Chapter 18: Ethers (EPOXIDES!) and SulfidesAn ether is the logical (and nearly terminal) conclusion of a series of water alkylations.Yes, that is a complicated sentence, and it does not make much sense. But it is the only way I canthink of (in my current, caffeine-deprived state) to describe this picture:OHH"alkylate"ORH"alkylate"ORR"alkylate"ORRRWater Alcohol Ether TrialkyloxoniumSalt (YECH!)Ethers come in a couple of flavors. There is the standard, dialkyl type:OOOOEther,Diethyl EtherEthyl ether(all 3 in common usage)Benzyl Methyl Ether Anisole (Phenyl Methyl Ether)Vinyl Methyl EtherAnd then there are the cyclic ethers – the names of these can be ugly, because they are often basedon the molecule from which the ether was derived, rather than as an accurate description of theether:OOOOOFuran Tetrahydrofuran (THF)Trimethylene Oxide (Oxetane)Ethylene OxideOxiraneEpoxidePropylene OxideUses of ethers:Unlike alcohols, ethers in general are unreactive. They are more commonly used asreaction solvents than as reactants – ethers thus make great protecting groups! The only realexceptions to this rule are the epoxides - the three-membered ring ethers. We will talk more aboutthe reactivity of these compounds later.Preparation of Ethers:The most common preparation of simple ethers uses the Williamson Ether Synthesis. Inshort, this preparation utilizes a deprotonated alcohol and an alkyl halide:In General:RO-+ R’BrNa+ORR’+ NaBrAn Example:HO OH2 NaHNaO ONa(+ 2 H2)2 CH3BrMeO OMeNotes and Restrictions:The alkoxide portion of the starting material is generally produced by the action of sodiumhydride (NaH). This hydride is the reagent of choice because the only by-product is hydrogen gas(a very strong driving force!) Because the alkoxide is very basic, the alkyl halide should beprimary - otherwise, deprotonation rather than nucleophilic attack is likely:ONaOONaBrBr+OH++SN2 @ 1° CE2 @ 3° CDestruction of Ethers:Now that you’ve gone through all the trouble of making an ether, we’re going to talk abouthow you tear them back apart. Ethers are generally cleaved by strong acids at high temperatures(i.e. at LEAST 2M acid at 100+°C). HBr and HI are the reagents of choice:OHBr (2M)H2O / 110°CHOBrOHBr (2M)H2O / 110°COH+CH3Br"H+"OHBrBecause they can form stable carbocations, tertiary, allylic and benzylic ethers can becleaved under much milder conditions, and form an alkene in place of the alkyl halide.Epoxides: (O)Because of the strain induced by the presence of a three-membered ring, epoxides aresignificantly more reactive than other ethers. Thus, they become useful in organic synthesis.Preparation:Epoxides are easily prepared from alkenes, by oxidation with a peroxyacid (often called aperacid). This is really the only non-stereospecific epoxidation method currently in use:3-chloroperoxybenzoic acidOOOHClOFor example:OOH OOCOOHMCPBAOOH OOCOOHOFrenolicinRing-Opening of epoxides:This is where the real synthetic utility of epoxides comes into play. As we discussed inChapter 17:1) Epoxides can be ring-opened to trans (or anti) 1,2-diols2) Metallated Species (RM) can be added to epoxides, to form primary alcohols.Here we will discuss a little more about the mechanism of these reactions, as well as howto predict where incoming nucleophiles will add.A) Acid-catalyzed ring-opening of epoxides.With simple, aqueous acids, epoxides ring-open to give the anti 1,2-diol. The mechanismis relatively straightforward:RCOOOHor H2O2OH3O+OHH2OOHOHHOHOHH2OIn this case, obviously, the nature of the epoxide is unimportant – the result is always theanti-diol.Epoxides can also be opened with anhydrous acids. The result in this case is a halohydrin(i.e. if you use anhydrous HCl, you get a chlorohydrin). With symmetrical epoxides, only oneproduct results. With unsymmetrical epoxides, mixtures are typically produced, significantlylessening the synthetic utility of the reaction.B) Nucleophilic ring-opening of epoxides.Epoxides can also be opened by aqueous base:RCOOOHor H2O2OHOOOHOHOHOHHIt is obvious from the mechanism that any strong nucleophile, not just hydroxide, will beable to ring-open an epoxide. As we saw in chapter 17, this leads to primary alcohols. But what ifthe epoxide is substituted? The really cool thing about the basic ring-opening of epoxides is thatthe nucleophile always attacks from the less-substituted side! We can thus set two stereocenters inthe molecule in one simple step:OHMCPBAOHOMgBrOHOHRing opening of epoxides by various nucleophiles is a very powerful tool in organicchemistry. You should be familiar with how this works!!! Here is another example:OHMCPBAOHOH2 / Pd-CaCO3Et3N / THFOHORS_HOHOHSRSulfidesSulfides are the sulfur analog of ethers. They are, however, much more reactive thanethers - they can be oxidized quite easily under relatively mild conditions. The oxidized sulfides(the sulfoxides, sulfones and mysteriously, sulfates):SH3CCH3SH3CCH3SSH3CCH3OOOOOOCH3H3COSmelly by-productof the Swern reaction[Ox]Dimethyl Sulfoxide (DMSO):Common Solvent,Also used for Drug Delivery - penetrates skin EASILY!Dimethyl SulfoneSulfide SulfoneSulfoxide Sulfate[Ox][Ox]?Dimethyl Sulfoxide:Highly Toxic & PowerfulAlkylating agent. Can it bemade by oxidizing thesulfone? Hmmmmm......SH3CCH3OSH3CCH3OOThe oxygen-sulfur bond is VERY polar – making any sort of nucleophilic attack on Sulfurquite easy. Recall the Swern reaction...(Lecture notes for Ch.