Grob fragmentation

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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.[1][2][3]

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:

Grob fragmentation

The reaction is named for the Swiss chemist Cyril A. Grob.

History[edit]

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:

Fragmentation Whitmore

Albert Eschenmoser in 1952 investigated the base catalysed fragmentation of certain beta hydroxy ketones:[5]

Fragmentation Eschenmoser 1952

The original work by Grob (1955) concerns the formation of 1,5-hexadiene from cis or trans 1,4-dibromocyclohexane by sodium metal:[1]

Grob fragmentation 1955

According to reviewers Prantz and Mulzer (2010) the name Grob fragmentation was chosen "in more or less glaring disregard of the earlier contributions".[6]

Reaction mechanism[edit]

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.

Further examples[edit]

Thapsigargin from Wieland–Miescher ketone[edit]

An example of a Grob-like fragmentation in organic synthesis is the expansion of the Wieland–Miescher ketone to thapsigargin:[7]

Scheme 2. Grob-like fragmentation

In this reaction, reduction of the ketone 1 with sodium borohydride yields alcohol 2, which is functionalized to the mesylate 3 with mesyl chloride in pyridine. Then reduction of the enone to allyl alcohol 4 with tri-tert-butoxyaluminum hydride in tetrahydrofuran followed by hydroboration with borane in THF yields the 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 the boron atom giving a borate complex which fragments. As each boron atom can hold three substrate molecules (R), the ultimate boron byproduct is trimethyl borate

Another example is an epoxy alcohol fragmentation reaction as part of the Holton Taxol total synthesis.

Synthesis of muscenone[edit]

The Grob fragmentation has been applied in the synthesis of the fragrance (+)−(R,Z)-5-muscenone:[8]

Scheme 3. (+)−(R,Z)-5-Muscenone synthesis

Reduction of 1 with NMe4BH(OAc)3 in AcOH and water gives 2. Then mesylation with pyridine and TsOH gives 3, and elimination with potassium tert-butoxide in tert-butanol gives 4.

See also[edit]

References[edit]

  1. ^ a b C. A. Grob and W. Baumann (1955), "Die 1,4-Eliminierung unter Fragmentierung". Helvetica Chimica Acta volume 38, issue 3, page 594. doi:10.1002/hlca.19550380306
  2. ^ Peter Weyerstahl, Helga Marschall (1991), "Fragmentation Reactions." (Review) In Comprehensive Organic Synthesis, volume 6, pages 1044-1065. ISBN 978-0-08-052349-1
  3. ^ Laszlo Kurti, Barbara Czako (2005), "Strategic applications of named reactions in organic synthesis" (Book) Academic Press. ISBN 0-12-429785-4
  4. ^ F. C. Whitmore and E. E. Stahly (1933). Journal of the American Chemical Society, volume 55, issue 10, page 4153. doi:10.1021/ja01337a042
  5. ^ A. Eschenmoser and A. Frey (1952), "Über die Spaltung des Mesylesters von 2-Methyl-2-oxymethyl-cyclopentanon mit Basen". Helvetica Chimica Acta, volume 35, issue 5, page 1660.doi:10.1002/hlca.19520350532
  6. ^ K. Prantz and J. Mulzer (2010), "Synthetic applications of the carbonyl generating Grob fragmentation". Chemical reviews, volume 110, issue 6, pages 3741–3766. doi:10.1021/cr900386h PMID 20163188
  7. ^ S. Ley, A. Antonello, E. Balskus, D. Booth, S. Christensen, E. Cleator. H. Gold, K. Högenauer, and others (2004), "Synthesis of the thapsigargins." Proceedings of the National Academy of Sciences of the United States of America, volume 101, issue 33, pages 12073–12078. doi:10.1073/pnas.0403300101 PMC 514437. PMID 15226504.
  8. ^ C. Fehr, A. Buzas, O. Knopff, J. De Saint Laumer (2010), "(+)-(R,Z)-5-Muscenone and (-)-(R)-muscone by enantioselective aldol reaction and Grob fragmentation". Chemistry, volume 16, issue 8, pages 2487–2495. doi:10.1002/chem.200902774. PMID 20077541.