Honestly the way I see it, Kakashi going for a head-chop is logical if he knows about Tsunade's special seal in her head. I mostly say this because we can relate the same instance to others' fights in the manga.
Raikiri is known as a very powerful jutsu because it's almost impossible to out-do in close quarter combat. If Kakashi gets in close, this could be another A vs Sasuke instance, where Sasuke uses his Sharingan to dodge the fatal blow to his face and instead gets through A's speed and hurts him. Normally I'd say this would be harder since Kakashi usually stabs with his Raikiri, but he has shown to use it in a slashing style against the Bijuu which pretty much confirms that he was able to (though I shouldn't need that to know it). IF he knows to go for the head, than it might kill her.
However I haven't given Tsunade her fair credit here (this is where underestimation plays its usual role). If Kakashi is simply going to run up and try to feint Tsunade, I doubt it's going to work. She has been known to change the whole terrain of a battlefield and disrupt an opponent's footing. It's her way of using her strength in a creative way. Plus since Sakura was able to figure out that Kakashi was hiding underground rather easily, Tsunade might be able to as well. Tsunade doesn't suck THAT bad at taijutsu - even when she was tired against a refreshed Kabuto because of the pill, she was able to push Kabuto away right after he disabled her muscles (A HUGE WEAKNESS FOR HER). That could have potentially done a lot of damage if she was at full strength.
With that in mind, you also have to factor in Kakashi's intelligence, clone feints, multitude of jutsu, and even Kamui. But to defend Tsunade once again, there is still Katsuyu to keep in mind. I cannot see Kakashi doing very well if Tsunade stays on top of her giant slug out of harm's way. That would mean Kakashi would be inclined to use Kamui, meaning she was one of the harder opponents to fight.
Now if he DOESN'T know about the seal, Tsunade should easily be able to surprise him once he impales her chest with Raikiri. She's been known to heal from around the same spot with Orochimaru, so this can easily become Kakuzu's surprise attack Version 2.