Wittig Reaction/Mechanism of Wittig Reaction!/Examples of Wittig reaction/use of Wittig reaction
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The Wittig reaction or Wittig
The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide (often called a Wittig reagent) to give an alkene and triphenylphosphine oxide.
Wittig Reaction
It is widely used in organic synthesis for the preparation of alkenes.[1][2][3] It should not be confused with the Wittig rearrangement.
Wittig reactions are most commonly used to couple aldehydes and ketones to singly-substituted triphenylphosphonium ylides. For the reaction with aldehydes, the double bond geometry is readily predicted based on the nature of the ylide. With unstabilised ylides (R3 = alkyl) this results in (Z)-alkene product with moderate to high selectivity. With stabilized ylides (R3 = ester or ketone), the (E)-alkene is formed with high selectivity. The (E)/(Z) selectivity is often poor with semistabilized ylides (R3 = aryl).[4]
To obtain the (E)-alkene for unstabilized ylides, the Schlosser modification of the Wittig reaction can be used. Alternatively, the Julia olefination and its variants also provide the (E)-alkene selectively. Ordinarily, the Horner–Wadsworth–Emmons reaction provides the (E)-enoate (α,β-unsaturated ester), just as the Wittig reaction does. To obtain the (Z)-enoate, the Still-Gennari modification of the Horner-Wadsworth-Emmons reaction can be used.
Contents
1 Reaction mechanism
1.1 Classical mechanism
1.2 Mechanism
2 Wittig reagents
2.1 Preparation
2.2 Structure of the ylide
3 Scope and limitations
3.1 Schlosser modification
4 Examples
5 History
6 See also
7 References
8 External links
Reaction mechanism
Classical mechanism
The steric bulk of the ylide 1 influences the stereochemical outcome of nucleophilic addition to give a predominance of the betaine 3 (cf. Bürgi–Dunitz angle). Note that for betaine 3 both R1 and R2 as well as PPh3+ and O− are positioned anti to one another.
Carbon-carbon bond rotation gives the betaine 4, which then forms the oxaphosphetane 5. Elimination gives the desired Z-alkene 7 and triphenylphosphine oxide 6. With simple Wittig reagents, the first step occurs easily with both aldehydes and ketones, and the decomposition of the betaine (to form 5) is the rate-determining step. However, with stabilised ylides (where R1 stabilises the negative charge) the first step is the slowest step, so the overall rate of alkene formation decreases and a bigger proportion of the alkene product is the E-isomer. This also explains why stabilised reagents fail to react well with sterically hindered ketones.
The mechanism of the Wittig reaction
Mechanism
Mechanistic studies have focused on unstabilized ylides, because the intermediates can be followed by NMR spectroscopy. The existence and interconversion of the betaine (3a and 3b) is subject of ongoing research.[5] For lithium-free Wittig reactions, most recent studies support a concerted formation of the oxaphosphetane without intervention of a betaine. In particular, phosphonium ylides 1 react with carbonyl compounds 2 via a [2+2] cycloaddition that is sometimes described as having [π2s+π2a] topology to directly form the oxaphosphetanes 4a and 4b. Under lithium-free conditions, the stereochemistry of the product 5 is due to the kinetically controlled addition of the ylide 1 to the carbonyl 2. When lithium is present, there may be equilibration of the intermediates, possibly via betaine species 3a and 3b.[6][7][8] Bruce E. Maryanoff and A. B. Reitz identified the issue about equilibration of Wittig intermediates and termed the process "stereochemical drift". For many years, the stereochemistry of the Wittig reaction, in terms of carbon-carbon bond formation, had been assumed to correspond directly with the Z/E stereochemistry of the alkene products. However, certain reactants do not follow this simple pattern. Lithium salts can also exert a profound effect on the stereochemical outcome.[9]
The mechanism of the Wittig reaction
Mechanisms differ for aliphatic and aromatic aldehydes and for aromatic and aliphatic phosphonium ylides. Evidence suggests that the Wittig reaction of unbranched aldehydes under lithium-salt-free conditions do not equilibrate and are therefore under kinetic reaction control.[10][11] E. Vedejs has put forth a theory to explain the stereoselectivity of stabilized and unstabilized Wittig reactions.[12]
Strong evidence indicated that under Li-free conditions, Wittig reactions involving unstabilized (R1= alkyl, H), semistabilized (R1 = aryl), and stabilized (R1 = EWG) Wittig reagents all proceed via a [2+2]/retro-[2+2] mechanism under kinetic control, with oxaphosphetane as the one and only intermediate.[13]
Wittig reagents
[Ph3PCH3]+Br-, typical phosphonium salt.
Preparation
Simple phosphoranes typically hydrolyze and oxidize readily. They are therefore prepared using air-free techniques. Phosphoranes are more air-stable when they contain an electron withdrawing group a
Wittig Reaction
It is widely used in organic synthesis for the preparation of alkenes.[1][2][3] It should not be confused with the Wittig rearrangement.
Wittig reactions are most commonly used to couple aldehydes and ketones to singly-substituted triphenylphosphonium ylides. For the reaction with aldehydes, the double bond geometry is readily predicted based on the nature of the ylide. With unstabilised ylides (R3 = alkyl) this results in (Z)-alkene product with moderate to high selectivity. With stabilized ylides (R3 = ester or ketone), the (E)-alkene is formed with high selectivity. The (E)/(Z) selectivity is often poor with semistabilized ylides (R3 = aryl).[4]
To obtain the (E)-alkene for unstabilized ylides, the Schlosser modification of the Wittig reaction can be used. Alternatively, the Julia olefination and its variants also provide the (E)-alkene selectively. Ordinarily, the Horner–Wadsworth–Emmons reaction provides the (E)-enoate (α,β-unsaturated ester), just as the Wittig reaction does. To obtain the (Z)-enoate, the Still-Gennari modification of the Horner-Wadsworth-Emmons reaction can be used.
Contents
1 Reaction mechanism
1.1 Classical mechanism
1.2 Mechanism
2 Wittig reagents
2.1 Preparation
2.2 Structure of the ylide
3 Scope and limitations
3.1 Schlosser modification
4 Examples
5 History
6 See also
7 References
8 External links
Reaction mechanism
Classical mechanism
The steric bulk of the ylide 1 influences the stereochemical outcome of nucleophilic addition to give a predominance of the betaine 3 (cf. Bürgi–Dunitz angle). Note that for betaine 3 both R1 and R2 as well as PPh3+ and O− are positioned anti to one another.
Carbon-carbon bond rotation gives the betaine 4, which then forms the oxaphosphetane 5. Elimination gives the desired Z-alkene 7 and triphenylphosphine oxide 6. With simple Wittig reagents, the first step occurs easily with both aldehydes and ketones, and the decomposition of the betaine (to form 5) is the rate-determining step. However, with stabilised ylides (where R1 stabilises the negative charge) the first step is the slowest step, so the overall rate of alkene formation decreases and a bigger proportion of the alkene product is the E-isomer. This also explains why stabilised reagents fail to react well with sterically hindered ketones.
The mechanism of the Wittig reaction
Mechanism
Mechanistic studies have focused on unstabilized ylides, because the intermediates can be followed by NMR spectroscopy. The existence and interconversion of the betaine (3a and 3b) is subject of ongoing research.[5] For lithium-free Wittig reactions, most recent studies support a concerted formation of the oxaphosphetane without intervention of a betaine. In particular, phosphonium ylides 1 react with carbonyl compounds 2 via a [2+2] cycloaddition that is sometimes described as having [π2s+π2a] topology to directly form the oxaphosphetanes 4a and 4b. Under lithium-free conditions, the stereochemistry of the product 5 is due to the kinetically controlled addition of the ylide 1 to the carbonyl 2. When lithium is present, there may be equilibration of the intermediates, possibly via betaine species 3a and 3b.[6][7][8] Bruce E. Maryanoff and A. B. Reitz identified the issue about equilibration of Wittig intermediates and termed the process "stereochemical drift". For many years, the stereochemistry of the Wittig reaction, in terms of carbon-carbon bond formation, had been assumed to correspond directly with the Z/E stereochemistry of the alkene products. However, certain reactants do not follow this simple pattern. Lithium salts can also exert a profound effect on the stereochemical outcome.[9]
The mechanism of the Wittig reaction
Mechanisms differ for aliphatic and aromatic aldehydes and for aromatic and aliphatic phosphonium ylides. Evidence suggests that the Wittig reaction of unbranched aldehydes under lithium-salt-free conditions do not equilibrate and are therefore under kinetic reaction control.[10][11] E. Vedejs has put forth a theory to explain the stereoselectivity of stabilized and unstabilized Wittig reactions.[12]
Strong evidence indicated that under Li-free conditions, Wittig reactions involving unstabilized (R1= alkyl, H), semistabilized (R1 = aryl), and stabilized (R1 = EWG) Wittig reagents all proceed via a [2+2]/retro-[2+2] mechanism under kinetic control, with oxaphosphetane as the one and only intermediate.[13]
Wittig reagents
[Ph3PCH3]+Br-, typical phosphonium salt.
Preparation
Simple phosphoranes typically hydrolyze and oxidize readily. They are therefore prepared using air-free techniques. Phosphoranes are more air-stable when they contain an electron withdrawing group a
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