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 !S SEEN IN 3ECTION TERTIARY ALCOHOLS WILL UNDERGO A SUBSTITUTION REACTION WHEN TREATED WITH a hydrogen halide.
OH HX X ± H2O
7E SAW THAT THIS REACTION PROCEEDS VIA AN 3N1 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). 7HEN THE STARTING MATERIAL IS AN ALCOHOL WE SAW THAT AN ADDITIONAL STEP IS REQUIRED IN ORDER TO PROTONATE THE HYDROXYL GROUP lRST 4HIS REACTION PROCEEDS VIA A CARBOCATION INTERMEDIATE AND IS therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SN AT AN APPRECIABLE RATE 7HEN DEALING WITH A PRIMARY alcohol, an SN PATHWAY IS REQUIRED IN ORDER TO CONVERT AN ALCOHOL INTO AN ALKYL HALIDE
SN2 Reactions with Alcohols Primary and secondary alcohols will undergo substitution reactions with a variety of reagents, all of which proceed via an SN PROCESS )N THIS SECTION WE WILL EXPLORE THREE SUCH REACTIONS THAT all employ an SN PROCESS
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 2ECALL FROM 3ECTION THAT ALCOHOLS UNDERGO ELIMINATION REACTIONS IN ACIDIC CONDITIONS )N 3ECTION WE SAW THAT ALCOHOLS CAN BE FORMED VIA A REDUCTION PROCESS )N THIS SECTION 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 OR TERTIARY ,ETS lRST CONSIDER THE OXIDATION OF A PRIMARY ALCOHOL 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 PROTON TRANSFER (OWEVER WHEN THE STARTING MATERIAL IS AN ALCOHOL AN ADDITIONAL STEP IS lRST HYDROXYL GROUP !S A RESULT PRIMARY ALCOHOLS CAN BE OXIDIZED TWICE 4HE lRST OXIDATION PRO- 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- 4HIS TRANSFORMATION CAN ALSO BE ACCOMPLISHED VIA AN % PATHWAY IF THE HYDROXYL GROUP IS lRST 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 ACCOMPLISH AN % 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 CHROMIUM TRIOXIDE #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 REARRANGEMENTS ARE OBSERVED IN % 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 ? ? 4HE MECHANISM OF OXIDATION WITH CHROMIC ACID HAS TWO MAIN STEPS -ECHANISM 4HE lRST STEP INVOLVES FORMATION OF A CHROMATE ESTER AND THE SECOND STEP IS AN % PROCESS TO FORM A 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
MEDICALLYSPEAKING 1. Primary alcohols will react with HBr via an SN PROCESS
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 4HE HYDROXYL GROUP IS lRST PROTONATED CONVERTING IT INTO AN EXCELLENT LEAVING GROUP FOLLOWED by an S PROCESS 4HIS REACTION WORKS WELL FOR ("R BUT DOES NOT WORK WELL FOR (#L 4O Cl I S N N REPLACE THE HYDROXYL GROUP WITH CHLORIDE :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. !S SEEN IN 3ECTION AN ALCOHOL CAN BE CONVERTED INTO A TOSYLATE FOLLOWED BY NUCLEOPHILIC 13.9 Reactions of Alcohols: Substitution and Elimination attack.
SN1 Reactions with Alcohols OH OTs – X !S SEEN IN 3ECTION TERTIARY ALCOHOLS WILL UNDERGO A SUBSTITUTION REACTION WHEN TREATED WITH TsCl X py a hydrogen halide. SN2 Bad Good OH HX X leaving group py= leaving group ± H2O N
7E SAW THAT THIS REACTION PROCEEDS VIA AN 3N1 mechanism. pyridine
5SING TOSYL CHLORIDE AND PYRIDINE THE HYDROXYL GROUP IS CONVERTED INTO A TOSYLATE GROUP AN Proton transfer Loss of a leaving group Nucleophilic attack excellent leaving group), which is susceptible to an SN PROCESS .OTICE THE STEREOCHEMICAL H OUTCOME OF THE PREVIOUS REACTION 4HE CONlGURATION OF THE CHIRALITY CENTER IS NOT INVERTED + – – + OH H Br O H2O Br Br during formation of the tosylate, but it is inverted during the SN PROCESS 4HE NET RESULT IS H INVERSION OF CONlGURATION
Recall that an S 1 mechanism has two core steps (loss of leaving group and nucleophilic attack). OH Br N 1) TsCl, py 7HEN THE STARTING MATERIAL IS AN ALCOHOL WE SAW THAT AN ADDITIONAL STEP IS REQUIRED IN ORDER TO 2) NaBr PROTONATE THE HYDROXYL GROUP lRST 4HIS REACTION PROCEEDS VIA A CARBOCATION INTERMEDIATE AND IS R S therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SN AT AN APPRECIABLE RATE 7HEN DEALING WITH A PRIMARY 3. 0RIMARY AND SECONDARY ALCOHOLS REACT WITH 3/#L or PBr via an SN PROCESS alcohol, an SN PATHWAY IS REQUIRED IN ORDER TO CONVERT AN ALCOHOL INTO AN ALKYL HALIDE
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 SN PROCESS )N THIS SECTION WE WILL EXPLORE THREE SUCH REACTIONS THAT all employ an SN PROCESS PBr3 Br
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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 2ECALL FROM 3ECTION THAT ALCOHOLS UNDERGO ELIMINATION REACTIONS IN ACIDIC CONDITIONS )N 3ECTION WE SAW THAT ALCOHOLS CAN BE FORMED VIA A REDUCTION PROCESS )N THIS SECTION 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 OR TERTIARY ,ETS lRST CONSIDER THE OXIDATION OF A PRIMARY ALCOHOL 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 PROTON TRANSFER (OWEVER WHEN THE STARTING MATERIAL IS AN ALCOHOL AN ADDITIONAL STEP IS lRST HYDROXYL GROUP !S A RESULT PRIMARY ALCOHOLS CAN BE OXIDIZED TWICE 4HE lRST OXIDATION PRO- 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. PRACTICALLYSPEAKING once, forming a ketone. Breath Tests to Measure Blood Alcohol Level OH O OH [O] H SO Ì >ÊÃÊ>Ê«À>ÀÞÊ>V °Ê/ iÀivÀi]ÊiÌ >ÊÜÊÀi>VÌÊÜÌ Ê Ý`â}Ê>}iÌÊÊÌ iÊÌÕLi]Ê>`Ê>ÊVÀÊV >}iÊVVÕÀðÊ/ iÊ 2 4 ± ¡ heat R R R R «Ì>ÃÃÕÊ `V À>ÌiÊ Ê >V`VÊ V`ÌÃÊ ÌÊ «À`ÕViÊ >ViÌVÊ iÝÌiÌÊ vÊ Ì iÊ VÀÊ V >}iÊ }ÛiÃÊ >Ê `V>ÌÊ vÊ Ì iÊ L`Ê H >V`° >V ÊVÌiÌ°Ê Major Minor Secondary alcohol Ketone / iÊ Ài>Ì >ÞâiÀ/ ÊÃÊL>Ãi`ÊÊÌ iÊÃ>iÊ`i>]ÊLÕÌÊÌÊÃÊÀiÊ O >VVÕÀ>Ìi°ÊÊi>ÃÕÀi`ÊÛÕiÊvÊLÀi>Ì ÊÃÊLÕLLi`ÊÌ ÀÕ} Ê>Ê LOOKING AHEAD Generally speaking, the ketone is not further oxidized. Tertiary alcohols do not have any pro- ± ± 2– H ± 3± >µÕiÕÃÊ >V`VÊ ÃÕÌÊ vÊ «Ì>ÃÃÕÊ `V À 4HIS TRANSFORMATION CAN ALSO BE ACCOMPLISHED VIA AN % PATHWAY IF THE HYDROXYL GROUP IS lRST ÀÊ>ÊiÝVi«ÌÊÌÊÌ ÃÊ tons at the A position, and as a result, they generally do not undergo oxidation: OH Cr2O7 Cr converted into a better leaving group, such as a tosylate. A strong base can then be employed to }iiÀ>ÊÀÕi]ÊÃiiÊ-iVÌÊ OH >Ìi]Ê >`Ê Ì iÊ V >}iÊ Ê VÀÊ ÃÊ i>ÃÕÀi`Ê ÜÌ Ê >Ê ÕÌÀ>ÛiÌÛÃLiÊ 166-®Ê ëiVÌÀ ACCOMPLISH AN % REACTION Óä°££]ÊÜ iÀiÊÜiÊÜÊi>ÀÊ OH Ethanol Reddish orange Acetic acid Green >LÕÌÊ>ÊëiV>ÊÝ`â}Ê [O] « ÌiÌiÀÊ -iVÌÊ £Ç°££®°Ê ÌÀ>ÀÞÊ ÌÊ no reaction Ài>}iÌÊÌ >ÌÊV>ÊÝ`âiÊ>Ê R R ««Õ>ÀÊLiiv]ÊÌÊÃÊÌÊ«ÃÃLiÊÌÊLi>ÌÊÌ iÊ iÌiÊÌÊvÀÊ>ÊiÃÌiÀ° R ÊÌ iÊ«ÀViÃÃ]ÊiÌ >ÊÃÊÝ`âi`]Ê>`ÊÌ iÊV ÀÕÊÀi>}iÌÊ ÌiÃÌÊLÞÊÃÕV}Ê>ÊLÀi>Ì ÊÌÊ TsCl NaOEt ÃÊÀi`ÕVi`°Ê/ iÊiÜÊV ÀÕÊV«Õ`ÊÃÊ>Ê`vviÀiÌÊVÀ]Ê ÀÊ ÀÃ}Ê ÜÌ Ê >Ê LÀi>Ì Ê OH py OTs A large number of reagents are available for oxidizing primary and secondary alcohols. The E2 >`ÊÌ iÀivÀi]ÊÌ iÊ«À}ÀiÃÃÊvÊÌ iÊÀi>VÌÊV>ÊLiÊÌÀi`Ê vÀià iiÀ°Ê / iÃiÊ ÌiV most common oxidizing reagent is chromic acid (H#R/), which can be formed either from LÞÊÌ iÊVÀÊV >}iÊvÀÊÀi``à À>}iÊÌÊ}Àii°Ê/ ÃÊÀi>V µÕiÃÊ } ÌÊ vÊ >Ê CHROMIUM TRIOXIDE #R/) or from sodium dichromate (Na#RO7) in aqueous acidic solution. ÌÊvÀi`ÊÌ iÊL>ÃÃÊvÀÊ>ÞÊvÊÌ iÊi>ÀÞÊLÀi>Ì ÊÌiÃÌÃÊÌ >ÌÊ «iÀÃ]ÊLÕÌÊÌ iÞÊܽÌÊ O >ÃÃiÃÃi`ÊÌ iÊiÛiÊvÊL`Ê>V °Ê Ài>Ì ÊÌiÃÌÃÊÌ >ÌÊÕÌâiÊ vÊ Ì iÊ «Ì>ÃÃÕÊ 4HE % PROCESS ALSO GENERALLY PRODUCES THE MORE SUBSTITUTED ALKENE AND NO CARBOCATION ± H3O Ì ÃÊÀi>VÌÊ>ÀiÊÃÌÊViÀV>ÞÊ>Û>>Li°Ê/ iÊÌiÃÌÊVÃÃÌÃÊ `V À>Ìi° REARRANGEMENTS ARE OBSERVED IN % PROCESSES Cr O O Acetone vÊ>ÊÌÕLi]ÊÜ iÀiÊiÊi`ÊÃÊvÌÌi`ÊÜÌ Ê>ÊÕÌ «iViÊ>`ÊÌ iÊ Chromium trioxide O Ì iÀÊi`Ê >ÃÊ>ÊL>}°Ê/ iÊÃ`iÊvÊÌ iÊÌÕLiÊVÌ>ÃÊÃ`ÕÊ `V À>ÌiÊÌ >ÌÊÃÊ>`ÃÀLi`ÊÌÊÌ iÊÃÕÀv>ViÊvÊ>ÊiÀÌÊÃ`]Ê HO Cr OH ÃÕV Ê>ÃÊÃV>Ê}i°ÊÃÊÌ iÊÕÃiÀÊLÜÃÊ>ÀÊÌ ÀÕ} ÊÌ iÊÌÕLiÊ>`Ê CONCEPTUAL CHECKPOINT O vÃÊÕ«ÊÌ iÊL>}]ÊÌ iÊ>V ÊÊÌ iÊÕÃiÀ½ÃÊLÀi>Ì ÊÀi>VÌÃÊÜÌ ÊÌ iÊ 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 ? ? 4HE MECHANISM OF OXIDATION WITH CHROMIC ACID HAS TWO MAIN STEPS -ECHANISM 4HE lRST STEP INVOLVES FORMATION OF A CHROMATE ESTER AND THE SECOND STEP IS AN % PROCESS TO FORM A carbon-oxygen P bond (rather than a carbon-carbon P bond).
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MEDICALLYSPEAKING 1. Primary alcohols will react with HBr via an SN PROCESS 4HE MECHANISMS FOR THESE TWO PATHWAYS ARE VERY SIMILAR 4HE lRST FEW STEPS CONVERT A BAD LEAVING group into a good leaving group, then the halide attacks in an SN PROCESS -ECHANISM 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 MECHANISM 13.6 THE REACTION BETWEEN SOCl AND AN ALCOHOL iÀÌiðÊ/ iÃiÊ>}iÌÃÊ>ÀiÊLiiÛi`ÊÌÊÌiÀviÀiÊÜÌ ÊÌ iÊViÊi Ì iÊÌÀi>ÌiÌÊvÊ>Ì iÌi½ÃÊvÌ]ÊVÊÌV ]Ê >`ÊÀ}ÜÀ°Ê + – 2 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 H2O Bad / / SN2 "`ÀÊ >ÌiÀà ]Ê>`Ê iÃiiÝ ° leaving group
OH O Cl 4HE HYDROXYL GROUP IS lRST PROTONATED CONVERTING IT INTO AN EXCELLENT LEAVING GROUP FOLLOWED – OH SOCl Cl S N by an SN PROCESS 4HIS REACTION WORKS WELL FOR ("R BUT DOES NOT WORK WELL FOR (#L 4O 2 ± ± Cl I py SO2 Cl REPLACE THE HYDROXYL GROUP WITH CHLORIDE :N#L is used as a catalyst. O Cl I Cl N OH HCl Cl Cl S ZnCl Cl Cl OH 2 O – Cl para-Chloro- Haloprogin Clioquinol Tolnaftate The catalyst is a Lewis acid that converts the hydroxyl group into a better leaving group. meta-xylenol H H N + Cl + Nuc attack Nuc attack ± O O Cl O Cl on a Lewis acid – loss of LG S – S S ZnCl2 O + – Cl O O OH ZnCl2 O Cl Cl H SN2 Good leaving group 2. !S SEEN IN 3ECTION AN ALCOHOL CAN BE CONVERTED INTO A TOSYLATE FOLLOWED BY NUCLEOPHILIC 13.9 Reactions of Alcohols: Substitution and Elimination attack.
SN1 Reactions with Alcohols OH OTs – X The reaction mechanism for PBr has similar characteristics, including conversion of the !S SEEN IN 3ECTION TERTIARY ALCOHOLS WILL UNDERGO A SUBSTITUTION REACTION WHEN TREATED WITH TsCl X HYDROXYL GROUP INTO A BETTER LEAVING GROUP FOLLOWED BY NUCLEOPHILIC ATTACK -ECHANISM py a hydrogen halide. SN2 Bad Good OH HX X leaving group py= leaving group ± H2O N
7E SAW THAT THIS REACTION PROCEEDS VIA AN 3N1 mechanism. pyridine
5SING TOSYL CHLORIDE AND PYRIDINE THE HYDROXYL GROUP IS CONVERTED INTO A TOSYLATE GROUP AN Proton transfer Loss of a leaving group Nucleophilic attack MECHANISM 13.7 THE REACTION BETWEEN PBr3 AND AN ALCOHOL excellent leaving group), which is susceptible to an SN PROCESS .OTICE THE STEREOCHEMICAL H OUTCOME OF THE PREVIOUS REACTION 4HE CONlGURATION OF THE CHIRALITY CENTER IS NOT INVERTED Br + – – + OH H Br O H2O Br Br during formation of the tosylate, but it is inverted during the SN PROCESS 4HE NET RESULT IS P Br H H + INVERSION OF CONlGURATION Br – OH O Br SN2 Br P ± Br ± HOPBr2 Recall that an S 1 mechanism has two core steps (loss of leaving group and nucleophilic attack). OH Br N 1) TsCl, py Bad Br 7HEN THE STARTING MATERIAL IS AN ALCOHOL WE SAW THAT AN ADDITIONAL STEP IS REQUIRED IN ORDER TO 2) NaBr leaving group PROTONATE THE HYDROXYL GROUP lRST 4HIS REACTION PROCEEDS VIA A CARBOCATION INTERMEDIATE AND IS Good R S leaving group therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SN AT AN APPRECIABLE RATE 7HEN DEALING WITH A PRIMARY 3. 0RIMARY AND SECONDARY ALCOHOLS REACT WITH 3/#L or PBr via an SN PROCESS alcohol, an SN PATHWAY IS REQUIRED IN ORDER TO CONVERT AN ALCOHOL INTO AN ALKYL HALIDE
SOCl2 Cl py SN2 Reactions with Alcohols Notice the similarity among all of the SN PROCESSES THAT WE HAVE SEEN IN THIS SECTION !LL INVOLVE Primary and secondary alcohols will undergo substitution reactions with a variety of reagents, OH the conversion of the hydroxyl group into a better leaving group followed by nucleophilic attack. all of which proceed via an SN PROCESS )N THIS SECTION WE WILL EXPLORE THREE SUCH REACTIONS THAT )F ANY OF THESE REACTIONS OCCURS AT A CHIRALITY CENTER INVERSION OF CONlGURATION IS TO BE EXPECTED all employ an SN PROCESS PBr3 Br
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13.10 Reactions of Alcohols: Oxidation 597 598 CHAPTER 13 Alcohols and Phenols 13.10 Reactions of Alcohols: Oxidation 599
13.10 Reactions of Alcohols: Oxidation 7HEN A PRIMARY ALCOHOL IS OXIDIZED WITH CHROMIC ACID A CARBOXYLIC ACID IS OBTAINED )T IS GENERALLY MECHANISM 13.8 OXIDATION OF AN ALCOHOL WITH CHROMIC ACID DIFlCULT TO CONTROL THE REACTION TO PRODUCE THE ALDEHYDE )N 3ECTION WE SAW THAT ALCOHOLS CAN BE FORMED VIA A REDUCTION PROCESS )N THIS SECTION WE STEP 1 will explore the reverse process, called oxidation, which involves an increase in oxidation state. R O Fast and R O OH O O reversible Na Cr O Oxidation OH ± HO Cr OH O Cr OH ± H O 2 2 7 OH O H H 2 R H2SO4 , H2O RH R OH R O R O
Chromate ester Alcohol Aldehyde Carboxylic H Reduction Difficult to isolate acid STEP 2 The outcome of an oxidation process depends on whether the starting alcohol is primary, R O O R )N ORDER TO PRODUCE THE ALDEHYDE AS THE lNAL PRODUCT IT IS NECESSARY TO USE A MORE SELECTIVE OXIDIZ- SECONDARY OR TERTIARY ,ETS lRST CONSIDER THE OXIDATION OF A PRIMARY ALCOHOL HH ± – O Cr OH O ± H O ± HCrO ing reagent, one that will react with the alcohol but will not react with the aldehyde. Many such H E2 3 3 REAGENTS ARE AVAILABLE INCLUDING PYRIDINIUM CHLOROCHROMATE 0## 0## IS FORMED FROM THE REAC- OH O O R O R [O] [O] tion between pyridine, chromium trioxide, and hydrochloric acid. Chromate ester R H R H R OH H + – Primary alcohol Aldehyde Carboxylic acid N ± CrO3 ± HCl NH CrO3Cl Notice that a primary alcohol has two protons at the A position (the carbon atom bearing the HYDROXYL GROUP !S A RESULT PRIMARY ALCOHOLS CAN BE OXIDIZED TWICE 4HE lRST OXIDATION PRO- Pyridine Pyridinium Chlorochromate duces an aldehyde, and then oxidation of the aldehyde produces a carboxylic acid. Secondary alcohols only have one proton at the A position so they can only be oxidized PRACTICALLYSPEAKING PCC once, forming a ketone. Breath Tests to Measure Blood Alcohol Level 7HEN 0## IS USED AS THE OXIDIZING AGENT AN ALDEHYDE IS PRODUCED AS THE MAJOR PRODUCT 5NDER these conditions, the aldehyde is not further oxidized to the carboxylic acid. OH O [O] ¡ Ì >ÊÃÊ>Ê«À>ÀÞÊ>V °Ê/ iÀivÀi]ÊiÌ >ÊÜÊÀi>VÌÊÜÌ Ê Ý`â}Ê>}iÌÊÊÌ iÊÌÕLi]Ê>`Ê>ÊVÀÊV >}iÊVVÕÀðÊ/ iÊ R R R R «Ì>ÃÃÕÊ `V À>ÌiÊ Ê >V`VÊ V`ÌÃÊ ÌÊ «À`ÕViÊ >ViÌVÊ iÝÌiÌÊ vÊ Ì iÊ VÀÊ V >}iÊ }ÛiÃÊ >Ê `V>ÌÊ vÊ Ì iÊ L`Ê OH O H >V`° >V ÊVÌiÌ°Ê PCC CH Cl Secondary alcohol Ketone / iÊ Ài>Ì >ÞâiÀ/ ÊÃÊL>Ãi`ÊÊÌ iÊÃ>iÊ`i>]ÊLÕÌÊÌÊÃÊÀiÊ R 2 2 RH O >VVÕÀ>Ìi°ÊÊi>ÃÕÀi`ÊÛÕiÊvÊLÀi>Ì ÊÃÊLÕLLi`ÊÌ ÀÕ} Ê>Ê LOOKING AHEAD Generally speaking, the ketone is not further oxidized. Tertiary alcohols do not have any pro- ± Primary Aldehyde ± 2– H ± 3± >µÕiÕÃÊ >V`VÊ ÃÕÌÊ vÊ «Ì>ÃÃÕÊ `V À ÀÊ>ÊiÝVi«ÌÊÌÊÌ ÃÊ tons at the A position, and as a result, they generally do not undergo oxidation: OH Cr2O7 Cr alcohol }iiÀ>ÊÀÕi]ÊÃiiÊ-iVÌÊ OH >Ìi]Ê >`Ê Ì iÊ V >}iÊ Ê VÀÊ ÃÊ i>ÃÕÀi`Ê ÜÌ Ê >Ê ÕÌÀ>ÛiÌÛÃLiÊ 166-®Ê ëiVÌÀ Óä°££]ÊÜ iÀiÊÜiÊÜÊi>ÀÊ OH Ethanol Reddish orange Acetic acid Green -ETHYLENE CHLORIDE #(#L IS TYPICALLY THE SOLVENT USED WHEN 0## IS EMPLOYED >LÕÌÊ>ÊëiV>ÊÝ`â}Ê [O] « ÌiÌiÀÊ -iVÌÊ £Ç°££®°Ê ÌÀ>ÀÞÊ ÌÊ no reaction Secondary alcohols are oxidized only once to form a ketone, which is stable under oxidizing con- Ài>}iÌÊÌ >ÌÊV>ÊÝ`âiÊ>Ê R R ««Õ>ÀÊLiiv]ÊÌÊÃÊÌÊ«ÃÃLiÊÌÊLi>ÌÊÌ iÊ DITIONS 4HEREFORE A SECONDARY ALCOHOL CAN BE OXIDIZED EITHER WITH CHROMIC ACID OR WITH 0## iÌiÊÌÊvÀÊ>ÊiÃÌiÀ° R ÊÌ iÊ«ÀViÃÃ]ÊiÌ >ÊÃÊÝ`âi`]Ê>`ÊÌ iÊV ÀÕÊÀi>}iÌÊ ÌiÃÌÊLÞÊÃÕV}Ê>ÊLÀi>Ì ÊÌÊ ÃÊÀi`ÕVi`°Ê/ iÊiÜÊV ÀÕÊV«Õ`ÊÃÊ>Ê`vviÀiÌÊVÀ]Ê ÀÊ ÀÃ}Ê ÜÌ Ê >Ê LÀi>Ì Ê A large number of reagents are available for oxidizing primary and secondary alcohols. The Na Cr O >`ÊÌ iÀivÀi]ÊÌ iÊ«À}ÀiÃÃÊvÊÌ iÊÀi>VÌÊV>ÊLiÊÌÀi`Ê vÀià iiÀ°Ê / iÃiÊ ÌiV 2 2 7 most common oxidizing reagent is chromic acid (H#R/), which can be formed either from H2SO4 , H2O LÞÊÌ iÊVÀÊV >}iÊvÀÊÀi``à À>}iÊÌÊ}Àii°Ê/ ÃÊÀi>V µÕiÃÊ } ÌÊ vÊ >Ê CHROMIUM TRIOXIDE #R/) or from sodium dichromate (Na#RO7) in aqueous acidic solution. ÌÊvÀi`ÊÌ iÊL>ÃÃÊvÀÊ>ÞÊvÊÌ iÊi>ÀÞÊLÀi>Ì ÊÌiÃÌÃÊÌ >ÌÊ «iÀÃ]ÊLÕÌÊÌ iÞÊܽÌÊ OH O O >ÃÃiÃÃi`ÊÌ iÊiÛiÊvÊL`Ê>V °Ê Ài>Ì ÊÌiÃÌÃÊÌ >ÌÊÕÌâiÊ vÊ Ì iÊ «Ì>ÃÃÕÊ ± H3O Ì ÃÊÀi>VÌÊ>ÀiÊÃÌÊViÀV>ÞÊ>Û>>Li°Ê/ iÊÌiÃÌÊVÃÃÌÃÊ `V À>Ìi° Cr R R RR O O Acetone vÊ>ÊÌÕLi]ÊÜ iÀiÊiÊi`ÊÃÊvÌÌi`ÊÜÌ Ê>ÊÕÌ «iViÊ>`ÊÌ iÊ Secondary Ketone Chromium trioxide O Ì iÀÊi`Ê >ÃÊ>ÊL>}°Ê/ iÊÃ`iÊvÊÌ iÊÌÕLiÊVÌ>ÃÊÃ`ÕÊ PCC `V À>ÌiÊÌ >ÌÊÃÊ>`ÃÀLi`ÊÌÊÌ iÊÃÕÀv>ViÊvÊ>ÊiÀÌÊÃ`]Ê alcohol HO Cr OH CH2Cl2 ÃÕV Ê>ÃÊÃV>Ê}i°ÊÃÊÌ iÊÕÃiÀÊLÜÃÊ>ÀÊÌ ÀÕ} ÊÌ iÊÌÕLiÊ>`Ê O vÃÊÕ«ÊÌ iÊL>}]ÊÌ iÊ>V ÊÊÌ iÊÕÃiÀ½ÃÊLÀi>Ì ÊÀi>VÌÃÊÜÌ ÊÌ iÊ O O 3ODIUM DICHROMATE IS LESS EXPENSIVE BUT 0## IS MORE GENTLE AND OFTEN PREFERRED IF OTHER SENSITIVE + – – + H2SO4 Na O Cr O Cr O Na Chromic acid functional groups are present in the compound. H2O O O Sodium dichromate 4HE MECHANISM OF OXIDATION WITH CHROMIC ACID HAS TWO MAIN STEPS -ECHANISM 4HE lRST STEP INVOLVES FORMATION OF A CHROMATE ESTER AND THE SECOND STEP IS AN % PROCESS TO FORM A carbon-oxygen P bond (rather than a carbon-carbon P bond).
klein_c13_564-621hr.indd 597 11/8/10 2:11 PM klein_c13_564-621hr.indd 598 11/8/10 2:11 PM klein_c13_564-621hr.indd 599 11/8/10 2:11 PM 592 CHAPTER 13 Alcohols and Phenols 13.9 Reactions of Alcohols: Substitution and Elimination 593 594 CHAPTER 13 Alcohols and Phenols
1. Primary alcohols will react with HBr via an SN PROCESS 4HE MECHANISMS FOR THESE TWO PATHWAYS ARE VERY SIMILAR 4HE lRST FEW STEPS CONVERT A BAD LEAVING group into a good leaving group, then the halide attacks in an SN PROCESS -ECHANISM SKILLBUILDER Nucleophilic attack ± Proton transfer loss of a leaving group 13.6 PROPOSING REAGENTS FOR THE CONVERSION OF AN ALCOHOL INTO AN ALKYL HALIDE H + – MECHANISM 13.6 THE REACTION BETWEEN SOCl2 AND AN ALCOHOL OH H Br O Br Br LEARN the skill `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° ± H H2O Bad SN2 leaving group OH Cl
4HE HYDROXYL GROUP IS lRST PROTONATED CONVERTING IT INTO AN EXCELLENT LEAVING GROUP FOLLOWED – OH SOCl Cl by an SN PROCESS 4HIS REACTION WORKS WELL FOR ("R BUT DOES NOT WORK WELL FOR (#L 4O 2 ± ± py SO2 Cl REPLACE THE HYDROXYL GROUP WITH CHLORIDE :N#L is used as a catalyst. Cl OH HCl Cl Cl S SOLUTION ZnCl2 O – / ÃÊÌÀ>ÃvÀ>ÌÊÃÊ>ÊÃÕLÃÌÌÕÌÊ«ÀViÃÃ]ÊÃÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌÊÕÃiÊ-N£ÊV` Cl ÌÃÊÀÊ- ÓÊV`ÌðÊ/ iÊiÞÊv>VÌÀÊÃÊÌ iÊÃÕLÃÌÀ>Ìi°Ê/ iÊÃÕLÃÌÀ>ÌiÊ iÀiÊÃÊÃiV`>ÀÞ]ÊÃÊ The catalyst is a Lewis acid that converts the hydroxyl group into a better leaving group. STEP 1 N H H >ÞâiÊÌ iÊÃÕLÃÌÀ>Ìi° iÌ iÀÊ-N£ÊÀÊ-NÓÊVÕ`ÊÌ iÀiÌV>ÞÊÜÀ°ÊÜiÛiÀ]ÊÜiÊ`½ÌÊ >ÛiÊ>ÊV ViÊÊÌ ÃÊV>Ãi°Ê/ iÊ N + Cl + ÌÀ>ÃvÀ>ÌÊÀiµÕÀiÃÊÛiÀÃÊvÊVw}ÕÀ>Ì]ÊÜ V ÊV>ÊÞÊLiÊ>VV«Ã i`ÊÛ>Ê-NÓÊ Nuc attack Nuc attack ± O O Cl O Cl STEP 2 – S – S S >Ê-N£Ê«ÀViÃÃÊÜÕ`Ê}ÛiÊÀ>Viâ>Ì]Ê>ÃÊÜiÊÃ>ÜÊÊ-iVÌÊÇ°x®°ÊÊ>``Ì]ÊÌ iÊÃÕLÃÌÀ>ÌiÊ on a Lewis acid loss of LG >ÞâiÊÌ iÊ ZnCl2 O ÜÕ`ÊiÞÊÕ`iÀ}Ê>ÊV>ÀLV>ÌÊÀi>ÀÀ>}iiÌÊvÊÃÕLiVÌi`ÊÌÊ-N£ÊV`ÌðÊÀÊLÌ Ê + – Cl O O ÃÌiÀiV iV>Ê OH ZnCl2 O Cl Cl ÕÌViÊ>`Ê vÊÌ iÃiÊÀi>ÃÃ]Ê>Ê-NÓÊ«ÀViÃÃÊÃÊÀiµÕÀi`°Ê H `iÌiÀiÊÜ iÌ iÀÊ- ÓÊ 7iÊ Ã>ÜÊ Ì ÀiiÊ `vviÀiÌÊ Ài>}iÌÃÊ vÀÊ «iÀvÀ}Ê >Ê - ÓÊ «ÀViÃÃ°Ê 7Ì Ê >Ê Ì Àii]Ê Ì iÊ SN2 Good N N ÃÊÀiµÕÀi`° leaving group Þ`ÀÝÞÊ}ÀÕ«ÊÃÊVÛiÀÌi`ÊÌÊ>ÊLiÌÌiÀÊi>Û}Ê}ÀÕ«]ÊvÜi`ÊLÞÊÕVi« VÊ>ÌÌ>V°ÊÞÊ 2. !S SEEN IN 3ECTION AN ALCOHOL CAN BE CONVERTED INTO A TOSYLATE FOLLOWED BY NUCLEOPHILIC vÊÌ iÊÌ ÀiiÊiÌ `ÃÊV>ÊLiÊÕÃi`° attack.
HCl, ZnCl2 OH Cl OH OTs – X The reaction mechanism for PBr has similar characteristics, including conversion of the STEP 3 TsCl X HYDROXYL GROUP INTO A BETTER LEAVING GROUP FOLLOWED BY NUCLEOPHILIC ATTACK -ECHANISM `iÌvÞÊÀi>}iÌÃÊÌ >ÌÊ py SN2 >V iÛiÊÌ iÊ«ÀViÃÃÊ 1) TsCl, py `iÌiÀi`ÊÊÃÌi«ÊÓ° 2) NaCl Bad Good leaving group py= leaving group SOCl2 , py N pyridine PRACTICE the skill 13.19 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã Êi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ> Ìð 5SING TOSYL CHLORIDE AND PYRIDINE THE HYDROXYL GROUP IS CONVERTED INTO A TOSYLATE GROUP AN MECHANISM 13.7 THE REACTION BETWEEN PBr3 AND AN ALCOHOL OH Br OH Br excellent leaving group), which is susceptible to an SN PROCESS .OTICE THE STEREOCHEMICAL OUTCOME OF THE PREVIOUS REACTION 4HE CONlGURATION OF THE CHIRALITY CENTER IS NOT INVERTED Br during formation of the tosylate, but it is inverted during the SN PROCESS 4HE NET RESULT IS P Br H + (a) (b) INVERSION OF CONlGURATION Br – OH O Br SN2 Br P ± Br ± HOPBr2 OH Br 1) TsCl, py Bad Br 2) NaBr leaving group Good Cl Br R S OH OH leaving group (c) (d)
3. 0RIMARY AND SECONDARY ALCOHOLS REACT WITH 3/#L or PBr via an SN PROCESS
SOCl2 Cl py (e) OH Cl (f) OH Br Notice the similarity among all of the SN PROCESSES THAT WE HAVE SEEN IN THIS SECTION !LL INVOLVE 13.20 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° OH the conversion of the hydroxyl group into a better leaving group followed by nucleophilic attack. APPLY the skill )F ANY OF THESE REACTIONS OCCURS AT A CHIRALITY CENTER INVERSION OF CONlGURATION IS TO BE EXPECTED
PBr3 Br OH Cl
need more PRACTICE? Try Problems 13.35a–c, 13.44f, 13.52r
klein_c13_564-621hr.indd 592 11/8/10 2:11 PM klein_c13_564-621hr.indd 593 11/8/10 2:11 PM klein_c13_564-621hr.indd 594 11/8/10 2:11 PM
598 CHAPTER 13 Alcohols and Phenols 13.10 Reactions of Alcohols: Oxidation 599 600 CHAPTER 13 Alcohols and Phenols
7HEN A PRIMARY ALCOHOL IS OXIDIZED WITH CHROMIC ACID A CARBOXYLIC ACID IS OBTAINED )T IS GENERALLY MECHANISM 13.8 OXIDATION OF AN ALCOHOL WITH CHROMIC ACID DIFlCULT TO CONTROL THE REACTION TO PRODUCE THE ALDEHYDE SKILLBUILDER STEP 1 13.7 PREDICTING THE PRODUCTS OF AN OXIDATION REACTION R O Fast and R O OH O O reversible Na Cr O OH ± HO Cr OH ± 2 2 7 H H O Cr OH H2O LEARN the skill *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÊÌ iÊvÜ}ÊÀi>VÌ° R H2SO4 , H2O RH R OH R O R O Chromate ester Alcohol Aldehyde Carboxylic OH CrO3 ± Difficult to isolate acid H O , acetone STEP 2 3 ? O R O R )N ORDER TO PRODUCE THE ALDEHYDE AS THE lNAL PRODUCT IT IS NECESSARY TO USE A MORE SELECTIVE OXIDIZ- SOLUTION HH – O Cr OH O ± H O± ± HCrO ing reagent, one that will react with the alcohol but will not react with the aldehyde. Many such H E2 3 3 ÊÀ`iÀÊÌÊ«Ài`VÌÊÌ iÊ«À`ÕVÌ]Ê`iÌvÞÊÜ iÌ iÀÊÌ iÊ>V ÊÃÊ«À>ÀÞÊÀÊÃiV`>ÀÞ°ÊÊÌ ÃÊ REAGENTS ARE AVAILABLE INCLUDING PYRIDINIUM CHLOROCHROMATE 0## 0## IS FORMED FROM THE REAC- R O R V>Ãi]ÊÌ iÊ>V ÊÃÊ«À>ÀÞ]Ê>`ÊÌ iÀivÀi]ÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌ iÊ«ÀViÃÃÊÜÊ«À`ÕViÊ tion between pyridine, chromium trioxide, and hydrochloric acid. STEP 1 >Ê>`i Þ`iÊÀÊ>ÊV>ÀLÝÞVÊ>V`\Ê Chromate ester `iÌvÞÊÜ iÌ iÀÊÌ iÊ O O >V ÊÃÊ«À>ÀÞÊÀÊ + – ÃiV`>ÀÞ° OH [O] H [O] OH N ± CrO3 ± HCl NH CrO3Cl STEP 2 vÊÌ iÊ>V ÊÃÊ Pyridinium Chlorochromate Pyridine «À>ÀÞ]ÊVÃ`iÀÊ Aldehyde Carboxylic acid Ü iÌ iÀÊ>Ê>`i Þ`iÊ PCC ÀÊ>ÊV>ÀLÝÞVÊ>V`ÊÃÊ / iÊ«À`ÕVÌÊÃÊ`iÌiÀi`ÊLÞÊÌ iÊV ViÊvÊÀi>}iÌ°Ê ÀÕÊÌÀÝ`iÊÊ>V`VÊV`ÌÃÊ PRACTICALLYSPEAKING LÌ>i`° vÀÃÊV ÀVÊ>V`]ÊÜ V ÊÜÊÝ`âiÊÌ iÊ>V ÊÌÜViÊÌÊ}ÛiÊÌ iÊV>ÀLÝÞVÊ>V`°ÊÊÀ`iÀÊ Breath Tests to Measure Blood Alcohol Level 7HEN 0## IS USED AS THE OXIDIZING AGENT AN ALDEHYDE IS PRODUCED AS THE MAJOR PRODUCT 5NDER these conditions, the aldehyde is not further oxidized to the carboxylic acid. ÌÊÃÌ«Ê>ÌÊÌ iÊ>`i Þ`i]Ê* ÊÜÕ`ÊLiÊÕÃi`ÊÃÌi>`° O Ì >ÊÃÊ>Ê«À>ÀÞÊ>V °Ê/ iÀivÀi]ÊiÌ >ÊÜÊÀi>VÌÊÜÌ Ê Ý`â}Ê>}iÌÊÊÌ iÊÌÕLi]Ê>`Ê>ÊVÀÊV >}iÊVVÕÀðÊ/ iÊ STEP 3 «Ì>ÃÃÕÊ `V À>ÌiÊ Ê >V`VÊ V`ÌÃÊ ÌÊ «À`ÕViÊ >ViÌVÊ iÝÌiÌÊ vÊ Ì iÊ VÀÊ V >}iÊ }ÛiÃÊ >Ê `V>ÌÊ vÊ Ì iÊ L`Ê OH O À>ÜÊÌ iÊ«À`ÕVÌ° OH CrO3 OH >V`° >V ÊVÌiÌ°Ê PCC ± CH Cl H3O , acetone / iÊ Ài>Ì >ÞâiÀ/ ÊÃÊL>Ãi`ÊÊÌ iÊÃ>iÊ`i>]ÊLÕÌÊÌÊÃÊÀiÊ R 2 2 RH O >VVÕÀ>Ìi°ÊÊi>ÃÕÀi`ÊÛÕiÊvÊLÀi>Ì ÊÃÊLÕLLi`ÊÌ ÀÕ} Ê>Ê ± Primary Aldehyde PRACTICE the skill 13.22 *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÀi>VÌð ± 2– H ± 3± >µÕiÕÃÊ >V`VÊ ÃÕÌÊ vÊ «Ì>ÃÃÕÊ `V À OH Cr2O7 Cr alcohol OH >Ìi]Ê >`Ê Ì iÊ V >}iÊ Ê VÀÊ ÃÊ i>ÃÕÀi`Ê OH ÜÌ Ê >Ê ÕÌÀ>ÛiÌÛÃLiÊ 166-®Ê ëiVÌÀ Ethanol Reddish orange Acetic acid Green -ETHYLENE CHLORIDE #(#L IS TYPICALLY THE SOLVENT USED WHEN 0## IS EMPLOYED HO O PCC « ÌiÌiÀÊ -iVÌÊ £Ç°££®°Ê ÌÀ>ÀÞÊ ÌÊ Secondary alcohols are oxidized only once to form a ketone, which is stable under oxidizing con- Na2Cr2O7 CH2Cl2 ««Õ>ÀÊLiiv]ÊÌÊÃÊÌÊ«ÃÃLiÊÌÊLi>ÌÊÌ iÊ H2SO4 , H2O DITIONS 4HEREFORE A SECONDARY ALCOHOL CAN BE OXIDIZED EITHER WITH CHROMIC ACID OR WITH 0## (a) H ? (b) ? ÊÌ iÊ«ÀViÃÃ]ÊiÌ >ÊÃÊÝ`âi`]Ê>`ÊÌ iÊV ÀÕÊÀi>}iÌÊ ÌiÃÌÊLÞÊÃÕV}Ê>ÊLÀi>Ì ÊÌÊ ÃÊÀi`ÕVi`°Ê/ iÊiÜÊV ÀÕÊV«Õ`ÊÃÊ>Ê`vviÀiÌÊVÀ]Ê ÀÊ ÀÃ}Ê ÜÌ Ê >Ê LÀi>Ì Ê OH Na2Cr2O7 >`ÊÌ iÀivÀi]ÊÌ iÊ«À}ÀiÃÃÊvÊÌ iÊÀi>VÌÊV>ÊLiÊÌÀi`Ê vÀià iiÀ°Ê / iÃiÊ ÌiV H xs CrO3 H2SO4 , H2O OH ± PCC LÞÊÌ iÊVÀÊV >}iÊvÀÊÀi``à À>}iÊÌÊ}Àii°Ê/ ÃÊÀi>V µÕiÃÊ } ÌÊ vÊ >Ê H3O (d) CH2Cl2 ÌÊvÀi`ÊÌ iÊL>ÃÃÊvÀÊ>ÞÊvÊÌ iÊi>ÀÞÊLÀi>Ì ÊÌiÃÌÃÊÌ >ÌÊ «iÀÃ]ÊLÕÌÊÌ iÞÊܽÌÊ (c) O acetone ? OH O ? >ÃÃiÃÃi`ÊÌ iÊiÛiÊvÊL`Ê>V °Ê Ài>Ì ÊÌiÃÌÃÊÌ >ÌÊÕÌâiÊ vÊ Ì iÊ «Ì>ÃÃÕÊ Ì ÃÊÀi>VÌÊ>ÀiÊÃÌÊViÀV>ÞÊ>Û>>Li°Ê/ iÊÌiÃÌÊVÃÃÌÃÊ `V À>Ìi° PCC Na2Cr2O7 R R RR OH OH CH2Cl2 H2SO4 , H2O vÊ>ÊÌÕLi]ÊÜ iÀiÊiÊi`ÊÃÊvÌÌi`ÊÜÌ Ê>ÊÕÌ «iViÊ>`ÊÌ iÊ (e) ? (f) ? Secondary Ketone Ì iÀÊi`Ê >ÃÊ>ÊL>}°Ê/ iÊÃ`iÊvÊÌ iÊÌÕLiÊVÌ>ÃÊÃ`ÕÊ PCC alcohol `V À>ÌiÊÌ >ÌÊÃÊ>`ÃÀLi`ÊÌÊÌ iÊÃÕÀv>ViÊvÊ>ÊiÀÌÊÃ`]Ê CH2Cl2 APPLY the skill 13.23 *À«ÃiÊ>ÊÃÞÌ iÃÃÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ìð ÃÕV Ê>ÃÊÃV>Ê}i°ÊÃÊÌ iÊÕÃiÀÊLÜÃÊ>ÀÊÌ ÀÕ} ÊÌ iÊÌÕLiÊ>`Ê O vÃÊÕ«ÊÌ iÊL>}]ÊÌ iÊ>V ÊÊÌ iÊÕÃiÀ½ÃÊLÀi>Ì ÊÀi>VÌÃÊÜÌ ÊÌ iÊ 3ODIUM DICHROMATE IS LESS EXPENSIVE BUT 0## IS MORE GENTLE AND OFTEN PREFERRED IF OTHER SENSITIVE O functional groups are present in the compound. H (a) Br H (b) O O
(c) (d)
need more PRACTICE? Try Problems 13.35e–f, 13.37, 13.48
klein_c13_564-621hr.indd 598 11/8/10 2:11 PM klein_c13_564-621hr.indd 599 11/8/10 2:11 PM klein_c13_564-621hr.indd 600 11/8/10 2:11 PM 13.9 Reactions of Alcohols: Substitution and Elimination 593 594 CHAPTER 13 Alcohols and Phenols 13.9 Reactions of Alcohols: Substitution and Elimination 595
OH 4HE MECHANISMS FOR THESE TWO PATHWAYS ARE VERY SIMILAR 4HE lRST FEW STEPS CONVERT A BAD LEAVING PRACTICALLYSPEAKING O O group into a good leaving group, then the halide attacks in an SN PROCESS -ECHANISM SKILLBUILDER HO Drug Metabolism HO 13.6 PROPOSING REAGENTS FOR THE CONVERSION OF AN ALCOHOL INTO AN ALKYL HALIDE OH ÀÕ}ÊiÌ>LÃÊÀiviÀÃÊÌÊÌ iÊÃiÌÊvÊÀi>VÌÃÊLÞÊÜ V Ê`ÀÕ}ÃÊ>ÀiÊ O UDP VÛiÀÌi`ÊÌÊÌ iÀÊV«Õ`ÃÊÌ >ÌÊ>ÀiÊiÌ iÀÊÕÃi`ÊLÞÊÌ iÊL`ÞÊ MECHANISM 13.6 THE REACTION BETWEEN SOCl2 AND AN ALCOHOL LEARN the skill `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° ÀÊiÝVÀiÌi`°Ê"ÕÀÊL`iÃÊ`ëÃiÊvÊÌ iÊi`V>ÌÃÊÜiÊ}iÃÌÊLÞÊ ROH Bad >ÊÛ>ÀiÌÞÊvÊiÌ>LVÊ«>Ì Ü>ÞÃ°Ê UDP-glucuronyl-transferase leaving group OH Cl "iÊ VÊ iÌ>LVÊ «>Ì Ü>ÞÊ ÃÊ V>i`Ê }ÕVÕÀVÊ >V`Ê VÕ}>Ì]Ê ÀÊ Ã«ÞÊ }ÕVÕÀ`>Ì°Ê / ÃÊ «ÀViÃÃÊ ÃÊ ± – –H OH SOCl2 Cl ÛiÀÞÊÃ>ÀÊÌÊ>ÊvÊÌ iÊ-NÓÊ«ÀViÃÃiÃÊÌ >ÌÊÜiÊÛiÃÌ}>Ìi`Ê ± SO ± Cl py 2 Ê Ì iÊ «ÀiÛÕÃÊ ÃiVÌ°Ê -«iVvV>Þ]Ê >Ê L>`Ê i>Û}Ê }ÀÕ«Ê Þ`ÀÝÞ®Ê ÃÊ vÀÃÌÊ VÛiÀÌi`Ê ÌÊ >Ê }`Ê i>Û}Ê }ÀÕ«]Ê v Cl OH Üi`Ê LÞÊ ÕVi« VÊ >ÌÌ>V°Ê ÕVÕÀ`>ÌÊ iÝ LÌÃÊ Ì iÊ Cl S SOLUTION O Ã>iÊÌÜÊiÞÊÃÌi«Ã°Ê O O – / ÃÊÌÀ>ÃvÀ>ÌÊÃÊ>ÊÃÕLÃÌÌÕÌÊ«ÀViÃÃ]ÊÃÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌÊÕÃiÊ-N£ÊV` HO HO O Cl STEP 1 ÌÃÊÀÊ-NÓÊV`ÌðÊ/ iÊiÞÊv>VÌÀÊÃÊÌ iÊÃÕLÃÌÀ>Ìi°Ê/ iÊÃÕLÃÌÀ>ÌiÊ iÀiÊÃÊÃiV`>ÀÞ]ÊÃÊ R 1. À>ÌÊvÊ1 *ÊÕÀ`ix½`« ë AD}ÕVÕÀVÊ OH H H >ÞâiÊÌ iÊÃÕLÃÌÀ>Ìi° iÌ iÀÊ-N£ÊÀÊ-NÓÊVÕ`ÊÌ iÀiÌV>ÞÊÜÀ°ÊÜiÛiÀ]ÊÜiÊ`½ÌÊ >ÛiÊ>ÊV ViÊÊÌ ÃÊV>Ãi°Ê/ iÊ N >V`®ÊvÀÊ}ÕVÃiÊÛÛiÃÊVÛiÀÃÊvÊ>ÊL>`Êi>Û}Ê b + Cl + ÌÀ>ÃvÀ>ÌÊÀiµÕÀiÃÊÛiÀÃÊvÊVw}ÕÀ>Ì]ÊÜ V ÊV>ÊÞÊLiÊ>VV«Ã i`ÊÛ>Ê-NÓÊ -Glucuronide O O Cl O Cl STEP 2 }ÀÕ«ÊÌÊ>Ê}`Êi>Û}Ê}ÀÕ«° S – S S >Ê-N£Ê«ÀViÃÃÊÜÕ`Ê}ÛiÊÀ>Viâ>Ì]Ê>ÃÊÜiÊÃ>ÜÊÊ-iVÌÊÇ°x®°ÊÊ>``Ì]ÊÌ iÊÃÕLÃÌÀ>ÌiÊ >ÞâiÊÌ iÊ / ÃÊ-NÓÊ«ÀViÃÃÊÀiµÕÀiÃÊ>ÊiâÞiÊ>ÊL}V>ÊV>Ì>ÞÃÌ®Ê O ÜÕ`ÊiÞÊÕ`iÀ}Ê>ÊV>ÀLV>ÌÊÀi>ÀÀ>}iiÌÊvÊÃÕLiVÌi`ÊÌÊ- £ÊV`ÌðÊÀÊLÌ Ê Cl O O ÃÌiÀiV iV>Ê N V>i`Ê1 *}ÕVÕÀÞÊÌÀ>ÃviÀ>Ãi°Ê/ iÊÀi>VÌÊ«ÀVii`ÃÊÛ>Ê ÕÌViÊ>`Ê vÊÌ iÃiÊÀi>ÃÃ]Ê>Ê-NÓÊ«ÀViÃÃÊÃÊÀiµÕÀi`°Ê OH ÛiÀÃÊvÊVw}ÕÀ>ÌÊ>ÃÊiÝ«iVÌi`ÊvÊ>Ê-NÓÊ«ÀViÃîÊÌÊ `iÌiÀiÊÜ iÌ iÀÊ- ÓÊ 7iÊ Ã>ÜÊ Ì ÀiiÊ `vviÀiÌÊ Ài>}iÌÃÊ vÀÊ «iÀvÀ}Ê >Ê - ÓÊ «ÀViÃÃ°Ê 7Ì Ê >Ê Ì Àii]Ê Ì iÊ Good N N «À`ÕViÊ>ÊB}ÕVÕÀ`i]ÊÜ V ÊÃÊ } ÞÊÜ>ÌiÀÊÃÕLiÊ>`ÊÃÊ ÃÊÀiµÕÀi`° Þ`ÀÝÞÊ}ÀÕ«ÊÃÊVÛiÀÌi`ÊÌÊ>ÊLiÌÌiÀÊi>Û}Ê}ÀÕ«]ÊvÜi`ÊLÞÊÕVi« VÊ>ÌÌ>V°ÊÞÊ leaving group O Ài>`ÞÊiÝVÀiÌi`ÊÊÌ iÊÕÀi°Ê HO vÊÌ iÊÌ ÀiiÊiÌ `ÃÊV>ÊLiÊÕÃi`° >ÞÊ vÕVÌ>Ê }ÀÕ«ÃÊ Õ`iÀ}Ê }ÕVÕÀ`>Ì]Ê LÕÌÊ >V HO OH ÃÊ>`Ê« iÃÊ>ÀiÊÌ iÊÃÌÊVÊV>ÃÃiÃÊvÊV«Õ`ÃÊÌ >ÌÊ HCl, ZnCl2 D-Glucose OH Õ`iÀ}ÊÌ ÃÊiÌ>LVÊ«>Ì Ü>Þ°ÊÀÊiÝ>«i]ÊÀ« i]Ê>ViÌ> OH Cl The reaction mechanism for PBr has similar characteristics, including conversion of the STEP 3 Bad LG « i]Ê>`ÊV À>« iVÊ>ÀiÊ>ÊiÌ>Lâi`ÊÛ>Ê}ÕVÕÀ`>Ì\ HYDROXYL GROUP INTO A BETTER LEAVING GROUP FOLLOWED BY NUCLEOPHILIC ATTACK -ECHANISM `iÌvÞÊÀi>}iÌÃÊÌ >ÌÊ >V iÛiÊÌ iÊ«ÀViÃÃÊ 1) TsCl, py N `iÌiÀi`ÊÊÃÌi«ÊÓ° 2) NaCl H OH OH H SOCl2 , py H NO Cl PRACTICE the skill 13.19 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã Êi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ> OH N O2N H Cl O O Ìð HO OH HO O O MECHANISM 13.7 THE REACTION BETWEEN PBr3 AND AN ALCOHOL OH Br OH Br HO HO Morphine Acetaminophen Chloramphenicol Br OH An opiate analgesic An analgesic (pain-relieving) An antibiotic used in eye drops HO used to treat severe pain and antipyretic (fever-reducing) agent, to treat bacterial conjuctivitis P Br H O O UDPGA sold under the trade name TylenolTM + (a) (b) O N OH Br O Br – S 2 Br O P OPO ± N ± P Br HOPBr2 N N O -O -O H Bad Br HO OH OH H leaving group OH H Good OH Cl OH Br Cl leaving group (c) (d) Good LG (called UDP) NO N O N H Cl O 2 HO OH HO O 1 *ÊÃÊ>ÊV«Õ`ÊÜÌ Ê>ÊÛiÀÞÊ}`Êi>Û}Ê}ÀÕ«°Ê/ ÃÊ (e) OH Cl (f) OH Br Morphine Acetaminophen Chloramphenicol Notice the similarity among all of the SN PROCESSES THAT WE HAVE SEEN IN THIS SECTION !LL INVOLVE >À}iÊi>Û}Ê}ÀÕ«AnÊà opiateÊV>i` analgesicÊ1 *°ÊÊÌ ÃÊÌÀ>ÃvÀ>Ì]An analgesicÊi (pain-relieving)Ê An antibiotic used in eye drops the conversion of the hydroxyl group into a better leaving group followed by nucleophilic attack. APPLY the skill 13.20 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° vÊÌ iÊ Þ`ÀÝÞÊused}ÀÕ«Ã to ÊtreatÊ}ÕVÃi severeÊ >à painÊLiiandÊVÛiÀÌi` antipyreticÊÌ (fever-reducing)Ê>Ê agent, to treat bacterial conjuctivitis TM )F ANY OF THESE REACTIONS OCCURS AT A CHIRALITY CENTER INVERSION OF CONlGURATION IS TO BE EXPECTED }`Êi>Û}Ê}ÀÕ«° sold under the trade name Tylenol Ê i>V Ê vÊ Ì iÃiÊ Ì ÀiiÊ V«Õ`Ã]Ê Ì iÊ } } Ìi`Ê Þ`ÀÝÞÊ 2. iÝÌ]Ê>Ê-NÓÊ«ÀViÃÃÊVVÕÀÃÊÊÜ V ÊÌ iÊ`ÀÕ}ÊLi}ÊiÌ>L âi`ÊÃÕV Ê>ÃÊ>Ê>V ®Ê>ÌÌ>VÃÊ1 *]ÊiÝ«i}ÊÌ iÊ}`Ê }ÀÕ«Ê >ÌÌ>VÃÊ 1 *°Ê ÕVÕÀ`>ÌÊ ÃÊ Ì iÊ >Ê iÌ>LVÊ OH Cl i>Û}Ê}ÀÕ«° «>Ì Ü>ÞÊLÞÊÜ V ÊÌ iÃiÊ`ÀÕ}ÃÊ>ÀiÊi>Ìi`ÊvÀÊÌ iÊL`Þ°
need more PRACTICE? Try Problems 13.35a–c, 13.44f, 13.52r
klein_c13_564-621hr.indd 593 11/8/10 2:11 PM klein_c13_564-621hr.indd 594 11/8/10 2:11 PM klein_c13_564-621hr.indd 595 11/8/10 2:11 PM
13.10 Reactions of Alcohols: Oxidation 599 600 CHAPTER 13 Alcohols and Phenols
7HEN A PRIMARY ALCOHOL IS OXIDIZED WITH CHROMIC ACID A CARBOXYLIC ACID IS OBTAINED )T IS GENERALLY DIFlCULT TO CONTROL THE REACTION TO PRODUCE THE ALDEHYDE SKILLBUILDER 13.7 PREDICTING THE PRODUCTS OF AN OXIDATION REACTION OH O O Na2Cr2O7 LEARN the skill *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÊÌ iÊvÜ}ÊÀi>VÌ° R H2SO4 , H2O RH R OH
Alcohol Aldehyde Carboxylic OH CrO3 Difficult to isolate acid ± H3O , acetone ? )N ORDER TO PRODUCE THE ALDEHYDE AS THE lNAL PRODUCT IT IS NECESSARY TO USE A MORE SELECTIVE OXIDIZ- SOLUTION ing reagent, one that will react with the alcohol but will not react with the aldehyde. Many such ÊÀ`iÀÊÌÊ«Ài`VÌÊÌ iÊ«À`ÕVÌ]Ê`iÌvÞÊÜ iÌ iÀÊÌ iÊ>V ÊÃÊ«À>ÀÞÊÀÊÃiV`>ÀÞ°ÊÊÌ ÃÊ REAGENTS ARE AVAILABLE INCLUDING PYRIDINIUM CHLOROCHROMATE 0## 0## IS FORMED FROM THE REAC- V>Ãi]ÊÌ iÊ>V ÊÃÊ«À>ÀÞ]Ê>`ÊÌ iÀivÀi]ÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌ iÊ«ÀViÃÃÊÜÊ«À`ÕViÊ tion between pyridine, chromium trioxide, and hydrochloric acid. STEP 1 >Ê>`i Þ`iÊÀÊ>ÊV>ÀLÝÞVÊ>V`\Ê `iÌvÞÊÜ iÌ iÀÊÌ iÊ O O >V ÊÃÊ«À>ÀÞÊÀÊ + – ÃiV`>ÀÞ° OH [O] H [O] OH N ± CrO3 ± HCl NH CrO3Cl STEP 2 vÊÌ iÊ>V ÊÃÊ Pyridinium Chlorochromate Pyridine «À>ÀÞ]ÊVÃ`iÀÊ Aldehyde Carboxylic acid Ü iÌ iÀÊ>Ê>`i Þ`iÊ PCC ÀÊ>ÊV>ÀLÝÞVÊ>V`ÊÃÊ / iÊ«À`ÕVÌÊÃÊ`iÌiÀi`ÊLÞÊÌ iÊV ViÊvÊÀi>}iÌ°Ê ÀÕÊÌÀÝ`iÊÊ>V`VÊV`ÌÃÊ LÌ>i`° 7HEN 0## IS USED AS THE OXIDIZING AGENT AN ALDEHYDE IS PRODUCED AS THE MAJOR PRODUCT 5NDER vÀÃÊV ÀVÊ>V`]ÊÜ V ÊÜÊÝ`âiÊÌ iÊ>V ÊÌÜViÊÌÊ}ÛiÊÌ iÊV>ÀLÝÞVÊ>V`°ÊÊÀ`iÀÊ these conditions, the aldehyde is not further oxidized to the carboxylic acid. ÌÊÃÌ«Ê>ÌÊÌ iÊ>`i Þ`i]Ê* ÊÜÕ`ÊLiÊÕÃi`ÊÃÌi>`° O STEP 3 OH O À>ÜÊÌ iÊ«À`ÕVÌ° OH CrO3 OH PCC ± H3O , acetone R CH2Cl2 RH
Primary Aldehyde PRACTICE the skill 13.22 *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÀi>VÌð alcohol OH
-ETHYLENE CHLORIDE #(#L IS TYPICALLY THE SOLVENT USED WHEN 0## IS EMPLOYED HO O PCC Secondary alcohols are oxidized only once to form a ketone, which is stable under oxidizing con- Na2Cr2O7 CH2Cl2 H2SO4 , H2O DITIONS 4HEREFORE A SECONDARY ALCOHOL CAN BE OXIDIZED EITHER WITH CHROMIC ACID OR WITH 0## (a) H ? (b) ? OH Na2Cr2O7 H xs CrO3 H2SO4 , H2O OH ± PCC H3O CH2Cl2 (c) O acetone ? (d) OH O ?
PCC Na2Cr2O7 R R RR OH OH CH2Cl2 H2SO4 , H2O (e) ? (f) ? Secondary Ketone PCC alcohol CH2Cl2 APPLY the skill 13.23 *À«ÃiÊ>ÊÃÞÌ iÃÃÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ìð O 3ODIUM DICHROMATE IS LESS EXPENSIVE BUT 0## IS MORE GENTLE AND OFTEN PREFERRED IF OTHER SENSITIVE O functional groups are present in the compound. H (a) Br H (b) O O
(c) (d)
need more PRACTICE? Try Problems 13.35e–f, 13.37, 13.48
klein_c13_564-621hr.indd 599 11/8/10 2:11 PM klein_c13_564-621hr.indd 600 11/8/10 2:11 PM 594 CHAPTER 13 Alcohols and Phenols 13.9 Reactions of Alcohols: Substitution and Elimination 595
OH PRACTICALLYSPEAKING O O SKILLBUILDER HO Drug Metabolism HO 13.6 PROPOSING REAGENTS FOR THE CONVERSION OF AN ALCOHOL INTO AN ALKYL HALIDE OH ÀÕ}ÊiÌ>LÃÊÀiviÀÃÊÌÊÌ iÊÃiÌÊvÊÀi>VÌÃÊLÞÊÜ V Ê`ÀÕ}ÃÊ>ÀiÊ O UDP VÛiÀÌi`ÊÌÊÌ iÀÊV«Õ`ÃÊÌ >ÌÊ>ÀiÊiÌ iÀÊÕÃi`ÊLÞÊÌ iÊL`ÞÊ LEARN the skill `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° ÀÊiÝVÀiÌi`°Ê"ÕÀÊL`iÃÊ`ëÃiÊvÊÌ iÊi`V>ÌÃÊÜiÊ}iÃÌÊLÞÊ ROH >ÊÛ>ÀiÌÞÊvÊiÌ>LVÊ«>Ì Ü>ÞÃ°Ê UDP-glucuronyl-transferase OH Cl "iÊ VÊ iÌ>LVÊ «>Ì Ü>ÞÊ ÃÊ V>i`Ê }ÕVÕÀVÊ >V`Ê VÕ}>Ì]Ê ÀÊ Ã«ÞÊ }ÕVÕÀ`>Ì°Ê / ÃÊ «ÀViÃÃÊ ÃÊ ± –H ÛiÀÞÊÃ>ÀÊÌÊ>ÊvÊÌ iÊ-NÓÊ«ÀViÃÃiÃÊÌ >ÌÊÜiÊÛiÃÌ}>Ìi`Ê Ê Ì iÊ «ÀiÛÕÃÊ ÃiVÌ°Ê -«iVvV>Þ]Ê >Ê L>`Ê i>Û}Ê }ÀÕ«Ê Þ`ÀÝÞ®Ê ÃÊ vÀÃÌÊ VÛiÀÌi`Ê ÌÊ >Ê }`Ê i>Û}Ê }ÀÕ«]Ê v OH SOLUTION Üi`Ê LÞÊ ÕVi« VÊ >ÌÌ>V°Ê ÕVÕÀ`>ÌÊ iÝ LÌÃÊ Ì iÊ O Ã>iÊÌÜÊiÞÊÃÌi«Ã°Ê O / ÃÊÌÀ>ÃvÀ>ÌÊÃÊ>ÊÃÕLÃÌÌÕÌÊ«ÀViÃÃ]ÊÃÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌÊÕÃiÊ-N£ÊV` HO HO O STEP 1 ÌÃÊÀÊ-NÓÊV`ÌðÊ/ iÊiÞÊv>VÌÀÊÃÊÌ iÊÃÕLÃÌÀ>Ìi°Ê/ iÊÃÕLÃÌÀ>ÌiÊ iÀiÊÃÊÃiV`>ÀÞ]ÊÃÊ R 1. À>ÌÊvÊ1 *ÊÕÀ`ix½`« ë AD}ÕVÕÀVÊ OH >ÞâiÊÌ iÊÃÕLÃÌÀ>Ìi° iÌ iÀÊ-N£ÊÀÊ-NÓÊVÕ`ÊÌ iÀiÌV>ÞÊÜÀ°ÊÜiÛiÀ]ÊÜiÊ`½ÌÊ >ÛiÊ>ÊV ViÊÊÌ ÃÊV>Ãi°Ê/ iÊ >V`®ÊvÀÊ}ÕVÃiÊÛÛiÃÊVÛiÀÃÊvÊ>ÊL>`Êi>Û}Ê b ÌÀ>ÃvÀ>ÌÊÀiµÕÀiÃÊÛiÀÃÊvÊVw}ÕÀ>Ì]ÊÜ V ÊV>ÊÞÊLiÊ>VV«Ã i`ÊÛ>Ê-NÓÊ -Glucuronide STEP 2 }ÀÕ«ÊÌÊ>Ê}`Êi>Û}Ê}ÀÕ«° >Ê-N£Ê«ÀViÃÃÊÜÕ`Ê}ÛiÊÀ>Viâ>Ì]Ê>ÃÊÜiÊÃ>ÜÊÊ-iVÌÊÇ°x®°ÊÊ>``Ì]ÊÌ iÊÃÕLÃÌÀ>ÌiÊ >ÞâiÊÌ iÊ / ÃÊ-NÓÊ«ÀViÃÃÊÀiµÕÀiÃÊ>ÊiâÞiÊ>ÊL}V>ÊV>Ì>ÞÃÌ®Ê ÜÕ`ÊiÞÊÕ`iÀ}Ê>ÊV>ÀLV>ÌÊÀi>ÀÀ>}iiÌÊvÊÃÕLiVÌi`ÊÌÊ- £ÊV`ÌðÊÀÊLÌ Ê ÃÌiÀiV iV>Ê N V>i`Ê1 *}ÕVÕÀÞÊÌÀ>ÃviÀ>Ãi°Ê/ iÊÀi>VÌÊ«ÀVii`ÃÊÛ>Ê ÕÌViÊ>`Ê vÊÌ iÃiÊÀi>ÃÃ]Ê>Ê-NÓÊ«ÀViÃÃÊÃÊÀiµÕÀi`°Ê OH ÛiÀÃÊvÊVw}ÕÀ>ÌÊ>ÃÊiÝ«iVÌi`ÊvÊ>Ê-NÓÊ«ÀViÃîÊÌÊ `iÌiÀiÊÜ iÌ iÀÊ-NÓÊ 7iÊ Ã>ÜÊ Ì ÀiiÊ `vviÀiÌÊ Ài>}iÌÃÊ vÀÊ «iÀvÀ}Ê >Ê -NÓÊ «ÀViÃÃ°Ê 7Ì Ê >Ê Ì Àii]Ê Ì iÊ «À`ÕViÊ>ÊB}ÕVÕÀ`i]ÊÜ V ÊÃÊ } ÞÊÜ>ÌiÀÊÃÕLiÊ>`ÊÃÊ ÃÊÀiµÕÀi`° Þ`ÀÝÞÊ}ÀÕ«ÊÃÊVÛiÀÌi`ÊÌÊ>ÊLiÌÌiÀÊi>Û}Ê}ÀÕ«]ÊvÜi`ÊLÞÊÕVi« VÊ>ÌÌ>V°ÊÞÊ O Ài>`ÞÊiÝVÀiÌi`ÊÊÌ iÊÕÀi°Ê HO vÊÌ iÊÌ ÀiiÊiÌ `ÃÊV>ÊLiÊÕÃi`° >ÞÊ vÕVÌ>Ê }ÀÕ«ÃÊ Õ`iÀ}Ê }ÕVÕÀ`>Ì]Ê LÕÌÊ >V HO OH ÃÊ>`Ê« iÃÊ>ÀiÊÌ iÊÃÌÊVÊV>ÃÃiÃÊvÊV«Õ`ÃÊÌ >ÌÊ HCl, ZnCl2 D-Glucose OH Õ`iÀ}ÊÌ ÃÊiÌ>LVÊ«>Ì Ü>Þ°ÊÀÊiÝ>«i]ÊÀ« i]Ê>ViÌ> OH Cl STEP 3 Bad LG « i]Ê>`ÊV À>« iVÊ>ÀiÊ>ÊiÌ>Lâi`ÊÛ>Ê}ÕVÕÀ`>Ì\ `iÌvÞÊÀi>}iÌÃÊÌ >ÌÊ >V iÛiÊÌ iÊ«ÀViÃÃÊ 1) TsCl, py N `iÌiÀi`ÊÊÃÌi«ÊÓ° 2) NaCl H OH OH H SOCl2 , py H NO Cl PRACTICE the skill 13.19 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã Êi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ> OH N O2N H Cl O O Ìð HO OH HO O O OH Br OH Br HO HO Morphine Acetaminophen Chloramphenicol OH An opiate analgesic An analgesic (pain-relieving) An antibiotic used in eye drops O O HO used to treat severe pain and antipyretic (fever-reducing) agent, to treat bacterial conjuctivitis UDPGA sold under the trade name TylenolTM (a) (b) O P OPO O N N N O -O -O H HO OH OH H OH H OH Cl OH Br Cl (c) (d) Good LG (called UDP) NO N O N H Cl O 2 HO OH HO O 1 *ÊÃÊ>ÊV«Õ`ÊÜÌ Ê>ÊÛiÀÞÊ}`Êi>Û}Ê}ÀÕ«°Ê/ ÃÊ (e) OH Cl (f) OH Br Morphine Acetaminophen Chloramphenicol >À}iÊi>Û}Ê}ÀÕ«AnÊà opiateÊV>i` analgesicÊ1 *°ÊÊÌ ÃÊÌÀ>ÃvÀ>Ì]An analgesicÊi (pain-relieving)Ê An antibiotic used in eye drops APPLY the skill 13.20 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° vÊÌ iÊ Þ`ÀÝÞÊused}ÀÕ«Ã to ÊtreatÊ}ÕVÃi severeÊ >à painÊLiiandÊVÛiÀÌi` antipyreticÊÌ (fever-reducing)Ê>Ê agent, to treat bacterial conjuctivitis TM }`Êi>Û}Ê}ÀÕ«° sold under the trade name Tylenol Ê i>V Ê vÊ Ì iÃiÊ Ì ÀiiÊ V«Õ`Ã]Ê Ì iÊ } } Ìi`Ê Þ`ÀÝÞÊ 2. iÝÌ]Ê>Ê-NÓÊ«ÀViÃÃÊVVÕÀÃÊÊÜ V ÊÌ iÊ`ÀÕ}ÊLi}ÊiÌ>L âi`ÊÃÕV Ê>ÃÊ>Ê>V ®Ê>ÌÌ>VÃÊ1 *]ÊiÝ«i}ÊÌ iÊ}`Ê }ÀÕ«Ê >ÌÌ>VÃÊ 1 *°Ê ÕVÕÀ`>ÌÊ ÃÊ Ì iÊ >Ê iÌ>LVÊ OH Cl i>Û}Ê}ÀÕ«° «>Ì Ü>ÞÊLÞÊÜ V ÊÌ iÃiÊ`ÀÕ}ÃÊ>ÀiÊi>Ìi`ÊvÀÊÌ iÊL`Þ° need more PRACTICE? Try Problems 13.35a–c, 13.44f, 13.52r
klein_c13_564-621hr.indd 594 11/8/10 2:11 PM klein_c13_564-621hr.indd 595 11/8/10 2:11 PM
600 CHAPTER 13 Alcohols and Phenols
SKILLBUILDER 13.7 PREDICTING THE PRODUCTS OF AN OXIDATION REACTION
LEARN the skill *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÊÌ iÊvÜ}ÊÀi>VÌ°
OH CrO3 ± H3O , acetone ? SOLUTION ÊÀ`iÀÊÌÊ«Ài`VÌÊÌ iÊ«À`ÕVÌ]Ê`iÌvÞÊÜ iÌ iÀÊÌ iÊ>V ÊÃÊ«À>ÀÞÊÀÊÃiV`>ÀÞ°ÊÊÌ ÃÊ V>Ãi]ÊÌ iÊ>V ÊÃÊ«À>ÀÞ]Ê>`ÊÌ iÀivÀi]ÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌ iÊ«ÀViÃÃÊÜÊ«À`ÕViÊ STEP 1 >Ê>`i Þ`iÊÀÊ>ÊV>ÀLÝÞVÊ>V`\Ê `iÌvÞÊÜ iÌ iÀÊÌ iÊ O O >V ÊÃÊ«À>ÀÞÊÀÊ ÃiV`>ÀÞ° OH [O] H [O] OH STEP 2 vÊÌ iÊ>V ÊÃÊ «À>ÀÞ]ÊVÃ`iÀÊ Aldehyde Carboxylic acid Ü iÌ iÀÊ>Ê>`i Þ`iÊ ÀÊ>ÊV>ÀLÝÞVÊ>V`ÊÃÊ / iÊ«À`ÕVÌÊÃÊ`iÌiÀi`ÊLÞÊÌ iÊV ViÊvÊÀi>}iÌ°Ê ÀÕÊÌÀÝ`iÊÊ>V`VÊV`ÌÃÊ LÌ>i`° vÀÃÊV ÀVÊ>V`]ÊÜ V ÊÜÊÝ`âiÊÌ iÊ>V ÊÌÜViÊÌÊ}ÛiÊÌ iÊV>ÀLÝÞVÊ>V`°ÊÊÀ`iÀÊ ÌÊÃÌ«Ê>ÌÊÌ iÊ>`i Þ`i]Ê* ÊÜÕ`ÊLiÊÕÃi`ÊÃÌi>`° O STEP 3 À>ÜÊÌ iÊ«À`ÕVÌ° OH CrO3 OH ± H3O , acetone
PRACTICE the skill 13.22 *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÀi>VÌð
OH HO O PCC Na2Cr2O7 CH2Cl2 H2SO4 , H2O (a) H ? (b) ? OH
H xs CrO3 OH ± PCC H3O CH2Cl2 (c) O acetone ? (d) ?
PCC Na2Cr2O7 OH OH CH2Cl2 H2SO4 , H2O (e) ? (f) ? APPLY the skill 13.23 *À«ÃiÊ>ÊÃÞÌ iÃÃÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ìð O
O H
(a) Br H (b) O O
(c) (d) need more PRACTICE? Try Problems 13.35e–f, 13.37, 13.48
klein_c13_564-621hr.indd 600 11/8/10 2:11 PM 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 Cl Cl OH para-Chloro- Haloprogin Clioquinol Tolnaftate meta-xylenol
13.9 Reactions of Alcohols: Substitution and Elimination
SN1 Reactions with Alcohols !S SEEN IN 3ECTION TERTIARY ALCOHOLS WILL UNDERGO A SUBSTITUTION REACTION WHEN TREATED WITH a hydrogen halide.
OH HX X ± H2O
7E SAW THAT THIS REACTION PROCEEDS VIA AN 3N1 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). 7HEN THE STARTING MATERIAL IS AN ALCOHOL WE SAW THAT AN ADDITIONAL STEP IS REQUIRED IN ORDER TO PROTONATE THE HYDROXYL GROUP lRST 4HIS REACTION PROCEEDS VIA A CARBOCATION INTERMEDIATE AND IS therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SN AT AN APPRECIABLE RATE 7HEN DEALING WITH A PRIMARY alcohol, an SN PATHWAY IS REQUIRED IN ORDER TO CONVERT AN ALCOHOL INTO AN ALKYL HALIDE
SN2 Reactions with Alcohols Primary and secondary alcohols will undergo substitution reactions with a variety of reagents, all of which proceed via an SN PROCESS )N THIS SECTION WE WILL EXPLORE THREE SUCH REACTIONS THAT all employ an SN PROCESS
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 2ECALL FROM 3ECTION THAT ALCOHOLS UNDERGO ELIMINATION REACTIONS IN ACIDIC CONDITIONS )N 3ECTION WE SAW THAT ALCOHOLS CAN BE FORMED VIA A REDUCTION PROCESS )N THIS SECTION 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 OR TERTIARY ,ETS lRST CONSIDER THE OXIDATION OF A PRIMARY ALCOHOL 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 PROTON TRANSFER (OWEVER WHEN THE STARTING MATERIAL IS AN ALCOHOL AN ADDITIONAL STEP IS lRST HYDROXYL GROUP !S A RESULT PRIMARY ALCOHOLS CAN BE OXIDIZED TWICE 4HE lRST OXIDATION PRO- 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- 4HIS TRANSFORMATION CAN ALSO BE ACCOMPLISHED VIA AN % PATHWAY IF THE HYDROXYL GROUP IS lRST 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 ACCOMPLISH AN % 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 CHROMIUM TRIOXIDE #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 REARRANGEMENTS ARE OBSERVED IN % 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 ? ? 4HE MECHANISM OF OXIDATION WITH CHROMIC ACID HAS TWO MAIN STEPS -ECHANISM 4HE lRST STEP INVOLVES FORMATION OF A CHROMATE ESTER AND THE SECOND STEP IS AN % PROCESS TO FORM A 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
MEDICALLYSPEAKING 1. Primary alcohols will react with HBr via an SN PROCESS
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 4HE HYDROXYL GROUP IS lRST PROTONATED CONVERTING IT INTO AN EXCELLENT LEAVING GROUP FOLLOWED by an S PROCESS 4HIS REACTION WORKS WELL FOR ("R BUT DOES NOT WORK WELL FOR (#L 4O Cl I S N N REPLACE THE HYDROXYL GROUP WITH CHLORIDE :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. !S SEEN IN 3ECTION AN ALCOHOL CAN BE CONVERTED INTO A TOSYLATE FOLLOWED BY NUCLEOPHILIC 13.9 Reactions of Alcohols: Substitution and Elimination attack.
SN1 Reactions with Alcohols OH OTs – X !S SEEN IN 3ECTION TERTIARY ALCOHOLS WILL UNDERGO A SUBSTITUTION REACTION WHEN TREATED WITH TsCl X py a hydrogen halide. SN2 Bad Good OH HX X leaving group py= leaving group ± H2O N
7E SAW THAT THIS REACTION PROCEEDS VIA AN 3N1 mechanism. pyridine
5SING TOSYL CHLORIDE AND PYRIDINE THE HYDROXYL GROUP IS CONVERTED INTO A TOSYLATE GROUP AN Proton transfer Loss of a leaving group Nucleophilic attack excellent leaving group), which is susceptible to an SN PROCESS .OTICE THE STEREOCHEMICAL H OUTCOME OF THE PREVIOUS REACTION 4HE CONlGURATION OF THE CHIRALITY CENTER IS NOT INVERTED + – – + OH H Br O H2O Br Br during formation of the tosylate, but it is inverted during the SN PROCESS 4HE NET RESULT IS H INVERSION OF CONlGURATION
Recall that an S 1 mechanism has two core steps (loss of leaving group and nucleophilic attack). OH Br N 1) TsCl, py 7HEN THE STARTING MATERIAL IS AN ALCOHOL WE SAW THAT AN ADDITIONAL STEP IS REQUIRED IN ORDER TO 2) NaBr PROTONATE THE HYDROXYL GROUP lRST 4HIS REACTION PROCEEDS VIA A CARBOCATION INTERMEDIATE AND IS R S therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SN AT AN APPRECIABLE RATE 7HEN DEALING WITH A PRIMARY 3. 0RIMARY AND SECONDARY ALCOHOLS REACT WITH 3/#L or PBr via an SN PROCESS alcohol, an SN PATHWAY IS REQUIRED IN ORDER TO CONVERT AN ALCOHOL INTO AN ALKYL HALIDE
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 SN PROCESS )N THIS SECTION WE WILL EXPLORE THREE SUCH REACTIONS THAT all employ an SN PROCESS PBr3 Br
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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 2ECALL FROM 3ECTION THAT ALCOHOLS UNDERGO ELIMINATION REACTIONS IN ACIDIC CONDITIONS )N 3ECTION WE SAW THAT ALCOHOLS CAN BE FORMED VIA A REDUCTION PROCESS )N THIS SECTION 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 OR TERTIARY ,ETS lRST CONSIDER THE OXIDATION OF A PRIMARY ALCOHOL 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 PROTON TRANSFER (OWEVER WHEN THE STARTING MATERIAL IS AN ALCOHOL AN ADDITIONAL STEP IS lRST HYDROXYL GROUP !S A RESULT PRIMARY ALCOHOLS CAN BE OXIDIZED TWICE 4HE lRST OXIDATION PRO- 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. PRACTICALLYSPEAKING once, forming a ketone. Breath Tests to Measure Blood Alcohol Level OH O OH [O] H SO Ì >ÊÃÊ>Ê«À>ÀÞÊ>V °Ê/ iÀivÀi]ÊiÌ >ÊÜÊÀi>VÌÊÜÌ Ê Ý`â}Ê>}iÌÊÊÌ iÊÌÕLi]Ê>`Ê>ÊVÀÊV >}iÊVVÕÀðÊ/ iÊ 2 4 ± ¡ heat R R R R «Ì>ÃÃÕÊ `V À>ÌiÊ Ê >V`VÊ V`ÌÃÊ ÌÊ «À`ÕViÊ >ViÌVÊ iÝÌiÌÊ vÊ Ì iÊ VÀÊ V >}iÊ }ÛiÃÊ >Ê `V>ÌÊ vÊ Ì iÊ L`Ê H >V`° >V ÊVÌiÌ°Ê Major Minor Secondary alcohol Ketone / iÊ Ài>Ì >ÞâiÀ/ ÊÃÊL>Ãi`ÊÊÌ iÊÃ>iÊ`i>]ÊLÕÌÊÌÊÃÊÀiÊ O >VVÕÀ>Ìi°ÊÊi>ÃÕÀi`ÊÛÕiÊvÊLÀi>Ì ÊÃÊLÕLLi`ÊÌ ÀÕ} Ê>Ê LOOKING AHEAD Generally speaking, the ketone is not further oxidized. Tertiary alcohols do not have any pro- ± ± 2– H ± 3± >µÕiÕÃÊ >V`VÊ ÃÕÌÊ vÊ «Ì>ÃÃÕÊ `V À 4HIS TRANSFORMATION CAN ALSO BE ACCOMPLISHED VIA AN % PATHWAY IF THE HYDROXYL GROUP IS lRST ÀÊ>ÊiÝVi«ÌÊÌÊÌ ÃÊ tons at the A position, and as a result, they generally do not undergo oxidation: OH Cr2O7 Cr converted into a better leaving group, such as a tosylate. A strong base can then be employed to }iiÀ>ÊÀÕi]ÊÃiiÊ-iVÌÊ OH >Ìi]Ê >`Ê Ì iÊ V >}iÊ Ê VÀÊ ÃÊ i>ÃÕÀi`Ê ÜÌ Ê >Ê ÕÌÀ>ÛiÌÛÃLiÊ 166-®Ê ëiVÌÀ ACCOMPLISH AN % REACTION Óä°££]ÊÜ iÀiÊÜiÊÜÊi>ÀÊ OH Ethanol Reddish orange Acetic acid Green >LÕÌÊ>ÊëiV>ÊÝ`â}Ê [O] « ÌiÌiÀÊ -iVÌÊ £Ç°££®°Ê ÌÀ>ÀÞÊ ÌÊ no reaction Ài>}iÌÊÌ >ÌÊV>ÊÝ`âiÊ>Ê R R ««Õ>ÀÊLiiv]ÊÌÊÃÊÌÊ«ÃÃLiÊÌÊLi>ÌÊÌ iÊ iÌiÊÌÊvÀÊ>ÊiÃÌiÀ° R ÊÌ iÊ«ÀViÃÃ]ÊiÌ >ÊÃÊÝ`âi`]Ê>`ÊÌ iÊV ÀÕÊÀi>}iÌÊ ÌiÃÌÊLÞÊÃÕV}Ê>ÊLÀi>Ì ÊÌÊ TsCl NaOEt ÃÊÀi`ÕVi`°Ê/ iÊiÜÊV ÀÕÊV«Õ`ÊÃÊ>Ê`vviÀiÌÊVÀ]Ê ÀÊ ÀÃ}Ê ÜÌ Ê >Ê LÀi>Ì Ê OH py OTs A large number of reagents are available for oxidizing primary and secondary alcohols. The E2 >`ÊÌ iÀivÀi]ÊÌ iÊ«À}ÀiÃÃÊvÊÌ iÊÀi>VÌÊV>ÊLiÊÌÀi`Ê vÀià iiÀ°Ê / iÃiÊ ÌiV most common oxidizing reagent is chromic acid (H#R/), which can be formed either from LÞÊÌ iÊVÀÊV >}iÊvÀÊÀi``à À>}iÊÌÊ}Àii°Ê/ ÃÊÀi>V µÕiÃÊ } ÌÊ vÊ >Ê CHROMIUM TRIOXIDE #R/) or from sodium dichromate (Na#RO7) in aqueous acidic solution. ÌÊvÀi`ÊÌ iÊL>ÃÃÊvÀÊ>ÞÊvÊÌ iÊi>ÀÞÊLÀi>Ì ÊÌiÃÌÃÊÌ >ÌÊ «iÀÃ]ÊLÕÌÊÌ iÞÊܽÌÊ O >ÃÃiÃÃi`ÊÌ iÊiÛiÊvÊL`Ê>V °Ê Ài>Ì ÊÌiÃÌÃÊÌ >ÌÊÕÌâiÊ vÊ Ì iÊ «Ì>ÃÃÕÊ 4HE % PROCESS ALSO GENERALLY PRODUCES THE MORE SUBSTITUTED ALKENE AND NO CARBOCATION ± H3O Ì ÃÊÀi>VÌÊ>ÀiÊÃÌÊViÀV>ÞÊ>Û>>Li°Ê/ iÊÌiÃÌÊVÃÃÌÃÊ `V À>Ìi° REARRANGEMENTS ARE OBSERVED IN % PROCESSES Cr O O Acetone vÊ>ÊÌÕLi]ÊÜ iÀiÊiÊi`ÊÃÊvÌÌi`ÊÜÌ Ê>ÊÕÌ «iViÊ>`ÊÌ iÊ Chromium trioxide O Ì iÀÊi`Ê >ÃÊ>ÊL>}°Ê/ iÊÃ`iÊvÊÌ iÊÌÕLiÊVÌ>ÃÊÃ`ÕÊ `V À>ÌiÊÌ >ÌÊÃÊ>`ÃÀLi`ÊÌÊÌ iÊÃÕÀv>ViÊvÊ>ÊiÀÌÊÃ`]Ê HO Cr OH ÃÕV Ê>ÃÊÃV>Ê}i°ÊÃÊÌ iÊÕÃiÀÊLÜÃÊ>ÀÊÌ ÀÕ} ÊÌ iÊÌÕLiÊ>`Ê CONCEPTUAL CHECKPOINT O vÃÊÕ«ÊÌ iÊL>}]ÊÌ iÊ>V ÊÊÌ iÊÕÃiÀ½ÃÊLÀi>Ì ÊÀi>VÌÃÊÜÌ ÊÌ iÊ 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 ? ? 4HE MECHANISM OF OXIDATION WITH CHROMIC ACID HAS TWO MAIN STEPS -ECHANISM 4HE lRST STEP INVOLVES FORMATION OF A CHROMATE ESTER AND THE SECOND STEP IS AN % PROCESS TO FORM A carbon-oxygen P bond (rather than a carbon-carbon P bond).
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MEDICALLYSPEAKING 1. Primary alcohols will react with HBr via an SN PROCESS 4HE MECHANISMS FOR THESE TWO PATHWAYS ARE VERY SIMILAR 4HE lRST FEW STEPS CONVERT A BAD LEAVING group into a good leaving group, then the halide attacks in an SN PROCESS -ECHANISM 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 MECHANISM 13.6 THE REACTION BETWEEN SOCl AND AN ALCOHOL iÀÌiðÊ/ iÃiÊ>}iÌÃÊ>ÀiÊLiiÛi`ÊÌÊÌiÀviÀiÊÜÌ ÊÌ iÊViÊi Ì iÊÌÀi>ÌiÌÊvÊ>Ì iÌi½ÃÊvÌ]ÊVÊÌV ]Ê >`ÊÀ}ÜÀ°Ê + – 2 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 H2O Bad / / SN2 "`ÀÊ >ÌiÀà ]Ê>`Ê iÃiiÝ ° leaving group
OH O Cl 4HE HYDROXYL GROUP IS lRST PROTONATED CONVERTING IT INTO AN EXCELLENT LEAVING GROUP FOLLOWED – OH SOCl Cl S N by an SN PROCESS 4HIS REACTION WORKS WELL FOR ("R BUT DOES NOT WORK WELL FOR (#L 4O 2 ± ± Cl I py SO2 Cl REPLACE THE HYDROXYL GROUP WITH CHLORIDE :N#L is used as a catalyst. O Cl I Cl N OH HCl Cl Cl S ZnCl Cl Cl OH 2 O – Cl para-Chloro- Haloprogin Clioquinol Tolnaftate The catalyst is a Lewis acid that converts the hydroxyl group into a better leaving group. meta-xylenol H H N + Cl + Nuc attack Nuc attack ± O O Cl O Cl on a Lewis acid – loss of LG S – S S ZnCl2 O + – Cl O O OH ZnCl2 O Cl Cl H SN2 Good leaving group 2. !S SEEN IN 3ECTION AN ALCOHOL CAN BE CONVERTED INTO A TOSYLATE FOLLOWED BY NUCLEOPHILIC 13.9 Reactions of Alcohols: Substitution and Elimination attack.
SN1 Reactions with Alcohols OH OTs – X The reaction mechanism for PBr has similar characteristics, including conversion of the !S SEEN IN 3ECTION TERTIARY ALCOHOLS WILL UNDERGO A SUBSTITUTION REACTION WHEN TREATED WITH TsCl X HYDROXYL GROUP INTO A BETTER LEAVING GROUP FOLLOWED BY NUCLEOPHILIC ATTACK -ECHANISM py a hydrogen halide. SN2 Bad Good OH HX X leaving group py= leaving group ± H2O N
7E SAW THAT THIS REACTION PROCEEDS VIA AN 3N1 mechanism. pyridine
5SING TOSYL CHLORIDE AND PYRIDINE THE HYDROXYL GROUP IS CONVERTED INTO A TOSYLATE GROUP AN Proton transfer Loss of a leaving group Nucleophilic attack MECHANISM 13.7 THE REACTION BETWEEN PBr3 AND AN ALCOHOL excellent leaving group), which is susceptible to an SN PROCESS .OTICE THE STEREOCHEMICAL H OUTCOME OF THE PREVIOUS REACTION 4HE CONlGURATION OF THE CHIRALITY CENTER IS NOT INVERTED Br + – – + OH H Br O H2O Br Br during formation of the tosylate, but it is inverted during the SN PROCESS 4HE NET RESULT IS P Br H H + INVERSION OF CONlGURATION Br – OH O Br SN2 Br P ± Br ± HOPBr2 Recall that an S 1 mechanism has two core steps (loss of leaving group and nucleophilic attack). OH Br N 1) TsCl, py Bad Br 7HEN THE STARTING MATERIAL IS AN ALCOHOL WE SAW THAT AN ADDITIONAL STEP IS REQUIRED IN ORDER TO 2) NaBr leaving group PROTONATE THE HYDROXYL GROUP lRST 4HIS REACTION PROCEEDS VIA A CARBOCATION INTERMEDIATE AND IS Good R S leaving group therefore most appropriate for tertiary alcohols. Secondary alcohols undergo SN1 more slowly, and primary alcohols will not undergo SN AT AN APPRECIABLE RATE 7HEN DEALING WITH A PRIMARY 3. 0RIMARY AND SECONDARY ALCOHOLS REACT WITH 3/#L or PBr via an SN PROCESS alcohol, an SN PATHWAY IS REQUIRED IN ORDER TO CONVERT AN ALCOHOL INTO AN ALKYL HALIDE
SOCl2 Cl py SN2 Reactions with Alcohols Notice the similarity among all of the SN PROCESSES THAT WE HAVE SEEN IN THIS SECTION !LL INVOLVE Primary and secondary alcohols will undergo substitution reactions with a variety of reagents, OH the conversion of the hydroxyl group into a better leaving group followed by nucleophilic attack. all of which proceed via an SN PROCESS )N THIS SECTION WE WILL EXPLORE THREE SUCH REACTIONS THAT )F ANY OF THESE REACTIONS OCCURS AT A CHIRALITY CENTER INVERSION OF CONlGURATION IS TO BE EXPECTED all employ an SN PROCESS PBr3 Br
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13.10 Reactions of Alcohols: Oxidation 597 598 CHAPTER 13 Alcohols and Phenols 13.10 Reactions of Alcohols: Oxidation 599
13.10 Reactions of Alcohols: Oxidation 7HEN A PRIMARY ALCOHOL IS OXIDIZED WITH CHROMIC ACID A CARBOXYLIC ACID IS OBTAINED )T IS GENERALLY MECHANISM 13.8 OXIDATION OF AN ALCOHOL WITH CHROMIC ACID DIFlCULT TO CONTROL THE REACTION TO PRODUCE THE ALDEHYDE )N 3ECTION WE SAW THAT ALCOHOLS CAN BE FORMED VIA A REDUCTION PROCESS )N THIS SECTION WE STEP 1 will explore the reverse process, called oxidation, which involves an increase in oxidation state. R O Fast and R O OH O O reversible Na Cr O Oxidation OH ± HO Cr OH O Cr OH ± H O 2 2 7 OH O H H 2 R H2SO4 , H2O RH R OH R O R O
Chromate ester Alcohol Aldehyde Carboxylic H Reduction Difficult to isolate acid STEP 2 The outcome of an oxidation process depends on whether the starting alcohol is primary, R O O R )N ORDER TO PRODUCE THE ALDEHYDE AS THE lNAL PRODUCT IT IS NECESSARY TO USE A MORE SELECTIVE OXIDIZ- SECONDARY OR TERTIARY ,ETS lRST CONSIDER THE OXIDATION OF A PRIMARY ALCOHOL HH ± – O Cr OH O ± H O ± HCrO ing reagent, one that will react with the alcohol but will not react with the aldehyde. Many such H E2 3 3 REAGENTS ARE AVAILABLE INCLUDING PYRIDINIUM CHLOROCHROMATE 0## 0## IS FORMED FROM THE REAC- OH O O R O R [O] [O] tion between pyridine, chromium trioxide, and hydrochloric acid. Chromate ester R H R H R OH H + – Primary alcohol Aldehyde Carboxylic acid N ± CrO3 ± HCl NH CrO3Cl Notice that a primary alcohol has two protons at the A position (the carbon atom bearing the HYDROXYL GROUP !S A RESULT PRIMARY ALCOHOLS CAN BE OXIDIZED TWICE 4HE lRST OXIDATION PRO- Pyridine Pyridinium Chlorochromate duces an aldehyde, and then oxidation of the aldehyde produces a carboxylic acid. Secondary alcohols only have one proton at the A position so they can only be oxidized PRACTICALLYSPEAKING PCC once, forming a ketone. Breath Tests to Measure Blood Alcohol Level 7HEN 0## IS USED AS THE OXIDIZING AGENT AN ALDEHYDE IS PRODUCED AS THE MAJOR PRODUCT 5NDER these conditions, the aldehyde is not further oxidized to the carboxylic acid. OH O [O] ¡ Ì >ÊÃÊ>Ê«À>ÀÞÊ>V °Ê/ iÀivÀi]ÊiÌ >ÊÜÊÀi>VÌÊÜÌ Ê Ý`â}Ê>}iÌÊÊÌ iÊÌÕLi]Ê>`Ê>ÊVÀÊV >}iÊVVÕÀðÊ/ iÊ R R R R «Ì>ÃÃÕÊ `V À>ÌiÊ Ê >V`VÊ V`ÌÃÊ ÌÊ «À`ÕViÊ >ViÌVÊ iÝÌiÌÊ vÊ Ì iÊ VÀÊ V >}iÊ }ÛiÃÊ >Ê `V>ÌÊ vÊ Ì iÊ L`Ê OH O H >V`° >V ÊVÌiÌ°Ê PCC CH Cl Secondary alcohol Ketone / iÊ Ài>Ì >ÞâiÀ/ ÊÃÊL>Ãi`ÊÊÌ iÊÃ>iÊ`i>]ÊLÕÌÊÌÊÃÊÀiÊ R 2 2 RH O >VVÕÀ>Ìi°ÊÊi>ÃÕÀi`ÊÛÕiÊvÊLÀi>Ì ÊÃÊLÕLLi`ÊÌ ÀÕ} Ê>Ê LOOKING AHEAD Generally speaking, the ketone is not further oxidized. Tertiary alcohols do not have any pro- ± Primary Aldehyde ± 2– H ± 3± >µÕiÕÃÊ >V`VÊ ÃÕÌÊ vÊ «Ì>ÃÃÕÊ `V À ÀÊ>ÊiÝVi«ÌÊÌÊÌ ÃÊ tons at the A position, and as a result, they generally do not undergo oxidation: OH Cr2O7 Cr alcohol }iiÀ>ÊÀÕi]ÊÃiiÊ-iVÌÊ OH >Ìi]Ê >`Ê Ì iÊ V >}iÊ Ê VÀÊ ÃÊ i>ÃÕÀi`Ê ÜÌ Ê >Ê ÕÌÀ>ÛiÌÛÃLiÊ 166-®Ê ëiVÌÀ Óä°££]ÊÜ iÀiÊÜiÊÜÊi>ÀÊ OH Ethanol Reddish orange Acetic acid Green -ETHYLENE CHLORIDE #(#L IS TYPICALLY THE SOLVENT USED WHEN 0## IS EMPLOYED >LÕÌÊ>ÊëiV>ÊÝ`â}Ê [O] « ÌiÌiÀÊ -iVÌÊ £Ç°££®°Ê ÌÀ>ÀÞÊ ÌÊ no reaction Secondary alcohols are oxidized only once to form a ketone, which is stable under oxidizing con- Ài>}iÌÊÌ >ÌÊV>ÊÝ`âiÊ>Ê R R ««Õ>ÀÊLiiv]ÊÌÊÃÊÌÊ«ÃÃLiÊÌÊLi>ÌÊÌ iÊ DITIONS 4HEREFORE A SECONDARY ALCOHOL CAN BE OXIDIZED EITHER WITH CHROMIC ACID OR WITH 0## iÌiÊÌÊvÀÊ>ÊiÃÌiÀ° R ÊÌ iÊ«ÀViÃÃ]ÊiÌ >ÊÃÊÝ`âi`]Ê>`ÊÌ iÊV ÀÕÊÀi>}iÌÊ ÌiÃÌÊLÞÊÃÕV}Ê>ÊLÀi>Ì ÊÌÊ ÃÊÀi`ÕVi`°Ê/ iÊiÜÊV ÀÕÊV«Õ`ÊÃÊ>Ê`vviÀiÌÊVÀ]Ê ÀÊ ÀÃ}Ê ÜÌ Ê >Ê LÀi>Ì Ê A large number of reagents are available for oxidizing primary and secondary alcohols. The Na Cr O >`ÊÌ iÀivÀi]ÊÌ iÊ«À}ÀiÃÃÊvÊÌ iÊÀi>VÌÊV>ÊLiÊÌÀi`Ê vÀià iiÀ°Ê / iÃiÊ ÌiV 2 2 7 most common oxidizing reagent is chromic acid (H#R/), which can be formed either from H2SO4 , H2O LÞÊÌ iÊVÀÊV >}iÊvÀÊÀi``à À>}iÊÌÊ}Àii°Ê/ ÃÊÀi>V µÕiÃÊ } ÌÊ vÊ >Ê CHROMIUM TRIOXIDE #R/) or from sodium dichromate (Na#RO7) in aqueous acidic solution. ÌÊvÀi`ÊÌ iÊL>ÃÃÊvÀÊ>ÞÊvÊÌ iÊi>ÀÞÊLÀi>Ì ÊÌiÃÌÃÊÌ >ÌÊ «iÀÃ]ÊLÕÌÊÌ iÞÊܽÌÊ OH O O >ÃÃiÃÃi`ÊÌ iÊiÛiÊvÊL`Ê>V °Ê Ài>Ì ÊÌiÃÌÃÊÌ >ÌÊÕÌâiÊ vÊ Ì iÊ «Ì>ÃÃÕÊ ± H3O Ì ÃÊÀi>VÌÊ>ÀiÊÃÌÊViÀV>ÞÊ>Û>>Li°Ê/ iÊÌiÃÌÊVÃÃÌÃÊ `V À>Ìi° Cr R R RR O O Acetone vÊ>ÊÌÕLi]ÊÜ iÀiÊiÊi`ÊÃÊvÌÌi`ÊÜÌ Ê>ÊÕÌ «iViÊ>`ÊÌ iÊ Secondary Ketone Chromium trioxide O Ì iÀÊi`Ê >ÃÊ>ÊL>}°Ê/ iÊÃ`iÊvÊÌ iÊÌÕLiÊVÌ>ÃÊÃ`ÕÊ PCC `V À>ÌiÊÌ >ÌÊÃÊ>`ÃÀLi`ÊÌÊÌ iÊÃÕÀv>ViÊvÊ>ÊiÀÌÊÃ`]Ê alcohol HO Cr OH CH2Cl2 ÃÕV Ê>ÃÊÃV>Ê}i°ÊÃÊÌ iÊÕÃiÀÊLÜÃÊ>ÀÊÌ ÀÕ} ÊÌ iÊÌÕLiÊ>`Ê O vÃÊÕ«ÊÌ iÊL>}]ÊÌ iÊ>V ÊÊÌ iÊÕÃiÀ½ÃÊLÀi>Ì ÊÀi>VÌÃÊÜÌ ÊÌ iÊ O O 3ODIUM DICHROMATE IS LESS EXPENSIVE BUT 0## IS MORE GENTLE AND OFTEN PREFERRED IF OTHER SENSITIVE + – – + H2SO4 Na O Cr O Cr O Na Chromic acid functional groups are present in the compound. H2O O O Sodium dichromate 4HE MECHANISM OF OXIDATION WITH CHROMIC ACID HAS TWO MAIN STEPS -ECHANISM 4HE lRST STEP INVOLVES FORMATION OF A CHROMATE ESTER AND THE SECOND STEP IS AN % PROCESS TO FORM A carbon-oxygen P bond (rather than a carbon-carbon P bond).
klein_c13_564-621hr.indd 597 11/8/10 2:11 PM klein_c13_564-621hr.indd 598 11/8/10 2:11 PM klein_c13_564-621hr.indd 599 11/8/10 2:11 PM 592 CHAPTER 13 Alcohols and Phenols 13.9 Reactions of Alcohols: Substitution and Elimination 593 594 CHAPTER 13 Alcohols and Phenols
1. Primary alcohols will react with HBr via an SN PROCESS 4HE MECHANISMS FOR THESE TWO PATHWAYS ARE VERY SIMILAR 4HE lRST FEW STEPS CONVERT A BAD LEAVING group into a good leaving group, then the halide attacks in an SN PROCESS -ECHANISM SKILLBUILDER Nucleophilic attack ± Proton transfer loss of a leaving group 13.6 PROPOSING REAGENTS FOR THE CONVERSION OF AN ALCOHOL INTO AN ALKYL HALIDE H + – MECHANISM 13.6 THE REACTION BETWEEN SOCl2 AND AN ALCOHOL OH H Br O Br Br LEARN the skill `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° ± H H2O Bad SN2 leaving group OH Cl
4HE HYDROXYL GROUP IS lRST PROTONATED CONVERTING IT INTO AN EXCELLENT LEAVING GROUP FOLLOWED – OH SOCl Cl by an SN PROCESS 4HIS REACTION WORKS WELL FOR ("R BUT DOES NOT WORK WELL FOR (#L 4O 2 ± ± py SO2 Cl REPLACE THE HYDROXYL GROUP WITH CHLORIDE :N#L is used as a catalyst. Cl OH HCl Cl Cl S SOLUTION ZnCl2 O – / ÃÊÌÀ>ÃvÀ>ÌÊÃÊ>ÊÃÕLÃÌÌÕÌÊ«ÀViÃÃ]ÊÃÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌÊÕÃiÊ-N£ÊV` Cl ÌÃÊÀÊ- ÓÊV`ÌðÊ/ iÊiÞÊv>VÌÀÊÃÊÌ iÊÃÕLÃÌÀ>Ìi°Ê/ iÊÃÕLÃÌÀ>ÌiÊ iÀiÊÃÊÃiV`>ÀÞ]ÊÃÊ The catalyst is a Lewis acid that converts the hydroxyl group into a better leaving group. STEP 1 N H H >ÞâiÊÌ iÊÃÕLÃÌÀ>Ìi° iÌ iÀÊ-N£ÊÀÊ-NÓÊVÕ`ÊÌ iÀiÌV>ÞÊÜÀ°ÊÜiÛiÀ]ÊÜiÊ`½ÌÊ >ÛiÊ>ÊV ViÊÊÌ ÃÊV>Ãi°Ê/ iÊ N + Cl + ÌÀ>ÃvÀ>ÌÊÀiµÕÀiÃÊÛiÀÃÊvÊVw}ÕÀ>Ì]ÊÜ V ÊV>ÊÞÊLiÊ>VV«Ã i`ÊÛ>Ê-NÓÊ Nuc attack Nuc attack ± O O Cl O Cl STEP 2 – S – S S >Ê-N£Ê«ÀViÃÃÊÜÕ`Ê}ÛiÊÀ>Viâ>Ì]Ê>ÃÊÜiÊÃ>ÜÊÊ-iVÌÊÇ°x®°ÊÊ>``Ì]ÊÌ iÊÃÕLÃÌÀ>ÌiÊ on a Lewis acid loss of LG >ÞâiÊÌ iÊ ZnCl2 O ÜÕ`ÊiÞÊÕ`iÀ}Ê>ÊV>ÀLV>ÌÊÀi>ÀÀ>}iiÌÊvÊÃÕLiVÌi`ÊÌÊ-N£ÊV`ÌðÊÀÊLÌ Ê + – Cl O O ÃÌiÀiV iV>Ê OH ZnCl2 O Cl Cl ÕÌViÊ>`Ê vÊÌ iÃiÊÀi>ÃÃ]Ê>Ê-NÓÊ«ÀViÃÃÊÃÊÀiµÕÀi`°Ê H `iÌiÀiÊÜ iÌ iÀÊ- ÓÊ 7iÊ Ã>ÜÊ Ì ÀiiÊ `vviÀiÌÊ Ài>}iÌÃÊ vÀÊ «iÀvÀ}Ê >Ê - ÓÊ «ÀViÃÃ°Ê 7Ì Ê >Ê Ì Àii]Ê Ì iÊ SN2 Good N N ÃÊÀiµÕÀi`° leaving group Þ`ÀÝÞÊ}ÀÕ«ÊÃÊVÛiÀÌi`ÊÌÊ>ÊLiÌÌiÀÊi>Û}Ê}ÀÕ«]ÊvÜi`ÊLÞÊÕVi« VÊ>ÌÌ>V°ÊÞÊ 2. !S SEEN IN 3ECTION AN ALCOHOL CAN BE CONVERTED INTO A TOSYLATE FOLLOWED BY NUCLEOPHILIC vÊÌ iÊÌ ÀiiÊiÌ `ÃÊV>ÊLiÊÕÃi`° attack.
HCl, ZnCl2 OH Cl OH OTs – X The reaction mechanism for PBr has similar characteristics, including conversion of the STEP 3 TsCl X HYDROXYL GROUP INTO A BETTER LEAVING GROUP FOLLOWED BY NUCLEOPHILIC ATTACK -ECHANISM `iÌvÞÊÀi>}iÌÃÊÌ >ÌÊ py SN2 >V iÛiÊÌ iÊ«ÀViÃÃÊ 1) TsCl, py `iÌiÀi`ÊÊÃÌi«ÊÓ° 2) NaCl Bad Good leaving group py= leaving group SOCl2 , py N pyridine PRACTICE the skill 13.19 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã Êi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ> Ìð 5SING TOSYL CHLORIDE AND PYRIDINE THE HYDROXYL GROUP IS CONVERTED INTO A TOSYLATE GROUP AN MECHANISM 13.7 THE REACTION BETWEEN PBr3 AND AN ALCOHOL OH Br OH Br excellent leaving group), which is susceptible to an SN PROCESS .OTICE THE STEREOCHEMICAL OUTCOME OF THE PREVIOUS REACTION 4HE CONlGURATION OF THE CHIRALITY CENTER IS NOT INVERTED Br during formation of the tosylate, but it is inverted during the SN PROCESS 4HE NET RESULT IS P Br H + (a) (b) INVERSION OF CONlGURATION Br – OH O Br SN2 Br P ± Br ± HOPBr2 OH Br 1) TsCl, py Bad Br 2) NaBr leaving group Good Cl Br R S OH OH leaving group (c) (d)
3. 0RIMARY AND SECONDARY ALCOHOLS REACT WITH 3/#L or PBr via an SN PROCESS
SOCl2 Cl py (e) OH Cl (f) OH Br Notice the similarity among all of the SN PROCESSES THAT WE HAVE SEEN IN THIS SECTION !LL INVOLVE 13.20 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° OH the conversion of the hydroxyl group into a better leaving group followed by nucleophilic attack. APPLY the skill )F ANY OF THESE REACTIONS OCCURS AT A CHIRALITY CENTER INVERSION OF CONlGURATION IS TO BE EXPECTED
PBr3 Br OH Cl
need more PRACTICE? Try Problems 13.35a–c, 13.44f, 13.52r
klein_c13_564-621hr.indd 592 11/8/10 2:11 PM klein_c13_564-621hr.indd 593 11/8/10 2:11 PM klein_c13_564-621hr.indd 594 11/8/10 2:11 PM
598 CHAPTER 13 Alcohols and Phenols 13.10 Reactions of Alcohols: Oxidation 599 600 CHAPTER 13 Alcohols and Phenols
7HEN A PRIMARY ALCOHOL IS OXIDIZED WITH CHROMIC ACID A CARBOXYLIC ACID IS OBTAINED )T IS GENERALLY MECHANISM 13.8 OXIDATION OF AN ALCOHOL WITH CHROMIC ACID DIFlCULT TO CONTROL THE REACTION TO PRODUCE THE ALDEHYDE SKILLBUILDER STEP 1 13.7 PREDICTING THE PRODUCTS OF AN OXIDATION REACTION R O Fast and R O OH O O reversible Na Cr O OH ± HO Cr OH ± 2 2 7 H H O Cr OH H2O LEARN the skill *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÊÌ iÊvÜ}ÊÀi>VÌ° R H2SO4 , H2O RH R OH R O R O Chromate ester Alcohol Aldehyde Carboxylic OH CrO3 ± Difficult to isolate acid H O , acetone STEP 2 3 ? O R O R )N ORDER TO PRODUCE THE ALDEHYDE AS THE lNAL PRODUCT IT IS NECESSARY TO USE A MORE SELECTIVE OXIDIZ- SOLUTION HH – O Cr OH O ± H O± ± HCrO ing reagent, one that will react with the alcohol but will not react with the aldehyde. Many such H E2 3 3 ÊÀ`iÀÊÌÊ«Ài`VÌÊÌ iÊ«À`ÕVÌ]Ê`iÌvÞÊÜ iÌ iÀÊÌ iÊ>V ÊÃÊ«À>ÀÞÊÀÊÃiV`>ÀÞ°ÊÊÌ ÃÊ REAGENTS ARE AVAILABLE INCLUDING PYRIDINIUM CHLOROCHROMATE 0## 0## IS FORMED FROM THE REAC- R O R V>Ãi]ÊÌ iÊ>V ÊÃÊ«À>ÀÞ]Ê>`ÊÌ iÀivÀi]ÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌ iÊ«ÀViÃÃÊÜÊ«À`ÕViÊ tion between pyridine, chromium trioxide, and hydrochloric acid. STEP 1 >Ê>`i Þ`iÊÀÊ>ÊV>ÀLÝÞVÊ>V`\Ê Chromate ester `iÌvÞÊÜ iÌ iÀÊÌ iÊ O O >V ÊÃÊ«À>ÀÞÊÀÊ + – ÃiV`>ÀÞ° OH [O] H [O] OH N ± CrO3 ± HCl NH CrO3Cl STEP 2 vÊÌ iÊ>V ÊÃÊ Pyridinium Chlorochromate Pyridine «À>ÀÞ]ÊVÃ`iÀÊ Aldehyde Carboxylic acid Ü iÌ iÀÊ>Ê>`i Þ`iÊ PCC ÀÊ>ÊV>ÀLÝÞVÊ>V`ÊÃÊ / iÊ«À`ÕVÌÊÃÊ`iÌiÀi`ÊLÞÊÌ iÊV ViÊvÊÀi>}iÌ°Ê ÀÕÊÌÀÝ`iÊÊ>V`VÊV`ÌÃÊ PRACTICALLYSPEAKING LÌ>i`° vÀÃÊV ÀVÊ>V`]ÊÜ V ÊÜÊÝ`âiÊÌ iÊ>V ÊÌÜViÊÌÊ}ÛiÊÌ iÊV>ÀLÝÞVÊ>V`°ÊÊÀ`iÀÊ Breath Tests to Measure Blood Alcohol Level 7HEN 0## IS USED AS THE OXIDIZING AGENT AN ALDEHYDE IS PRODUCED AS THE MAJOR PRODUCT 5NDER these conditions, the aldehyde is not further oxidized to the carboxylic acid. ÌÊÃÌ«Ê>ÌÊÌ iÊ>`i Þ`i]Ê* ÊÜÕ`ÊLiÊÕÃi`ÊÃÌi>`° O Ì >ÊÃÊ>Ê«À>ÀÞÊ>V °Ê/ iÀivÀi]ÊiÌ >ÊÜÊÀi>VÌÊÜÌ Ê Ý`â}Ê>}iÌÊÊÌ iÊÌÕLi]Ê>`Ê>ÊVÀÊV >}iÊVVÕÀðÊ/ iÊ STEP 3 «Ì>ÃÃÕÊ `V À>ÌiÊ Ê >V`VÊ V`ÌÃÊ ÌÊ «À`ÕViÊ >ViÌVÊ iÝÌiÌÊ vÊ Ì iÊ VÀÊ V >}iÊ }ÛiÃÊ >Ê `V>ÌÊ vÊ Ì iÊ L`Ê OH O À>ÜÊÌ iÊ«À`ÕVÌ° OH CrO3 OH >V`° >V ÊVÌiÌ°Ê PCC ± CH Cl H3O , acetone / iÊ Ài>Ì >ÞâiÀ/ ÊÃÊL>Ãi`ÊÊÌ iÊÃ>iÊ`i>]ÊLÕÌÊÌÊÃÊÀiÊ R 2 2 RH O >VVÕÀ>Ìi°ÊÊi>ÃÕÀi`ÊÛÕiÊvÊLÀi>Ì ÊÃÊLÕLLi`ÊÌ ÀÕ} Ê>Ê ± Primary Aldehyde PRACTICE the skill 13.22 *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÀi>VÌð ± 2– H ± 3± >µÕiÕÃÊ >V`VÊ ÃÕÌÊ vÊ «Ì>ÃÃÕÊ `V À OH Cr2O7 Cr alcohol OH >Ìi]Ê >`Ê Ì iÊ V >}iÊ Ê VÀÊ ÃÊ i>ÃÕÀi`Ê OH ÜÌ Ê >Ê ÕÌÀ>ÛiÌÛÃLiÊ 166-®Ê ëiVÌÀ Ethanol Reddish orange Acetic acid Green -ETHYLENE CHLORIDE #(#L IS TYPICALLY THE SOLVENT USED WHEN 0## IS EMPLOYED HO O PCC « ÌiÌiÀÊ -iVÌÊ £Ç°££®°Ê ÌÀ>ÀÞÊ ÌÊ Secondary alcohols are oxidized only once to form a ketone, which is stable under oxidizing con- Na2Cr2O7 CH2Cl2 ««Õ>ÀÊLiiv]ÊÌÊÃÊÌÊ«ÃÃLiÊÌÊLi>ÌÊÌ iÊ H2SO4 , H2O DITIONS 4HEREFORE A SECONDARY ALCOHOL CAN BE OXIDIZED EITHER WITH CHROMIC ACID OR WITH 0## (a) H ? (b) ? ÊÌ iÊ«ÀViÃÃ]ÊiÌ >ÊÃÊÝ`âi`]Ê>`ÊÌ iÊV ÀÕÊÀi>}iÌÊ ÌiÃÌÊLÞÊÃÕV}Ê>ÊLÀi>Ì ÊÌÊ ÃÊÀi`ÕVi`°Ê/ iÊiÜÊV ÀÕÊV«Õ`ÊÃÊ>Ê`vviÀiÌÊVÀ]Ê ÀÊ ÀÃ}Ê ÜÌ Ê >Ê LÀi>Ì Ê OH Na2Cr2O7 >`ÊÌ iÀivÀi]ÊÌ iÊ«À}ÀiÃÃÊvÊÌ iÊÀi>VÌÊV>ÊLiÊÌÀi`Ê vÀià iiÀ°Ê / iÃiÊ ÌiV H xs CrO3 H2SO4 , H2O OH ± PCC LÞÊÌ iÊVÀÊV >}iÊvÀÊÀi``à À>}iÊÌÊ}Àii°Ê/ ÃÊÀi>V µÕiÃÊ } ÌÊ vÊ >Ê H3O (d) CH2Cl2 ÌÊvÀi`ÊÌ iÊL>ÃÃÊvÀÊ>ÞÊvÊÌ iÊi>ÀÞÊLÀi>Ì ÊÌiÃÌÃÊÌ >ÌÊ «iÀÃ]ÊLÕÌÊÌ iÞÊܽÌÊ (c) O acetone ? OH O ? >ÃÃiÃÃi`ÊÌ iÊiÛiÊvÊL`Ê>V °Ê Ài>Ì ÊÌiÃÌÃÊÌ >ÌÊÕÌâiÊ vÊ Ì iÊ «Ì>ÃÃÕÊ Ì ÃÊÀi>VÌÊ>ÀiÊÃÌÊViÀV>ÞÊ>Û>>Li°Ê/ iÊÌiÃÌÊVÃÃÌÃÊ `V À>Ìi° PCC Na2Cr2O7 R R RR OH OH CH2Cl2 H2SO4 , H2O vÊ>ÊÌÕLi]ÊÜ iÀiÊiÊi`ÊÃÊvÌÌi`ÊÜÌ Ê>ÊÕÌ «iViÊ>`ÊÌ iÊ (e) ? (f) ? Secondary Ketone Ì iÀÊi`Ê >ÃÊ>ÊL>}°Ê/ iÊÃ`iÊvÊÌ iÊÌÕLiÊVÌ>ÃÊÃ`ÕÊ PCC alcohol `V À>ÌiÊÌ >ÌÊÃÊ>`ÃÀLi`ÊÌÊÌ iÊÃÕÀv>ViÊvÊ>ÊiÀÌÊÃ`]Ê CH2Cl2 APPLY the skill 13.23 *À«ÃiÊ>ÊÃÞÌ iÃÃÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ìð ÃÕV Ê>ÃÊÃV>Ê}i°ÊÃÊÌ iÊÕÃiÀÊLÜÃÊ>ÀÊÌ ÀÕ} ÊÌ iÊÌÕLiÊ>`Ê O vÃÊÕ«ÊÌ iÊL>}]ÊÌ iÊ>V ÊÊÌ iÊÕÃiÀ½ÃÊLÀi>Ì ÊÀi>VÌÃÊÜÌ ÊÌ iÊ 3ODIUM DICHROMATE IS LESS EXPENSIVE BUT 0## IS MORE GENTLE AND OFTEN PREFERRED IF OTHER SENSITIVE O functional groups are present in the compound. H (a) Br H (b) O O
(c) (d)
need more PRACTICE? Try Problems 13.35e–f, 13.37, 13.48
klein_c13_564-621hr.indd 598 11/8/10 2:11 PM klein_c13_564-621hr.indd 599 11/8/10 2:11 PM klein_c13_564-621hr.indd 600 11/8/10 2:11 PM 13.9 Reactions of Alcohols: Substitution and Elimination 593 594 CHAPTER 13 Alcohols and Phenols 13.9 Reactions of Alcohols: Substitution and Elimination 595
OH 4HE MECHANISMS FOR THESE TWO PATHWAYS ARE VERY SIMILAR 4HE lRST FEW STEPS CONVERT A BAD LEAVING PRACTICALLYSPEAKING O O group into a good leaving group, then the halide attacks in an SN PROCESS -ECHANISM SKILLBUILDER HO Drug Metabolism HO 13.6 PROPOSING REAGENTS FOR THE CONVERSION OF AN ALCOHOL INTO AN ALKYL HALIDE OH ÀÕ}ÊiÌ>LÃÊÀiviÀÃÊÌÊÌ iÊÃiÌÊvÊÀi>VÌÃÊLÞÊÜ V Ê`ÀÕ}ÃÊ>ÀiÊ O UDP VÛiÀÌi`ÊÌÊÌ iÀÊV«Õ`ÃÊÌ >ÌÊ>ÀiÊiÌ iÀÊÕÃi`ÊLÞÊÌ iÊL`ÞÊ MECHANISM 13.6 THE REACTION BETWEEN SOCl2 AND AN ALCOHOL LEARN the skill `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° ÀÊiÝVÀiÌi`°Ê"ÕÀÊL`iÃÊ`ëÃiÊvÊÌ iÊi`V>ÌÃÊÜiÊ}iÃÌÊLÞÊ ROH Bad >ÊÛ>ÀiÌÞÊvÊiÌ>LVÊ«>Ì Ü>ÞÃ°Ê UDP-glucuronyl-transferase leaving group OH Cl "iÊ VÊ iÌ>LVÊ «>Ì Ü>ÞÊ ÃÊ V>i`Ê }ÕVÕÀVÊ >V`Ê VÕ}>Ì]Ê ÀÊ Ã«ÞÊ }ÕVÕÀ`>Ì°Ê / ÃÊ «ÀViÃÃÊ ÃÊ ± –H – OH SOCl2 Cl ÛiÀÞÊÃ>ÀÊÌÊ>ÊvÊÌ iÊ-NÓÊ«ÀViÃÃiÃÊÌ >ÌÊÜiÊÛiÃÌ}>Ìi`Ê ± SO ± Cl py 2 Ê Ì iÊ «ÀiÛÕÃÊ ÃiVÌ°Ê -«iVvV>Þ]Ê >Ê L>`Ê i>Û}Ê }ÀÕ«Ê Þ`ÀÝÞ®Ê ÃÊ vÀÃÌÊ VÛiÀÌi`Ê ÌÊ >Ê }`Ê i>Û}Ê }ÀÕ«]Ê v Cl OH Üi`Ê LÞÊ ÕVi« VÊ >ÌÌ>V°Ê ÕVÕÀ`>ÌÊ iÝ LÌÃÊ Ì iÊ Cl S SOLUTION O Ã>iÊÌÜÊiÞÊÃÌi«Ã°Ê O O – / ÃÊÌÀ>ÃvÀ>ÌÊÃÊ>ÊÃÕLÃÌÌÕÌÊ«ÀViÃÃ]ÊÃÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌÊÕÃiÊ-N£ÊV` HO HO O Cl STEP 1 ÌÃÊÀÊ-NÓÊV`ÌðÊ/ iÊiÞÊv>VÌÀÊÃÊÌ iÊÃÕLÃÌÀ>Ìi°Ê/ iÊÃÕLÃÌÀ>ÌiÊ iÀiÊÃÊÃiV`>ÀÞ]ÊÃÊ R 1. À>ÌÊvÊ1 *ÊÕÀ`ix½`« ë AD}ÕVÕÀVÊ OH H H >ÞâiÊÌ iÊÃÕLÃÌÀ>Ìi° iÌ iÀÊ-N£ÊÀÊ-NÓÊVÕ`ÊÌ iÀiÌV>ÞÊÜÀ°ÊÜiÛiÀ]ÊÜiÊ`½ÌÊ >ÛiÊ>ÊV ViÊÊÌ ÃÊV>Ãi°Ê/ iÊ N >V`®ÊvÀÊ}ÕVÃiÊÛÛiÃÊVÛiÀÃÊvÊ>ÊL>`Êi>Û}Ê b + Cl + ÌÀ>ÃvÀ>ÌÊÀiµÕÀiÃÊÛiÀÃÊvÊVw}ÕÀ>Ì]ÊÜ V ÊV>ÊÞÊLiÊ>VV«Ã i`ÊÛ>Ê-NÓÊ -Glucuronide O O Cl O Cl STEP 2 }ÀÕ«ÊÌÊ>Ê}`Êi>Û}Ê}ÀÕ«° S – S S >Ê-N£Ê«ÀViÃÃÊÜÕ`Ê}ÛiÊÀ>Viâ>Ì]Ê>ÃÊÜiÊÃ>ÜÊÊ-iVÌÊÇ°x®°ÊÊ>``Ì]ÊÌ iÊÃÕLÃÌÀ>ÌiÊ >ÞâiÊÌ iÊ / ÃÊ-NÓÊ«ÀViÃÃÊÀiµÕÀiÃÊ>ÊiâÞiÊ>ÊL}V>ÊV>Ì>ÞÃÌ®Ê O ÜÕ`ÊiÞÊÕ`iÀ}Ê>ÊV>ÀLV>ÌÊÀi>ÀÀ>}iiÌÊvÊÃÕLiVÌi`ÊÌÊ- £ÊV`ÌðÊÀÊLÌ Ê Cl O O ÃÌiÀiV iV>Ê N V>i`Ê1 *}ÕVÕÀÞÊÌÀ>ÃviÀ>Ãi°Ê/ iÊÀi>VÌÊ«ÀVii`ÃÊÛ>Ê ÕÌViÊ>`Ê vÊÌ iÃiÊÀi>ÃÃ]Ê>Ê-NÓÊ«ÀViÃÃÊÃÊÀiµÕÀi`°Ê OH ÛiÀÃÊvÊVw}ÕÀ>ÌÊ>ÃÊiÝ«iVÌi`ÊvÊ>Ê-NÓÊ«ÀViÃîÊÌÊ `iÌiÀiÊÜ iÌ iÀÊ- ÓÊ 7iÊ Ã>ÜÊ Ì ÀiiÊ `vviÀiÌÊ Ài>}iÌÃÊ vÀÊ «iÀvÀ}Ê >Ê - ÓÊ «ÀViÃÃ°Ê 7Ì Ê >Ê Ì Àii]Ê Ì iÊ Good N N «À`ÕViÊ>ÊB}ÕVÕÀ`i]ÊÜ V ÊÃÊ } ÞÊÜ>ÌiÀÊÃÕLiÊ>`ÊÃÊ ÃÊÀiµÕÀi`° Þ`ÀÝÞÊ}ÀÕ«ÊÃÊVÛiÀÌi`ÊÌÊ>ÊLiÌÌiÀÊi>Û}Ê}ÀÕ«]ÊvÜi`ÊLÞÊÕVi« VÊ>ÌÌ>V°ÊÞÊ leaving group O Ài>`ÞÊiÝVÀiÌi`ÊÊÌ iÊÕÀi°Ê HO vÊÌ iÊÌ ÀiiÊiÌ `ÃÊV>ÊLiÊÕÃi`° >ÞÊ vÕVÌ>Ê }ÀÕ«ÃÊ Õ`iÀ}Ê }ÕVÕÀ`>Ì]Ê LÕÌÊ >V HO OH ÃÊ>`Ê« iÃÊ>ÀiÊÌ iÊÃÌÊVÊV>ÃÃiÃÊvÊV«Õ`ÃÊÌ >ÌÊ HCl, ZnCl2 D-Glucose OH Õ`iÀ}ÊÌ ÃÊiÌ>LVÊ«>Ì Ü>Þ°ÊÀÊiÝ>«i]ÊÀ« i]Ê>ViÌ> OH Cl The reaction mechanism for PBr has similar characteristics, including conversion of the STEP 3 Bad LG « i]Ê>`ÊV À>« iVÊ>ÀiÊ>ÊiÌ>Lâi`ÊÛ>Ê}ÕVÕÀ`>Ì\ HYDROXYL GROUP INTO A BETTER LEAVING GROUP FOLLOWED BY NUCLEOPHILIC ATTACK -ECHANISM `iÌvÞÊÀi>}iÌÃÊÌ >ÌÊ >V iÛiÊÌ iÊ«ÀViÃÃÊ 1) TsCl, py N `iÌiÀi`ÊÊÃÌi«ÊÓ° 2) NaCl H OH OH H SOCl2 , py H NO Cl PRACTICE the skill 13.19 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã Êi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ> OH N O2N H Cl O O Ìð HO OH HO O O MECHANISM 13.7 THE REACTION BETWEEN PBr3 AND AN ALCOHOL OH Br OH Br HO HO Morphine Acetaminophen Chloramphenicol Br OH An opiate analgesic An analgesic (pain-relieving) An antibiotic used in eye drops HO used to treat severe pain and antipyretic (fever-reducing) agent, to treat bacterial conjuctivitis P Br H O O UDPGA sold under the trade name TylenolTM + (a) (b) O N OH Br O Br – S 2 Br O P OPO ± N ± P Br HOPBr2 N N O -O -O H Bad Br HO OH OH H leaving group OH H Good OH Cl OH Br Cl leaving group (c) (d) Good LG (called UDP) NO N O N H Cl O 2 HO OH HO O 1 *ÊÃÊ>ÊV«Õ`ÊÜÌ Ê>ÊÛiÀÞÊ}`Êi>Û}Ê}ÀÕ«°Ê/ ÃÊ (e) OH Cl (f) OH Br Morphine Acetaminophen Chloramphenicol Notice the similarity among all of the SN PROCESSES THAT WE HAVE SEEN IN THIS SECTION !LL INVOLVE >À}iÊi>Û}Ê}ÀÕ«AnÊà opiateÊV>i` analgesicÊ1 *°ÊÊÌ ÃÊÌÀ>ÃvÀ>Ì]An analgesicÊi (pain-relieving)Ê An antibiotic used in eye drops the conversion of the hydroxyl group into a better leaving group followed by nucleophilic attack. APPLY the skill 13.20 `iÌvÞÊÌ iÊÀi>}iÌÃÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>VV«Ã ÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ì° vÊÌ iÊ Þ`ÀÝÞÊused}ÀÕ«Ã to ÊtreatÊ}ÕVÃi severeÊ >à painÊLiiandÊVÛiÀÌi` antipyreticÊÌ (fever-reducing)Ê>Ê agent, to treat bacterial conjuctivitis TM )F ANY OF THESE REACTIONS OCCURS AT A CHIRALITY CENTER INVERSION OF CONlGURATION IS TO BE EXPECTED }`Êi>Û}Ê}ÀÕ«° sold under the trade name Tylenol Ê i>V Ê vÊ Ì iÃiÊ Ì ÀiiÊ V«Õ`Ã]Ê Ì iÊ } } Ìi`Ê Þ`ÀÝÞÊ 2. iÝÌ]Ê>Ê-NÓÊ«ÀViÃÃÊVVÕÀÃÊÊÜ V ÊÌ iÊ`ÀÕ}ÊLi}ÊiÌ>L âi`ÊÃÕV Ê>ÃÊ>Ê>V ®Ê>ÌÌ>VÃÊ1 *]ÊiÝ«i}ÊÌ iÊ}`Ê }ÀÕ«Ê >ÌÌ>VÃÊ 1 *°Ê ÕVÕÀ`>ÌÊ ÃÊ Ì iÊ >Ê iÌ>LVÊ OH Cl i>Û}Ê}ÀÕ«° «>Ì Ü>ÞÊLÞÊÜ V ÊÌ iÃiÊ`ÀÕ}ÃÊ>ÀiÊi>Ìi`ÊvÀÊÌ iÊL`Þ°
need more PRACTICE? Try Problems 13.35a–c, 13.44f, 13.52r
klein_c13_564-621hr.indd 593 11/8/10 2:11 PM klein_c13_564-621hr.indd 594 11/8/10 2:11 PM klein_c13_564-621hr.indd 595 11/8/10 2:11 PM
13.10 Reactions of Alcohols: Oxidation 599 600 CHAPTER 13 Alcohols and Phenols
7HEN A PRIMARY ALCOHOL IS OXIDIZED WITH CHROMIC ACID A CARBOXYLIC ACID IS OBTAINED )T IS GENERALLY DIFlCULT TO CONTROL THE REACTION TO PRODUCE THE ALDEHYDE SKILLBUILDER 13.7 PREDICTING THE PRODUCTS OF AN OXIDATION REACTION OH O O Na2Cr2O7 LEARN the skill *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÊÌ iÊvÜ}ÊÀi>VÌ° R H2SO4 , H2O RH R OH
Alcohol Aldehyde Carboxylic OH CrO3 Difficult to isolate acid ± H3O , acetone ? )N ORDER TO PRODUCE THE ALDEHYDE AS THE lNAL PRODUCT IT IS NECESSARY TO USE A MORE SELECTIVE OXIDIZ- SOLUTION ing reagent, one that will react with the alcohol but will not react with the aldehyde. Many such ÊÀ`iÀÊÌÊ«Ài`VÌÊÌ iÊ«À`ÕVÌ]Ê`iÌvÞÊÜ iÌ iÀÊÌ iÊ>V ÊÃÊ«À>ÀÞÊÀÊÃiV`>ÀÞ°ÊÊÌ ÃÊ REAGENTS ARE AVAILABLE INCLUDING PYRIDINIUM CHLOROCHROMATE 0## 0## IS FORMED FROM THE REAC- V>Ãi]ÊÌ iÊ>V ÊÃÊ«À>ÀÞ]Ê>`ÊÌ iÀivÀi]ÊÜiÊÕÃÌÊ`iV`iÊÜ iÌ iÀÊÌ iÊ«ÀViÃÃÊÜÊ«À`ÕViÊ tion between pyridine, chromium trioxide, and hydrochloric acid. STEP 1 >Ê>`i Þ`iÊÀÊ>ÊV>ÀLÝÞVÊ>V`\Ê `iÌvÞÊÜ iÌ iÀÊÌ iÊ O O >V ÊÃÊ«À>ÀÞÊÀÊ + – ÃiV`>ÀÞ° OH [O] H [O] OH N ± CrO3 ± HCl NH CrO3Cl STEP 2 vÊÌ iÊ>V ÊÃÊ Pyridinium Chlorochromate Pyridine «À>ÀÞ]ÊVÃ`iÀÊ Aldehyde Carboxylic acid Ü iÌ iÀÊ>Ê>`i Þ`iÊ PCC ÀÊ>ÊV>ÀLÝÞVÊ>V`ÊÃÊ / iÊ«À`ÕVÌÊÃÊ`iÌiÀi`ÊLÞÊÌ iÊV ViÊvÊÀi>}iÌ°Ê ÀÕÊÌÀÝ`iÊÊ>V`VÊV`ÌÃÊ LÌ>i`° 7HEN 0## IS USED AS THE OXIDIZING AGENT AN ALDEHYDE IS PRODUCED AS THE MAJOR PRODUCT 5NDER vÀÃÊV ÀVÊ>V`]ÊÜ V ÊÜÊÝ`âiÊÌ iÊ>V ÊÌÜViÊÌÊ}ÛiÊÌ iÊV>ÀLÝÞVÊ>V`°ÊÊÀ`iÀÊ these conditions, the aldehyde is not further oxidized to the carboxylic acid. ÌÊÃÌ«Ê>ÌÊÌ iÊ>`i Þ`i]Ê* ÊÜÕ`ÊLiÊÕÃi`ÊÃÌi>`° O STEP 3 OH O À>ÜÊÌ iÊ«À`ÕVÌ° OH CrO3 OH PCC ± H3O , acetone R CH2Cl2 RH
Primary Aldehyde PRACTICE the skill 13.22 *Ài`VÌÊÌ iÊ>ÀÊÀ}>VÊ«À`ÕVÌÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÀi>VÌð alcohol OH
-ETHYLENE CHLORIDE #(#L IS TYPICALLY THE SOLVENT USED WHEN 0## IS EMPLOYED HO O PCC Secondary alcohols are oxidized only once to form a ketone, which is stable under oxidizing con- Na2Cr2O7 CH2Cl2 H2SO4 , H2O DITIONS 4HEREFORE A SECONDARY ALCOHOL CAN BE OXIDIZED EITHER WITH CHROMIC ACID OR WITH 0## (a) H ? (b) ? OH Na2Cr2O7 H xs CrO3 H2SO4 , H2O OH ± PCC H3O CH2Cl2 (c) O acetone ? (d) OH O ?
PCC Na2Cr2O7 R R RR OH OH CH2Cl2 H2SO4 , H2O (e) ? (f) ? Secondary Ketone PCC alcohol CH2Cl2 APPLY the skill 13.23 *À«ÃiÊ>ÊÃÞÌ iÃÃÊvÀÊi>V ÊvÊÌ iÊvÜ}ÊÌÀ>ÃvÀ>Ìð O 3ODIUM DICHROMATE IS LESS EXPENSIVE BUT 0## IS MORE GENTLE AND OFTEN PREFERRED IF OTHER SENSITIVE O functional groups are present in the compound. H (a) Br H (b) O O
(c) (d)
need more PRACTICE? Try Problems 13.35e–f, 13.37, 13.48
klein_c13_564-621hr.indd 599 11/8/10 2:11 PM klein_c13_564-621hr.indd 600 11/8/10 2:11 PM