It plays quite differently. With 1-2, the strategic question is whether to buy a potion at all. With 3-5, you're pretty much always going to buy a potion, the question is how many potions and in what order to buy the potion-cost cards.
If you use 5 cards from alchemy, you're going to get similar-looking kingdoms pretty often, because alchemy just doesn't have that many cards.
I'd suggest playing it both ways! Sometimes do one, sometimes the other.
For a while, the way I'd randomize my sets IRL is that I'd randomly pick one expansion to "focus" on, pick 3 cards from that expansion, and then randomly pick the other 7 (which might include some from that expansion too!). This way, when I played an "alchemy-focused" game I'd get 3-4 alchemy cards, whereas in other games I'd usually get 0-1.