Alpha-Ketol Rearrangement
Encyclopedia
The α-ketol rearrangement is the acid
-, base
-, or heat-induced 1,2-migration of an alkyl or aryl group in an α-hydroxy ketone
or aldehyde
to give an isomeric product.
(1)
This rearrangement differs from similar isomerizations of carbohydrates, which involve the migration of hydrogen and proceed through discrete enediol intermediates. These include the Lobry–de Bruyn–van Ekenstein transformation, the Heyns and Amadori rearrangement
s, and the Voight and Bilik reactions. α-hydroxy imines may also undergo the rearrangement, although the thermodynamic driving force to amino ketones is often weak (in the absence of protic acids; see below).
Advantages: Large thermodynamic energy differences between reactants and products can be harnessed to drive these reactions to completion. Reaction progress can also be influenced through conformational control and often exhibit asymmetric induction.
Disadvantages: Because the reaction is reversible and thermodynamically controlled, it cannot be used to synthesize unstable α-hydroxy carbonyl products. Ideal conditions are often difficult to pinpoint and can require extensive catalyst screening.
(2)
When metal
salts are used to promote rearrangement, stereoelectronic effects derived from chelation
to the metal salt can enhance the speed and selectivity of the reaction. In the conversion of 1 to 2, for instance, coordination of both the hydroxyl and carbonyl groups to aluminum facilitates rapid, selective migration of the bond to the one-carbon bridge. Similar stereoelectronic effects were observed in studies of the rearrangement of 17-hydroxy-20-ketosteroids
. In this case, Lewis-acidic conditions switched the sense of stereoselectivity observed for the base-catalyzed process.
(3)
α-Hydroxy imines may also undergo rearrangement to amino ketones. Hammett analysis and a very negative entropy of activation
suggest that the reaction proceeds in a single step through a concerted transition state
. As a result, subtle conformational and steric factors can play a role in the speed and extent of these reactions. Allylic transposition has been observed in migrations of allyl
groups, but propargyl
groups undergo simple alkyl migration.
provided 4 in 34% ee
.
(4)
If the relative orientation of the carbonyl and hydroxy group can be controlled (through intramolecular hydrogen bonding, for instance), stereoselectivity can be achieved. This conformational control forces the migrating group to form its new bond to a single face of the carbonyl group.
(5)
Alkoxyallenes with an α-hydroxy substituent may provide allylic alcohols after rearrangement. Ring expansion provides the thermodynamic driving force in this case.
(6)
Steroidal ketols have been subjected to rearrangement conditions to give steroids of different ring sizes. These rearrangements often proceed with a high degree of stereocontrol.
(7)
Bridged ketols also undergo rearrangement, oftentimes stereospecifically.
(8)
α-Hydroxy aldehydes have a strong thermodynamic preference for rearrangement to the corresponding ketols in the absence of steric or other factors.
Rearrangements of α-hydroxy imine
s are more difficult to predict because of the small energy differences between isomers. One synthetically useful application of this rearrangement is to the synthesis of spirocycles: fused hydroxyimines can rearrange to give the corresponding spiro isomers.
(9)
Synthesis of α-hydroxy carbonyl compounds is most commonly accomplished by either chain extension or oxidation of carbonyl compounds. In conjunction with aldehydes and ketones, tosyl isocyanides can be used to form α-hydroxy ketones after hydroylsis of the resulting oxazolines. The sp-hybridized isocyanide carbon becomes the carbonyl carbon of the product. A variety of reagents exist to oxidize enolates to α-hydroxy carbonyl compounds—in the example here, oxy-Cope rearrangement generates an enolate, which is then oxidized in the presence of molecular oxygen.
(10)
Lewis acids have been shown to work well as catalysts; however coordination of the catalyst has important stereoelectronic consequences. Additionally, under thermal conditions, intramolecular hydrogen bonding may influence the product distribution. Conditions for the rearrangement of α-hydroxy imines are similar, although the resulting amino ketone products are usually isolated as the corresponding acid salts.
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
-, base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
-, or heat-induced 1,2-migration of an alkyl or aryl group in an α-hydroxy ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
or aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
to give an isomeric product.
Introduction
Like other ketogenic rearrangements, the α-ketol rearrangement involves the transformation of an alkoxide into a carbonyl group with concomitant movement of the bonding electrons of the migrating group towards an adjacent trigonal center. A distinctive feature of this particular rearrangement, however, is its reversibility—as a result, the more stable α-hydroxy carbonyl compound is favored. A general scheme for the rearrangement is shown below.(1)
This rearrangement differs from similar isomerizations of carbohydrates, which involve the migration of hydrogen and proceed through discrete enediol intermediates. These include the Lobry–de Bruyn–van Ekenstein transformation, the Heyns and Amadori rearrangement
Amadori rearrangement
The amadori rearrangement is an organic reaction describing the acid or base catalyzed isomerization or rearrangement reaction of the N-glycoside of an aldose or the glycosylamine to the corresponding 1-amino-1-deoxy-ketose...
s, and the Voight and Bilik reactions. α-hydroxy imines may also undergo the rearrangement, although the thermodynamic driving force to amino ketones is often weak (in the absence of protic acids; see below).
Advantages: Large thermodynamic energy differences between reactants and products can be harnessed to drive these reactions to completion. Reaction progress can also be influenced through conformational control and often exhibit asymmetric induction.
Disadvantages: Because the reaction is reversible and thermodynamically controlled, it cannot be used to synthesize unstable α-hydroxy carbonyl products. Ideal conditions are often difficult to pinpoint and can require extensive catalyst screening.
Prevailing mechanism
Under basic conditions, the reation is initiated by deprotonation of the hydroxyl group. Substrates must lack α-hydrogens to prevent competitive reactions involving enolates. Under Brønsted- or Lewis-acidic conditions, coordination to the carbonyl oxygen occurs first, and under thermal conditions, intramolecular proton transfer takes place at the same time as migration. The reversibility of the reaction implies that reaction products are more thermodynamically stable than the corresponding starting materials. Starting materials incorporating ring strain, for instance, will rearrange to products lacking strain.(2)
When metal
Metal
A metal , is an element, compound, or alloy that is a good conductor of both electricity and heat. Metals are usually malleable and shiny, that is they reflect most of incident light...
salts are used to promote rearrangement, stereoelectronic effects derived from chelation
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
to the metal salt can enhance the speed and selectivity of the reaction. In the conversion of 1 to 2, for instance, coordination of both the hydroxyl and carbonyl groups to aluminum facilitates rapid, selective migration of the bond to the one-carbon bridge. Similar stereoelectronic effects were observed in studies of the rearrangement of 17-hydroxy-20-ketosteroids
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
. In this case, Lewis-acidic conditions switched the sense of stereoselectivity observed for the base-catalyzed process.
(3)
α-Hydroxy imines may also undergo rearrangement to amino ketones. Hammett analysis and a very negative entropy of activation
Entropy
Entropy is a thermodynamic property that can be used to determine the energy available for useful work in a thermodynamic process, such as in energy conversion devices, engines, or machines. Such devices can only be driven by convertible energy, and have a theoretical maximum efficiency when...
suggest that the reaction proceeds in a single step through a concerted transition state
Transition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
. As a result, subtle conformational and steric factors can play a role in the speed and extent of these reactions. Allylic transposition has been observed in migrations of allyl
Allyl
An allyl group is a substituent with the structural formula H2C=CH-CH2R, where R is the connection to the rest of the molecule. It is made up of a methylene , attached to a vinyl group . The name is derived from the Latin word for garlic, Allium sativum. Theodor Wertheim isolated an allyl...
groups, but propargyl
Propargyl
In organic chemistry, propargyl is an alkyl functional group of 2-propynyl with the structure HC≡C−CH2−, derived from the alkyne propyne.The term propargylic refers to a saturated position on a molecular framework next to an alkynyl group...
groups undergo simple alkyl migration.
Enantioselective variants
Although examples of enantioselective α-ketol rearrangements starting from achiral α-hydroxy ketones are fairly limited, a number of examples of 1,2-asymmetric induction (due to stereoelectronic factors) have been observed. In one example of an enantioselective process, use of nickel(II) diacetoacetonate and pyboxBisoxazoline ligand
In chemistry, bisoxazoline ligands are chiral ligands based on a bis oxazoline skeleton and used in combination with a metal compound in asymmetric synthesis as a chiral catalyst . Three frequently encountered such ligands are PyBOX, tBuBOX and PhBOX...
provided 4 in 34% ee
Enantiomeric excess
The enantiomeric excess of a substance is a measure of how pure it is. In this case, the impurity is the undesired enantiomer .-Definition:...
.
(4)
If the relative orientation of the carbonyl and hydroxy group can be controlled (through intramolecular hydrogen bonding, for instance), stereoselectivity can be achieved. This conformational control forces the migrating group to form its new bond to a single face of the carbonyl group.
Scope and limitations
The scope of rearrangements of α-hydroxy ketones and aldehydes is limited only by the fact that the product must be more thermodynamically stable than the starting material. In some cases, very subtle structural differences dictate the favored direction of isomerization. For instance, according to the "Favorskii rule," an empirical guideline with numerous exceptions, products with the carbonyl group adjacent to a methyl group or distal to a phenyl group are favored over the corresponding isomers. In many subtle cases, such as the one below, decreased nonbonding interactions in dominant conformations of the favored isomers are often invoked(5)
Alkoxyallenes with an α-hydroxy substituent may provide allylic alcohols after rearrangement. Ring expansion provides the thermodynamic driving force in this case.
(6)
Steroidal ketols have been subjected to rearrangement conditions to give steroids of different ring sizes. These rearrangements often proceed with a high degree of stereocontrol.
(7)
Bridged ketols also undergo rearrangement, oftentimes stereospecifically.
(8)
α-Hydroxy aldehydes have a strong thermodynamic preference for rearrangement to the corresponding ketols in the absence of steric or other factors.
Rearrangements of α-hydroxy 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...
s are more difficult to predict because of the small energy differences between isomers. One synthetically useful application of this rearrangement is to the synthesis of spirocycles: fused hydroxyimines can rearrange to give the corresponding spiro isomers.
(9)
Comparison with other methods
Ketol isomerizations of secondary α-hydroxy carbonyl compounds, which proceed via tautomerization, are probably the closest relative of the α-ketol rearrangement discussed here. Also closely related are carbohydrate rearrangements such as the Lobry–de Bruyn–van Ekenstein transformation, which involve conversion to the open form followed by rearrangement and re-closing.Synthesis of α-hydroxy carbonyl compounds is most commonly accomplished by either chain extension or oxidation of carbonyl compounds. In conjunction with aldehydes and ketones, tosyl isocyanides can be used to form α-hydroxy ketones after hydroylsis of the resulting oxazolines. The sp-hybridized isocyanide carbon becomes the carbonyl carbon of the product. A variety of reagents exist to oxidize enolates to α-hydroxy carbonyl compounds—in the example here, oxy-Cope rearrangement generates an enolate, which is then oxidized in the presence of molecular oxygen.
(10)
Typical conditions
The most common experimental procedures for the rearrangement of α-ketols involve simple heating or exposure to a base or an acid. However, discovering the ideal conditions for the reaction often requires extensive optimization—simple Bronsted acids and bases do not always work well. Group 13Group 13
"The Group Thirteen" network was a Jewish collaborationist organisation in the Warsaw Ghetto during the Second World War. The Thirteen took its informal name from the address of its main office in Leszno Street 13. The group was founded in December 1940 and led by Abraham Gancwajch, the former...
Lewis acids have been shown to work well as catalysts; however coordination of the catalyst has important stereoelectronic consequences. Additionally, under thermal conditions, intramolecular hydrogen bonding may influence the product distribution. Conditions for the rearrangement of α-hydroxy imines are similar, although the resulting amino ketone products are usually isolated as the corresponding acid salts.