Flown both 135 and 121, freight, commuter, major , and on demand. Neither is harder than the other in terms of the regs to operate under. 121 does have the problem of being much more heavily regulated. Paperwork MUST be 100% correct, I have seen guys pick up a violation 6 or 7 months after the flight because of a paperwork error that the FAA just got around to auditing. Under 135 if you complete the flight without attracting attention your pretty much home free.
121 Captain involves alot of cover your behind type of stuff. You are ensuring the safety of flight as well as making sure you don't get boned on a stupid technical error, that probably wasn't even your doing. I saw a fueling error (less than 300 lbs worth) cause a guy to have to dance the carpet with the CP and Feds 3 months after it happened. The bad part was he took off with 300 lbs less than min fuel required, but since the fueler screwed the paperwork he never knew it until the CP called. (300 lbs is undetectable when your dealing with 35,000 lbs of fuel and old analog fuel guages)
In the 135 world this would have never come up.
So to answer the question, is 121 harder ....No, it just requires stronger coffee in the morning to avoid legal gotchas.