1) Initially routing diagram 2 is the better of the two.
2) It is always best to avoid running digital lines (or their ground returns) close to or over ADC lines, even if they are considered constant or slow. There can often be moderate levels of digital noise even on stable digital lines.
3) Consider moving the IO-expander right up against the MCU to ...
When both devices are not connected in any other way except for their output and input terminals, you can just connect as described: connect GND to one of the diff. input-pins and signal to the other diff. input-pin.
connections in any other way include shared earth or chasis or signal ground.
EDIT after new presented information
Devices that allow for ...
Powering it via IO pin protection diode would make the GND to be a diode drop higher than the IO pin voltage. It might work better because of how different devices have different MIDI OUT buffers, not all MIDI OUT interfaces are alike, some are driven with push-pull output drivers, some are driven with open-drain outputs.
Yes you need a shared ground. The reason it works is because everything connected to your PC and share supply grounds. But it also means that the supply ground will be the reference to all your signals, which isn't ideal.
Ideally all communication lines include a signal ground, which is tied to the main ground of each PCB through appropriate PCB layout. ...
Do NOT split the grounds underneath the IC. A single ground plane is fine. Instead, keep all analog components to the North and all digital components to the south west. That way, digital return currents are less likely to stray into the area where the analog return currents are circulating.
Is your issue cross talk with your ADC's own digital ...
Why not reposition components to make life easier.
Reposition the components such that the return currents do not cross the analogue or digital domains.
A flow like below would ensure the digital noise into the analogue domain is kept to a minimum. Suitable placement of ferrite beads and 10nF capacitors will help.