Assuming it is mainly clock-speed that is the complicating factor, how much faster than 16MHz could one safely run a microcontroller at, using simple double-sided PCB's, and a bit of care routing the PCB?
I don't think you can make that assumption. "Maple" increased clock speed, increased board density (many more IOs than Arduino) and tried to increase A-D resolution, all at the same time. A tough job. And some chips are famous for being "noisier" than other chips, despite similar clock speeds. Good show on the Maple team actually paying attention to such things; I don't know if other would-be "improvers" take the same care.