A mechanistically guided approach is developed to predict electrophile compatibility in the palladium/norbornene (Pd/NBE) cooperative catalysis for the ipso/ortho difunctionalization of aryl halides. A key challenge in these reactions is to identify orthogonal electrophile and aryl hali de starting materials that react selectively with different transition metal complexes in separate oxidative addition events in the catalytic cycle. We performed detailed experimental and computational mechanistic studies to identify the catalytically active Pd(II) intermediate and the substrate-dependent mechanisms in reactions with various types of carbon and nitrogen electrophiles. We introduced the concept of electrophile compatibility score (ECS) to rationally select electrophiles based on the orthogonal reactivity of electrophile and aryl halide towards the Pd(0) and Pd(II) complexes. This approach was applied to predict electrophile compatibility in the Pd/NBE cooperative catalysis with a variety of electrophilic coupling partners used in alkylation, arylation, amination, and acylation reactions.