Well, minus the War of 1812, I truly believe the United States would have been at war with Spain no later than 1820. There were numerous disputes between the two countries that had led to continuous tension since immediately following the 1783 Treaty of Paris.
--Status of West Florida
--Cost of Trade down the Mississippi
--Spanish support for Native state in both Northwest and Southwest portions of the US.
--Spanish support for secessionists in Kentucky region
After the Louisiana Purchase a number of other conflicts arose.
--Agreeing on a border encompassing the Mississippi Watershed
--Control of New Orleans
--Settlement and control of Florida
--Control of the eastern portion of Texas
--American access to the Pacific Ocean
Furthermore American support for the independence movements occurring throughout Latin America angered Spain.