The most significant factor in propelling the nation toward disunion was the Mexican War. Concluded in 1848, it, as Ralph Waldo Emerson predicted, "poisoned" the politics of the United States by pushing the expansion of slavery to the forefront. The Compromise of 1850 was one significant event that helped to propel the nation toward civil war, primarily because a more robust Fugitive Slave Act, included as a concession to southern slaveholders, outraged Northerners, intensifying the justifiable belief that a "slave power" controlled national politics.
The Kansas-Nebraska Act of 1854 was another event that pushed the nation toward disunion. Its sponsor, Stephen Douglas, was a key figure in this process by urging the repeal of the Missouri Compromise and the use of popular sovereignty as a means to resolve the issue of slavery in the territories encompassed by the Louisiana Purchase. This led to the emergence of the Republican Party, which was devoted to halting the spread of slavery to the western territories, and was seen as an existential threat by southern proslavery forces. It also created a crisis in Kansas, which erupted into civil war—"Bleeding Kansas"—as antislavery forces battled "border ruffians" determined to establish a proslavery government there. In the presidential election of 1856, the collapse of the second two-party system became a reality as the Republicans, loathed by Southern slaveholders, replaced the Whigs in opposition to the Democrats.
In 1857, a Supreme Court decision in Dred Scott v. Sandford, a case involving an enslaved man suing for his freedom after living in the Wisconsin Territory, where slavery was illegal, divided the nation even further. One year later, a Senate campaign in Illinois between Douglas, a Democrat, and a Republican named Abraham Lincoln brought the latter into national prominence. It also fatally divided the Democratic Party, enabling the decisive event in the collapse of the Union, the election of Lincoln to the presidency in 1860. Seven states in the Deep South reacted to the election by seceding from the Union, a decision that brought the nation to the brink of war when Abraham Lincoln took office in March of 1861.
There were many more events that contributed to the collapse of the Union in 1860, but these national political events were undoubtedly central to the process.