"train fatigue?" you've driven in Germany, right? It is an easy place, IMO, to drive in but personally I don't find it nearly as relaxing as taking the train but to each their own.

once on the train its relaxing I agree, but planning and figuring things out and walking to and fro and checking schedules and looking for deals, etc. can be anything but relaxing. I will be taking the train out of Amsterdam into Germany so will have some train time (done that before)

I don't know when in September you are thinking of but there a couple of big conferences taking place in Amsterdam. One the IBC is well know for booking all the hotels. This year it is from 6-12 September. Hopefully you are arriving after that.
Another one is on from 17-20 September, but I don't think that is as big.
If you haven't already booked accommodation can I suggest you do so asap. If there is no room in Amsterdam consider Haarlem instead.

The only advantage to hiring a car in Germany is that you can explore some of the countryside that way, rather than sticking to cities.
Why not think about the Mosel rather than the Rhine. A much nicer river and valley imho.

"So for 5 or 6 nights in Germany - would you stay in Rhine valley area, then hit Dusseldorf and Heidelberg?"

Hard to say. It's not clear what you're looking for, exactly.

The Rhine is majestic. The Mosel is nice as well - in a quieter, more feminine way.

Cologne: On Day 1 in Germany, I'd make a stop there for 4-5 hours to see some big city sights (use station lockers for bags.) Then take a train to the Middle Rhine Valley, which is south of Koblenz, and spend at least 2 nights there, at least 3 if you venture up the Mosel. There's something for everyone in these river valleys - castles, villages, wineries, river cruisese, and great natural scenery. Boppard is a good small town for access to both rivers.

http://www.welterbe-mittelrheintal.de/index.php?id=318&L=3
http://www.mosel-reisefuehrer.de/moselhighengl/moselhighlightsengl.html
http://flyhahn.com/regions/holiday-regions-germany-frankfurt-hahn.htm

But I would take issue with hetismij2's suggestion that trains limit you to cities. Trains run along both sides of the Rhine from Cologne south to Rüdesheim and Bingen and stop in every tiny village on the way. Area daypasses make hopping on and off very easy. Trains between Koblenz and Trier connect dozens of villages along the Mosel as well and provide great river scenery too.

If doing that much train travel then consider by all means the Germany-Benelux Railpass, valid on trains in Germany, Blegim, Netherlands and Luxembourg - total freedom to hop any train anytime - full fares that provide for such spontaneous travel can often be really expensive - online discounts are train-specific and must be booked far in advance to guarantee availability - so the lure of a pass is also to be able to amble down to the station and hop any train anytime. Check out these superb sites IMO for lots on trains in those countries - www.seat61.com; www.ricksteves.com and http://www.budgeteuropetravel.com/id9.html.

TTT

A multi-country railpass like PalenQ suggests may be a good idea, but it depends on your other destinations in Germany.

A regular full priced ticket between Amsterdam and the German border at Zevenaar is only 28€. So if indeed you travel long distances within Germany as well (like to Berlin or Munich) it might be best, if A'dam is your only destination in the Benelux area, to have a Germany-only railpass and to get just a one-way ticket to Germany from A'dam on top of that.

With 5 or 6 days in Germany, you really have only enough time to visit two destinations. So it shouldn't be terribly stressful to find train connections for a small handful of trips. If you do short trips from a travel base - for example, Boppard, mentioned above - a local multi-day railpass in the Middle Rhine like the VRM mini-group ticket lets you hop on local trains spontaneously for 3 fulldays 40€.

http://www.vrminfo.de/en/tickets-and-fares/ticket-offers/leisure-ticket/

What I meant by limiting you is that with a car you can get out into the countryside, and visit more small villages, enjoy stopping at something which takes your fancy or for a picnic by a lake r whatever.

I think maybe a combination of train and car would be good for OP. Not everyone enjoys endless train travel and the restrictions it imposes on you.

You can get an ICE ticket from the Netherlands to Cologne for only €19 second class, or €39 for first class.

russ makes a great suggestion - the Germany only railpass is much cheaper per day than the Germany-Benelux Pass.

I personally find driving more fatiguing than train travel - especially on German trains that are so plush - driving in cities can be hectic - I enjoy sitting back and watching the scenery roll by rather than having to pay attention to the road when driving.

I would head for Munich, where you don't want a car because of parking and traffic. They have a great public transportation system. If you decide to head for nearby Mad King Ludwig country you may want to rent a car for convenience. Munich has a lot to offer and it has a lot of air service to make it easy to fly home from. You could train to Munich from Cologne after you stop to see the cathedral there.