What was the hardest death for Thanatos to reap?

Probably none. His understanding of souls extends to the idea that they will come back once they reach asphodel. Death is not the end as far as he is concerned. Merely a process. My view of the sons of Nyx (Thanatos, Hypnos and Charon included) is that they deal solely with the dead themselves and have very little connection to the human grieving process. So anyone Thanatos reaps is coming back to the world above eventually and him doing his job, at least he feels, is what makes that possible.