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In the presidential election of 1824 he appeared as a strong supporter of William H. Crawford, and received the electoral vote of Georgia for vice-president, but steered clear of the controversy which followed the choice of John Quincy Adams as President. He early recognized the potential of Andrew Jackson as a presidential candidate. By 1827 he had emerged as the principal northern leader for Andrew Jackson. Van Buren became the President's most trusted adviser, and Jackson referred to him as, "a true man with no guile." In 1828 he was elected governor of New York for the term beginning January 1, 1829, and resigned his seat in the Senate. However, on the 5th of March he was appointed by President Jackson as Secretary of State, an office which probably had been assured to him before the election, and he resigned the governorship. As Secretary of State he took care to keep on good terms the group known as the "kitchen cabinet," politicians who acted as Jackson's advisers. He won Jackson's lasting regard by showing courtesy to Mrs. John H. Eaton, wife of the Secretary of War, a woman with whom the wives of other cabinet officers had refused to associate. His service as Secretary of State was largely without incident or controversy. He did prepare for the settlement of long-standing claims against France and opened trade with the British West India colonies. After a breach between Jackson and Henry Calhoun, Van Buren was clearly the most prominent candidate for the vice-presidency. Jackson in December 1829 had already made known his own wish that Van Buren should receive the nomination. In April 1831 Van Buren resigned as Secretary of State, though he did not leave office until June. In August he was appointed minister to England, and arrived in London in September. In May of the following year, the first ever Democratic convention had nominated him for vice-president on the Jackson ticket, despite strong opposition from many states.
In the election of 1832 he received 189 electoral votes, while Jackson received 219 for President. Jackson was now determined to make Van Buren president in 1836, and spent a great deal of his energy to accomplishing that goal. In May 1835 Van Buren was unanimously nominated by the Democratic convention at Baltimore, but his presidential victory represented more of a victory for Jackson than for Van Buren. Van Buren followed "in the footsteps of his illustrious predecessor," and took over all but one of Jackson's cabinet. In 1837 an economic crisis ensued resulting in the failure of hundreds of banks and businesses. Thousands of citizens lost their lands, and for about five years the United States was wracked by the worst depression in its history. Despite this crisis Van Buren proved to be of statesmanlike character by meeting it with great firmness. He devoted himself to maintaining the solvency of the national Government and opposed not only the creation of a new Bank of the United States but also the placing of Government funds in state banks. He fought for the establishment of an independent treasury system to handle Government transactions. As for Federal aid to internal improvements, he cut off expenditures so completely that the Government even sold the tools it had used on public works. Van Buren was unanimously re-nominated by the Democrats in 1840, but was defeated by the Whigs for re-election. Following the expiration of his term Van Buren retired to his estate at Kinderhook. He did not, however, withdraw from politics or cease to be a figure of national importance.
He expected to be nominated by the Democratic party for the presidency in 1844. As a staunch opponent of the expansion of slavery he blocked the annexation of Texas because it assuredly would add to slave territory and might bring war with Mexico. His position proved to be his demise, however, and in the Democratic convention, though he had a majority of the votes, he did not have the two thirds which the convention required. After eight ballots his name was withdrawn. In 1848 he was once again nominated for the presidency running on the "Free Soil" ticket, but was unsuccessful in his bid for the candidacy. He died of asthma in Kinderhook on July 24, 1862.