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Wittig Reaction

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The Wittig reaction is a valuable method for the formation of olefins from aldehydes and ketones. The term "phosphorus ylide" is indissolubly linked with the Wittig reaction being along with the related Horner-Wadsworth-Emmons olefination. The typical WIttig reaction using either preformed ylides or those generated from the corresponding phosphonium salts was applied for construction of double bond in the total synthesis of Resolvin, the polycyclic natural product. 

Wittig reaction often proceeds at room temperature, it is not uncommon to apply heat, for example from a sand bath. It goes by many names including phosphorus ylide and phosphorane. The name refers to the fact that the phosphorus atom in a Wittig reagent is formally phosphorus.

Preparation of Phosphorus Ylides

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The well known reaction of phosphorus ylides is their reaction with carbonyl compounds (aldehydes and ketones) to give alkenes. This alkenation methodology is universally known as the wittig reaction. 

Phosphorus Ylides

The Wittig reaction is very useful for the introduction of exocyclic double bond. For example, cyclohexanone is converted into methylenecyclohexane in 99% yield. 

Methylenecyclohexane

Phosphorus ylide reacts with aldehydes or ketone to form an intermediate betaine, which collapsed into oxaphosphetane. Elimination of triphenylphosphine oxide yields alkene.

Definition

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Wittig reagents are prepared from alkyl halides in two steps. A methyl, primary or secondary alkyl halide is first reacted with triphenylphosphine causing an SN2 displacement of the halide leaving group. 

Wittig Reagent

Nucleophilic Wittig reagents react with aldehydes or ketone electrophiles to furnish alkene products. To properly predict the product of a Wittig reaction, the carbonyl oxygen is replaced by the carbon group of the Wittig reagent, converting the C=O double bond into a C=C double bond. 

Wittig Reaction

Mechanism

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The mechanism involves addition of the carbanion nucleophile to the electrophilic carbon of the carbonyl, followed by a breakdown of the resulting oxa-phosphetane intermediate. A molecule of triphenylphosphine oxide (Ph3P=O) is generated along with the alkene product. 

Wittig Reaction Mechanism

Examples of Ylide Formation

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The term ylide was introduced by George Wittig reaction in 1953. Since then the chemistry of ylides flourished rapidly and has become a powerful and versatile synthetic tool for the synthesis of carbon-carbon bonds.

1. Nitrogen ylides 

The nitrogen ylides are formed as intermediates in the Sommelet rearrangement. The methods is used for the conversion of the tetraalkylammonium halides into tertiary aromatic amines. 

Nitrogen Ylides
2. Sulfur ylides

Sulfur ylides are prepared by the deprotonation of the corresponding sulfonium salts. These ylides are stabilized and are formally zwitterions in which a carbanion is stabilized by interaction with an adjacent sulfonium center. Dimethylsulfonium methylide is more reactive and less stable. 

Sulfur Ylides

Examples

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Some of the examples of Wittig reactions are given below.

The synthesis of $\beta$-carotene from vitamin A for use in foods is an important application of the Wittig reaction in the industry. 

Beta Carotene

Wittig reaction to couple two advanced intermediates, a phosphonium salt and an aldehyde . The phosphonium salt was prepared using the primary alkyl iodide, triphenylphosphine, base and high pressure. The total synthesis of alkaloid buflavin was achieved in the laboratory. The reaction afforded the corresponding Z and E enecarbamates in good yield and with high E-selectivity. 

Buflavin

Limitation & Use

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The main limitation of Wittig reaction with carboxylic acid derivatives is the poor reactivity of non-activated esters, especially amides with alkylidene phosphoranes. The addition of a P-ylides to a carboxylic ester is possible when the ylides are sufficiently reactive or the esters are activated. 

E Z Isomer of Propanol

All the formation of the new carbon-carbon double bond proceeds regio specifically that is at the position of the original carbonyl function. Furthermore the starting materials namely carbonyl compounds and phosphonium salts generally are readily accessible and the phosphorus ylides do not need to be isolated. As the Wittig reaction is carried out generally under mild conditions, alkaline or virtually neutral medium, it is an excellent method for the synthesis of the sensitive carotenoids.

Wittig Reaction Uses