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	Tuesday 07th February 2012 12:31

	Wittig Reaction: The Horner-Wadsworth-Emmons Modification The stereoselective formation of alkenes from aldehydes or ketones utilising phosphonates (phosphorous esters) is known as the Horner-Wadsworth-Emmons modification of the Wittig reaction. The reaction is named after Leopold Horner who published the work in 1958 with Wippel and Hoffman. William Wadsworth and William Emmons further elucidated the reaction in 1961. This is a modification of the Wittig reaction, and requires an understanding of the classic reaction to appreciate the benefits and nuances.
	1. General Scheme
	Scheme H1: The HWE modification of the Wittig reaction
	2. Mechanism The first step of the mechanism is the formation of the phosphonate carbanion (the analogue of the Wittig reaction's phosphorous ylide ), by the removal of a proton at the α-carbon by a base (setting up the resonance shown in Scheme H2. This carbanion is more nucleophilic than the corresponding ylide, and as a result react under milder conditions, and even to reagents that would not react under traditional Wittig conditions.
	Scheme H2: Formation of the phosphonate carbanion.
	The Nucleophilic addition to a ketone or aldehyde (reaction with an aldehyde is shown below for simplicity) can happen either syn- or anti- to give the two transition states shown below. If we recall from the Wittig reaction, that the formation of the syn-transition state is slower than that of the anti- due to steric hindrance between the R- groups (shown as R³ and R¹O in the syn-TS), we should expect that the product would give the (Z)-alkene as the major product. However this is not the case with the HWE modification. Here, the rate determining step is not the formation of the transition state, but in fact the formation of the phosphorous-oxygen bond between phosphonate and carbonyl. The formation of the trans-oxaphosphetane is faster than that of the cis-oxaphosphetane, and so the (E)-alkene product is the major product. The full mechanism for this is not fully understood, but it is given that in general the (E)-products are favoured, and can be further encouraged by increasing the size of the R-groups on the carbonyl. Likewise, reducing the R-group size on the carbonyl can reduce selectivity the (E)-product, to a mixed yield, and in the case of a strongly dissociating metallic base, can give strong (Z)- selectivity.
	Scheme H3: Reaction of the nucleophilic addition transition material to afford an alkene.
	3. Control / Isomerism
	As described above, this HWE modification generally gives the (E)-product (or a higher preference to the (E)-product) in mixed yields, when reacting with ketones. However the product outcome is largely substrate dependant. In order to increase the (E)-alkene product, use large R-groups on the carbonyl, and a weakly dissociating base. In order to increase the (Z)-alkene product, use small R-groups on the carbonyl, and a strongly dissociating base.
	4. Reaction Notes
	Preparation of the starting alkyl phosphonates is easier and cheaper than the formation of the phosphonium salts used in the classical Wittig reaction. Aldehydes react much faster than ketones. The phosphonate carbanion is more nucleophilic the corresponding ylide: reaction conditions are generally much milder than the classical Wittig reaction. It is possible to perform the HWE olefination on substrates that would not undergo the classical Wittig reaction (e.g. hindered ketones). Phosphonates are water soluble, and so removal from the product is far simpler in the work up. For base sensitive substrates, the use of a weak amine base and a metal salt can be used.
	5. Further Reading
	Horner, Hoffman and Wippel. Chem. Ber. 1958, 91, 61-63. Wadsworth and Emmons. J. Am. Chem. Soc 1961, 83, 1733-1738. Wadsworth and Emmons. J. Org Chem. 1965, 30, 680-685. Kürti and Czakó; Strategic Applications of Named Reactions in Organic Synthesis. 1st edn., 212-213. (Elsevier Academic Press, 2005)

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