The Wittig reaction is an olefination reaction in organic chemistry. Let’s explain its mechanism and stereoselectivity using some examples and 3D models!
Interactive 3D model of methylenetriphenylphosphorane (simplest Wittig reagent)
Wittig reaction mechanism
Step 1 – Wittig reagent generation: Every Wittig reaction is based on a carbonyl compound and a Wittig reagent. This is a phosphonium ylide species that can be drawn in two resonance structures: the neutral phosphorane structure or the ylide structure.
Chemists generate this species by deprotonating a precursor, a phosphonium (positive charged phosphorous) salt, with strong base. The choice and strength of the base depends on the stabilization of the Wittig reagent (see below). A Wittig reagent that can stabilize the negative charge through other groups can be formed by using a milder base.
How does this work in the laboratory? To avoid cross-reactions (you might know that carbonyls can also be deprotonated by strong bases), chemists add the carbonyl to the reaction only after the base was used to deprotonate the phosphonium. At the very bottom, you can find two exemplary procedures. Some Wittig reagents are so stable that they can be isolated.
Step 2 – Olefination: The ylide/phosphorane is very nucleophilic at the carbon, so it can intermolecularly attack the electrophilic carbonyl carbon. At the same time, the oxygen is nucleophilic and attacks the electrophilic phosphorous. This step likely occurs in a one-step [2+2] addition [see reference 1]. The four-membered ring product is called an oxaphosphetane.
The ring can fragment the ‘opposite way that it was made’ – releasing triphenylphosphine oxide (the driving force) and our alkene product. This is why the Wittig reaction can be classified as an olefination reaction.
The orientation of substituents at the oxaphosphetane determines the stereoselectivity of the reaction. There are two chiral centres on the ring – so cis and trans diastereomers are formed. The stereochemistry of the oxaphosphetane translates into the product following the retro-[2+2]. Cis leads to (Z), trans leads to (E). Here, we note that because the Wittig reagent is a so-called non-stabilized ylide, the (Z) olefin is preferred (see below).
What type of betaine is this? What diastereomer do you expect in the product?
What is the Driving force in the Wittig Reaction?
This is a common question for students. The driving force of the Wittig reaction is the oxidation of triphenylphosphine to form triphenylphosphine oxide or Ph₃P=O. This new phosphorus-oxygen double bond is very strong, making its formation highly favorable from a energetic (thermodynamic) standpoint.
You could say there is also a kinetic driving force as the ylide reagent is highly nucleophilic and thus, reactive with the electrophilic carbonyl starting material.
Stabilized ylides and non-stabilized ylides
Depending on the substituents attached to the α-carbon (next to the phosphorous), ylides are categorized into stabilized or non-stabilized ylides. The stability refers to the ability of the substituent to stabilize the negative charge.
Stabilized ylides have electron-withdrawing groups (EWGs) attached to the α-carbon. These can include carbonyls like esters, or nitriles. The mesomeric effect of electron-withdrawing groups stabilizes the negative charge through resonance.
This makes the Wittig reagent less reactive but more selective, usually favouring the more thermodynamically stable (E)-alkene product. These Wittig reactions can operate at higher temperatures.
Non-stabilized ylides lack such electron-withdrawing groups and feature alkyl groups. Due to the lack of stability (there is no resonance with alkyl groups), non-stabilized ylides are more reactive. They usually form the kinetically favoured (Z)-alkene product. To maintain stability and the kinetic selectivity, reactions with these ylides are performed at low temperatures.
Semi-stabilized ylides aryl or alkenyl substituents. They fall between the stabilized and non-stabilized ylides and their stereoselectivity is typically poor, leading to similar (E) and (Z) alkene mixtures.
Question for you: Which type of ylide is easier to form by deprotonation? What are their rough pKa values in DMSO?
➡️ Stabilized ylides are more easily formed by deprotonation as they are by definition compounds that stabilize the negative charge on carbon. This means the respective conjugative acid has a lower pKa value (i.e., is more acidic).
Is the Wittig Reaction Concerted or Step-wise?
Over much of its history, the Wittig reaction has been described as a stepwise ionic process. Instead of concerted (one-step) [2+2] cycloaddition, it was assumed that the addition to the carbonyl proceeds step-wise, forming a betaine intermediate. However, modern research suggests that the cycloaddition is more likely [ref 1].
But hey, if your course teaches you the step-wise one, just write that one. Rather get full marks than trying to be right and a smart ass 🙂
Wittig Reaction: Advanced Example [Ref 2]
Here’s a final question (2nd year undergrad level):
What is the mechanism of this two-step sequence? Is the ylide stabilized?
The answer is given below to avoid spoilers.
If you liked this post, feel free to check out other articles on my page!
Wittig reaction conditions [ref 3]: non-stabilized ylide
Under an N2 atmosphere, methyltriphenylphosphonium bromide (40 mg, 0.113 mmol) was suspended in dry THF (1 mL) in a Schlenk tube at 0 °C. BuLi (2.5 M in hexane, 45 μL, 0.113 mmol) was added dropwise. After stirring for 30 min at this temperature, the mixture was cooled to –78 °C, compound 20 (22 mg, 0.057 mmol) was added dropwise as a solution in THF (1 mL). The reaction was continued at the same temperature for 1 h and then at 0 °C for 30 min. Water (1 mL) was added to quench the reaction and the mixture was extracted with CH2Cl2 (3 × 2 mL). The organic extracts were then combined, dried with anhydrous Na2SO4, filtered, concentrated, and purified with by chromatography on silica gel (pentane/EtOAc, 2:1) to give compound 21 (22 mg, >99 % yield).
Wittig reaction conditions [ref 4]: stabilized ylide
To a solution of aldehyde (+)-17 (1.40 g, 2.81 mmol, 1 equiv) in dry THF (35 mL) was added crystalline (α-carbomethoxyethylidene)triphenylphosphorane (1.96 g, 5.62 mmol, 2 equiv). The reaction mixture was stirred and heated from room temperature to 50 °C for 2 h under argon. The solvent was then removed under reduced pressure. The residue was purified by flash chromatography (PE/EtOAc 4/1) to give the ester (+)-18 as a white solid (1.31 g, 82%).
Wittig Reaction answer [Ref 2]:
The advanced example above is a Wittig reaction, followed by a Claisen rearrangement. The latter is a [3,3]-sigmatropic rearrangement, a type of pericyclic reaction. It converts allyl vinyl ethers to γ,δ-unsaturated carbonyls. This is an interesting transformation as it looks like it preserves the aldehyde, but moves it one carbon further away from the aromatic ring.
The ylide substituent (-OR) is a mixture of electron-withdrawing (sigma-effect) and electron-donating (mesomeric effect). Thus, one can argue the ylide is semi-stabilized. This is reflected in the rather close ratio of (E) to (Z) alkene after the Wittig. Fortunately, the mixture is not an issue as the Claisen rearrangement gives the same product regardless of diastereomer in this system.
Wittig Reaction references:
- [1] Stereochemistry and Mechanism in the Wittig Reaction | E. Vedejs, M. J. Peterson | Topics in Stereochemistry 1994, Volume 21, 1
- [2] Total synthesis of (±)-coerulescine and (±)-horsfiline | Beilstein J. Org. Chem. 2010, 6, 876
- [3] Concise Total Synthesis of Dihydrocorynanthenol, Protoemetinol, Protoemetine, 3-epi-Protoemetinol and Emetine | Shuangzheng Lin, Luca Deiana, Abrehet Tseggai, Armando Córdova | European Journal of Chemistry 2012, 2012, 2, 398-408
- [4] Total Synthesis of (−)-Chanoclavine I and an Oxygen-Substituted Ergoline Derivative | Jia-Tian Lu, Zi-Fa Shi, Xiao-Ping Cao | J. Org. Chem. 2017, 82, 15, 7774–7782
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