When you no longer really believe (or never did believe) in one of the fundamental pillars of the EU e.g. ever closer union. If you don't believe in that then

When you no longer really believe (or never did believe) in one of the fundamental pillars of the EU e.g. ever closer union. If you don't believe in that then it's your duty to leave and let those that do continue forwards with an ever closer union. The UK joined really hoping to push the EU more towards a confederation which it would've felt comfortable in, the whole "working from the inside" thing that people are always saying is the best way to influence the EU. But ultimately a majority of the rest of the EU wants much closer integration than the UK would've ever been comfortable with... so here we are.