Hi,
I think that the F-450 pickups will all be 4X4, but I am not sure on the older ones. F-450 cab and chassis are in 2 WD, but not the F-450 pickup body from the factory. Not to say you will not find a 2WD F-450 made from a cab and chassis.
I would rather have a toolbox body on a cab and chassis F-450, with the rear 40 gallon tank, and then install a new midship 53 gallon fuel tank from Transferflow.com This would give me about 900 miles of capacity while towing, and the ability to travel from state to state, and park the trailer before going to buy fuel. Not so that I can drive 45 hours straight, but to not need to tow the fifth wheel into a gas station!
You might not end up liking the older F-350's though. The 2011 came with a brand new engine design, and it has proven to be a great engine so far. It has a completely new design, the fresh air goes into the sides of the engine, while the exhaust goes out the center, directly into the turbocharger. This reduced Noise, Vibration, Harshness. Ford calls it reduced NVH.
If you do pick a 2008 - 2010 F-350, then make sure that it gets a engine coolant filter installed as soon as possible. That engine will be noisy compared to the 2011 and later engines. I would stay away from the 6 liter International engines. They where in the 2003 - 2006/7 trucks.
The F-450 normally came with a 4.30:1 rear axle ratio. If you are looking for optimal fuel mileage, you probably will not find that in the F-450. But it will have plenty of power!
Good luck on your search!
Fred.