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.

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.

aza-Grob fragmentation[edit]

3-aza-Grob fragmentation is variation which takes place when an electrofuge and nucleofuge are situated at positions 1 and 5 on a secondary or tertiary amine chain with the nitrogen at the 3 position.[9][10] The reaction products are an electrofugal fragment, an imine, and a nucleofugal fragment (such as an alcohol).

3-Aza-Grob Fragmentation Scheme

3-aza-Grob fragmentation can proceed with several different nucleofuges. The reaction mechanism has been reported to begin with the reduction of an ether protected amide to form a secondary alcohol. Fragmentation then takes place in a concerted step to form the reaction products.

3-Aza-Grob Fragmentation Mechanism

The scope of the reaction has been found to cover THF and tetrahydrothiophene protecting groups using various hydride agents.[11]

See also[edit]

References[edit]

  1. ^ a b Grob, C. A.; Baumann, W. (1955). "Die 1,4-Eliminierung unter Fragmentierung". Helvetica Chimica Acta 38 (3): 594–610. doi:10.1002/hlca.19550380306. 
  2. ^ name=WeyerstahlTrost, ed.-in-chief: Barry M.; Fleming, Ian (1991). Comprehensive organic synthesis : selectivity, strategy, and efficiency in modern organic chemistry (1st ed. ed.). Amsterdam [u.a.]: Elsevier. pp. 1044–1065. ISBN 978-0-08-052349-1. 
  3. ^ Kürti, László; Czakó, Barbara (2007). Strategic applications of named reactions in organic synthesis : background and detailed mechanisms ; 250 named reactions (Pbk. ed., [Nachdr.]. ed.). Amsterdam [u.a.]: Elsevier Academic Press. ISBN 0-12-429785-4. 
  4. ^ Whitmore, Frank C.; Stahly, E. E. (October 1933). "The Common Basis of Intramolecular Rearrangements. II. The Dehydration of Di-tert-butylcarbinol and the Conversion of the Resulting Nonenes to Trimethylethylene and Isobutylene". Journal of the American Chemical Society 55 (10): 4153–4157. doi:10.1021/ja01337a042. 
  5. ^ Eschenmoser, A.; Frey, A. (1 August 1952). "Uber die Spaltung des Mesylesters von 2-Methyl-2-oxymethyl-cyclopentanon mit Basen". Helvetica Chimica Acta 35 (5): 1660–1666. doi:10.1002/hlca.19520350532. 
  6. ^ Prantz, Kathrin; Mulzer, Johann (9 June 2010). "Synthetic Applications of the Carbonyl Generating Grob Fragmentation". Chemical Reviews 110 (6): 3741–3766. doi:10.1021/cr900386h. 
  7. ^ Ley, S. V.; Antonello, A.; Balskus, E. P.; Booth, D. T.; Christensen, S. B.; Cleator, E.; Gold, H.; Hogenauer, K.; Hunger, U.; Myers, R. M.; Oliver, S. F.; Simic, O.; Smith, M. D.; Sohoel, H.; Woolford, A. J. A. (28 June 2004). "Synthesis of the thapsigargins". Proceedings of the National Academy of Sciences 101 (33): 12073–12078. doi:10.1073/pnas.0403300101. 
  8. ^ Fehr, Charles; Buzas, Andrea K.; Knopff, Oliver; de Saint Laumer, Jean-Yves (22 February 2010). "(+)-(R,Z)-5-Muscenone and (−)-(R)-Muscone by Enantioselective Aldol Reaction and Grob Fragmentation". Chemistry - A European Journal 16 (8): 2487–2495. doi:10.1002/chem.200902774. 
  9. ^ Wang, Jeh-Jeng; Hu, Wan-Ping; Chung, Hung-Wei; Wang, Li-Fang; Hsu, Mei-Hui (October 1998). "A new and novel amide bond cleavage of N-methoxymethylpyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones by hydride reduction via 3-aza-Grob fragmentation". Tetrahedron 54 (43): 13149–13154. doi:10.1016/S0040-4020(98)00795-9. 
  10. ^ Wang, Jeh-Jeng; Hu, Wan-Ping (July 1999). "Novel 3-Aza-Grob Fragmentation in Hydride Reduction of Ether-Protected Aromatic Lactams". The Journal of Organic Chemistry 64 (15): 5725–5727. doi:10.1021/jo990549k. 
  11. ^ Hu, Wan-Ping; Wang, Jeh-Jeng; Tsai, Pei-Ching (June 2000). "Novel Examples of 3-Aza-Grob Fragmentation". The Journal of Organic Chemistry 65 (13): 4208–4209. doi:10.1021/jo000252i.