Grob fragmentation
Encyclopedia
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. 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
).
of di(tert-butyl)carbinol yielding trimethylethylene and isobutylene
, 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 teriary 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 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.
varies with reactant and reaction conditions with the fragmentation taking place in a concerted reaction
or taking place in two steps with a carbocation
ic 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.
is the expansion of the Wieland-Miescher ketone
(1 in scheme 2) to Thapsigargin
.
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)
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
taking place when an electrofuge
Electrofuge
An electrofuge is a leaving group which does not retain the bonding pair of electrons from its previous bond with another species.After this reaction an electrofuge may possess either a positive or a neutral charge; this is governed by the nature of the specific reaction.An example would be the...
and nucleofuge
Nucleofuge
A nucleofuge is a leaving group which retains the lone pair from its previous bond with another species...
are situated in positions 1 and 3 on an aliphatic chain. The reaction product is an electrofugal fragment (carbonium ion
Carbonium ion
A carbonium ion is a carbocation of the penta- or tetracoordinated nonclassical type such as an ion of the type R5C+.- Methanium:The parent compound methanium or CH5+ is protonated methane and a superacid. This ion exists as a reactive intermediate in the interstellar medium and can be produced in...
, acylium ion), an unsaturated fragment (alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
, alkyne
Alkyne
Alkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...
, imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
) and a nucleofugal fragment (leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
such as tosyl
Tosyl
A tosyl group is CH3C6H4SO2. This group is usually derived from the compound 4-toluenesulfonyl chloride, CH3C6H4SO2Cl, which forms esters and amides of toluenesulfonic or tosylic acid...
, hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
).
| Grob fragmentation |
|---|
History
An early instance of fragmentation is the dehydrationDehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
of di(tert-butyl)carbinol yielding trimethylethylene and isobutylene
Isobutylene
Isobutylene is a hydrocarbon of significant industrial importance. It is a four-carbon branched alkene , one of the four isomers of butylene. At standard temperature and pressure it is a colorless flammable gas.-Uses:...
, a reaction described in 1933 by Frank C. Whitmore
Frank C. Whitmore
Frank Clifford Whitmore , nicknamed "Rocky", was a prominent chemist who submitted significant evidence for the existence of carbocation mechanisms in organic chemistry.He was born in 1887 in the town of North Attleborough, Massachusetts....
. This reaction proceeds by formation of a secondary carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
followed by a rearrangement reaction
Rearrangement reaction
A rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another atom in the same molecule...
to a more stable teriary carbocation and elimination of a t-butyl cation.
| Fragmentation reaction Whitmore 1933 |
|---|
Albert Eschenmoser
Albert Eschenmoser
Albert Eschenmoser is a Swiss chemist working at the ETH Zurich and The Scripps Research Institute.His work together with Lavoslav Ružička on terpenes and the postulation of squalene cyclization to form lanosterol improved the insight into steroid biosynthesis.In the early 1960s, Eschenmoser began...
in 1952 investigated the base catalysed fragmentation of certain beta hydroxy ketones
Hydroxy ketone
A hydroxy ketone in organic chemistry is a functional group consisting of a ketone flanked by a hydroxyl group. In the two main classes the hydroxyl group can be placed in the alpha position or in the beta position .* An alpha-hydroxy ketone is called an acyloin* Prominent beta-hydroxy ketones...
| Fragmentation reaction Eschenmoser 1952 |
|---|
The original work published by Grob (1955) concerns the formation of 1,5-hexadiene from cis or trans 1,4-dibromocyclohexane by sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
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.
| Grob fragmentation 1955 |
|---|
Reaction mechanism
The reaction mechanismReaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
varies with reactant and reaction conditions with the fragmentation taking place in a concerted reaction
Concerted reaction
In chemistry, a concerted reaction is a chemical reaction in which all bond breaking and bond making occurs in a single step. Reactive intermediates or other unstable high energy intermediates are not involved. Concerted reaction rates tend not to depend on solvent polarity ruling out large buildup...
or taking place in two steps with a carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
ic 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 synthesisOrganic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
is the expansion of the Wieland-Miescher ketone
Wieland-Miescher ketone
The Wieland–Miescher ketone is a racemic bicyclic diketone and is a versatile synthon which has so far been employed in the total synthesis of more than 50 natural products, predominantly sesquiterpenoids, diterpenes and steroids possessing possible biological properties including anticancer,...
(1 in scheme 2) to Thapsigargin
Thapsigargin
Thapsigargin is non-competitive inhibitor of a class of enzymes known by the acronym SERCA, which stands for sarco / endoplasmic reticulum Ca2+ ATPase. Structurally, thapsigargin is classified as a sesquiterpene lactone, and is extracted from a plant, Thapsia garganica. It is a tumor promoter in...
.
| Scheme 2. Grob-like fragmentation in Thapsigargin synthesis |
|---|
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)
| Scheme 3. (+)-(R,Z)-5-Muscenone synthesis |
|---|