There's a huge name recognition gap here which has caused Clinton to look unstoppable in 2016 - the fact that she is within the margin of error with the Republicans here should bring some concern to Democrats, though it is still very early.
I don't think the margin of error ever makes a huge difference difference here. Name recognition or not, Paul and Rubio are poor fits for Colorado, which is filled with moderates, so I doubt Hillary would lose it to either of them. At this point, most voters aren't even thinking about the race, but if it did come down to Hillary and either of these two Republicans, it's clear who would have the advantage.
Colorado legalized pot, how is that a disadvantage to Paul? Clinton is very statist.