The problem would be fallout with any size bomb, depending on the winds.
Well, if you wanted maximum destruction of soft targets (and cities count as "soft" for this purpose) you want a fairly high altitude airburst. The fireball never quite touches the ground so you don't suck up a lot of material to be neutron activated and made radioactive. The fallout in that case is minimal, and what fallout there is tends to be short half-life.
Yes, in another forum I hang out with folk who are knowledgeable on the subject and it so happens that this subject has come up recently (not nuking Chicago, but the use of nukes against population centers in general).