What Is Wittig Reaction?
The Wittig reaction is the chemical reaction that changes a carbonyl compound (an aldehyde or a ketone) to an alkene when it is treated with a phosphonium ylide (also called Wittig reagent). The generic conversion is Fig 1. The ylide [e.g., triphenylphosphine (Ph3P)] is formed from the phosphonium salt (e.g., Ph3P⁺–CH2R) by deprotonation with a strong base. The by-product, triphenylphosphine oxide (Ph3P=O), is removed in the course of purification. The ability of the Wittig reaction to change the course of synthetic planning, with its predictability and stereoselectivity, was recognized by the Nobel Committee, which awarded Wittig the Nobel Prize for Chemistry in 1979.
The real power of this reaction is in its regiospecificity – the position of the new carbon-carbon double bond is unambiguously defined, as it forms between the carbonyl carbon and the ylide carbon. In this it is different from elimination methods, which may give isomeric mixtures. The reaction is also extraordinarily versatile, as di-, tri-, and tetra-substituted alkenes can be formed with a controllable degree of stereocontrol, depending on the nature of the ylide and reaction conditions.
- Reagents:
a) Phosphonium salts (commonly triphenylphosphonium halides, e.g. Ph3P+–CH2R X-) and their corresponding phosphorus ylides (Ph3P=CR2) generated by deprotonation.
b) Strong, non-nucleophilic bases for ylide formation (e.g. n-BuLi, s-BuLi, NaHMDS, KHMDS, t-BuOK).
c) Typical aprotic solvents (THF, diethyl ether, toluene) and inert atmosphere. - Reactants: Carbonyl compounds (aldehydes and ketones).
- Products: Alkenes; Ph3P=O as a by-product.
- Reaction Type: Carbonyl olefination / C=C bond formation.
- Related Reactions: Horner-Wadsworth-Emmons (HWE) reaction, Peterson olefination, Tebbe olefination, and Schlosser modification.
Fig 1. Wittig reaction and its mechanism. [1]
Mechanism of Wittig Reaction
Classic textbooks present the Wittig mechanism in two broad perspectives:
1. Stepwise (betaine → oxaphosphetane → alkene + phosphine oxide):
Nucleophilic attack of the ylide carbon on the carbonyl carbon forms a betaine (a zwitterionic phosphonium alkoxide). Intramolecular cyclization of the betaine gives a four-membered oxaphosphetane. Collapse of the oxaphosphetane yields the alkene and phosphine oxide.
2. Concerted [2+2]-like pathway:
For some substrates/conditions, formation of the oxaphosphetane may be concerted, without a long-lived betaine intermediate.
Classification of Ylides and Stereochemical Consequences
The nature of the R' substituent on the ylide is the primary determinant of reactivity and stereoselectivity. Ylides are broadly classified into three categories:
- Stabilized Ylides (R' = EWG, e.g., -COOR, -CN, -Ph):
These ylides are less nucleophilic and more stable, often isolable as solids.
They react more slowly and typically yield the more thermodynamically stable (E)-alkene as the major product. This selectivity arises from betaine equilibration that favors the anti arrangement, leading to the trans oxaphosphetane.
- Non-Stabilized Ylides (R' = Alkyl):
These are highly reactive, nucleophilic species that are generally generated and used in situ under inert conditions.
The reaction is often under kinetic control and favors the formation of the (Z)-alkene. This is explained by the initial approach of the ylide to the carbonyl, where minimal steric repulsion between the substituents leads to the formation of the cis oxaphosphetane.
- Semi-Stabilized Ylides (R' = Allyl, Vinyl, Aryl):
Their properties are intermediate between stabilized and non-stabilized ylides.
Stereoselectivity is often poor, yielding mixtures of (E)- and (Z)-alkenes.
Schlosser Modification: This variant allows for the stereoselective synthesis of (E)-alkenes from non-stabilized ylides. It involves the treatment of the initially formed betaine (or lithiated oxaphosphetane) with an alkyl lithium, followed by protonation and subsequent decomposition, which inverts the stereochemistry to give the trans product.
Application Examples of Wittig Reaction
- Example 1: Jin Luo et al. synthesized 3-methylthio-1-phenyl-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-4-one derivatives using a tandem azawidtig reaction. [2]
- Example 2: Shun Hirasawa et al. reported a practical and scalable method for synthesizing ASP3627, which uses a six-step tandem reaction including DIBAL reduction, hydrolysis, Wittig reaction, and cyclization. A total of 30 kg of high-purity ASP3627 was finally produced in excellent overall yield. [3]
Fig 2. Synthetic examples via Wittig reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 570-572.
- Luo, Jin, et al. Synthetic Communications 50.5 (2020): 692-699.
- Hirasawa, Shun, Takashi Kikuchi, et al. Organic Process Research & Development 23.11 (2019): 2378-2387.
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