Through the use of an automated system, we successfully computed reaction barriers for 1288 out of 1540 possible tetrazine combinations, demonstrating an 84% success rate without the need for manual intervention. This high e iciency showcases the potential of our method to expedite the discovery and optimization of bioorthogonal reactions, which are crucial for in vivo applications such as drug delivery and diagnostic imaging.