So this kinda brings up a point I have been struggling with....
Almost everyone quotes costs as per hour for operating. I fully understand this and why this is the standard.
However, when trips between 2 cities is the standard mission, I am more concerend with cost of that trip and considering a twin can accomplish in less time at a higher per hour cost, shouldn't this be taken into consideration as total cost comparison? And for flying the same number of missions the slower plane reaches TBO sooner since taking longer each flight.
Really doesn't matter I guess..... I'm just trying to rationalize and justify to myself what I already really know is most likely to happen
Ultimately, the $/hour just an easy way of looking at it. The true costs are divided into fixed (insurance, hangar, annual) and variable (fuel and additional MX). If you fly a plane 0 hours per year, it has an infinite cost per hour. The other reality is that the first year will cost more in most cases, and then after that you'll have years when you basically fly for fuel, and years when you put a lot of money in. These averages just help you give an idea of budgeting, and everyone's situation is different. If you are an A&P yourself and have a cheap hangar, your fixed costs will be much lower. Fuel is the other big variable since around the country 100LL can range from under $5 to over $8.
You are right that it goes into a $/mile eventually, which you'll figure out, and in part of the budgeting you need to figure out total trip cost. When I'm figuring out what a trip is going to cost (something I have to do regularly for the non-profit), it basically comes down to an assumption of average speed including average winds and then my average hourly cost. It works pretty well, and I'm usually within 5%. In the end, though, the fast plane is going to typically cost you more $/mile.
I also don't think you're getting ahead of yourself, this is just the sort of issue that comes up when you have a family of more than 2 kids. Once you get to that point, a 4-place single simply won't cut it, and while 3 kids could work in some of the 6-place singles, a Malibu is really the only one that will work for 4 kids. At 5, the single-engine options are a complete joke unless you go turboprop. I would suggest you spend some time starting out with your ratings in the smaller planes, but I bought my Aztec as my first plane at 225 hours total time, and I was considering a 340, so not appreciably different than what you're looking at. I was first talking to people about buying a 310 when I had under 100 hours from a friend of mine.
The catch here is really making sure that you have a good instructor (who turns into a babysitter) for at a hundred hours (my thought is several hundred) if you jump into a pressurized piston twin. Your family is on board, a good instructor is the cheapest insurance you can buy. The NTSB is riddled with fatalities where an entire family (usually of the same size as yours) gets taken out when a single pilot, usually pretty inexperienced, is flying a big and capable aircraft (what the mission requires) and has no idea what he's doing. The recent PC12 thread shows that, then there was the TBM a few years ago in NJ, and a 421 that killed an entire family over a very simple engine failure at cruise. The experienced pilot more than anything will help you with the decision making, weather avoidance, and failure management that will come up as you are building that skill set yourself. I had one such student in a Chieftain who I spent about 100 hours with. Not only did we have a blast flying together, but I was able to teach him the sort of things that are best learned slowly over time with experience. The firehose method only goes so far. Number of hours per year is a concern for proficiency as well, and if you don't fly much then the babysitter may not go away, but that's fine. Two pilots in these planes really is better.
As far as the plane itself goes, the GTSIO-520 in the 421 is generally defended by its owners and operators because they love the quiet operation, but it has proven over the years to be more cantankerous and more expensive to operate than its direct drive equivalent, the 414. The speed is not appreciably different between the two planes (and a RAM VII 414 will do the same speed as an equivalent age 421). The big issue with 421s is that they seem to have a higher failure rate (especially right after rotation), I suspect in large part to their tendency to lose prime on the oil pump, which if undetected will kill the bearings and take out the engine at the worst possible moment. The Navajo (Lycoming powered) is a real workhorse and a simpler overall airplane, and I think more reliable. If you don't need pressurization, it's a good option. You'd probably want a Chieftain, but for me personally, I'd go with a short body and Panther conversion.
Feel free to PM me if you want to discuss options. Once I bought my Aztec, I never turned back to piston singles. After all, iFlyTwins.
You really need a cabin-class pressurized twin, with a potty in the back as a necessity. I wish you luck! 
) If you haven't already, read the Killing Zone. It is a great book for someone in the early stages of their flying career and may even influence what you ultimately choose.