Grob fragmentation
A Grob fragmentation, named for the British chemist Cyril A. Grob, is an elimination reaction taking place when an electrofuge and nucleofuge are situated in positions 1 and 3 on an aliphatic chain.[1][2][3] The reaction product is an electrofugal fragment (carbonium ion, acylium ion), an unsaturated fragment (alkene, alkyne, imine) and a nucleofugal fragment (leaving group such as tosyl, hydroxyl).
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| Grob fragmentation |
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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.[4] This reaction proceeds by formation of a secondary carbocation followed by a rearrangement reaction to a more stable teriary carbocation and elimination of a t-butyl cation.
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| Fragmentation reaction Whitmore 1933 |
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Albert Eschenmoser in 1952 investigated the base catalysed fragmentation of certain beta hydroxy ketones [5]
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| Fragmentation reaction Eschenmoser 1952 |
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The original work published 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 in 2010 the name Grob fragmentation was chosen in more or less glaring disregard of the earlier contributions.[6]
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| Grob fragmentation 1955 |
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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 mode of elimination is anti.
Scope
An example of a Grob-like fragmentation in organic synthesis is the expansion of the Wieland-Miescher ketone (1 in scheme 2) to Thapsigargin.[7][8]
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| Scheme 2. Grob-like fragmentation in Thapsigargin synthesis |
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Another example is an epoxy alcohol fragmentation reaction as part of the Holton Taxol total synthesis.
The Grob fragmentation has been applied in the synthesis of the fragrance muscenone (scheme 3) [9][10]
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| Scheme 3. (+)-(R,Z)-5-Muscenone synthesis |
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See also
References
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- ^ Weyerstahl, P.; Marschall, H. Comp. Org. Syn. 1991, 6, 1044-1065. (Review)
- ^ Strategic Applications of Named Reactions in Organic Synthesis Laszlo Kurti, Barbara Czako Academic Press (March 4, 2005) ISBN 0-12-429785-4
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- ^ Reaction details: Organic reduction of Wieland-Miescher ketone with sodium borohydride to alcohol 2 followed by functionalizion to mesylate 3 with mesyl chloride in pyridine. Then reduction of enone to allyl alcohol 4 with tri-tert-butoxyaluminum hydride in tetrahydrofuran followed by hydroboration with borane in THF to borane 5 (only one substituent displayed for clarity). The Grob fragmentation to 6 takes place with sodium methoxide in methanol at reflux. A methoxide group attacks boron giving the borate complex which fragments. As each boron atom can hold three substrate molecules (R), the ultimate boron byproduct is trimethyl borate
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- ^ reduction of 1 with NMe4BH(OAc)3 in AcOH/water gves 2, mesylation (pyridine / TsOH) gives 3, elimination (tert-butanol / Potassium tert-butoxide) gives 4