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UK CHE 232 - Ethers, epoxides and sulfides

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Ethers, epoxides and sulfides An ether is the logical (and nearly terminal) conclusion of a series of water alkylations: OH H"alkylate"OR H"alkylate"OR R"alkylate"OR RRWater Alcohol Ether TrialkyloxoniumSalt (YECH!) Ethers come in a couple of flavors. There is the standard, dialkyl type: O OOOEther,Diethyl EtherEthyl ether(all 3 in common usage)Benzyl Methyl Ether Anisole (Phenyl Methyl Ether)Vinyl Methyl Ether And then there are the cyclic ethers – the names of these can be ugly, because they are often based on the molecule from which the ether was derived, rather than as an accurate description of the ether: O OOOOFuran Tetrahydrofuran (THF)Trimethylene Oxide (Oxetane)Ethylene OxideOxiraneEpoxidePropylene Oxide Uses of ethers: Unlike alcohols, ethers in general are unreactive. They are more commonly used as reaction solvents than as reactants – ethers thus make great protecting groups! The only real exceptions to this rule are the epoxides - the three-membered ring ethers. We will talk more about the reactivity of these compounds later. Preparation of Ethers: The most common preparation of simple ethers uses the Williamson Ether Synthesis. In short, this preparation utilizes a deprotonated alcohol and an alkyl halide: In General: R O-+ R' BrNa+ORR'+ NaBr An Example: HO OH2 NaHNaO ONa(+ 2 H2)2 CH3BrMeO OMe Notes and Restrictions: The alkoxide portion of the starting material is generally produced by the action of sodium hydride (NaH). This hydride is the reagent of choice because the only by-product ishydrogen gas (a very strong driving force!) Because the alkoxide is very basic, the alkyl halide should be primary - otherwise, deprotonation rather than nucleophilic attack is likely: ONaOONaBrBr+OH++SN2 @ 1° CE2 @ 3° C Destruction of Ethers: Now that you’ve gone through all the trouble of making an ether, we’re going to talk about how 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+"OHBr Because they can form stable carbocations, tertiary, allylic and benzylic ethers can be cleaved 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 are significantly 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 a peracid). This is really the only non-stereospecific epoxidation method currently in use:3-chloroperoxybenzoic acidOOOHClO For example: OOH OOCOOHMCPBAOOH OOCOOHOFrenolicin Ring-Opening of epoxides: This is where the real synthetic utility of epoxides comes into play. As we discussed earlier: 1) Epoxides can be ring-opened to trans (or anti) 1,2-diols 2) 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 how to 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 mechanism is relatively straightforward: RCOOOHor H2O2OH3O+O HH2OOHOHHOHOHH2O In this case, obviously, the nature of the epoxide is unimportant – the result is always the anti-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 one product results. With unsymmetrical epoxides, mixtures are typically produced, significantly lessening the synthetic utility of the reaction. B) Nucleophilic ring-opening of epoxides. Epoxides can also be opened by aqueous base: RCOOOHor H2O2OHOOOHOHOHOH H It is obvious from the mechanism that any strong nucleophile, not just hydroxide, will be able to ring-open an epoxide. As we saw in before, this leads to primary alcohols. But what if the epoxide is substituted? The really cool thing about the basic ring-opening of epoxides is that the nucleophile always attacks from the less-substituted side! We can thus set two stereocenters in the molecule in one simple step: OHMCPBAOHOMgBrOHOH Ring opening of epoxides by various nucleophiles is a very powerful tool in organic chemistry. You should be familiar with how this works!!! Here is another example: OHMCPBAOHOH2 / Pd-CaCO3Et3N / THFOHORS_HOHOHSR Sulfides Sulfides are the sulfur analog of ethers. They are, however, much more reactive than ethers - they can be oxidized quite easily under relatively mild conditions. The oxidized sulfides (the sulfoxides, sulfones and mysteriously, sulfates):SH3C CH3SH3C CH3S SH3C CH3O OOOOOCH3H3COSmelly 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......SH3C CH3OSH3C CH3OO The oxygen-sulfur bond is VERY polar – making any sort of nucleophilic attack on Sulfur quite easy. Recall the Swern


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UK CHE 232 - Ethers, epoxides and sulfides

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