Organic Chemistry I

Home , Haloalkane, Intramolecular reaction, Leaving group, Phosphite ester, Phosphorus tribromide, Phosphorus triiodide

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, Structure and Function (7th edition) By P. Vollhardt and N. Schore, Elsevier, 2014 1 336 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

In Summary Another mode of reactivity of carbocations, in addition to regular SN1 and E1 processes, is rearrangement by hydride or alkyl shifts. In such rearrangements, the migrating group delivers its bonding electron pair to a positively charged carbon neighbor, exchanging places with the charge. Rearrangement may lead to a more stable cation—as in the conversion of a secondary cation into a tertiary one. Primary alcohols also can 336 CHAPTER undergo9 Further rearrangement, Reactions but ofthey Alcohols do so by andconcerted the Chemistry pathways and of notEthers through the inter- mediacy of primary cations.

In Summary Another mode of reactivity of carbocations, in addition to regular SN1 and E1 processes, is rearrangement by hydride or alkyl shifts. In such rearrangements, the 9-4migrating ESTERS group deliversFROM its ALCOHOLS bonding electron AND pair to HALOALKANE a positively charged SYNTHESIS carbon neighbor, exchanging places with the charge. Rearrangement may lead to a more stable cation—as Reactionin the of conversion alcohols with of a carboxylic secondary cation acids converts into a tertiary them one. to organic Primary esters, alcohols also also called can carboxylatesundergo rearrangement, or alkanoates but (Table they 2-3).do so Theyby concerted are formally pathways derived and not from through the carboxylicthe inter- acids mediacyby replacement of primary of thecations. hydroxy group with alkoxy. One can formulate a corresponding set of inorganic esters derived from inorganic acids, such as those based on phosphorus and sulfur in various oxidation states. In such inorganic esters, the attachment of the 9-4 ESTERS FROMOrganic ALCOHOLS and Inorganic AND EstersHALOALKANE SYNTHESIS

ReactionO of alcohols withO carboxylic HO acids converts them toO organic esters,O also called carboxylatesB or alkanoatesB (Table 2-3). G They are formally derivedB from the M carboxylic 9.4 ESTERS FROMacidsC byALCOHOLS replacementHO OOofAND Pthe hydroxyOHHALOALKANE group withPO OHalkoxy.SYNTHESIS OneROO canS formulateOH a correspondingSOOH R OH A D B D set of inorganic esters OHderived from inorganicHO acids, such asO those based onHO phosphorus Reaction of alcoholsA carboxylicand sulfur withacid in carboxylic variousPhosphoric oxidation acidacids states. Phosphorousconverts In such acid them inorganicto A sulfonic esters,organic acid the attachmentesters,Sulfurousalso of acid thecalled carboxylates or alkanoates. (An organic acid) Organic and Inorganic(Inorganic Esters acids)

O O O O HO HO O O OO B B B B G G B B MM C C OOPHO OROHOOOЈ P OH POOROPOЈ OH OOSR ROOORSOOHЈ SSOOOROHO Ј R ORЈ R OHA A D D B B DD OH OH HO HO O O HOHO A carboxylic acid Phosphoric acid Phosphorous acid A sulfonic acid Sulfurous acid A carboxylate ester(An organic A phosphate acid) ester A phosphite ester(Inorganic A sulfonate acids) ester A sulfite ester (An organic ester) (Inorganic esters) O O HO O O heteroatomB turns the normallyB poor leavingG group OH in alcoholsB into a good leavingM group C OOPHO ORO Ј POORO Ј OOSR ORO Ј SOORO Ј R(highlightedORЈ in the greenA boxes), which D can be used in the B synthesis of haloalkanesD (see also Section 9-2). We haveOH already mentionedHO the good leaving-groupO abilityHO of sulfate and A carboxylatesulfonate ester groups Ain phosphate SN2 reactions ester (Section A phosphite 6-7). ester Here, we A sulfonateshall see ester how speci A! sulfite c phosphorus ester (Anand organic sulfur ester) reagents accomplish this task: (Inorganic esters)

ϩ heteroatom turns the normallyReagent poor leaving group OHX inϪ alcohols into a good leaving group (highlighted in ROH theO green boxes), whichR canO L be used in the synthesisROX of haloalkanes (see Alcohol Inorganic Haloalkane also Section 9-2). We have already mentioned the good leaving-group ability of sulfate and 2 ester sulfonate groups in SN2 reactions (Section 6-7). Here, we shall see how speci! c phosphorus and sulfur reagents accomplish this task:

Alcohols react with carboxylicϩ acids to give organic esters Reagent XϪ Alcohols react with carboxylicROHO acids in theR O presenceL of catalyticRO X amounts of a strong Alcohol Inorganic Haloalkane inorganic acid, such as H2SO4 or HCl, to give organic esters and water, a process called ester esteri! cation. Starting materials and products in this transformation form an equilibrium that can be shifted in either direction. The formation and reactions of organic esters will be presentedAlcohols in detail react in Chapters with carboxylic19 and 20. acids to give organic esters Alcohols react with carboxylic acids in the presence of catalytic amounts of a strong Esterification inorganic acid, such as H2SO4 or HCl, to give organic esters and water, a process called esteri! cation.O Starting materials and products in thisO transformation form an equilibrium that can be Bshifted in either direction. The Hformationϩ andB reactions of organic esters will be presented 3inCOHCH detail ϩϩin ChaptersCH3CH 1922OH and 20. CH3COCH CH3 HOH Acetic acid Ethanol Ethyl acetate solvent Esterification O O B Hϩ B 3COHCH ϩϩCH3CH22OH CH3COCH CH3 HOH Acetic acid Ethanol Ethyl acetate solvent 336 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

In Summary Another mode of reactivity of carbocations, in addition to regular SN1 and E1 processes, is rearrangement by hydride or alkyl shifts. In such rearrangements, the migrating group delivers its bonding electron pair to a positively charged carbon neighbor, exchanging places with the charge. Rearrangement may lead to a more stable cation—as in the conversion of a secondary cation into a tertiary one. Primary alcohols also can undergo rearrangement, but they do so by concerted pathways and not through the inter- mediacy of primary cations.

9-4 ESTERS FROM ALCOHOLS AND HALOALKANE SYNTHESIS

Reaction of alcohols with carboxylic acids converts them to organic esters, also called carboxylates or alkanoates (Table 2-3). They are formally derived from the carboxylic acids by replacement of the hydroxy group with alkoxy. One can formulate a corresponding set of inorganic esters derived from inorganic acids, such as those based on phosphorus and sulfur in various oxidation states. In such inorganic esters, the attachment of the Organic and Inorganic Esters

O O HO O O B B G B M C HOOOP OH POOH ROOS OH SOOH R OH A D B D OH HO O HO A carboxylic acid Phosphoric acid Phosphorous acid A sulfonic acid Sulfurous acid (An organic acid) (Inorganic acids)

O O HO O O B B G B M C OOPHO ORO Ј POORO Ј OOSR ORO Ј SOORO Ј R ORЈ A D B D OH HO O HO A carboxylate ester A phosphate ester A phosphite ester A sulfonate ester A sulfite ester (An organic ester) (Inorganic esters)

heteroatom turns the normally poor leaving group OH in alcohols into a good leaving group (highlighted in the green boxes), which can be used in the synthesis of haloalkanes (see also Section 9-2). We have already mentioned the good leaving-group ability of sulfate and sulfonate groups in SN2 reactions (Section 6-7). Here, we shall see how speci! c phosphorus and sulfur reagents accomplish this task:

ϩ Reagent XϪ ROHO ROL ROX Alcohol Inorganic Haloalkane ester

Alcohols react with carboxylic acids to give organic esters Alcohols react with carboxylic acids in the presence of catalytic amounts of a strong inorganic acid, such as H2SO4 or HCl, to give organic esters and water, a process called esteri! cation. Starting materials and products in this transformation form an equilibrium Alcohols react with carboxylicthatacids can be inshiftedthe in presenceeither direction.of Thecatalytic formationamounts and reactionsof of aorganicstrong esters will be presented in detail in Chapters 19 and 20. inorganic acid, such as H2SO4 or HCl, to give organic esters and water, a process called esterification (an equilibrium). 9-4 Esters from Alcohols andEsterification Haloalkane Synthesis CHAPTER 9 337 O O B Hϩ B 3COHCH ϩϩCH3CH22OH CH3COCH CH3 HOH Haloalkanes can be madeAcetic from acid alcoholsEthanol through Ethyl acetate inorganic esters solvent Haloalkanes canBecausebe ofmade the dif! cultiesfrom andalcohols complicationsthrough that can inorganicbe encounteredesters in the acid-catalyzed conversions of alcohols into haloalkanes (Section 9-2), several alternatives have been devel- Although written as H3PO3, oped. These methods rely on a number of inorganic reagents that are capable of changing phosphorous acid is a These methodsthe hydroxyrely on functiona number into a goodof inorganicleaving group reagentsunder milder thatconditions.are capableThus, primaryof andchanging mixturethe of two tautomers: hydroxy functionsecondaryinto aalcoholsgood reactleaving with phosphorusgroup under tribromide,milder a readilyconditions available .commercial com- O OH

B A pound, to give bromoalkanes and phosphorous acid. This method constitutes a general way C PH PHE H ( OH HO OH Primary and secondaryof making bromoalkanesalcohols fromreact alcohols.with All phosphorusthree bromine atomstribromide are transferredto fromgive phos-bromoalkanesHO and phosphorousphorusacid to alkyl. All groups.three bromine atoms are transferred to alkyl groups. Major Minor Phosphorous acid Bromoalkane Synthesis by Using PBr3

(CH3CH2)2O 3 A ϩ PBr3 3 A ϩ H3PO3 OH Br ReactionR 47% 3-Pentanol Phosphorus 3-Bromopentane Phosphorous 3 tribromide acid

What is the mechanism of action of PBr3? In the ! rst step, the alcohol attacks the phosphorus reagent as a nucleophile to form a protonated inorganic ester, a derivative of phosphorous acid. Mechanism Step 1 Br PBr ϩ 2 i i Ϫ RCH2š"OH ϩϩðP OOBr"šð RCH2 Oš ðBr"šð f f Br H

Next, HOPBr2, a good leaving group, is displaced (SN2) by the bromide generated in step 1, producing the haloalkane.

Step 2 PBr ϩ 2 Ϫ f ðBr"šð ϩ RCH2 OšO RCH2 Br"šð ϩ HOPBr"š 2 i H

This method of haloalkane synthesis is especially ef! cient because HOPBr2 continues to react successively with two more molecules of alcohol, converting them into haloalkane as well. CH3(CH2)14CH2OH

2 RCH2>OH ϩ HOPBr>>2 2 RCH2Br) ϩ H3PO3 ppp P, I2, ⌬ What if, instead of a bromoalkane, we want the corresponding iodoalkane? The required CH (CH ) CH I phosphorus triiodide, PI , is best generated in the reaction mixture in which it will be used, 3 2 14 2 3 85% because it is a reactive species. We do this by adding red elemental phosphorus and elemental iodine to the alcohol (margin). The reagent is consumed as soon as it is formed. ϩ A chlorinating agent commonly used to convert alcohols into chloroalkanes is thionyl H3PO3 chloride, SOCl2. Simply warming an alcohol in its presence results in the evolution of SO2 and HCl and the formation of the chloroalkane.

Chloroalkane Synthesis with SOCl2

CH3CH2CH2OH ϩ SOCl2 CH3CH2CH2Cl ϩ OPSPO ϩ HCl ReactionR 91%

Mechanistically, the alcohol RCH2OH again ! rst forms an inorganic ester, RCH2O2SCl. 9-4 Esters from Alcohols and Haloalkane Synthesis CHAPTER 9 337

9-4 Esters from Alcohols and Haloalkane Synthesis CHAPTER 9 337 Haloalkanes can be made from alcohols through inorganic esters 9-4 Esters from Alcohols and Haloalkane Synthesis CHAPTER 9 337 BecauseHaloalkanes of the dif! canculties be and made complications from alcoholsthat can be throughencountered in the acid-catalyzed conversionsinorganic of alcoholsesters into haloalkanes (Section 9-2), several alternatives have been devel- Although written as H3PO3, oped. These methods rely on a number of inorganic reagents that are capable of changing phosphorous acid is a Because of the dif! culties and complications that can be encountered in the acid-catalyzed the hydroxyHaloalkanes function caninto abe good made leaving from group alcohols under milder through conditions. Thus, primary and mixture of two tautomers: conversions of alcohols into haloalkanes (Section 9-2), several alternatives have been devel- Although written as H3PO3, secondaryinorganic alcohols esters react with phosphorus tribromide, a readily available commercial com- O OH

oped. These methods rely on a number of inorganic reagents that are capable of changing phosphorousB acid is a A pound,Because to give of thebromoalkanes dif! culties andand complications phosphorous thatacid. can This be encounteredmethod constitutes in the acid-catalyzed a general way mixtureC of two tautomers: the hydroxy function into a good leaving group under milder conditions. Thus, primary and PH PHE conversions of alcohols into haloalkanes (Section 9-2), several alternatives have been devel- AlthoughH ( OHwritten as H POHO, OH of secondarymaking bromoalkanes alcohols react from with alcohols.phosphorus All tribromide, three bromine a readily atoms available are transferred commercial from com- phos- HOO 3 OH3

oped. These methods rely on a number of inorganic reagents that are capable of changing phosphorousB acid is a A phoruspound, to to alkyl give groups.bromoalkanes and phosphorous acid. This method constitutes a general way C Major Minor PH PHE the hydroxy function into a good leaving group under milder conditions. Thus, primary and Hmixture( OH of two tautomers:HO OH of making bromoalkanes from alcohols. All three bromine atoms are transferred from phos- HO Phosphorous acid secondary alcohols reactBromoalkane with phosphorus Synthesis tribromide, by Usinga readily PBr available3 commercial com- O OH

phorus to alkyl groups. MajorB MinorA pound, to give bromoalkanes and phosphorous acid. This method constitutes a general way C PH Phosphorous acid PHE H OH HO OH of making bromoalkanesBromoalkane from alcohols. Synthesis All three bromineby Using atoms PBr3 are transferred from phos- ( (CH3CH2)2O HO phorus3 to alkylA groups.ϩ PBr3 3 A ϩ H3PO3 Major Minor OH Br Phosphorous acid (CH3CH2)2O Bromoalkane Synthesis by Using PBr3 ReactionR 3 A ϩ PBr3 3 47%A ϩ H3PO3 OH Br 3-Pentanol Phosphorus 3-Bromopentane Phosphorous ReactionR tribromide (CH3CH2)2O 47% acid 3 3-PentanolA ϩ PhosphorusPBr3 3 3-BromopentaneA ϩ PhosphorousH3PO3 OH Br What is the mechanism oftribromide action of PBr ? In the ! rst step, the alcoholacid attacks the ReactionR 3 47% phosphorus reagent as a nucleophile to form a protonated inorganic ester, a derivative of What is 3-Pentanol the mechanism of Phosphorus action of PBr3? In the3-Bromopentane ! rst step, the alcoholPhosphorous attacks the phosphorousphosphorus acid. reagent as a nucleophiletribromide to form a protonated inorganic ester, a derivativeacid of phosphorous acid. Mechanism Step 1 What is the mechanism of action of PBr3? In the ! rst step, the alcohol attacks the Mechanismphosphorusof action reagentof PBr as3: a nucleophile to form a protonated inorganic ester, a derivative of Mechanism Stepphosphorous 1 acid. Br PBr ϩ 2 Step 1 The alcohol attacks theBrphosphorusi reagent as a nucleophilePBri to form a protonated RCH šOH ϩϩP Brš RCH ϩOš 2 Brš Ϫ Mechanism inorganic ester,Step a1 derivative2" of phosphorousði OO"ð acid. 2 i ð"ð RCH šOH ϩϩfðP OOBršð RCH Oš f ðBršð Ϫ 2" Br " 2 H " Brf f PBr2 Br i ϩ Hi š š š š Ϫ Next, HOPBrRCH2, 2"O a H goodϩϩ leavingðP OO Br" group,ð is displacedRCH2 (SON2) by the bromideðBr"ð generated in Next, HOPBr , a good leavingf group, is displaced (S 2)f by the bromide generated in step 1, producing the2 haloalkane.Br N step 1, producing the haloalkane. H Next, HOPBr , a good leaving group, is displaced (S 2) by the bromide generated in Step 2 HOPBrStep 2 2, a good leaving2 group, is displaced (SN2) Nby the bromide generated in step Stepstep 2 1, producing the haloalkane. 1, producing the haloalkane. PBr ϩ PBr2 ϩ 2 Step 2 Ϫ ff ðBršð Ϫ ϩ RCH2 OšO RCH2 Bršð ϩ HOPBrš 2 ð"Br"šð ϩ RCH2 OšO RCH2 Br"š"ð ϩ HOPBr"š" 2 ii PBr ϩHH 2 Ϫ f ðBr"šð ϩ RCH2 OšO RCH2 Br"šð ϩ HOPBr"š 2 ThisThis method method of of haloalkane haloalkane synthesissynthesisi is especially efef! !cient cient because because HOPBr HOPBr continues2 continues This method is especially efficient becauseH HOPBr continues to react successively2 with to toreact react successively successively with with two two moremore moleculesmolecules ofof alcohol,alcohol,2 converting converting them them into into haloalkane haloalkane two moreas asmoleculeswell. well.This methodof alcohol, of haloalkaneconverting synthesisthem is especiallyinto haloalkane ef! cient because. HOPBr continues 2 CHCH3(CH3(CH2)14CH2)142CHOH2OH to react successively with two more molecules of alcohol, converting them into haloalkane > >> 2 2RCH RCH2>OH2OH ϩϩ HOPBrHOPBr>>22 22 RCH RCH2Br2Br)) ϩϩ HH3PO3PO3 3 as well. pppppp P, I2, ⌬ CH (CH ) CHP,OH I2, ⌬ 4 3 2 14 2 WhatWhat if, if, instead instead2 RCH of 2ofpp>OH a a bromoalkane, bromoalkane,ϩ HOPBrp>> 2wewe want thethe correspondingcorresponding2 RCH2Br )iodoalkane? iodoalkane?ϩ H3PO The3 The required required CH3(CH2P,) I142, CH⌬ 2I phosphorus triiodide, PI3, is best generated in the reaction mixture in which it will be used, CH3(CH2)14CH2I phosphorus triiodide, PI3, is best generated in the reaction mixture in which it will be used, 85% becauseWhat it is if, a insteadreactive of species. a bromoalkane, We do this we by want adding the corresponding red elemental iodoalkane?phosphorus Theand requiredelemen- 85% because it is a reactive species. We do this by adding red elemental phosphorus and elemen- CH3(CH2)14CH2I talphosphorus iodine to thetriiodide, alcohol PI (margin).3, is best generatedThe reagent in theis consumedreaction mixture as soon in aswhich it is itformed. will be used, ϩ tal iodine to the alcohol (margin). The reagent is consumed as soon as it is formed. 85% ϩ becauseA chlorinating it is a reactive agent species. commonly We doused this to by convert adding alcoholsred elemental into chloroalkanesphosphorus and is elemen- thionyl A chlorinating agent commonly used to convert alcohols into chloroalkanes is thionyl chloride,tal iodine SOCl to the. Simply alcohol warming (margin). an The alcohol reagent in itsis consumedpresence resultsas soon in as the it evolutionis formed. of SO Hϩ3PO3 2 2 H3PO3 chloride,and HClA SOClchlorinating and 2the. Simply formation agent warming commonly of the anchloroalkane. alcoholused to inconvert its presence alcohols results into chloroalkanes in the evolution is thionyl of SO 2 and chloride,HCl and SOCl the formation. Simply warming of the chloroalkane. an alcohol in its presence results in the evolution of SO H3PO3 2 Chloroalkane Synthesis with SOCl 2 and HCl and the formation of the chloroalkane. 2 Chloroalkane Synthesis with SOCl2 CH3CH2CH2OH ϩ SOCl2 CH3CH2CH2Cl ϩ OPSPO ϩ HCl ReactionR Chloroalkane Synthesis with SOCl2 CH3CH2CH2OH ϩ SOCl2 CH3CH91%2CH2Cl ϩ OPSPO ϩ HCl ReactionR CH3CH2CH2OH ϩ SOCl2 CH3CH91%2CH2Cl ϩ OPSPO ϩ HCl ReactionR Mechanistically, the alcohol RCH2OH again ! rst 91%forms an inorganic ester, RCH2O2SCl. Mechanistically, the alcohol RCH2OH again ! rst forms an inorganic ester, RCH2O2SCl. Mechanistically, the alcohol RCH2OH again ! rst forms an inorganic ester, RCH2O2SCl. 9-4 Esters from Alcohols and Haloalkane Synthesis CHAPTER 9 337

Haloalkanes can be made from alcohols through inorganic esters Because of the dif! culties and complications that can be encountered in the acid-catalyzed conversions of alcohols into haloalkanes (Section 9-2), several alternatives9-4 Esters have frombeen devel-Alcohols andAlthough Haloalkane written Synthesisas H3PO3, CHAPTER 9 337 oped. These methods rely on a number of inorganic reagents that are capable of changing phosphorous acid is a the hydroxy function into a good leaving group under milder conditions. Thus, primary and mixture of two tautomers: secondary alcohols react with phosphorus tribromide, a readily available commercial com- O OH

Haloalkanes can be made from alcohols throughB A pound, to give bromoalkanes and phosphorous acid. This method constitutes a general way C inorganic esters PH PHE of making bromoalkanes from alcohols. All three bromine atoms are transferred from phos- H ( OH HO OH Because of the dif! culties and complications that can be encounteredHO in the acid-catalyzed phorus to alkyl groups. Major Minor conversions of alcohols into haloalkanes (Section 9-2), several alternatives have been devel- Although written as H3PO3, Phosphorous acid oped. These methods rely on a number of inorganic reagents that are capable of changing phosphorous acid is a Bromoalkane Synthesis by Using PBr3 the hydroxy function into a good leaving group under milder conditions. Thus, primary and mixture of two tautomers: secondary alcohols react with phosphorus tribromide, a readily available commercial com- O OH

B A

(CH3CH2)2O pound, to give bromoalkanes and phosphorous acid. This method constitutes a general way C 3 A ϩ PBr 3 A ϩ H PO PH PHE 3 of making bromoalkanes from alcohols. All3 three3 bromine atoms are transferred from phos- H ( OH HO OH OH Br ReactionR HO phorus to alkyl groups.47% Major Minor Phosphorous acid 3-Pentanol Phosphorus 3-BromopentaneBromoalkanePhosphorous Synthesis by Using PBr3 tribromide acid

What is the mechanism of action of PBr ? In the ! rst step, the alcohol(CH attacks3CH2)2O the 33 A ϩ PBr3 3 A ϩ H3PO3 phosphorus reagent as a nucleophile to form a protonatedOH inorganic ester, a derivative of Br ReactionR phosphorous acid. 47% 3-Pentanol Phosphorus 3-Bromopentane Phosphorous Mechanismacid Step 1 tribromide Br What is the mechanismPBr of action of PBr3? In the ! rst step, the alcohol attacks the phosphorus reagentϩ as a 2 nucleophile to form a protonated inorganic ester, a derivative of i i Ϫ RCH2š"OH ϩϩðP OOBr"šð phosphorousRCH acid.2 Oš ðBr"šð f f Mechanism Br Step 1 H

Next, HOPBr2, a good leaving group, is displaced (SN2) by Br the bromide generated in PBr2 i ϩ i step 1, producing the haloalkane. Ϫ RCH2š"OH ϩϩðP OOBr"šð RCH2 Oš ðBr"šð f f Br H Step 2

Next, HOPBr2, a good leaving group, is displaced (SN2) by the bromide generated in PBr2 ϩ step 1, producing the haloalkane. Ϫ f ðBr"šð ϩ RCH2 OšO RCH2 Br"šð ϩ HOPBr"š 2 i H Step 2 PBr What if, instead of a bromoalkane, we wantϩ the2 corresponding iodoalkane? The required This method of haloalkane synthesis is especially ef! cient because HOPBrf continues phosphorus triiodide, PI ,ðisBršbestð Ϫ ϩgeneratedRCH OšOin the2 reactionRCmixture,H Bršð ϩbecauseHOPBrš it is a reactive to react successively with two more molecules of alcohol,3 " converting 2them into haloalkane 2 " " 2 species. i as well. H CH3(CH2)14CH2OH This method of haloalkane synthesis is especially ef! cient because HOPBr2 continues 2 RCH2pp>OH ϩ HOPBrp>>2 2 RCH2Br) ϩ H3PO3 It prepares byto reactadding successivelyred elementalwith two morephosphorus molecules of alcohol,and converting them intoP, I 2haloalkane, ⌬ elemental iodineasto well.the alcohol. The reagent is consumed as What if, instead of a bromoalkane, we want the corresponding iodoalkane? The required CH3(CH2)14CH2OH soon as it is formed. > >>CH3(CH2)14CH2I phosphorus triiodide, PI3, is best generated in the reaction2 RCH2 ppOHmixtureϩ inHOPBr whichp 2 it will be used, 2 RCH2Br) ϩ H3PO3 85% P, I2, ⌬ because it is a reactive species. We do this by adding red elemental phosphorus and elemen- What if, instead of a bromoalkane, we want the corresponding iodoalkane? The required tal iodine to the alcohol (margin). The reagent is consumed as soon as it is formed. ϩ CH (CH ) CH I phosphorus triiodide, PI , is best generated in the reaction mixture in which it will be used, 3 2 14 2 A chlorinating agent commonly used to convert alcohols into3 chloroalkanes is thionyl 85% because it is a reactive species. We do this by adding red elemental phosphorus and elemen- chloride, SOCl . Simply warming an alcohol in its presence results in the evolution of SO H3PO3 2 tal iodine to the alcohol (margin). The reagent is consumed2 as soon as it is formed. ϩ and HCl and the formation of the chloroalkane. A chlorinating agentA chlorinatingcommonly agentused commonlyto convert used to convertalcohols alcoholsinto intochloroalkanes chloroalkanes is thionylis thionyl chloride, SOCl . Simply warming an alcohol in its presence results in the evolution of SO H3PO3 Chloroalkane Synthesis with2 SOCl2 2 chloride, SOCl2.andSimply HCl andwarming the formationan alcohol of the chloroalkane.results in the evolution of SO2 and HCl and the CH CH CH OH ϩformationSOCl of the chloroalkaneCH CH CH .Cl ϩ OPSPO ϩ HCl ReactionR 3 2 2 2 3 2 2 Chloroalkane Synthesis with SOCl 91% 2 CH3CH2CH2OH ϩ SOCl2 CH3CH2CH2Cl ϩ OPSPO ϩ HCl ReactionR Mechanistically, the alcohol RCH2OH again ! rst forms an inorganic ester, RCH2O2SCl.91%

5 Mechanistically, the alcohol RCH2OH again ! rst forms an inorganic ester, RCH2O2SCl. 338 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers 338 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

338 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers Step 1 Mechanism: Step 1 ð ððO ðO Oð B Step 1 The alcoholStepRCH 1 OH formsððanO inorganic ester, RCHð O SCl. Mechanism B S šCl 2 B B 2 2 S H" ð Mechanism OðS HšClð E H E ððSO ð " RCH OOšH ϩϩðšCl šClð RCH OOð Hϩ ϩ ððšCl Ϫ E HB EB ϩ Ϫ 2 " " " 2 " " Mechanism RCH2OOšH ϩϩðšCl šClð RCH2OOðS šCl H ϩ ððšCl " " S " " H" ð " E H E RCH OOšH ϩϩšCl šCl RCH OOð Hϩ ϩ šCl Ϫ 2 " ð" " ð 2 " ðð" The chloride ion created in this process then acts as a nucleophile and attacks the ester, an The chloride ion created in this process then acts as a nucleophile and attacks the ester, an S 2 reaction yielding one molecule each of SO and HCl. S 2 reaction yielding one molecule each of SO and HCl. N 2 Step 2 The chlorideN Theion chloridecreated ion createdin this in thisprocess process thenthen acts2 actsas a nucleophileas a nucleophile and attacks the andester, anattacks the S 2 reaction yielding one molecule each of SO and HCl. Step 2 StepN 2 2 ester, an SN2 reaction yielding one molecule each of SO2 and HCl. Oð Step 2 ð ð ðO B B Clš OSð Clšð S H "ð ð B H " E ϩ Ϫ E ϩ Ϫ S HClšð š H ϩϩClšðð CH2 OOð ðClš OCH2R ϩ ýOPSPO ý ϩ HClšð H ϩϩCl"šðð CH2 O"Oð " ðCl" OCH2R ϩ ½ýOPSPO ½ ý ϩ HClš"ð " " " ½ ½ " ϩ Ϫ f E š f H ϩϩCl"šðð CH2 O"Oð ðCl" OCH2R ϩ ½ýOPSPO ½ ý ϩ HClš"ð R R f (CH CH ) Nð R (CH3CH2)3Nð 3 2 3 The reaction works better in the presence of an amine, which neutralizes the hydrogen N,N-Diethylethanamine(CH3CH2)3Nð The reaction works better in the presence of an amine, which neutralizesN , theN-Diethylethanamine hydrogen (Triethylamine)N,N-Diethylethanamine chlorideThe reaction generated. works One better such reagent in the presence is N,N-diethylethanamine of an amine, which (triethylamine), neutralizes the which(Triethylamine) hydrogen forms chloride generated. One such reagent is N,N-diethylethanamine (triethylamine), which forms The(Triethylamine)ϩ reaction worksthechloride correspondingbetter generated.in the ammonium Onepresence such chloridereagentof is under Nan,N-diethylethanamine aminethese conditions.to neutralize (triethylamine), which formsϩ the corresponding ammonium chloride under these conditions. HCl ϩ the corresponding ammonium chloride under these conditions. HCl the HhydrogenCl chloride. One such reagent is triethylamine, which Alkyl sulfonates are versatile substrates for Alkyl sulfonates are versatile substrates for forms the correspondingAlkyl ammoniumsulfonates arechloride versatileunder substratesthese conditions for . ϩ substitution reactions ϩ substitution reactions (CH CH ) NH ϩClϪ substitution reactions Ϫ 6 3 2 3 Ϫ The inorganic esters in the reactions of SOCl are special examples of leaving(CH3CH groups2)3NH Cl (CH3CH2)3NH Cl The inorganic esters in the reactions of SOCl2 are special examples of leaving groups The inorganic esters in the reactions of SOCl2 are special examples of leaving groups derived from sulfur-based acids. They are related2 to the sulfonates (Section 6-7). Alkyl derived from sulfur-based acids. They are related to the sulfonates (Section 6-7). Alkyl derived from sulfur-based acids. They are related to the sulfonates (Section 6-7). Alkyl sulfonatessulfonates contain contain excellent excellent leaving leaving groups groups and and can can be be readily prepared prepared from from the the corre- corre- sulfonates contain excellent leaving groups and can be readily prepared from the corre- spondingsponding sulfonyl sulfonyl chlorides chlorides and and an an alcohol. alcohol. A A mild mild basebase such as pyridinepyridine or or a a tertiary tertiary amine amine sponding sulfonyl chlorides and an alcohol. A mild base such as pyridine or a tertiary amine is oftenis often added added to toremove remove the the HCl HCl formed. formed. is often added to remove the HCl formed.

SynthesisSynthesis of of an an Alkyl Alkyl Sulfonate Sulfonate Synthesis of an Alkyl Sulfonate

CHCH3 3 O O CHCH3 OO A A B B AA BB CH3 O CH3 O CH CHCH OHCHϩϩSCl N CH CHCH OSCH ϩ N ClϪϪ A B A B CH3CHCH3 2OHCH2 ϩϩ3S3Cl !N! CH33CHCH2OSCH33 ϩ NϩϩCl Ϫ B B BB AA CH3CHCH2OHCHϩϩ3SCl !N CH3CHCH2OSCH3 ϩ NϩCl O O OO HH B B A 2-Methyl-1-propanol2-Methyl-1-propanol Methanesulfonyl Methanesulfonyl PyridinePyridine 2-Methylpropyl2-Methylpropyl PyridiniumPyridinium O O H chloridechloride methanesulfonatemethanesulfonate hydrochloridehydrochloride 2-Methyl-1-propanol Methanesulfonyl Pyridine 2-Methylpropyl Pyridinium (Mesyl(Mesyl chloride) chloride) (2-Methylpropyl(2-Methylpropyl mesylate)mesylate) chloride methanesulfonate hydrochloride (Mesyl chloride) (2-Methylpropyl mesylate) UnlikeUnlike the the inorganic inorganic esters esters derived derived from from phosphorus phosphorus tribromidetribromide andand thionylthionyl chloride, chloride, alkyl alkyl sulfonatessulfonates are are often often crystalline crystalline solids solids that that cancan bebe isolatedisolated and puripuri!! eded beforebefore further further reac- reac- Unlike the inorganic esters derived from phosphorus tribromide and thionyl chloride, alkyl tion. They then can be used in reactions with a variety of nucleophiles to give the corre- tion. They then can be used in reactions with a variety of nucleophiles to give the corre- sulfonates are often crystalline solids that can be isolated and puri! ed before further reac- sponding products of nucleophilic substitution. sponding products of nucleophilic substitution. tion. They then can be used in reactions with a variety of nucleophiles to give the corre- Sulfonate Intermediates in Nucleophilic Displacement sponding products of nucleophilic substitution. Sulfonate Intermediatesof the Hydroxy in Group Nucleophilic in Alcohols Displacement of the Hydroxy Group in Alcohols Sulfonate Intermediates in Nucleophilic Displacement O of the Hydroxy Group in Alcohols OB ROOH RROOSRB Ј ONu ROOH RROOSRB Ј ONu O BO B O ROOH RROOSRЈ ONu B O The displacement of sulfonate groups by halide ions (Cl2, Br2, I2) readily yields the cor- 2 2 2 Theresponding displacement haloalkanes, of sulfonate particularly groups by with halide primary ions and (Cl secondary, Br , I ) systems, readily inyields which the S cor-N2 respondingreactivity haloalkanes,is good. In addition, particularly however, with alkyl primary sulfonates and secondaryallow replacement systems, of inthe which hydroxy S 2 N The displacement of sulfonate groups by halide ions (Cl2, Br2, I2) readily yields the cor- reactivity is good. In addition, however, alkyl sulfonates allow replacement of the hydroxy responding haloalkanes, particularly with primary and secondary systems, in which SN2 reactivity is good. In addition, however, alkyl sulfonates allow replacement of the hydroxy 338 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

Step 1

O Oð ðð ð B Mechanism B S šCl S H" ð E H E ϩ Ϫ RCH2O"OšH ϩϩð"šCl "šClð RCH2O"Oð H ϩ ððš"Cl

The chloride ion created in this process then acts as a nucleophile and attacks the ester, an SN2 reaction yielding one molecule each of SO2 and HCl. Step 2 Oð ð B S HClš"ð ϩ Ϫ E š H ϩϩCl"šðð CH2 O"Oð ðCl" OCH2R ϩ ½ýOPSPO ½ ý ϩ HClš"ð f R (CH3CH2)3Nð N,N-DiethylethanamineAlkyl sulfonatesTheare reactionversatile works substrates better in the presencefor substitution of an amine, reactions which neutralizes the hydrogen (Triethylamine) chloride generated. One such reagent is N,N-diethylethanamine (triethylamine), which forms ϩ the corresponding ammonium chloride under these conditions. HTheCl inorganic esters in the reactions of SOCl2 are special examples of leaving groups derived from sulfurAlkyl-based sulfonatesacids. They are areversatilerelated substratesto the sulfonates for . substitution reactions ϩ Ϫ (CH3CHAlkyl2)3NH Clsulfonates contain excellent leaving groups and can be readily prepared from the The inorganic esters in the reactions of SOCl2 are special examples of leaving groups corresponding sulfonylderived fromchlorides sulfur-basedand an acids.alcohol They are. related to the sulfonates (Section 6-7). Alkyl sulfonates contain excellent leaving groups and can be readily prepared from the corre- A mild base suchspondingas pyridine sulfonylor chloridesa tertiary and anamine alcohol.is Aoften mild baseadded such toas pyridineremove or thea tertiaryHCl amineformed . is often added to remove the HCl formed.

Synthesis of an Alkyl Sulfonate

CH3 O CH3 O A B A B Ϫ CH3CHCH2OHCHϩϩ3SCl !N CH3CHCH2OSCH3 ϩ NϩCl B B A O O H 2-Methyl-1-propanol Methanesulfonyl Pyridine 2-Methylpropyl Pyridinium chloride methanesulfonate hydrochloride (Mesyl chloride) (2-Methylpropyl mesylate)

7 Unlike the inorganic esters derived from phosphorus tribromide and thionyl chloride, alkyl sulfonates are often crystalline solids that can be isolated and puri! ed before further reaction. They then can be used in reactions with a variety of nucleophiles to give the corresponding products of nucleophilic substitution.

Sulfonate Intermediates in Nucleophilic Displacement of the Hydroxy Group in Alcohols O B ROOH RROOSRЈ ONu B O

The displacement of sulfonate groups by halide ions (Cl2, Br2, I2) readily yields the corresponding haloalkanes, particularly with primary and secondary systems, in which SN2 reactivity is good. In addition, however, alkyl sulfonates allow replacement of the hydroxy 338 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

Step 1

O Oð ðð ð B Mechanism B S šCl S H" ð E H E ϩ Ϫ RCH2O"OšH ϩϩð"šCl "šClð RCH2O"Oð H ϩ ððš"Cl

The chloride ion created in this process then acts as a nucleophile and attacks the ester, an SN2 reaction yielding one molecule each of SO2 and HCl. Step 2 Oð ð B S HClš"ð ϩ Ϫ E š H ϩϩCl"šðð CH2 O"Oð ðCl" OCH2R ϩ ½ýOPSPO ½ ý ϩ HClš"ð f R (CH3CH2)3Nð N,N-Diethylethanamine The reaction works better in the presence of an amine, which neutralizes the hydrogen (Triethylamine) chloride generated. One such reagent is N,N-diethylethanamine (triethylamine), which forms ϩ the corresponding ammonium chloride under these conditions. HCl Alkyl sulfonates are versatile substrates for substitution reactions ϩ Ϫ (CH3CH2)3NH Cl The inorganic esters in the reactions of SOCl2 are special examples of leaving groups derived from sulfur-based acids. They are related to the sulfonates (Section 6-7). Alkyl sulfonates contain excellent leaving groups and can be readily prepared from the corresponding sulfonyl chlorides and an alcohol. A mild base such as pyridine or a tertiary amine is often added to remove the HCl formed.

Synthesis of an Alkyl Sulfonate

CH3 O CH3 O A B A B Ϫ CH3CHCH2OHCHϩϩ3SCl !N CH3CHCH2OSCH3 ϩ NϩCl B B A O O H 2-Methyl-1-propanol Methanesulfonyl Pyridine 2-Methylpropyl Pyridinium Unlike the inorganicchlorideesters derived from phosphorusmethanesulfonatetribromide and thionylhydrochloridechloride, alkyl sulfonates are often(Mesyl chloride)crystalline solids that can(2-Methylpropylbe isolated mesylate)and purified before further reaction.Unlike the inorganic esters derived from phosphorus tribromide and thionyl chloride, alkyl sulfonates are often crystalline solids that can be isolated and puri! ed before further reac- They thention.can Theybe thenused canin bereactions used in reactionswith a variety with a varietyof nucleophiles of nucleophilesto togive givethe thecorresponding corre- productsspondingof nucleophilic products substitutionof nucleophilic. substitution.

Sulfonate Intermediates in Nucleophilic Displacement of the Hydroxy Group in Alcohols O B ROOH RROOSRЈ ONu B O

The displacement of sulfonate groups by halide ions (Cl2, Br2, I2) readily yields the The displacement of sulfonate groups by halide ions (Cl2, Br2, I2) readily yields the cor- corresponding haloalkanes, particularly with primary and secondary systems, in which SN2 responding haloalkanes, particularly with primary and secondary systems, in which SN2 reactivityreactivityis good is. good. In addition, however, alkyl sulfonates allow replacement of the hydroxy

8 9-5 Names and Physical Properties of Ethers CHAPTER 9 339 9-5 Names and Physical Properties of Ethers CHAPTER 9 339

Alkyl sulfonatesgroup by anyallow good replacementnucleophile: Theyof arethe not hydroxylimited to halidesgroup alone,by any as isgood the casenucleophile with : They are hydrogen,group phosphorus,by any good and nucleophile: thionyl halides. They are not limited to halides alone, as is the case with not limited hydrogen,to halides phosphorus,alone, as andis thionylthe case halides.with hydrogen, phosphorus, and thionyl halides. Substitution Reactions of Alkyl Sulfonates Substitution Reactions of Alkyl Sulfonates Oðð Oðð B B Oðð Ϫ Ϫ Oðð CH3CH2CH2OOOš#OSCHB 3 ϩ ððš#I CH3CH2CH2Oš#Ið ϩ ðš#OSOOCH3 B B Ϫ B Ϫ CH3CH2CH2OOOš#OSCH3 ϩ ððš#I CH3CH2CH2Oš#Ið ϩ ðš#OSOOCH3 ðOð B Oðð B ðOð 90% Oðð 90% šOðð Ϫ A Ϫ šOSPPšO šOðð # # A H Oðð O šOSPPšO A B # # Ϫ O O CH3OC OOH#šOSO ðð OCH3 ϩ CH3CH2#šSð CH3CHO#šSCH2CH3 ϩ A A B B A š š Ϫ š CHCH3O3 C OOO#OSðð O OCH3 ϩ CH3CH2#Sð CH3CH3CHO#SCH2CH3 ϩ A B A O 85% CH3 CH3 Oðð CH3 O

85% CH3 OH0 9 Exercise 9-10 Try It Yourself 1. CH3SO2Cl

2. NaI What is the product of the reaction sequence shown in the margin? OH0

1. CH3SO2Cl Exercise 9-10 Try It Yourself % 2. NaI CH

What is the product of the reaction sequence shown in the margin? 3 % Exercise 9-11 Try It Yourself CH3 Supply reagents with which you would prepare the following haloalkanes from the corresponding alcohols.Exercise 9-11 Try It Yourself Br Supply reagents with which you would prepare the following haloalkanes from the corresponding alcohols. (a) I(CH2)6I (b) (CH3CH2)3CCl (c) Br

(a) I(CH2)6I (b) (CH3CH2)3CCl (c) In Summary Alcohols react with carboxylic acids by loss of water to furnish organic esters. They also react with inorganic halides, such as PBr3, SOCl2, and RSO2Cl, by loss of HX to produce inorganic esters. These inorganic esters contain good leaving groups in nucleo- philicIn substitutions Summary thatAlcohols are, for react example, with carboxylicdisplaced by acids halide by ionsloss toof givewater the to corresponding furnish organic esters. haloalkanes.They also react with inorganic halides, such as PBr3, SOCl2, and RSO2Cl, by loss of HX to produce inorganic esters. These inorganic esters contain good leaving groups in nucleophilic substitutions that are, for example, displaced by halide ions to give the corresponding 9-5haloalkanes. NAMES AND PHYSICAL PROPERTIES OF ETHERS CH3#šOCH2CH3 Ethers may be thought of as derivatives of alcohols in which the hydroxy proton has been Methoxyethane replaced9-5 by an alkylNAMES group. AND We now PHYSICAL introduce this PROPERTIES class of compounds OF systematically. ETHERS This š section gives the rules for naming ethers and describes some of their physical properties. CHCH3 3#OCH2CH3 A Ethers may be thought of as derivatives of alcohols in which the hydroxy proton has been Methoxyethane CH3CH2#šOCCH3 In thereplaced IUPAC by an system, alkyl group. ethers We now are introduce alkoxyalkanes this class of compounds systematically. This A section gives the rules for naming ethers and describes some of their physical properties. CH3 CH3 The IUPAC system for naming ethers treats them as alkanes that bear an alkoxy substituent— 2-Ethoxy-2-methylpropane A that is, as alkoxyalkanes. The smaller substituent is considered part of the alkoxy group and CH3CH2#šOCCH3 the larger chain de! nes the stem. A In the IUPAC system, ethers are alkoxyalkanes CH In common names, the names of the two alkyl groups are followed by the word ether. 3 The IUPAC system for naming ethers treats them as alkanes that bear an alkoxy substituent— 2-Ethoxy-2-methylpropane Hence, CH OCH is dimethyl ether, CH OCH CH is ethyl methyl ether, and so forth. that is, 3as alkoxyalkanes.3 The smaller3 substituent2 3 is considered part of the alkoxy group and the larger chain de! nes the stem. In common names, the names of the two alkyl groups are followed by the word ether. Hence, CH3OCH3 is dimethyl ether, CH3OCH2CH3 is ethyl methyl ether, and so forth. 9-5 Names and Physical Properties of Ethers CHAPTER 9 339 group by any good nucleophile: They are not limited to halides alone, as is the case with hydrogen, phosphorus, and thionyl halides. 9-5 Names and Physical Properties of Ethers CHAPTER 9 339 Substitution Reactions of Alkyl Sulfonates group by any good nucleophile: They are not limited to halides alone, as is the case with Oðð Oðð hydrogen, phosphorus, and thionyl halides. B B Ϫ Ϫ CH3CH2CH2OOOš#OSCH3 ϩ ððš#I CH3CH2CH2Oš#Ið ϩ ðš#OSOOCH3 Substitution Reactions of AlkylB Sulfonates B ðOð Oðð 90% Oðð Oðð B B CH CH CH OOOšOSCH ϩ šI Ϫ CH CH CH OšI ϩ Ϫ šOSOOCH 3 2 2 # 3 ðð# 3 2 2 #ð ð# 3 šOðð Ϫ B B A ðOð Oðð šOSPPšO 90% # # H Oðð O A B š š Ϫ š CH3OC OO#OSO OCH3 ϩ CH3CH2#Sð CHϪ3CHO#SCH2CH3 ϩ A B šOðð A A CH3 Oðð CH3 š#OSPPš#O O 85% CH3 H Oðð O A B Ϫ

CH3OC OOšOSO OCH3 ϩ CH3CH2šSð CH3CHOšSCH2CH3 ϩ # # # OH0 A B Exercise 9-10 Try It Yourself A 1. CH3SO2Cl 2. NaI CH3 Oðð CH3

What is the product of the reaction sequence85% shown in the margin? O CH3 %

CH3 OH0 Exercise 9-10 Try It YourselfExercise 9-11 Try It Yourself 1. CH3SO2Cl 2. NaI

What is the product of the reaction Supplysequence reagents shown with in the which margin? you would prepare the following haloalkanes from the corresponding % alcohols. CH Br 3

Exercise 9-11 Try It Yourself 9.5 NAMES AND PHYSICAL PROPERTIES OF ETHERS (a) I(CH2)6I (b) (CH3CH2)3CCl (c) Supply reagents with which you would prepare the following haloalkanes from the corresponding alcohols. Ethers may be thought of as derivatives of alcohols in which the hydroxy proton has been Br In Summary Alcohols react with carboxylic acids by loss of waterreplaced to furnishby anorganicalkyl esters.group . They also react with inorganic halides, such as PBr3, SOCl2, and RSO2Cl, by loss of HX (a) I(CH2)6I (b) (CH3CHto 2produce)3CCl inorganic(c) esters. These inorganic esters contain goodIn theleavingIUPAC groupssystem, in nucleo-ethers are alkoxyalkanes philic substitutions that are, for example, displaced by halide ions to give the corresponding haloalkanes. The IUPAC system for naming ethers treats them as alkanes that bear an alkoxy In Summary Alcohols react with carboxylic acids by loss of water to furnish organic esters. substituent. The smaller substituent is considered part of the alkoxy group and the larger They also react with inorganic halides, such as PBr3, SOCl2, and RSO2Cl, by loss of HX chain defines the stem. to produce inorganic esters. These 9-5inorganic NAMES esters contain AND good PHYSICAL leaving groups PROPERTIES in nucleo- OF ETHERS philic substitutions that are, for example, displaced by halide ions to give the corresponding š 340 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers In common names, the names of CHthe3#OtwoCH2CHalkyl3 groups are followed by the word ether. haloalkanes. Methoxyethane Ethers may be thought of as derivatives of alcohols in which theHence, hydroxyCH proton3OCH 3hasis beendimethyl ether, CH3OCH2CH3 is ethyl methyl ether, and so forth. replaced by an alkyl group. We now introduce this class of compounds systematically. This š Ethers are generally fairly unreactive (except for strained cyclic derivatives; see Section 9-9) section gives the rules for naming ethers and describes some of their physical properties. CH3 ðOCH3 9-5 NAMES AND PHYSICAL PROPERTIES OF ETHERS A % and are therefore frequently used as solvents in organic reactions. Some of these ether sol- CH CH šOCCH ? OCHš 2CH3 vents are cyclic; they may even contain several ether functions. All have common names. CH3#šOCH2CH3 3 2# 3 # In the IUPAC system, ethers are alkoxyalkanes A Ethers may be thought of as derivatives of alcohols in which the hydroxy proton has been Methoxyethane CH3 Ether Solvents and Their Names The IUPAC system for naming ethers treats them as alkanes that bear an alkoxy substituent— 2-Ethoxy-2-methylpropane cis-1-Ethoxy-2- replaced by an alkyl group. We now introduce this class of compounds systematically. This methoxycyclopentane CH 10 section gives the rules for namingthat ethers is, as andalkoxyalkanes. describes some The ofsmaller their substituentphysical properties. is considered part of the alkoxy group3 and O the larger chain de! nes the stem. A CH3CH2#šOCCH3 In common names, the names of the two alkyl groups are followed by the wordA ether. In the IUPAC system, ethers are alkoxyalkanes CH CH OCH CH O CH OCH CH OCH O Hence, CH3OCH3 is dimethyl ether, CH3OCH2CH3 is ethyl methyl ether, and so CHforth.3 3 2 2 3 3 2 2 3 The IUPAC system for naming ethers treats them as alkanes that bear an alkoxy substituent— 2-Ethoxy-2-methylpropane Ethoxyethane 1,4-Dioxacyclohexane 1,2-Dimethoxyethane Oxacyclopentane (Diethyl ether) (1,4-Dioxane) (Glycol dimethyl ether, (Tetrahydrofuran, that is, as alkoxyalkanes. The smaller substituent is considered part of the alkoxy group and glyme) THF) the larger chain de! nes the stem. In common names, the names of the two alkyl groups are followed by the word ether. Cyclic ethers are members of a class of cycloalkanes in which one or more carbons have Hence, CH3OCH3 is dimethyl ether, CH3OCH2CH3 is ethyl methyl ether, and so forth. been replaced by a heteroatom—in this case, oxygen. (A heteroatom is de! ned as any atom except carbon and hydrogen.) Cyclic compounds of this type, called heterocycles, are discussed more fully in Chapter 25. The simplest system for naming cyclic ethers is based on the oxacycloalkane stem, in which the pre! x oxa indicates the replacement of carbon by oxygen in the ring. Thus, three- membered cyclic ethers are oxacyclopropanes (other names used are oxiranes, epoxides, and ethylene oxides), four-membered systems are oxacyclobutanes, and the next two higher homologs are oxacyclopentanes (tetrahydrofurans) and oxacyclohexanes (tetrahydropyrans). The compounds are numbered by starting at the oxygen and proceeding around the ring.

The absence of hydrogen bonding affects the physical properties of ethers

Polyethers solvate metal ions: crown ethers and ionophores Model Building Cyclic polyethers that contain multiple ether functional groups based on the 1,2-ethanediol unit are called crown ethers, so named because the molecules adopt a crown-like conformation in the crystalline state and, presumably, in solution. The polyether 18-crown-6 is shown in Figure 9-3. The number 18 refers to the total number of atoms in the ring, and 6 to the number of oxygens. The electrostatic potential map on the right of Figure 9-3 shows

Table 9-1 Boiling Points of Ethers and the Isomeric 1-Alkanols Boiling Boiling Ether Name point (8C) 1-Alkanol point (8C)

CH3OCH3 Methoxymethane 223.0 CH3CH2OH 78.5 (Dimethyl ether)

CH3OCH2CH3 Methoxyethane 10.8 CH3CH2CH2OH 82.4 (Ethyl methyl ether)

CH3CH2OCH2CH3 Ethoxyethane 34.5 CH3(CH2)3OH 117.3 (Diethyl ether)

(CH3CH2CH2CH2)2O 1-Butoxybutane 142 CH3(CH2)7OH 194.5 (Dibutyl ether) 340 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

Ethers are generally fairly unreactive (except for strained cyclic derivatives; see Section 9-9) ðšOCH3 Ethers are generally fairly unreactive (except for strained cyclic derivatives) and are % and are therefore frequently used as solvents in organic reactions. Some of these ether sol- therefore frequently used as solvents in organic reactions. Some of these ether solvents are ? OCHš# 2CH3 vents are cyclic; they may even contain several ether functions. All have common names. cyclic, all have common names. Ether Solvents and Their Names cis-1-Ethoxy-2- methoxycyclopentane O

CH3CH2OCH2CH3 O CH3OCH2CH2OCH3 O Ethoxyethane 1,4-Dioxacyclohexane 1,2-Dimethoxyethane Oxacyclopentane (Diethyl ether) (1,4-Dioxane) (Glycol dimethyl ether, (Tetrahydrofuran, glyme) THF)

Cyclic ethers are members of a class of cycloalkanes in which one or more carbons have Cyclic ethers arebeenmembers replaced byof a heteroatoma class of—incycloalkanes this case, oxygen.in which (A heteroatomone or is morede! nedcarbons as any have been replaced byatoma exceptheteroatom carbon and— inhydrogen.)this case, Cyclicoxygen compounds. of this type, called heterocycles, are discussed more fully in Chapter 25. The simplest system for naming cyclic ethers is based on the oxacycloalkane stem, in A heteroatom whichis defined the pre! asx oxaany indicatesatom theexcept replacementcarbon of carbonand byhydrogen oxygen in the. Cyclic ring. Thus,compounds three- of this type, calledmemberedheterocycles cyclic ethers. are oxacyclopropanes (other names used are oxiranes, epoxides, and ethylene oxides), four-membered systems are oxacyclobutanes, and the next two higher homologs are oxacyclopentanes (tetrahydrofurans) and oxacyclohexanes (tetrahydropyrans). The compounds are numbered by starting at the oxygen and proceeding around the ring. 11

The absence of hydrogen bonding affects the physical properties of ethers

Table 9-1 Boiling Points of Ethers and the Isomeric 1-Alkanols Boiling Boiling Ether Name point (8C) 1-Alkanol point (8C)

CH3OCH3 Methoxymethane 223.0 CH3CH2OH 78.5 (Dimethyl ether)

CH3OCH2CH3 Methoxyethane 10.8 CH3CH2CH2OH 82.4 (Ethyl methyl ether)

CH3CH2OCH2CH3 Ethoxyethane 34.5 CH3(CH2)3OH 117.3 (Diethyl ether)

(CH3CH2CH2CH2)2O 1-Butoxybutane 142 CH3(CH2)7OH 194.5 (Dibutyl ether) The simplest system for naming cyclic ethers is based on the oxacycloalkane stem, in which the prefix oxa indicates the replacement of carbon by oxygen in the ring.

Thus, three-membered cyclic ethers are oxacyclopropanes (other names used are oxiranes, epoxides, and ethylene oxides), four-membered systems are oxacyclobutanes, and the next two higher homologs are oxacyclopentanes (tetrahydrofurans) and oxacyclohexanes (tetrahydropyrans).

The compounds are numbered by starting at the oxygen and proceeding around the ring.

The absence of hydrogen bonding affects the physical properties of ethers

The molecular formula of simple alkoxyalkanes is CnH2n+2O, identical with that of the alkanols.

12 340 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

Ethers are generally fairly unreactive (except for strained cyclic derivatives; see Section 9-9) ðšOCH3 % and are therefore frequently used as solvents in organic reactions. Some of these ether sol- ? OCHš# 2CH3 vents are cyclic; they may even contain several ether functions. All have common names.

Ether Solvents and Their Names cis-1-Ethoxy-2- methoxycyclopentane O

CH3CH2OCH2CH3 O CH3OCH2CH2OCH3 O Ethoxyethane 1,4-Dioxacyclohexane 1,2-Dimethoxyethane Oxacyclopentane (Diethyl ether) (1,4-Dioxane) (Glycol dimethyl ether, (Tetrahydrofuran, glyme) THF)

Cyclic ethers are members of a class of cycloalkanes in which one or more carbons have been replaced by a heteroatom—in this case, oxygen. (A heteroatom is de! ned as any atom except carbon and hydrogen.) Cyclic compounds of this type, called heterocycles, are discussed more fully in Chapter 25. The simplest system for naming cyclic ethers is based on the oxacycloalkane stem, in which the pre! x oxa indicates the replacement of carbon by oxygen in the ring. Thus, three- membered cyclic ethers are oxacyclopropanes (other names used are oxiranes, epoxides, and ethylene oxides), four-membered systems are oxacyclobutanes, and the next two higher homologs are oxacyclopentanes (tetrahydrofurans) and oxacyclohexanes (tetrahydropyrans). The compounds are numbered by starting at the oxygen and proceeding around the ring.

The absence of hydrogen bonding affects the physical properties of ethers

The molecular formula of simple alkoxyalkanes is CnH2n12O, identical with that of the alkanols. However, because of the absence of hydrogen bonding, the boiling points of ethers are much lower than those of the corresponding isomeric alcohols (Table 9-1). The two smallest members of the series are water miscible, but ethers become less water soluble as the hydrocarbon residues increase in size. For example, methoxymethane is completely water soluble, whereas ethoxyethane forms only an approximately 10% aqueous solution. Because of the absence of hydrogen bonding, the boiling points of ethers are much lower than those of the corresponding isomeric alcohols. Polyethers solvate metal ions: crown ethers and ionophores Model BuildingThe two smallestCyclic polyethersmembers thatof containthe seriesmultiple areetherwater functionalmiscible, groups basedbut etherson the 1,2-ethanediolbecome less water unit are called crown ethers, so named because the molecules adopt a crown-like conforma- soluble as thetion hydrocarbon in the crystallineresidues state and,increase presumably,in size in solution.. The polyether 18-crown-6 is shown in Figure 9-3. The number 18 refers to the total number of atoms in the ring, and 6 For example,to themethoxymethane number of oxygens. Theis completely electrostatic potentialwater mapsoluble, on the whereasright of Figureethoxyethane 9-3 shows forms only an approximately 10% aqueous solution.

Table 9-1 Boiling Points of Ethers and the Isomeric 1-Alkanols Boiling Boiling Ether Name point (8C) 1-Alkanol point (8C)

CH3OCH3 Methoxymethane 223.0 CH3CH2OH 78.5 (Dimethyl ether)

CH3OCH2CH3 Methoxyethane 10.8 CH3CH2CH2OH 82.4 (Ethyl methyl ether)

CH3CH2OCH2CH3 Ethoxyethane 34.5 CH3(CH2)3OH 117.3 (Diethyl ether)

(CH3CH2CH2CH2)2O 1-Butoxybutane 142 CH3(CH2)7OH 194.5 (Dibutyl ether) 13 Polyethers solvate metal ions: crown ethers and ionophores

Cyclic polyethers that contain multiple ether functional groups based on the 1,2-ethanediol unit are called crown ethers, adopt a crown-like conformation in the crystalline state.

Polyether 18-crown-6: The number 18 refers to the total number of atoms in the ring, and 6 to the number of oxygens.

The electrostatic potential map shows9-5that Namesthe and Physicalinside Propertiesof the ringof Ethersis quiteCHAPTERelectron 9 rich341due to the electron pairs on the ether oxygens, which renders them Lewis basic.

O O

O O OOO

In this perspective, six of the In this perspective, two of the O atoms H atoms are hidden by the are masked by the attached carbons attached carbons (marked by (marked by arrows). 14 arrows).

Figure 9-3 The crown-like structural arrangement of 18-crown-6.

that the inside of the ring is quite electron rich due to the electron pairs on the ether oxygens, which renders them Lewis basic. These lone pairs give cyclic polyethers striking solvating power, in which several such oxygen atoms may surround and bind metal cations. Crown ethers are therefore capable of solubilizing ordinary salts in organic solvents. For example, potassium permanganate (KMnO4), a deep-violet solid, is completely insol- uble in benzene but readily dissolves when 18-crown-6 is added. This solution is useful because it allows oxidations with potassium permanganate to be carried out in organic solvents. Dissolution is possible by effective solvation of the metal ion by the six crown oxygens.

! ! O !O !O ! ! ! ! OO O O O O ؉ ! ! ! ! K KMnO , C H 4 6 6 Kϩ MnO Ϫ O O 4 O O ! !O O ! !O ! ! ! ! ! ! !O !O

؉ ؊ 18-Crown-6 [K 18-Crown-6] MnO4 Space-! lling model of the cation [K1 18-crown-6]. The size of the “cavity” in the crown ether can be tailored to allow for the selective binding of only certain cations—namely, those whose ionic radius is best accommodated by the polyether. This concept has been extended successfully into three dimensions by the synthesis of polycyclic ethers, also called cryptands (kryptos, Greek, hidden), which are highly selective in alkali and other metal binding (Figure 9-4). The signi! cance of these

+ Figure 9-4 The binding of a cation by a polycyclic ether (cryptand) to form a complex (cryptate). The ½OÂ ½OÂ ½O) ýOÂ + system shown selectively binds the potassium ion, with a binding K constant of K 5 1010. The order of Nð ðN Nð ðN 1 1 1 ýOk ýOk + ýOk ýOk selectivity is K . Rb . Na . Cs1 . Li1. The binding constant ýOk ðOk ýOk ðOk for lithium is about 100. Thus, the total range within the series of alkali metals spans eight orders of magnitude. A cryptand A cation A cryptate complex 9-5 Names and Physical Properties of Ethers CHAPTER 9 341

O O

O O OOO

In this perspective, six of the In this perspective, two of the O atoms H atoms are hidden by the are masked by the attached carbons attached carbons (marked by (marked by arrows). arrows).

Figure 9-3 The crown-like structural arrangement of 18-crown-6. The electron lone pairs give cyclic polyethers striking solvating power, in which several such oxygenthatatoms the insidemay surround of the ringand is quitebind metal electroncations rich due. Crown to the ethers electronare pairstherefore on the ethercapable of solubilizingoxygens,ordinary which saltsrendersin themorganic Lewissolvents basic. These. lone pairs give cyclic polyethers striking solvating power, in which several such oxygen atoms may surround and bind metal cat-

For example,ions. Crownpotassium ethers are thereforepermanganate capable of(KMnO solubilizing4), a ordinarydeep- saltsviolet in organicsolid, solvents.is completely insolubleForin example,benzene potassiumbut readily permanganatedissolves (KMnOwhen418), a- crowndeep-violet-6 is solid,added is. completelyThis solution insol-is useful becauseubleit inallows benzeneoxidations but readilywith dissolvespotassium when 18-crown-6permanganate is added.to Thisbe carriedsolution outis usefulin organic solventsbecause. it allows oxidations with potassium permanganate to be carried out in organic solvents. Dissolution is possible by effective solvation of the metal ion by the six crown Dissolutionoxygens.is possible by effective solvation of the metal ion by the six crown oxygens.

! ! O !O !O ! ! ! ! OO O O O O ؉ ! ! ! ! K KMnO , C H 4 6 6 Kϩ MnO Ϫ O O 4 O O ! !O O ! !O ! ! ! ! ! ! !O !O

؉ ؊ 18-Crown-6 [K 18-Crown-6] MnO4 Space-! lling model of the cation [K151 18-crown-6]. The size of the “cavity” in the crown ether can be tailored to allow for the selective binding of only certain cations—namely, those whose ionic radius is best accommodated by the polyether. This concept has been extended successfully into three dimensions by the synthesis of polycyclic ethers, also called cryptands (kryptos, Greek, hidden), which are highly selective in alkali and other metal binding (Figure 9-4). The signi! cance of these

O O

O O OOO

In this perspective, six of the In this perspective, two of the O atoms H atoms are hidden by the are masked by the attached carbons attached carbons (marked by (marked by arrows). arrows).

Figure 9-3 The crown-like structural arrangement of 18-crown-6.

! ! O !O !O ! ! ! ! OO O O O O ؉ ! ! ! ! K KMnO , C H 4 6 6 Kϩ MnO Ϫ O O 4 O The size of the “cavity”Oin! the crown!O ether can beOtailored! to!O allow for the selective binding of only certain cations—! namely,! those! whose ionic! radius! !is best accommodated by the O O polyether. ! ! ؉ ؊ 18-Crown-6 [K 18-Crown-6] MnO4 Space-! lling model of the cation [K1 18-crown-6]. This concept has been extended successfully into three dimensions by the synthesis of polycyclic ethers,The sizealso of thecalled “cavity”cryptands in the crown ( etherkryptos can , be Greek, tailored tohidden), allow for thewhich selectiveare highly selective inbindingalkali ofand onlyother certainmetal cations—namely,binding. those whose ionic radius is best accommodated by the polyether. This concept has been extended successfully into three dimensions by the synthesis of polycyclic ethers, also called cryptands (kryptos, Greek, hidden), which are The significancehighly selectiveof these in alkalicompounds and otherwas metalrecognized binding (Figureby 9-4).the Theaward signiof! cancethe Nobel of these Prize in chemistry in 1987, shared by Cram, Lehn, and Pedersen.

+ Figure 9-4 The binding of a cation by a polycyclic ether (cryptand) to form a complex (cryptate). The ½OÂ ½OÂ ½O) ýOÂ + system shown selectively binds the potassium ion, with a binding K constant of K 5 1010. The order of Nð ðN Nð ðN 1 1 1 ýOk ýOk + ýOk ýOk selectivity is K . Rb . Na . Cs1 . Li1. The binding constant ýOk ðOk ýOk ðOk for lithium is about 100. Thus, the total range within the series of alkali metals spans eight orders of magnitude. A cryptand A cation A cryptate complex 16 Crown ethers and cryptands are often called ion transport agents and are part of the general class of ionophores (-phoros, Greek, bearing, hence “ion bearing”), compounds that organize themselves around cations by coordination.

In general, the result of this interaction is that the polar hydrophilic nature of the ion is masked by a hydrophobic shell, hence making the ion much more soluble in nonpolar solvents.

In nature, ionophores can transport ions through hydrophobic cell membranes. The ion balance between the inside and outside of the cell is carefully regulated to ensure cell survival, and therefore any undue disruption causes cell destruction.

This property is put to medicinal use in fighting invading organisms with polyether antibiotics. However, because ion transport affects nerve transmission, some naturally occurring ionophores are also deadly neurotoxins.

17 9.6 WILLIAMSON ETHER SYNTHESIS

Ethers are prepared by SN2 reactions

The simplest way to synthesize an ether is to have an alkoxide (as an excellent

nucleophiles) react with a primary haloalkane or a sulfonate ester under typical SN2 conditions. 9-6 Williamson Ether Synthesis CHAPTER 9 343 The alcohol from which the alkoxide is derived can be used as the solvent (if inexpensive), be used as the solvent (if inexpensive), but other polar molecules, such as dimethyl sulfoxide but other polar molecules,(DMSO) orsuch hexamethylphosphoricas dimethyl triamidesulfoxide (HMPA),(DMSO) are often betteror hexamethylphosphoric (Table 6-5). triamide (HMPA), are often better. Williamson Ether Syntheses

CH3CH2CH2CH2OH, 14 h or DMSO, 9.5 h 344 CHAPTER 9 Further ReactionsšOð ϪofNa Alcoholsϩ ϩ and theCl Chemistryðð of Ethers O # # ϪNaϩClϪ ½ Â 60% (butanol solvent) 95% (DMSO solvent) 1-Butoxybutane

Ϫ ϩ

A A A H šO Na HOA šCH (CH ) CH #ð DMSO # 2 2 15 3 ϩϪ ϩϩCH3(CH2)15CH2 š#OSO2CH3 Na ðš#OSO2CH3 REAL LIFE: NATURE 9-1 Chemiluminescence of 1,2-Dioxacyclobutanes 91% EOH OOO O Cyclopentoxyheptadecane AA O 18 A HOϪ }~C OC ⌬ B 3)2C(CH OC(CH3)2 Ϫ HC3 & ( CH 3 2 CH33 CCH ϩ hv Nucleophile: red Because alkoxides are strong bases, their use ϪinBr ,ether synthesis is restricted to primary A CH3 CH 3 Electrophile: blue unhindered alkylating agents; otherwise,Br a signiϪ!H cantOOH amount of E2 product is formed Leaving group: green (Section 7-8). A 2-bromohydroperoxide 3,3,4,4-Tetramethyl-1,2-dioxacyclobutane Acetone (A 1,2-dioxetane)

An intramolecular Williamson-type reaction of a special kind Bioluminescence is extraordinarily ef! cient. For example, Exerciseis that9-12 in which a 2-bromohydroperoxide is the reactant. The the ! re" y converts about 40% of the energy of the underlying product is a 1,2-dioxacyclobutane (1,2-dioxetane). This com- chemical process into visible light. For your calibration, a The followingpound isethers unusual can, becausein principle, it decomposes be made by to more the correspondingthan one Williamson ethernormal synthesis. light bulb is only 10% ef! cient, most of the (electric) Considercarbonyl the relative compounds merits ofwith your emission approaches. of light (a) (chemilumines-1-Ethoxybutane; (b) 2-methoxypentane;energy being emitted as heat. (c) propoxycyclohexane;cence). Dioxacyclobutanes (d) 1,4-diethoxybutane. seem to be responsible [Cautions: Alkoxidesfor the are strong bases. What is wrong withbioluminescence 4-bromo-1-butanol of certain as a startingspecies materialin nature. for Terrestrial (d)?] organisms, such as the ! re" y, the glowworm, and certain click beetles, are well-known light emitters. However, most bioluminescent species live in the ocean; they range from Cyclic ethersmicroscopic can bacteria be preparedand plankton toby ! sh. intramolecular The emitted light serves many purposes and seems to be important in court- Williamsonship and synthesis communication, sex differentiation, ! nding prey, The Williamsonand hiding ether from synthesis or scaring is off also predators. applicable to the preparation of cyclic ethers, starting from Anhaloalcohols. example of Figurea chemiluminescent 9-5 depicts themolecule reaction in natureof hydroxide ion with a bromoalcohol.is The! re" blacky luciferin. curved The lines base denote oxidation the chainof this of molecule carbon atomsfur- linking the functional groups. Thenishes mechanism a dioxacyclobutanone consists of initialintermediate formation that decomposesof a bromoalkoxide by fast proton transfer toin the a manner base, followed analogous by to ring that closureof 3,3,4,4-tetramethyl-1,2- to furnish the cyclic ether. The ring closure Reminder on Entropy is an exampledioxacyclobutane of an intramolecular to give a complexdisplacement. heterocycle, Cyclic carbon ether formation is usually much Positive (favorable) with faster thandioxide, the side and reaction emitted shown light. in Figure 9-5, namely intermolecular displacement of increasing disorder or (more bromide by hydroxide to give a diol. The reason is entropy (Section 2-1). In the intra- rigorously) increasing H molecular reaction, the two reactingNN centers? areCOH in the same molecule; in the transition dispersal of the energy ~ Base, O2 state, one molecule of bromoalkoxideCCO turns intoB two molecules of products, the ether and content of the system. O the leaving group.HO In the intermolecularSS reaction, the alkoxide and the electrophile have to be brought together at an entropicFirefly luciferin cost to the transition state, and, overall, the number of molecules stays the same. In those cases in which the intermolecular SN2 reaction competes with its intramolecular counterpart, the intermolecularOOO process can be effectively sup- NNA A pressed by using high dilution conditions, whichOO Cdrastically reduce the rate of bimolecular M processes (Section 2-1). CCO O Intramolecular ϪWilliamsonO synthesisSS allows the preparation of cyclic ethers of various sizes, including small1,2-Dioxacyclobutanone rings. intermediate

NNO Ϫ O H CCO O ϩϩCO2 hv O Ϫ Intramolecular Ϫ OH SS ring closure O OMaleϩ andBr femaleϪ ﬁ reﬂ ies glowing in concert. Fast ϪHOOH CH2 OBr Fast CH2 OBr Cyclic ether

Intermolecular S 2 reaction Ϫ N HO H2 OBrC ϩ OH Slow HO OH

Ϫ ϩ

A A A H šO Na HOA šCH (CH ) CH #ð DMSO # 2 2 15 3 ϩϪ ϩϩCH3(CH2)15CH2 š#OSO2CH3 Na ðš#OSO2CH3

91% Cyclopentoxyheptadecane

Nucleophile: red Because alkoxides are strong bases, their use in ether synthesis is restricted to primary Electrophile: blue unhindered alkylating agents; otherwise, a signi! cant amount of E2 product is formed Leaving group: green (Section 7-8).

Exercise 9-12 The following ethers can, in principle, be made by more than one Williamson ether synthesis. Consider the relative merits of your approaches. (a) 1-Ethoxybutane; (b) 2-methoxypentane; (c) propoxycyclohexane; (d) 1,4-diethoxybutane. [Cautions: Alkoxides are strong bases. What is wrong with 4-bromo-1-butanol as a starting material for (d)?]

Cyclic ethers can be prepared by intramolecular Williamson synthesis The Williamson ether synthesis is also applicable to the preparation of cyclic ethers, starting from haloalcohols. Figure 9-5 depicts the reaction of hydroxide ion with a bromoalcohol. The black curved lines denote the chain of carbon atoms linking the functional groups. The mechanism consists of initial formation of a bromoalkoxide by fast proton transfer to the base, followed by ring closure to furnish the cyclic ether. The ring closure Reminder on Entropy is an example of an intramolecular displacement. Cyclic ether formation is usually much Positive (favorable) with faster than the side reaction shown in Figure 9-5, namely intermolecular displacement of increasing disorder or (more bromide by hydroxide to give a diol. The reason is entropy (Section 2-1). In the intra- rigorously) increasing molecular reaction, the two reacting centers are in the same molecule; in the transition dispersal of the energy state, one molecule of bromoalkoxide turns into two molecules of products, the ether and content of the system. the leaving group. In the intermolecular reaction, the alkoxide and the electrophile have to Becausebealkoxides brought togetherare strong at an entropicbases, costtheir to theuse transitionin ether state,synthesis and, overall,is restrictedthe number toof primary unhinderedmoleculesalkylating stays theagents same.; Inotherwise, those casesa insignificant which the intermolecularamount of E S2N2product reaction competesis formed . with its intramolecular counterpart, the intermolecular process can be effectively sup- Cyclic etherspressed canby usingbe preparedhigh dilutionby conditions,intramolecular which drasticallyWilliamson reduce thesynthesis rate of bimolecular processes (Section 2-1). The WilliamsonIntramolecularether synthesisWilliamson synthesisis also allowsapplicable the preparationto the ofpreparation cyclic ethers ofof variouscyclic ethers, starting fromsizes, haloalcoholsincluding small. rings.

O H O Ϫ O Ϫ Intramolecular OH ring closure O ϩ Br Ϫ Fast ϪHOOH CH2 OBr Fast CH2 OBr Cyclic ether

Intermolecular S 2 reaction Ϫ N HO H2 OBrC ϩ OH Slow HO OH

Figure 9-5 The mechanism of cyclic ether synthesis from a bromoalcohol and hydroxide ion (upper reactions). A competing but slower side reaction, direct displacement of bromide by 19 hydroxide, is also shown (lower reaction). The curved lines denote a chain of carbon atoms. The mechanism consists of initial formation of a bromoalkoxide by fast proton transfer to the base, followed by ring closure to furnish the cyclic ether. The ring closure is an example of an intramolecular displacement.

Cyclic ether formation is usually much faster than the intermolecular displacement of bromide by hydroxide to give a diol. The reason is entropy.

In the intramolecular reaction, the two reacting centers are in the same molecule; in the transition state, one molecule of bromoalkoxide turns into two molecules of products, the ether and the leaving group.

In the intermolecular reaction, the alkoxide and the electrophile have to be brought together at an entropic cost to the transition state, and, overall, the number of molecules stays the same.

In those cases in which the intermolecular SN2 reaction competes with its intramolecular counterpart, the intermolecular process can be effectively suppressed by using high dilution conditions, which drastically reduce the rate of bimolecular processes.

20 9-6 Williamson Ether Synthesis CHAPTER 9 345 Intramolecular Williamson synthesis allows the preparation of cyclic ethers of various sizes, including small rings. Cyclic Ether Synthesis The blue dot indicates the carbon atom in the product 23 Ϫ Ϫ that corresponds to the site of H"šOCH2CH2Br"šð ϩ HO"šð ϩϩBr"šðð H"šOH ½ÂO ring closure in the starting 1 material. Oxacyclopropane (Oxirane, ethylene oxide)

4 Model Building 3 5 Ϫ Ϫ HšO(CH2)4CH2Bršð ϩϩHOšð Bršðð ϩ HšOH " " " 2 6 " " ½ÂO 1 Oxacyclohexane (Tetrahydropyran) O − To compare the structures and hence energies of the transition states of the intramolecular Williamson ether synthesisExercise 9-13: enthalpic and entropic contributions. The product of the reaction of 5-bromo-3,3-dimethyl-1-pentanol with hydroxide is a cyclic ether. Suggest a mechanism for its formation. Enthalpy reflects changes not only in bond strengths during a reaction, but also in strainFavorable. Entropy is related to changes in the extent of order (or energy dispersal) in the system. entropy overrides21 Br Ring size controls the speed of cyclic ether formation strain k A comparison of the relative rates of cyclic ether formation reveals a surprising fact: Three- 3 membered rings form quickly, about as fast as ! ve-membered rings. Six-membered ring systems, four-membered rings, and the larger oxacycloalkanes are generated more slowly. O − Relative Rates of Cyclic Ether Formation

k3 $ k5 . k6 . k4 $ k7 . k8

kn 5 reaction rate, n 5 ring size Increasing rate of ring closure What effects are at work here? Since we are concerned with rates, we need to compare Low strain overrides the structures and hence energies of the transition states of the intramolecular Williamson unfavorable ether synthesis. We shall ! nd that the answer is composed of both enthalpic and entropic entropy Br contributions (Section 2-1). Recall that enthalpy re" ects changes not only in bond strengths k during a reaction, but also in strain (Section 4-2). Entropy, on the other hand, is related to 5 changes in the extent of order (or energy dispersal) in the system. What are the differences between the various transition states for ring formation with respect to these quantities? As we proceed from larger ring to three-membered ring closures, the most obvious enthalpy effect is ring strain. If it were dominant, the most strained rings should be formed

at the lowest rate, even though the full effect of strain may not be felt in the structure of k the respective transition states. However, this is not observed, and we need to look for other − factors that complicate this simple analysis. One such factor is entropy. No strain: O To understand how entropy comes into play, put yourself into the position of the nucleo- overrides unfavorable philic, negatively charged oxygen in search of the backside of the electrophilic carbon entropy Br bearing the leaving group. Clearly, the closer you are to the target, the easier it is to ! nd k it. If the target is remote, the intervening chain has to be arranged or “ordered” in such a 6 way as to bring it closer to you. This is more dif! cult when the chain gets longer. In molecular terms, to reach the transition state for ring formation, the opposite ends of the O − molecule must approach each other. In the ensuing conformation, rotation about the intervening bonds becomes restricted, and energy dispersal in the molecule is reduced: The entropy change is unfavorable (negative). This effect is most severe for long chains, making the formation of medium-sized and larger rings relatively most dif! cult. In addition, their rates of formation suffer from eclipsing, gauche, and transannular strain (Section 4-5). In contrast, cyclization of Strain and shorter chains requires less restriction of bond rotation and therefore a smaller unfavorable reduc- unfavorable entropy tion in entropy: Three- to six-membered rings are generated relatively quickly. In fact, on entropy team up Br grounds alone, the relative rates for ring closure should be k3 . k4 . k5 . k6. Superposition of ring strain effects then leads to the observed trends listed above (see also margin structures). k4 9-6 Williamson Ether Synthesis CHAPTER 9 345

Cyclic Ether Synthesis The blue dot indicates the carbon atom in the product 23 Ϫ Ϫ that corresponds to the site of H"šOCH2CH2Br"šð ϩ HO"šð ϩϩBr"šðð H"šOH ½ÂO ring closure in the starting 9-6 Williamson Ether1 Synthesis CHAPTER 9 345 material. Oxacyclopropane (Oxirane, ethylene oxide)

4 Model Building Cyclic Ether Synthesis 3 5 The blue dot indicates the Ϫ Ϫ H"šO(CH2)4CH2Br"šð ϩϩHO"šð Br"šðð ϩ H"šOHcarbon atom in the product 23 2 6 HšOCH CH Brš ϩ HOš Ϫ ϩϩBrš ½ÂOϪ HšOH that corresponds to the site of " 2 2 "ð "ð "ðð 1 " ½ÂO ring closure in the starting 1 Oxacyclohexane (Tetrahydropyran) material. Oxacyclopropane O − (Oxirane, ethylene oxide) Exercise 9-13 The product of the reaction4 of 5-bromo-3,3-dimethyl-1-pentanol with hydroxide is a cyclic ether.M odel Building 9-6 Williamson Ether Synthesis CHAPTER 9 345 Suggest a mechanism3 for its5 formation. Ϫ Ϫ Favorable H"šO(CH2)4CH2Br"šð ϩϩHO"šð Br"šðð ϩ H"šOH entropy 2 6 overrides Br CyclicRing Ether size Synthesis controls½ÂO the speed of cyclic etherThe formation blue dot indicates the strain 1 k A comparison of the relative rates of cyclic ether formation revealscarbon atom a surprising in the product fact: Three- 3 23 Ϫ Oxacyclohexane Ϫ that corresponds to the site of H"šOCH2CH2Br"šð ϩ HO"šð membered rings form quickly,ϩϩ Br"š aboutðð as fastH"š OH as ! ve-membered rings. Six-membered ring ½ÂO(Tetrahydropyran) ring closure in the starting systems, four-membered1 rings, and the larger oxacycloalkanes are generated more slowly. material. − O − Oxacyclopropane Relative Rates of Cyclic Ether Formation O (Oxirane, ethylene oxide)

k3 $ k5 . k6 . k4 $ k7 . k8 Exercise 9-13 4 kn 5 reaction rate, n 5 ring size Model Building Increasing rate of ring closure Ring size controls3 the5 speed of cyclic ether formation The product of the reaction of 5-bromo-3,3-dimethyl-1-pentanolϪ What effects are at work here?Ϫ with Since hydroxide we are concerned is a cyclic with rates,ether. we need to compare Low strain HšO(CH2)4CH2Bršð ϩϩHOšð Bršðð ϩ HšOH overrides " " " 2 6 " " Suggest a mechanism for its formation.the structures and hence energies of the transition states of the intramolecular Williamson unfavorable Three-membered½ÂOrings form quickly, about as fast as five-membered rings. Six-membered ether synthesis.1 We shall ! nd that the answer is composed of both enthalpic andFavorable entropic entropy Br ring systems,contributionsOxacyclohexanefour (Section-membered 2-1). Recallrings, that enthalpyand re" theects changeslarger not onlyoxacycloalkanes in bond strengths are generated more entropy k5 slowly. during(Tetrahydropyran) a reaction, but also in strain (Section 4-2). Entropy, on the other hand, isoverrides related to Br Ring size controls the speedchanges ofin the cyclic extent of orderether (or energy formation dispersal) in the system. WhatO − are the straindifferences between the various transition states for ring formation with respect to these quantities? k3 A comparisonExercise 9-13 of the relative rates of cyclicAs we ether proceed formation from larger reveals ring to three-membereda surprising fact: ring closures, Three- the most obvious enthalpy effect is ring strain. If it were dominant, the most strained rings should be formed memberedThe product rings of the form reaction quickly, of 5-bromo-3,3-dimethyl-1-pentanol about as fast as ! ve-membered with hydroxide is a rings.cyclic ether. Six-membered ring at the lowest rate, even though the full effect of strain may not be felt in the structure of k Suggest a mechanism for its formation. systems, four-membered rings, andthe the respective larger transitionoxacycloalkanes states. However, are this generated is not observed, more and slowly. we need to look for other Favorable − − factors that complicate this simple analysis. One such factorentropy is entropy. No strain: O O Relative RatesTo of understand Cyclic howEther entropy Formation comes into play, put yourselfoverrides into the positionBr of the nucleo- overrides Ring size controls the speed of cyclic ether formation strain unfavorable philic, negatively charged oxygen in search of the backside of the electrophilic carbon entropy k3 Br A comparison of the relative rates ofk 3cyclic $bearing k 5ether . the kformation6 leaving. k4 $ group.reveals k7 . Clearly,a ksurprising8 the closerfact: Three- you are to the target, the easier it is to ! nd k6 membered rings form quickly, aboutk n as5it. fastreactionIf the as target! ve-memberedrate, is n remote, 5 ring rings. thesize intervening Six-membered chain ringhas to be arranged or “ordered” in such a Increasing rate of ring closure systems, four-membered rings, and the waylarger as oxacycloalkanes to bring it closer are to generatedyou. This ismore more slowly. dif! cult when the chain gets longer. − What effects are at work here? Since we are concerned with rates, we need to compare OLow strain − Relative Rates of CyclicIn molecular Ether terms,Formation to reach the transition state for ring formation, the opposite ends of the O the structures and hence energies ofmolecule the transition must approach states each other.of the In the intramolecular ensuing conformation, Williamson rotation about theoverrides intervening k $ k .bonds k . becomes k $ k .restricted, k and energy dispersal in the molecule is reduced: The entropyunfavorable change ether synthesis. We shall ! nd 3 that5 the6 answer4 7 is composed8 of both enthalpic and entropic entropy

kn 5 reactionis unfavorable rate, n 5 ring (negative). size This effect is most severe for long chains, making the formationIncreasing rate of ring closure of Br contributions (Section 2-1). Recall medium-sizedthat enthalpy and relarger" ects rings changes relatively mostnot difonly! cult. in In bond addition, strengths their rates of formation suf- What effects are at work here? Since we are concerned with rates, we need to compare Low strain k fer from eclipsing, gauche, and transannular strain (Section 4-5). In contrast, cyclization of 5 duringthe astructures reaction, and buthence also energies in strain of the transition(Section states 4-2). of Entropy,the intramolecular on the Williamson other hand, overridesis related to Strain and shorter chains requires less restriction of bond rotation and thereforeunfavorable a smaller unfavorable reduc- unfavorable changesether insynthesis. the extent We shall of !order nd that (or the energyanswer is dispersal) composed of in both the enthalpic system. and What entropic are theentropy differences entropy tion in entropy: Three- to six-membered rings are generated relatively quickly. In fact,Br on entropy contributions (Section 2-1). Recall that enthalpy re" ects changes not only in bond strengths team up Br between the various transition statesgrounds for ringalone, formationthe relative rates with for ringrespect closure to should these be kquantities? . k . k .k k . Superposition of during a reaction, but also in strain (Section 4-2). Entropy, on the other hand, is related to 3 4 5 5 6 22 ring strain effects then leads to the observed trends listed above (see also margin structures). k4 Aschanges we in proceed the extent fromof order larger (or energy ring dispersal) to three-membered in the system. What ring are closures,the differences the most obvious enthalpybetween effect the various is ring transition strain. states If it for were ring dominant,formation with the respect most to strained these quantities? rings should be formed at the lowestAs we proceedrate, even from though larger ring the to full three-membered effect of ringstrain closures, may thenot most be felt obvious in the structure of k the respectiveenthalpy effect transition is ring strain. states. If it wereHowever, dominant, this the is most not strained observed, rings shouldand we be formedneed to look for other at the lowest rate, even though the full effect of strain may not be felt in the structure of k − O factorsthe respectivethat complicate transition states.this simpleHowever, analysis. this is not observed,One such and factorwe need is to entropy.look for other No strain: − overrides Tofactors understand that complicate how this entropy simple comesanalysis. intoOne suchplay, factor put yourselfis entropy. into the position ofNo the strain: nucleo- O unfavorable To understand how entropy comes into play, put yourself into the position of the nucleo- overrides philic, negatively charged oxygen in search of the backside of the electrophilicunfavorable carbon entropy Br philic, negatively charged oxygen in search of the backside of the electrophilic carbon entropy Br bearingbearing the the leaving leaving group.group. Clearly, Clearly, the closerthe closeryou are youto the are target, to thethe easier target, it is theto ! easiernd it is to ! nd k k6 it. Ifit. the If thetarget target isis remote, the the intervening intervening chain haschain to be has arranged to be or arranged“ordered” inor such “ordered” a in such 6a way wayas toas tobring bring itit closer to toyou. you. This This is more is difmore! cult difwhen! cult the chainwhen gets the longer. chain gets longer. − In molecularIn molecular terms,terms, to to reach reach the transitionthe transition state for state ring formation,for ring theformation, opposite ends the of opposite the ends of theO − molecule must approach each other. In the ensuing conformation, rotation about the intervening O moleculebonds becomesmust approach restricted, andeach energy other. dispersal In the in ensuingthe molecule conformation, is reduced: The rotation entropy change about the intervening bondsis unfavorablebecomes restricted,(negative). This and effect energy is most dispersal severe for in long the chains, molecule making is the reduced: formation The of entropy change is unfavorablemedium-sized (negative). and larger rings This relatively effect most is difmost! cult. severe In addition, for theirlong rates chains, of formation making suf- the formation of fer from eclipsing, gauche, and transannular strain (Section 4-5). In contrast, cyclization of Strain and medium-sizedshorter chains and requires larger less restrictionrings relatively of bond rotation most anddif !therefore cult. In a smalleraddition, unfavorable their rates reduc- of formationunfavorable suf- entropy fer fromtion in eclipsing,entropy: Three- gauche, to six-membered and transannular rings are generated strain relatively (Section quickly. 4-5). In fact, In on contrast, entropy cyclizationteam up of Br Strain and shortergrounds chains alone, requires the relative less rates restriction for ring closure of bond should rotation be k3 . and k4 . therefore k5 . k6. Superposition a smaller ofunfavorable reduc- unfavorable ring strain effects then leads to the observed trends listed above (see also margin structures). k4 entropy tion in entropy: Three- to six-membered rings are generated relatively quickly. In fact, on entropy team up Br grounds alone, the relative rates for ring closure should be k3 . k4 . k5 . k6. Superposition of ring strain effects then leads to the observed trends listed above (see also margin structures). k4 346 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

– Recent studies have shown that entropy alone cannot explain why three-membered rings are generated fastest. A second enthalpic phenomenon, which has been called the proximity O effect, operates, especially in 2-haloalkoxides. To understand it, you need to remember that all SN2 reactions suffer to a varying degree from steric hindrance of the nucleophile (Sec- tion 6-10). In 2-haloalkoxides (and related three-membered ring precursors), the nucleophilic Br part of the molecule is so close to the electrophilic carbon that part of the strain of the transition state is already present in the ground state. In other words, the molecule is acti- The oxygen in 2-bromoethoxide vated along the reaction coordinate of the “normal” (unstrained) substitution process. This is “pushing” into the electrophilic rate-accelerating proximity effect is dramatically reduced in four-membered ring synthesis carbon. (and so is the entropy advantage), while the ring strain is still large; therefore, ring closure The intramolecularto Williamsonoxacyclobutanessynthesis is comparativelyis stereospecificslow (see also space-! lling models in margin). As we – shall ! nd, the general conclusions reached in this section apply also to other ring closing transformations that we shall encounter in later chapters. OThe Williamson ether synthesis proceeds with inversion of configuration at the carbon bearing the leaving group, in accord with expectations based on an S 2 mechanism. The intramolecular Williamson synthesis is stereospeciﬁN c The Williamson ether synthesis proceeds with inversion of con! guration at the carbon bearing The attackingBr nucleophile approaches the electrophilic carbon from the opposite side of the the leaving group, in accord with expectations based on an SN2 mechanism. The attacking leaving group. Onlynucleophileone conformation approaches theof electrophilicthe haloalkoxide carbon fromcan the oppositeundergo sideefficient of the leavingsubstitution group. . Only one conformation of the haloalkoxide can undergo ef! cient substitution. For example, The oxygen in 3-bromopropoxide is at a comfortableFor example, distance fromoxacyclopropane oxacyclopropane formationformation requiresrequires an anti an arrangementanti arrangement of the nucleophileof andthe thenucleophile leaving

the electrophilicand carbon.the leaving groupgroup.. The The alternativealternative twotwo gauchegauche conformationsconformations cannot give thecannot productgive (Figurethe 9-6).product.

Ϫ Ϫ Ϫ ½

@ @ @

G G

ðOšð H ðOšð Brš ð ðOšðG D O & & " &

Brš ð D H Inversion DG C C C C " C Ϫ

G G C G C C G C C G C G C G C ϩ Brš" ðð H ( H ( H ( S HD( R ( H D H H H Brš" ð HH Gauche: unsuitable Gauche: unsuitable Anti: correct conformation for SN2 for SN2 for SN2

Figure 9-6 Only the anti conformation of a 2-bromoalkoxide allows for oxacyclopropane formation. The two gauche conformers cannot undergo intramolecular backside attack at the Model Building bromine-bearing carbon. 23

Working with the Concepts: Stereochemistry of the Solved Exercise 9-14 Intramolecular Williamson Ether Synthesis (1R,2R)-2-Bromocyclopentanol reacts rapidly with sodium hydroxide to yield an optically inactive product. In contrast, the (1S,2R) isomer is much less reactive. Explain. What you are being asked to do is to explain a result. So, you need to consider mechanisms. How to begin? Draw the structures of the two isomeric substrates (even better, build models!), so you can visualize their differences:

) RR ) ) SR ) H@ @ Br HO@ @ Br OH H H H (1R,2R)-2-Bromocyclopentanol (1S,2R)-2-Bromocyclopentanol The nucleophilic oxygen and the Here the nucleophile and leaving leaving group are trans (anti) group are cis (syn)

Information needed? Given the mechanistic options available to these compounds, how might their stereochemical difference affect their reactivity? Proceed. • Figure 9-6 showed us that base treatment of 2-haloalkanols deprotonates the OH group. The resulting alkoxide then displaces the neighboring halide to produce an oxacyclopropane. Unlike the situation shown in Figure 9-6, however, our two 2-bromocyclopentanols contain a