13.9 Reactions of Alcohols: Substitution and Elimination 591 MEDICALLYSPEAKING Phenols as Antifungal Agents >ÞÊ« iÃÊ>`ÊÌ iÀÊ`iÀÛ>ÌÛiÃÊiÝ LÌÊÌ«V>Ê>ÌvÕ}>Ê«À« / iÃiÊV«Õ`Ã]Ê>ÃÊÜiÊ>ÃÊ>ÞÊÌ iÀÃ]Ê>ÀiÊÕÃi`ÊÊ iÀÌiðÊ/ iÃiÊ>}iÌÃÊ>ÀiÊLiiÛi`ÊÌÊÌiÀviÀiÊÜÌ ÊÌ iÊViÊi Ì iÊÌÀi>ÌiÌÊvÊ>Ì iÌi½ÃÊvÌ]ÊVÊÌV ]Ê >`ÊÀ}ÜÀ°Ê LÀ>iÊvÕVÌÊvÊvÕ}°Ê/ iÊvÜ}Ê>ÀiÊÕÃÌÊ>ÊviÜÊiÝ>«ið />vÌ>ÌiÊ ÃÊ Ì iÊ >VÌÛiÊ }Ài`iÌÊ Ê />VÌ/]Ê "`ÀÊ >ÌiÀÃ/]Ê>`Ê iÃiiÝ/° OH O Cl Cl I S N O Cl I N Alcohols and Phenols Cl Cl OH para-Chloro- Haloprogin Clioquinol Tolnaftate meta-xylenol Klein, D. (2012). Alcohols and Phenols. En Organic Chemistry (pp. 591- 600). USA: Wiley. 13.9 Reactions of Alcohols: Substitution and Elimination SN1 Reactions with Alcohols !SSEENIN3ECTION TERTIARYALCOHOLSWILLUNDERGOASUBSTITUTIONREACTIONWHENTREATEDWITH a hydrogen halide. OH HX X ± H2O 7ESAWTHATTHISREACTIONPROCEEDSVIAAN3N1 mechanism. Proton transfer Loss of a leaving group Nucleophilic attack H + – – + OH H Br O H2O Br Br H Recall that an SN1 mechanism has two core steps (loss of leaving group and nucleophilic attack). 7HENTHESTARTINGMATERIALISANALCOHOL WESAWTHATANADDITIONALSTEPISREQUIREDINORDERTO PROTONATETHEHYDROXYLGROUPlRST4HISREACTIONPROCEEDSVIAACARBOCATIONINTERMEDIATEANDIS therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SNATANAPPRECIABLERATE7HENDEALINGWITHAPRIMARY alcohol, an SNPATHWAYISREQUIREDINORDERTOCONVERTANALCOHOLINTOANALKYLHALIDE SN2 Reactions with Alcohols Primary and secondary alcohols will undergo substitution reactions with a variety of reagents, all of which proceed via an SNPROCESS)NTHISSECTION WEWILLEXPLORETHREESUCHREACTIONSTHAT all employ an SNPROCESS Espacio de Formación Multimodal klein_c13_564-621hr.indd 591 11/8/10 2:11 PM 596 CHAPTER 13 Alcohols and Phenols 13.10 Reactions of Alcohols: Oxidation 597 E1 and E2 Reactions with Alcohols 13.10 Reactions of Alcohols: Oxidation 2ECALLFROM3ECTIONTHATALCOHOLSUNDERGOELIMINATIONREACTIONSINACIDICCONDITIONS )N3ECTION WESAWTHATALCOHOLSCANBEFORMEDVIAAREDUCTIONPROCESS)NTHISSECTION WE will explore the reverse process, called oxidation, which involves an increase in oxidation state. H2SO4 OH ± H O heat 2 Oxidation OH O This transformation follows an E1 mechanism: H Reduction The outcome of an oxidation process depends on whether the starting alcohol is primary, Proton transfer Loss of LG Proton transfer SECONDARY ORTERTIARY,ETSlRSTCONSIDERTHEOXIDATIONOFAPRIMARYALCOHOL O OH O O HOS HO H O [O] [O] –H O O + 2 H H H OH O + H R R H R OH H H Primary alcohol Aldehyde Carboxylic acid Recall that the two core steps of an E1 mechanism are loss of a leaving group followed by a Notice that a primary alcohol has two protons at the A position (the carbon atom bearing the PROTONTRANSFER(OWEVER WHENTHESTARTINGMATERIALISANALCOHOL ANADDITIONALSTEPISlRST HYDROXYLGROUP !SARESULT PRIMARYALCOHOLSCANBEOXIDIZEDTWICE4HElRSTOXIDATIONPRO- required in order to protonate the hydroxyl group. This reaction proceeds via a carbocation duces an aldehyde, and then oxidation of the aldehyde produces a carboxylic acid. intermediate and is therefore best for tertiary alcohols. Also recall that elimination generally Secondary alcohols only have one proton at the A position so they can only be oxidized favors the more substituted alkene. once, forming a ketone. OH O OH [O] H SO 2 4 ± ¡ heat R R R R H Major Minor Secondary alcohol Ketone LOOKING AHEAD Generally speaking, the ketone is not further oxidized. Tertiary alcohols do not have any pro- 4HISTRANSFORMATIONCANALSOBEACCOMPLISHEDVIAAN%PATHWAYIFTHEHYDROXYLGROUPISlRST ÀÊ>ÊiÝVi«ÌÊÌÊÌ ÃÊ tons at the A position, and as a result, they generally do not undergo oxidation: converted into a better leaving group, such as a tosylate. A strong base can then be employed to }iiÀ>ÊÀÕi]ÊÃiiÊ-iVÌÊ ACCOMPLISHAN%REACTION Óä°££]ÊÜ iÀiÊÜiÊÜÊi>ÀÊ OH >LÕÌÊ>ÊëiV>ÊÝ`â}Ê [O] no reaction Ài>}iÌÊÌ >ÌÊV>ÊÝ`âiÊ>Ê R R iÌiÊÌÊvÀÊ>ÊiÃÌiÀ° R TsCl NaOEt OH py OTs E2 A large number of reagents are available for oxidizing primary and secondary alcohols. The most common oxidizing reagent is chromic acid (H#R/), which can be formed either from CHROMIUMTRIOXIDE#R/) or from sodium dichromate (Na#RO7) in aqueous acidic solution. O 4HE % PROCESS ALSO GENERALLY PRODUCES THE MORE SUBSTITUTED ALKENE AND NO CARBOCATION ± H3O REARRANGEMENTSAREOBSERVEDIN%PROCESSES Cr O O Acetone Chromium trioxide O HO Cr OH CONCEPTUAL CHECKPOINT O O O + – – + 13.21 *Ài`VÌÊÌ iÊ«À`ÕVÌÃÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ìð H2SO4 Na O Cr O Cr O Na Chromic acid H2O OH O O H SO 2 4 1) TsCl, py heat OH Sodium dichromate ­>®Ê Ê ­L®Ê 2) NaOEt ? ? 4HEMECHANISMOFOXIDATIONWITHCHROMICACIDHASTWOMAINSTEPS-ECHANISM 4HE lRSTSTEPINVOLVESFORMATIONOFACHROMATEESTER ANDTHESECONDSTEPISAN%PROCESSTOFORMA carbon-oxygen P bond (rather than a carbon-carbon P bond). klein_c13_564-621hr.indd 596 11/8/10 2:11 PM klein_c13_564-621hr.indd 597 11/8/10 2:11 PM 13.9 Reactions of Alcohols: Substitution and Elimination 591 592 CHAPTER 13 Alcohols and Phenols 1. Primary alcohols will react with HBr via an S PROCESS MEDICALLYSPEAKING N Phenols as Antifungal Agents Nucleophilic attack ± Proton transfer loss of a leaving group >ÞÊ« iÃÊ>`ÊÌ iÀÊ`iÀÛ>ÌÛiÃÊiÝ LÌÊÌ«V>Ê>ÌvÕ}>Ê«À« / iÃiÊV«Õ`Ã]Ê>ÃÊÜiÊ>ÃÊ>ÞÊÌ iÀÃ]Ê>ÀiÊÕÃi`ÊÊ H iÀÌiðÊ/ iÃiÊ>}iÌÃÊ>ÀiÊLiiÛi`ÊÌÊÌiÀviÀiÊÜÌ ÊÌ iÊViÊi Ì iÊÌÀi>ÌiÌÊvÊ>Ì iÌi½ÃÊvÌ]ÊVÊÌV ]Ê >`ÊÀ}ÜÀ°Ê + – / OH H Br O Br Br LÀ>iÊvÕVÌÊvÊvÕ}°Ê/ iÊvÜ}Ê>ÀiÊÕÃÌÊ>ÊviÜÊiÝ>«ið />vÌ>ÌiÊ ÃÊ Ì iÊ >VÌÛiÊ }Ài`iÌÊ Ê />VÌ ]Ê H ± H O S 2 2 "`ÀÊ >ÌiÀÃ/]Ê>`Ê iÃiiÝ/° N OH O Cl 4HEHYDROXYLGROUPISlRSTPROTONATED CONVERTINGITINTOANEXCELLENTLEAVINGGROUP FOLLOWED by an S PROCESS4HISREACTIONWORKSWELLFOR("RBUTDOESNOTWORKWELLFOR(#L4O Cl I S N N REPLACETHEHYDROXYLGROUPWITHCHLORIDE :N#L is used as a catalyst. O Cl I N OH HCl Cl ZnCl Cl Cl OH 2 para-Chloro- Haloprogin Clioquinol Tolnaftate The catalyst is a Lewis acid that converts the hydroxyl group into a better leaving group. meta-xylenol Nuc attack Nuc attack ± on a Lewis acid – loss of LG ZnCl2 + – OH ZnCl2 O Cl Cl H SN2 2. !SSEENIN3ECTION ANALCOHOLCANBECONVERTEDINTOATOSYLATE FOLLOWEDBYNUCLEOPHILIC 13.9 Reactions of Alcohols: Substitution and Elimination attack. SN1 Reactions with Alcohols OH OTs – X !SSEENIN3ECTION TERTIARYALCOHOLSWILLUNDERGOASUBSTITUTIONREACTIONWHENTREATEDWITH TsCl X py a hydrogen halide. SN2 Bad Good OH HX X leaving group py= leaving group ± H2O N 7ESAWTHATTHISREACTIONPROCEEDSVIAAN3N1 mechanism. pyridine 5SINGTOSYLCHLORIDEANDPYRIDINE THEHYDROXYLGROUPISCONVERTEDINTOATOSYLATEGROUPAN Proton transfer Loss of a leaving group Nucleophilic attack excellent leaving group), which is susceptible to an SNPROCESS.OTICETHESTEREOCHEMICAL H OUTCOMEOFTHEPREVIOUSREACTION4HECONlGURATIONOFTHECHIRALITYCENTERISNOTINVERTED + – – + OH H Br O H2O Br Br during formation of the tosylate, but it is inverted during the SNPROCESS4HENETRESULTIS H INVERSIONOFCONlGURATION Recall that an S 1 mechanism has two core steps (loss of leaving group and nucleophilic attack). OH Br N 1) TsCl, py 7HENTHESTARTINGMATERIALISANALCOHOL WESAWTHATANADDITIONALSTEPISREQUIREDINORDERTO 2) NaBr PROTONATETHEHYDROXYLGROUPlRST4HISREACTIONPROCEEDSVIAACARBOCATIONINTERMEDIATEANDIS R S therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SNATANAPPRECIABLERATE7HENDEALINGWITHAPRIMARY 3. 0RIMARYANDSECONDARYALCOHOLSREACTWITH3/#L or PBr via an SNPROCESS alcohol, an SNPATHWAYISREQUIREDINORDERTOCONVERTANALCOHOLINTOANALKYLHALIDE SOCl2 Cl py SN2 Reactions with Alcohols Primary and secondary alcohols will undergo substitution reactions with a variety of reagents, OH all of which proceed via an SNPROCESS)NTHISSECTION WEWILLEXPLORETHREESUCHREACTIONSTHAT all employ an SNPROCESS PBr3 Br klein_c13_564-621hr.indd 591 11/8/10 2:11 PM klein_c13_564-621hr.indd 592 11/8/10 2:11 PM 596 CHAPTER 13 Alcohols and Phenols 13.10 Reactions of Alcohols: Oxidation 597 598 CHAPTER 13 Alcohols and Phenols E1 and E2 Reactions with Alcohols 13.10 Reactions of Alcohols: Oxidation MECHANISM 13.8 OXIDATION OF AN ALCOHOL WITH CHROMIC ACID 2ECALLFROM3ECTIONTHATALCOHOLSUNDERGOELIMINATIONREACTIONSINACIDICCONDITIONS )N3ECTION WESAWTHATALCOHOLSCANBEFORMEDVIAAREDUCTIONPROCESS)NTHISSECTION WE STEP 1 will explore the reverse process, called oxidation, which involves an increase in oxidation state. O Fast and O H2SO4 R R OH ± H O reversible heat 2 Oxidation OH ± HO Cr OH O Cr OH ± H O OH O H H 2 R O R O This transformation follows an E1 mechanism: Chromate ester H Reduction STEP 2 The outcome of an oxidation process depends on whether the starting alcohol is primary, R O O R Proton transfer Loss of LG Proton transfer – SECONDARY ORTERTIARY,ETSlRSTCONSIDERTHEOXIDATIONOFAPRIMARYALCOHOL HH ± ± ± O Cr OH O H3O HCrO3 O H E2 OH O O R O R HOS HO H O [O] [O] –H O O + 2 H H H Chromate ester OH O + H R R H R OH H H Primary alcohol Aldehyde Carboxylic acid Recall that the two core steps of an E1 mechanism are loss of a leaving group followed by a Notice that a primary alcohol has two protons at the A position (the carbon atom bearing the PROTONTRANSFER(OWEVER WHENTHESTARTINGMATERIALISANALCOHOL ANADDITIONALSTEPISlRST HYDROXYLGROUP !SARESULT PRIMARYALCOHOLSCANBEOXIDIZEDTWICE4HElRSTOXIDATIONPRO- required in order to protonate the hydroxyl group. This reaction proceeds via a carbocation duces an aldehyde, and then oxidation of the aldehyde produces a carboxylic acid. intermediate and is therefore best for tertiary alcohols. Also recall that elimination generally Secondary alcohols only have one proton at the A position so they can only be oxidized