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Spring 2012 Dr. Halligan CHM 236 Chapter 10 • Reactions of Alcohols, Ethers, Epoxides, Amines, and Sulfur-Containing Compounds © 2011 Pearson Education, Inc. Ch. 10 Overview • • • • • Conversion of Alcohols to Alkyl Halides and Sulfonate Esters Substitution reactions of activated alcohols (ROH with better LG’s) Dehydration of alcohols via Elimination Reactions Oxidation of Alcohols Nucleophilic Substitution Reactions of Ethers • Nucleophilic Substitution Reactions of Epoxides • Amines Do Not Undergo Substitution or Elimination Reactions • Quaternary Ammonium Hydroxiudes Undergo Elimination Reactions • Phase-Transfer Catalysts • Thiols, Sulfides, and Sulfonium Salts 2 © 2011 Pearson Education, Inc. Substitution Reactions of Alcohols • The OH group of an alcohol is a terrible LG. Why? • We must convert the OH group to a better LG before doing a substitution reaction. • In this chapter, we will use HCl, HBr, HI, ZnCl2, PBr2, SOCl2, and R’SO2Cl/py to convert OH to a better LG. OH + Br Br + OH strong base (you need a weak/stable base) 3 © 2011 Pearson Education, Inc. Alcohols and ethers have to be activated before they can undergo a substitution or an elimination reaction: Convert the strongly basic leaving group (OH–) into the good leaving group, H2O (a weaker base): Only weakly basic nucleophiles can be used © 2011 Pearson Education, Inc. 4 Primary, secondary, and tertiary alcohols all undergo nucleophilic substitution reactions with HI, HBr, and HCl: 5 © 2011 Pearson Education, Inc. Secondary and tertiary alcohols undergo SN1 reactions with hydrogen halides: 6 © 2011 Pearson Education, Inc. Primary alcohols undergo SN2 reactions with hydrogen halides: Reaction carried out in 48% aqueous HBr. Recall that Br– is an excellent nucleophile in water. 7 © 2011 Pearson Education, Inc. ZnCl2 can be used to catalyze certain SN2 reactions: ZnCl2 functions as a Lewis acid that complexes strongly with the lone-pair electrons on oxygen: 8 © 2011 Pearson Education, Inc. The Lucas Reagent Anhydrous ZnCl2 in conc HCl Distinguishes primary, secondary, and tertiary lowmolecular-weight alcohols The Lucas reaction: ZnCl2 ROH + HCl RCl Positive test: Solution becomes cloudy Test results and mechanisms at room temperature: • Primary: No reaction SN2 • Secondary: Reaction in ~5 minutes SN2 and SN1 • Tertiary, allylic, and benzylic: Reaction immediate SN1 9 © 2011 Pearson Education, Inc. Look out for rearrangement product in the SN1 reaction of the secondary or tertiary alcohol: 10 © 2011 Pearson Education, Inc. Other Methods for Converting Alcohols into Alkyl Halides Utilization of phosphorus tribromide: Other phosphorus reagents can be used: PBr3, phosphorus tribromide PCl3, phosphorus trichloride PCl5, phosphorus pentachloride POCl3, phosphorus oxychloride © 2011 Pearson Education, Inc. 11 Activation by SOCl2 Pyridine is generally used as a solvent and also acts as a base: 12 © 2011 Pearson Education, Inc. The Artificial Sweetener Splenda (Sucralose) Could Splenda be a cellular alkylating agent? No, it is too polar to enter a cell. 13 © 2011 Pearson Education, Inc. 14 © 2011 Pearson Education, Inc. Summary: Converting of Alcohols to Alkyl Halides Recommended procedures: 15 © 2011 Pearson Education, Inc. Converting Alcohols into Sulfonate Esters 16 © 2011 Pearson Education, Inc. Several sulfonyl chlorides are available to activate OH groups: 17 © 2011 Pearson Education, Inc. Dehydration of Secondary and Tertiary Alcohols by an E1 Pathway To prevent the rehydration of the alkene product, one needs to remove the product as it is formed 18 © 2011 Pearson Education, Inc. The major product is the most stable alkene product: The most stable alkene product has the most stable transition state 19 © 2011 Pearson Education, Inc. The rate of dehydration reflects the ease with which the carbocation is formed: 20 © 2011 Pearson Education, Inc. Look out for carbocation rearrangement: 21 © 2011 Pearson Education, Inc. Complex Alcohol Rearrangements in Strong Acid 22 © 2011 Pearson Education, Inc. Pinicol Rearrangement Protonate alcohol: Eliminate water: Rearrange carbocation: Deprotonate: H3 C CH3 H 3C Resonance-stabilized oxocarbocation CH3 O 23 © 2011 Pearson Education, Inc. Ring Expansion and Contraction Show the mechanism for this reaction: •Protonate the alcohol. •Eliminate water. •Rearrange carbocation to afford the more stable cyclohexane ring. •Deprotonate. 24 © 2011 Pearson Education, Inc. Primary Alcohols Undergo Dehydration by an E2 Pathway 25 © 2011 Pearson Education, Inc. The Stereochemical Outcome of the E1 Dehydration Alcohols and ethers undergo SN1/E1 reactions unless they would have to form a primary carbocation 26 © 2011 Pearson Education, Inc. A Milder Way to Dehydrate an Alcohol 27 © 2011 Pearson Education, Inc. Oxidation by Chromium (VI) 28 © 2011 Pearson Education, Inc. Oxidation of Alcohols Oxidation by chromic acid: Secondary alcohols are oxidized to ketones 29 © 2011 Pearson Education, Inc. Primary alcohols are oxidized to aldehydes and eventually carboxylic acids: Mechanism: 30 © 2011 Pearson Education, Inc. The oxidation of aldehydes to acids requires the presence of water: In the absence of water, the oxidation stops at the aldehyde: PCC, a methylene chloride–soluble reagent: No water present 31 © 2011 Pearson Education, Inc. A tertiary alcohol cannot be oxidized and is converted to a stable chromate ester instead: O O Cr O O No hydrogen on this carbon Di-tert-Butyl Chromate 32 © 2011 Pearson Education, Inc. Amines do not undergo substitution reactions because NH2– is a very strong base (a very poor leaving group): Protonation of the amine moiety does not solve the problem: 33 © 2011 Pearson Education, Inc. Nucleophilic Substitution Reactions of Ethers Ethers, like alcohols, can be activated by protonation: 34 © 2011 Pearson Education, Inc. Ether cleavage: an SN1 reaction: Ether cleavage: an SN2 reaction: 35 © 2011 Pearson Education, Inc. Reagents such as SOCl2 and PCl3 can activate alcohols but not ethers Ethers are frequently used as solvents because only they react with hydrogen halides 36 © 2011 Pearson Education, Inc. Nucleophilic Substitution Reactions of Epoxides Recall Section 4.9 37 © 2011 Pearson Education, Inc. Epoxides are more reactive than ethers in nucleophilic substitution reactions because of ring strain: 38 © 2011 Pearson Education, Inc. Acid-Catalyzed Epoxide Ring Opening HBr: Aqueous acid: 39 © 2011 Pearson Education, Inc. Acidic methanol: Stereospecificity of epoxide ring opening: Reason: Back-side attack of water on protonated epoxide: A trans diol 40 © 2011 Pearson Education, Inc. Reaction of an epoxide in the presence of methanol and acid Regioselectivity: Mechanism: 41 © 2011 Pearson Education, Inc. When a nucleophile attacks an unprotonated epoxide, the reaction is a pure SN2 reaction: Therefore: 42 © 2011 Pearson Education, Inc. Epoxides Are Synthetically Useful Reagents Enantiomers 43 © 2011 Pearson Education, Inc. Epoxy resins are the strongest adhesives known: Amine nucleophile mediated epoxide ring opening: 44 © 2011 Pearson Education, Inc. Arene Oxides 45 © 2011 Pearson Education, Inc. Arene oxide fate: Enantiomers 46 © 2011 Pearson Education, Inc. Mechanism for arene oxide rearrangement: 47 © 2011 Pearson Education, Inc. Arene oxides as a carcinogen: DNA backbone 48 © 2011 Pearson Education, Inc. BENZO[a]PYRENE EPOXIDATION Not all smokers get cancer Benzopyrenes in chimneys were responsible for cancer of the scrotum in “chimneyboys.” The connection between cancer and chimney soot was made by Percivall Pott in 1775. 49 © 2011 Pearson Education, Inc. Reactions of 4° Ammonium Hydroxides • A fully alkylated amino group (quaternary), makes a good enough LG for the “E2” Hofmann Elimination Reaction. • If the 4° amino group was protonated, the E2 base, would just deprotonate the 4° amino group and there would be no E2 reaction. 50 © 2011 Pearson Education, Inc. Hofmann Elimination Favors anti-Zaitsev Products • Do you remember the 3 exceptions for E2 reactions in terms of predicting the major products? • Usually, the more substituted alkene is the major product except if there is a big bulky base, possibility of conjugation or a Fluorine LG. • Here, the quaternary ammonium salt is a relatively slow LG just like Fluorine. As the E2 base comes in to abstract the proton, a negative charge starts to build up on the B-carbon. Remember that carbanion stability is the opposite of carbocation stability. © 2011 Pearson Education, Inc. 51 Crown Ethers The ability of a host to bond only certain guests is an example of molecular recognition 52 © 2011 Pearson Education, Inc. Thiols are sulfur analogs of alcohols: Thiols form strong complexes with heavy metal cations Thiols are stronger acids (pKa = 10) than alcohols Thiols are not good at hydrogen bonding 53 © 2011 Pearson Education, Inc. In protic solvent, thiolate ions are better nucleophiles than alkoxide ions: Sulfur is an excellent nucleophile because its electron cloud is polarized 54 © 2011 Pearson Education, Inc.