Assessment of Stereoselectivity of Wittig Reaction with 60 MHz 1H NMR Spectroscopy

The Wittig reaction is a high-yielding, versatile synthetic procedure used to construct carbon-carbon double bonds. Unlike other sp2 bond forming reactions this can be used to provide convenient access to a cis–stereochemistry. At the time the reaction was discovered by Georg Wittig, thiscis– confirmation was not reliably afforded by other synthetic means.

To access cis- stereochemistry, typically a Wittig Reagent is formed in situ through a basic SN2 reactionbetween triphenylphosphine and a primary or secondary alkyl halide. This affords a phosphonium salt that can be deprotonated with an appropriate base to afford the phosphorane/phosphorus ylide (depending on how you draw the Lewis Structure).

The Wittig reaction is then reacted with an aldehyde or ketone to generate the C-C double bond and triphenylphosphine oxide. Given the highly stereoselective nature of this reaction, it is thought to proceed via a concerted [2+2] cycloaddition mechanism where a 4-membered oxaphosphetane intermediate is formed.

This reaction is used industrially to generate agrochemicals, nutritional supplements, prostaglandins,textiles and dyes, and flavour/fragrance compounds.[1] Here we detail the synthesis of ethyl cinnamate, which has a fruity, spicy smell.

We chose a solvent free procedure for its simplicity.[2] It uses a pre-prepared stabilized Wittig reagent and doesn’t require anhydrous conditions or caustic bases. Once the reaction is completed in 10-15 min, a 1D 1H NMR can be acquired for benzaldehyde, the Wittig reagent, the crude product and the precipitate formed over the course of the reaction. Additionally, 31P{1H} could be used on the Wittig reagent and precipitate formed during the reaction if desired.

Figure 2: Stacked 31P{1H} NMR plots of Wittig Regent and isolated precipitate.

In the 1D spectrum of the conjugated alkene, it appears as though only one vinyl resonance is resolved, the second one overlaps with the aromatic multiplet. These overlapping peaks can be resolved using 2D methods, such as COSY and/or the JRES experiment shown below. The COSY spectrum shows 2 isolated spin systems – the ethyl fragment and the vinyl groups. The JRES separates the chemical shift and the coupling constant, the main peaks exhibit a 3JH-H of 16 Hz, at both 6.25 ppm and 7.70 ppm.

Figure 4: JRES of isolated crude product from Wittig Reagent collected 17 min.

Zooming in on the JRES also clearly shows a smaller coupling constant of 12.6 Hz, suggesting that although selective for a trans, there is a small cis component formed over the course of the reaction.

Density Functional Theory (DFT) calculations[3] can used to correlate experimental trends to relative energy of the oxaphosphetane transition states that give rise to the cis– or trans- isomers. For the trans- product, 1,3-interactions dominate and the phenyl group of the benzaldehyde is in an equatorial position whereas thecis– product would be formed through axial substituent, 1,2-interaction. The relative energy difference can be used to predict a cis/trans ratio that correlates with experimental data.

For additional experimental details, explanations, figures and/or data please see the application note here,watch the Mestrelab Research hosted webinar, and don’t hesitate to contact us at sales@nanalysis.com for more information!

[1] Pommer, H.; Angew. Chem. Int. Ed. 1977; 16, 423
[2] Nguygen, K. C.; Weizman, H. J. Chem. Educ. 2007, 84, 119
[3] Such as these ones shown here, kindly performed by Prof. Len Mueller at the University of California, Riverside