This is why I always break up long air trips as evenly as I can, so as to shorten the longer legs. From where I am, the usual closest airport for international connections is O'Hare, but no thank you. I'm either going to NYC or LAX from here, so that the over-the-water leg will be shorter. (I've never been south of the equator, but if I was headed that way I'm sure I'd go via Miami; though I've been told that the jet lag effect isn't as bad when you're moving N-S. Still, a flight to Argentina or Brazil would be pretty darned long!))
Flying domestically I'd rather do non-stop, but when it comes to crossing an ocean, I want to start out more or less on the shore before the part where they can't land it until we get there. (I also almost always fly to Ireland first if I can, then continue from there after a bit of a break with my feet on the ground.)
I'm not at all afraid of flying, but the older I get, the more claustrophobic I feel on planes; probably because the seats have been getting smaller as I've gotten a bit larger over time. I also don't sleep much on planes, even with meds, so a full day or night of flying always seems endless and exhausting. Trains don't bother me nearly as much; push comes to shove I can get off when it stops and get back on a later train. (I don't take trains in the US except in the NE corridor, where that's actually possible.)