But for a longer flight I would aim for 2+2 option. The main reason that a longer flight is likely to include a meal service of some type (even if its buy-on-board or byo) and one parent supervising two young feeders may not be overly successful.
It is unlikely that the 3.5MO will have an airplane meal..still on the bottle or just starting to eat baby food. It is likely that the 3.5 MO will be sleeping for most of the flight.
The younger the children the more I would tend towards the 2+2 to provide one-on-one supervision/entertainment.
My 4-YO son took his first flight (3.5 HRS) when he was 2.5-MO old and his second flight (3.5 HRS) when he was 7-MO old. Both flights left PHX at 10:30 AM and except for 10 minutes on both outbound flights as well as the both return flights (both left at 6:00 PM), he was asleep.