If you're into the yuppie bar thing, swing by the West Village, around 6th Ave. It's always bustling on weekends, and there are also a lot of sex shops on 6th Ave in the single digit streets if you and your wife are looking to get naughty.
I don't know if you're into strip clubs, but there's still quite a few in the city.
If your wife is looking for something a bit more chilled the fuck out than Soho to do shopping, there are a lot of expensive boutiques in Hoboken, which is reachable via the PATH Train. The PATH is not connected to the normal NYC subway. To get there, you have to take the PATH train from 33rd, 23rd, 14th, 9th, or Christopher St. to the Hoboken station. Then just walk over to Washington St. and check out the stores. A lot of good restaurants too. Sushi Lounge, Bangkok City, Amanda's (way up on 10th St. or so), and Elysian Cafe spring to mind. You can also take a walk along the waterfront for some sweet views of the city.
If you don't mind going far afield, and want some really good Asian food, check out Flushing, Queens. The Chinatown there is more spread out, so it's not as jampacked and fucking crazy as Manhattan's Chinatown, but it's actually larger and (maybe?) more populous. Good eats and lots of Asian-oriented shopping.
Midtown is kind of boring, imho. It's very touristy and there isn't a lot to do that's affordable. Same thing for Times Square. Again, if you're into crazy ass shopping, the neighborhood in the 50s and 60s in Midtown are good for that stuff. There's also the Apple Store in Columbus Square.
Another fun thing to do, if it's nice weather, is to walk across the bridges together. It's kind of loud because of the cars and trains going by, but the view is stellar. Williamsburg, Manhattan, and Brooklyn Bridges are all good.
Also, you might want to try the DUMBO area of Brooklyn (DUMBO stands for "Down Under Manhattan Bridge") which you can get to via the F train (get off at the York St. stop). Lots of artist stuff happening over there. It's very gentrified, but there's a DUMBO Festival every year around this time where all the artists open their studios up to the general public and you can see some really nifty stuff.
The Lower East Side's lost most of its grit, but in turn has become much safer for tourists and visitors. Tompkins Square Park, once the home to a giant tent city full of the homeless, has been fenced up and is now a peaceful, walkable park for yuppies and their dogs. Quirkier, more off-beat shopping can be found here, along with some more affordable restaurants. There are still projects along the water on the East Side, so keep that in mind. I haven't heard about any real dangerous violence coming out of there in a while though.
In Little Italy, I ate at Da Nico's forever ago, and I enjoyed the hell out of it. But I was a kid, so who knows?
Washington Square Park is under construction for the duration, so don't waste your time. This really sucks, because in the evenings, musicians would come out, and there would be singalongs and dancealongs and it was great. I'm very bitter about this. They wanted to move the damn fountain so it was in line with the arch, but no real New Yorker gave a shit, to be honest.
Since you're going to be out during the school year, you might want to check out the theatres at Columbia, NYU and other colleges in the area and you might catch a real gem on the cheap. You won't get student ticket prices, but it's a damn sight better than Broadway. If you're into theatre, I recommend playbill.com and theatremania.com to see what's up.
For nightlife, Club Planet is a good place to start, but it's a lot of flash and not a whole lot of substance. If you just want to wander around and take your chances, give the Meatpacking District on the west end of 14th St. a try. It's very slick, chic, and in vogue. The Apartment is a fun club. Wherever you go in that area, dress well.
There's also the Continental in the East Village (
http://www.yelp.com/biz/continental-new-york-2) 5 shots. 10 dollars. You get the idea. You wanna get fucking tanked on the cheap? Here's the place to go. Get your shots, then head over to the Meatpacking District where getting a beer requires a credit check.
For a unique twist, check out the Beauty Bar on 14th St. It's a bar and occasionally a dance club (when the back is open) set in an old 50s style beauty salon. It's often packed, usually with people in their 20s and 30s.
Hope that helps.
