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19.13 the Wittig Alkene Synthesis 933 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 933 19.13 THE WITTIG ALKENE SYNTHESIS 933 PROBLEMS 19.32 Draw the structures of all aldehydes or ketones that could in principle give the following product after application of either the Wolff–Kishner or Clemmensen reduction. H3C CH2CH(CH3)2 L L 19.33 Outline a synthesis of 1,4-dimethoxy-2-propylbenzene from hydroquinone (p-hydroxyphenol) and any other reagents. 19.13 THE WITTIG ALKENE SYNTHESIS Our tour through aldehyde and ketone chemistry started with simple additions; then addition followed by substitution (acetal formation); then additions followed by elimination (imine and enamine formation). Another addition–elimination reaction, called the Wittig alkene synthe- sis, is an important method for preparing alkenes from aldehydes and ketones. An example of the Wittig alkene synthesis is the preparation of methylenecyclohexane from cyclohexanone. 1 1 A | A | O CH_ 2 PPh3 CH2 Ph3P O _ (19.70) 1 + 3 anL ylid + L 1 3 triphenylphosphine cyclohexanone methylenecyclohexane oxide The Wittig synthesis is especially important because it gives alkenes in which the position of the double bond is unambiguous; in other words, the Wittig synthesis is completely regios- elective.Itcanbeusedforthepreparationofalkenesthatwouldbedifficulttoprepareby other reactions. For example, methylenecyclohexane, which is readily prepared by the Wittig synthesis (Eq. 19.70), cannot be prepared by dehydration of 1-methylcyclohexanol; 1- methylcyclohexene is obtained instead, because alcohol dehydration gives the alkene iso- mer(s) in which the double bond has the greatest number of alkyl substituents (Sec. 10.1). OH " H2SO4 " CH3 H2O CH3 L + 1-methylcyclohexene H2SO4 (19.71) A CH2 (little or none formed) methylenecyclohexane The nucleophile in the Wittig alkene synthesis is a type of ylid. An ylid (sometimes spelled ylide) is any compound with opposite charges on adjacent, covalently bound atoms, each of which has an electronic octet. 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 934 934 CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS each charged atom has a complete octet Ph _ Ph "P| CH2 L L 2 Ph" an ylid Because phosphorus, like sulfur (Sec. 10.9), can accommodate more than eight valence elec- trons, a phosphorus ylid has an uncharged resonance structure. phosphorus shares 10 electrons _ Ph3|P CH2 Ph3P A CH2 (19.72) L 2 Although the structures of phosphorus ylids are sometimes written with phosphorus– carbon double bonds, the charged structures, in which each atom has an octet of electrons, are very important contributors. The mechanism of the Wittig alkene synthesis, like the mechanisms of other carbonyl reactions, involves the reaction of a nucleophile at the carbonyl carbon. The nucleophile in the Wittig synthesis is the anionic carbon of the ylid. The anionic oxygen in the resulting species re- acts with phosphorus to form an oxaphosphetane intermediate. (An oxaphosphetane is a satu- rated four-membered ring containing both oxygen and phosphorus as ring atoms.) 1 1 C" O C" O _ $C A O H2C.. |PPh3 % L 1 3 % L 3 (19.73a) 1 3 L H2C " PPh3 H2C " PPh" 3 ) an ylid L L | an oxaphosphetane Under the usual reaction conditions, the oxaphosphetane spontaneously undergoes a b-elimi- nation to give the alkene and the by-product triphenylphosphine oxide. 1 1 C" O C O % % L 3 % S 3 (19.73b) H2C " PPh" 3 CH2 + PPh3 L oxaphosphetane the alkene triphenylphosphine product oxide The ylid starting material in the Wittig synthesis is prepared by the reaction of an alkyl halide with triphenylphosphine (Ph3P) in an SN2 reaction to give a phosphonium salt. 1 1 2 days | (19.74a) Ph3P H3C Br Ph3P CH3 Br _ 3 + L 1 3 benzene L 3 1 3 triphenylphosphine methyl bromide methyltriphenylphosphonium bromide (a phosphonium salt; 99% yield) The phosphonium salt can be converted into its conjugate base, the ylid, by reaction with a strong base such as an organolithium reagent. 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 935 19.13 THE WITTIG ALKENE SYNTHESIS 935 | | _ (19.74b) Ph3P CH2 Br_ Ph3P CH2 H CH2CH2CH2CH3 LiBr L anL ylid2 + L butane + "H Li CH2CH2CH2CH3 L butyllithium To plan the preparation of an alkene by the Wittig synthesis, consider the origin of each part of the product, and then reason deductively. Thus, one carbon of the alkene double bond orig- inates from the alkyl halide used to prepare the ylid; the other is the carbonyl carbon of the aldehyde or ketone: R1 R3 R1 R3 R3 R3 A A | _ | (19.75) $C C $ $C O Ph3P C $ Ph3P CH$ Br_ Ph3P Br CH$ + L 2 L 3 + L R)2 R) 4 R)2 R) 4 R) 4 R) 4 aldehyde or ylid base alkyl halide ketone + (Again, the arrows used in this retrosynthetic analysis are read “implies as starting material.”) This analysis also shows that, in principle, two Wittig syntheses are possible for any given alkene; in the other possibility, the R1 and R2 groups could originate from the alkyl halide and the R3 and R4 groups from the aldehyde or ketone. However, remember that the reaction used to form the phosphonium salt is an SN2 reaction; consequently, this reaction is fastest with methyl and primary alkyl halides. In other words, most Wittig syntheses are planned so that the most re- active alkyl halide can be used as one of the starting materials. One problem with the Wittig alkene synthesis is that it gives mixtures of E and Z isomers. Ph H Ph Ph Ph3P 1) Ph Li, ether PhCH Cl PhCH |PPh Cl CCA CCA (19.76) 2 2 3 _ 2) PhCHL A O $ $ $ $ L + H) Ph) HH) ) (62% yield) (20% yield) Although certain modifications of the Wittig synthesis that avoid this problem have been de- veloped, these are outside the scope of our discussion. Study Problem 19.6 Outline two Wittig alkene syntheses of 2-methyl-1-hexene. Is one synthesis preferred over the other? Why? Solution The analysis in Eq. 19.75 suggests that the “right-hand” part of the alkene can be de- rived from the ketone 2-hexanone: _ H2C A CCH2CH2CH2CH3 Ph3|P CH2 O A CCH2CH2CH2CH3 (19.77) L 2 + "CH3 "CH3 2-methyl-1-hexene 2-hexanone Ph3P CH3I 3 +methyl iodide Another possibility, however, is that the “left-hand” part of the alkene is derived from formalde- hyde: 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 936 936 CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS _ H2C A CCH2CH2CH2CH3 Ph3|P C CH2CH2CH2CH3 Ph3P Br CHCH2CH2CH2CH3 (19.78) L 2 L 3 + L "CH3 "CH3 "CH3 2-methyl-1-hexene H2C A O 2-bromohexane +formaldehyde Although both syntheses seem reasonable, the latter one (Eq. 19.78) would require an SN2 reac- tion of triphenylphosphine with a secondary alkyl halide, whereas the former one (Eq. 19.77) would require an SN2 reaction of triphenylphosphine with a methyl halide. The first reaction is preferred because methyl halides are much more reactive than secondary alkyl halides (Sec. 9.4C). Discovery of the Wittig Alkene Synthesis The Wittig alkene synthesis is named for Georg Wittig (1897–1987), who was Professor of Chemistry at the University of Heidelberg. Wittig and his co-workers discovered the alkene synthesis in the course of other work in phosphorus chemistry; they had not set out to develop this reaction explic- itly. Once the significance of the reaction was recognized, it was widely exploited.Wittig shared the 1979 Nobel Prize in Chemistry with H. C. Brown (Sec. 19.8). The Wittig reaction is not only important as a laboratory reaction; it has also been industrially useful. For example, it is an important reaction in the industrial synthesis of vitamin A derivatives. PROBLEMS 19.34 Give the structure of the alkene(s) formed in each of the following reactions. Ph3P butyllithium acetone (a) CH3CH2I Ph3P butyllithium benzaldehyde (b) CH3Br 19.35 Outline a Wittig synthesis for each of the following alkenes; give two Wittig syntheses of the compound in part (a). (a) (b) CH3 CH3O CHA CH L L L H2CA" CCH2CH3 (mixture of cis and trans) (c) CH3CH A N 19.14 OXIDATION OF ALDEHYDES TO CARBOXYLIC ACIDS Aldehydes can be oxidized to carboxylic acids. KMnO /NaOH H O CH CH CH CH CH CHA O 4 3 | CH CH CH CH CH CO H (19.79) 3 2 2 2 H O 3 2 2 2 2 L 2 L "C2H5 "C2H5 2-ethylhexanal 2-ethylhexanoic acid (78% yield).
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