Final answer:
The major exception to Zaitzev's principle is the Hofmann elimination, where the least substituted alkene is favored due to the use of bulky leaving groups and sterically-hindered bases, such as tert-butoxide, which cause steric hindrance.
Step-by-step explanation:
The one "major" exception to Zaitzev's principle, which states that in an elimination reaction, the most substituted (stable) alkene product is usually preferred, is the Hofmann elimination. This is a scenario in which the least substituted alkene, which is generally the less stable product, is favored. The classic case where Hofmann elimination becomes the major pathway is when bulky leaving groups and strong sterically-hindered bases are used during the reaction. A common example of a base used in Hofmann eliminations is tert-butoxide.
The preferential formation of the least substituted alkene can be attributed to steric hindrance that interferes with the base's access to the more substituted, bulkier hydrogen atoms. As a result, the base abstracts the less hindered hydrogen atom, leading to the formation of the least substituted alkene despite Zaitzev's principle suggesting otherwise.