In chemistry, a Grob fragmentation is an elimination reaction that breaks a neutral aliphatic chain into three fragments: a positive ion spanning atoms 1 and 2 (the "electrofuge"), an unsaturated neutral fragment spanning positions 3 and 4, and a negative ion (the "nucleofuge") comprising the rest of the chain. For example, the positive ion may be a carbenium, carbonium or acylium ion; the neutral fragment could be an alkene, alkyne, or imine; and the negative fragment could be a tosyl or hydroxyl ion: The reaction is named for the Swiss chemist . Alternately, atom 1 could begin as an anion, in which case it becomes neutral rather than going from neutral to cationic. History An early instance of fragmentation is the dehydration of di(tert-butyl)methanol yielding 2-methyl-2-butene and isobutene, a reaction described in 1933 by Frank C. Whitmore. This reaction proceeds by formation of a secondary carbocation followed by a rearrangement reaction to a more stable tertiary carbocation and elimination of a t-butyl cation: Albert Eschenmoser in 1952 investigated the base catalysed fragmentation of certain beta hydroxy ketones: The original work by Grob (1955) concerns the formation of 1,5-hexadiene from cis- or trans-1,4-dibromocyclohexane by sodium metal: According to reviewers Prantz and Mulzer (2010), the name Grob fragmentation was chosen "in more or less glaring disregard of the earlier contributions". Reaction mechanism The reaction mechanism varies with reactant and reaction conditions with the fragmentation taking place in a concerted reaction or taking place in two steps with a carbocationic intermediate when the nucleofuge leaves first or taking place in two steps with an anionic intermediate when the electrofuge leaves first. The carbanionic pathway is more common and is facilitated by the stability of the cation formed and the leaving group ability of the nucleofuge. With cyclic substrates, the preferred geometry of elimination is for the sigma bond that drives out the leaving group to being anti to it, analogous to the conformational orientation in the E2 mechanism of elimination reactions. Examples Thapsigargin from Wieland–Miescher ketone An example of a Grob-like fragmentation in organic synthesis is the expansion of the Wieland–Miescher ketone to thapsigargin: In this reaction, diastereoselective reduction of the ketone 1 with sodium borohydride yields alcohol 2, which is functionalized to the mesylate 3 with mesyl chloride in pyridine. The selectivity of the initial reduction of ketone 1 is a result of borohyride approaching from the bottom face to avoid steric