"Matched pairs" is optimum for 2008 and earlier.
In 2009 and later, optimum is (any size) triples.
The penalty for installing two or four is small, probably about five percent in memory testing. The real-world penalty for that mis-match is probably negligible.
Slots 3 and 4 are "shared". Install the big one in slot 1 (or 2) but not 3 or 4 or the memory wizard will yell at you, and tell you to change it.
Some 4GB and larger DIMMs do not play nice with other, smaller DIMMs.
So be certain to buy from a Mac-centric vendor who can tell YOU what will work in your Mac, guaranteed or your money back. Lifetime replacement warranty is the standard. Don't settle for less or you may end up owning some excellent DIMMs that do not happen to work in your Mac.
Your Mac Pro (65 lb. tower) uses Error-Correcting-Code (ECC) memory. Installing non-ECC memory is not a good way to save money in the long run.