Del Potro walked away from that marathon five setter with his first and only grand slam title, breaking Federer's unprecedented steak of five straight U.S. Open championships.
The big-serving Del Potro won the most memorable match of the tournament so far this year when he fought off two match points to rally back from two sets down to defeat sixth-seeded Dominic Thiem on Monday.
Federer, who sat out the Cincinnati Masters last month due to a back injury, needed five sets to get through the first two rounds before settling down and winning his next two contests in straight sets.
With rain forecast for Wednesday, the match will likely take place under the closed roof of Arthur Ashe Stadium, which will amplify the volume of the raucous New York crowd.
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Prior to that match Madison Keys will try to continue the march of American women into the semi-finals when she battles unseeded Estonian Kaia Kanepi and world number one Rafael Nadal will face 19-year-old Russian Andrey Rublev.
(Reporting by Rory Carroll; Editing by Toby Davis)
