Organic Chemistry I

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, Structure and Function (7th edition) By P. Vollhardt and N. Schore, Elsevier, 2014 1 9-7 Synthesis of Ethers: Alcohols and Mineral Acids CHAPTER 9 347

ring that restricts the conformational freedom around the bond connecting the two functional groups. In the (1R,2R) isomer, the alkoxide oxygen and the halogen are arranged trans to each other and hence in perfect alignment for intramolecular backside displacement of bromide by alkoxide. The resulting oxacyclopropane has a mirror plane and is meso and achiral.

ϩ " Brš " Fast " ) RR ) ) ) H@ @ Br HH¥ @ Ϫ O "Oðð H Meso

• In contrast, the (1S,2R) isomer contains the same functions on the same side of the ! ve- membered ring. To proceed to (the same) product, a frontside displacement is needed, which is much more dif! cult. Thus, the alkoxide derived from the 1R,2R-diastereomer reacts faster than that generated from the 1S,2R-isomer.

Exercise 9-15 Try It Yourself Bromoalcohol A transforms rapidly in the presence of sodium hydroxide to give the corresponding oxacyclopropane, whereas its diastereomer B does not. Why? [Caution: Unlike the previous problem, both substrates are trans-bromoalcohols. Hint: Draw the most stable cyclohexane chair conformers of both isomers (Section 4-4) and picture the respective transition states for the intramolecular Williamson ether synthesis.]

Br Br % ´ ∞OH ]OH

0 0 C(CH3)3 C(CH3)3 A B

In Summary Ethers are prepared by the Williamson synthesis, an SN2 reaction of an alkoxide with a haloalkane. This reaction works best with primary halides or sulfonates that do not undergo ready elimination. Cyclic ethers are formed by the intramolecular version of this method. The relative rates of ring closure in this case are highest for three- and ! ve-membered rings.

9.7 SYNTHESIS OF ETHERS: ALCOHOLS AND MINERAL ACIDS 9-7 SYNTHESIS OF ETHERS: ALCOHOLS AND MINERAL ACIDS An even simpler, albeit less selective, route to ethers is the reaction of a strong inorganic acid (e.gAn., Heven2SO simpler,4) with albeitan alcohol less selective,. Protonation route toof ethersthe OHis thegroup reactionin oneof a alcoholstrong inorganicgenerates water as a leaving group. acid (e.g., H2SO4) with an alcohol. Protonation of the OH group in one alcohol generates water as a leaving group. Nucleophilic displacement of this leaving group by a second Nucleophilicalcoholdisplacement then results in ofthethis correspondingleaving group alkoxyalkane.by a second alcohol then results in the corresponding alkoxyalkane.

Alcohols give ethers by both SN2 and SN1 mechanisms Alcohols give ethers by both S 2 and S 1 mechanisms We have learned that treatingN primary alcoholsN with HBr or HI furnishes the corresponding haloalkanes through intermediate alkyloxonium ions (Section 9-2). However, when strong When nonnucleophilicstrong nonnucleophilic acids—such acids,as sulfuricsuch acid—areas sulfuric used at elevatedacid, aretemperatures,used at the elevatedmain temperatures,productsthe aremain ethers.products are ethers.

Symmetrical Ether Synthesis from a Primary Alcohol with Strong Acid ReactionR H SO , 130ЊC 2 CH CH OH 2 4 CH CH OCH CH ϩ HOH 3 2 Relatively high 3 2 2 3 temperature 2 348 InCHAPTERthis reaction, 9 theFurtherstrongest Reactionsnucleophile of Alcoholspresent andin thesolution Chemistryis the unprotonatedof Ethers starting alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, the ultimate products being an ether and water. In this reaction, the strongest nucleophile present in solution is the unprotonated starting alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, Only symmetric ethersthe ultimatecan beproductsprepared being byan etherthis methodand water.. Mechanism

Mechanism of Ether Synthesis from Primary Alcohols: Protonation and SN2

CH3CH2šOH H CH3CH2 CH3CH2 ϩ ϩ š ϩ H ϩf SN2 f ϩ Ϫ H f ϩ ϩϩCH3CH2OO O OH H2šO šO ϩ H3Oð ϩ " " ϩ " Ϫ H i i š ϩ H i CH3CH2šOH H CH3CH2 CH3CH2 š CH3CH2šOH š

E2 Mechanism for Only symmetric ethers can be prepared by this method. the Acid-Catalyzed At even higher temperatures (see footnote on p. 329), elimination of water to generate Dehydration of an alkene is observed. This reaction proceeds by an E2 mechanism (Sections 7-7 and 11-7), 3 1-Propanol in which the neutral alcohol serves as the base that attacks the alkyloxonium ion (margin). H ½ÂO Alkene Synthesis from a Primary Alcohol and Strong Acid at Elevated Temperature: E2 H A H A H2SO4, 180ЊC CH3CHCH2OH CH3CHPCH2 ϩ HOH Â Relatively high O 1-Propanol temperature Propene ϩ HH Secondary and tertiary ethers can also be made by acid treatment of secondary and tertiary alcohols. However, in these cases, a carbocation is formed initially and is then trapped by an alcohol (SN1), as described in Section 9-2. ϩ H2O

Symmetrical Ether Synthesis from a Secondary Alcohol

SN1 Mechanism for OH the Acid-Catalyzed A H SO , 40ºC 2 CH CCH 2 4 (CH ) CHOCH(CH ) ϩ HOH ϩ Hϩ Ether Formation 3 3 Relatively low 3 2 3 2 A temperature from 2-Propanol H 75% 2-Propanol 2-(1-Methylethoxy)propane (Diisopropyl ether) H ½ÂO The major side reaction follows the E1 pathway (Sections 9-2, 9-3, and 11-7), which, again, becomes dominant at higher temperatures. ϩ It is harder to synthesize ethers containing two different alkyl groups, because mixing two alcohols in the presence of an acid usually results in mixtures of all three possible products. However, mixed ethers containing one tertiary and one primary or secondary alkyl substituent can be prepared in good yield in the presence of dilute acid. Under these condi- H tions, the much more rapidly formed tertiary carbocation is trapped by the other alcohol. ϩ šO

Synthesis of a Mixed Ether from a Tertiary Alcohol

CH3 CH3 A A 15% aqueous H2SO4, 40ºC CH3COHϩ CH3CH2OH (excess) CH3COCH2CH3 A Ϫ HOH A šOð ϩ Hϩ CH3 CH3 95% 2-Ethoxy-2-methylpropane 348 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

In this reaction, the strongest nucleophile present in solution is the unprotonated starting348 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, the ultimate products being an ether and water. Mechanism In this reaction, the strongest nucleophile present in solution is the unprotonated starting Mechanism of Ether Synthesis from Primary Alcohols: Protonation and S 2 alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, N the ultimate products being an ether and water. Mechanism CH3CH2šOH H CH3CH2 CH3CH2 ϩ ϩ Mechanism of Ether Synthesis from Primary Alcohols: Protonation and S 2 š ϩ H ϩf SN2 f ϩ Ϫ H f ϩ N ϩϩCH3CH2OO O OH H2šO šO ϩ H3Oð Ϫ Hϩ " " ϩ Hϩ " i i š i CH CH šOH H CH CH CH CH 3 2 H CH3CH2 CH3CH2 CH3CH2šOH 3 2 3 2 ϩ ϩ š ϩ H ϩf SN2 f ϩ Ϫ H f ϩ ϩϩCH3CH2OO O OH H2šO šO ϩ H3Oð š ϩ " " ϩ " Ϫ H i i ϩ H i CH3CH2šOH š CH3CH2šOH H CH3CH2 CH3CH2 š š At even higher temperatures, elimination of water to generate an alkene is observed. This CH3CH2šOH E2 Mechanism for Only symmetricreaction ethersproceeds can beby preparedan E2 bymechanism, this method. in which the neutral alcohol serves as the base š the Acid-Catalyzed At thateven attackshigher temperaturesthe alkyloxonium (see footnoteion. on p. 329), elimination of water to generate Dehydration of an alkene is observed. This reaction proceeds by an E2 mechanism (Sections 7-7 and 11-7),E2 Mechanism for Only symmetric ethers can be prepared by this method. 1-Propanol in which the neutral alcohol serves as the base that attacks the alkyloxonium ion (margin).the Acid-Catalyzed At even higher temperatures (see footnote on p. 329), elimination of water to generate Dehydration of an alkene is observed. This reaction proceeds by an E2 mechanism (Sections 7-7 and 11-7), H 1-Propanol in which the neutral alcohol serves as the base that attacks the alkyloxonium ion (margin). ½ÂO Alkene Synthesis from a Primary Alcohol and Strong Acid at Elevated Temperature: E2 H O Alkene Synthesis from a Primary Alcohol and Strong Acid H ½Â A H at Elevated Temperature: E2 A H SO , 180ЊC H CH CHCH OH 2 4 CH CHPCH ϩ HOH A H 3 2 Relatively high 3 2 A Â H2SO4, 180ЊC O 1-Propanol temperature Propene CH3CHCH2OH CH3CHPCH2 ϩ HOH ϩ Â Relatively high HH O 1-Propanol temperature Propene ϩ Secondary and tertiary ethers can also be made by acid treatment of secondary and HH tertiary alcohols. However, in these cases, a carbocation is formed initially and is then Secondary and tertiary ethers can also be made by acid treatment of secondary and trapped by an alcohol (S 1), as described in Section 9-2. tertiary alcohols. However, in these cases, a carbocation is formed initially and is then ϩ H O N 2 trapped by an alcohol (SN1), as described in Section 9-2. ϩ H2O Symmetrical Ether Synthesis from a Secondary Alcohol Symmetrical Ether Synthesis from a Secondary Alcohol 4 SN1 Mechanism for OH SN1 Mechanism for OH the Acid-Catalyzed A H SO , 40ºC 2 4 ϩ the Acid-Catalyzed A H SO , 40ºC 2 CH3CCH3 (CH3)2CHOCH(CH3)2 ϩ HOH ϩ H 2 4 ϩ Ether Formation Relatively low 2 CH3CCH3 (CH3)2CHOCH(CH3)2 ϩ HOH ϩ H A Ether Formation A Relatively low from 2-Propanol temperature temperature H 75% from 2-Propanol H 75% 2-Propanol 2-(1-Methylethoxy)propane 2-Propanol 2-(1-Methylethoxy)propane (Diisopropyl ether) (Diisopropyl ether) H H ½ÂO ½ÂO The major side reaction follows the E1 pathway (Sections 9-2, 9-3, and 11-7), which, again, The major side reaction follows the E1 pathway (Sections 9-2, 9-3, and 11-7), which, again, becomes dominant at higher temperatures. becomes dominant at higher temperatures. ϩ ϩ It is harder to synthesize ethers containing two different alkyl groups, because mixing It is harder to synthesize ethers containing two different alkyl groups, because mixing two alcohols in the presence of an acid usually results in mixtures of all three possible two alcohols in the presence of an acid usually results in mixtures of all three possible products. However, mixed ethers containing one tertiary and one primary or secondary alkyl products. However, mixed ethers containing one tertiary and one primary or secondary alkyl substituent can be prepared in good yield in the presence of dilute acid. Under these condi- substituent can be prepared in good yield in the presence of dilute acid. Under these condi- H tions, the much more rapidly formed tertiary carbocation is trapped by the other alcohol. H tions, the much more rapidly formed tertiary carbocation is trapped by the other alcohol. ϩ šO ϩ šO Synthesis of a Mixed Ether from a Tertiary Alcohol Synthesis of a Mixed Ether from a Tertiary Alcohol CH3 CH3 A A CH3 CH3 15% aqueous H2SO4, 40ºC CH3COHϩ CH3CH2OH (excess) CH3COCH2CH3 A A Ϫ HOH 15% aqueous H2SO4, 40ºC A A CH3COHϩ CH3CH2OH (excess) CH3COCH2CH3 A Ϫ HOH A šOð ϩ Hϩ CH3 CH3 95% šOð ϩ Hϩ CH3 CH3 95% 2-Ethoxy-2-methylpropane 2-Ethoxy-2-methylpropane 348 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

In this reaction, the strongest nucleophile present in solution is the unprotonated starting alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, 348 the ultimate products being an ether and water. CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers Mechanism

Mechanism of Ether Synthesis from Primary Alcohols: Protonation and SN2 In this reaction, the strongest nucleophile present in solution is the unprotonated starting CH3CH2šOH H CH3CH2 CH3CH2 alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, ϩ ϩ š ϩ H ϩf SN2 f ϩ Ϫ H f ϩ ϩϩCH3CH2OO O OH H2šO šO ϩ H3Oð the ultimate products being an ether and water. ϩ " " ϩ " Ϫ H i i š ϩ H i Mechanism CH3CH2šOH H CH3CH2 CH3CH2 š Mechanism of Ether Synthesis from Primary Alcohols: Protonation and SN2 CH3CH2šOH š CH3CH2šOH H CH3CH2 CH3CH2 ϩ Hϩ ϩ S 2 Ϫ Hϩ ϩ š f N f ϩ f E2 Mechanism for Only symmetric ethers can be prepared by this method. ϩϩCH3CH2OO O OH H2šO šO ϩ H3Oð ϩ " " ϩ " At even higher temperatures (see footnote on p. 329), elimination of water to generate Ϫ H i i š ϩ H i the Acid-Catalyzed CH3CH2šOH H CH3CH2 CH3CH2 Dehydration of an alkene is observed. This reaction proceeds by an E2 mechanism (Sections 7-7 and 11-7), š 1-Propanol in which the neutral alcohol serves as the base that attacks the alkyloxonium ion (margin). CH3CH2šOH H š ½ÂO Alkene Synthesis from a Primary Alcohol and Strong Acid at Elevated Temperature: E2 H E2 Mechanism for Only symmetric ethers can be prepared by this method. A H A At even higher temperatures (see footnote on p. 329), elimination of water to generate H2SO4, 180ЊC the Acid-Catalyzed CH3CHCH2OH CH3CHPCH2 ϩ HOH an alkene is observed. This reaction proceeds by an E2 mechanism (Sections 7-7 and 11-7), Â Relatively high Dehydration of O 1-Propanol temperature Propene ϩ 1-Propanol in which the neutral alcohol serves as the base that attacks the alkyloxonium ion (margin). HH Secondary and tertiary ethers can also be made by acid treatment of secondary and H tertiary alcohols. However, in these cases, a carbocation is formed initially and is then ½ÂO Alkene Synthesis from a Primary Alcohol and Strong Acid trapped by an alcohol (SN1), as described in Section 9-2. at Elevated Temperature: E2 ϩ H2O H A H Symmetrical Ether Synthesis from a Secondary Alcohol A H2SO4, 180ЊC CH CHCH OH CH CHPCH ϩ HOH S 1 Mechanism for OH 3 2 Relatively high 3 2 N Â Secondary and tertiary ethers can also be made by acid treatment of the Acid-Catalyzed A H SO , 40ºC 1-Propanol temperature Propene 2 4 ϩ O 2 CH3CCH3 (CH3)2CHOCH(CH3)2 ϩ HOH ϩ H ϩ secondary and tertiary alcohols. A carbocation is formed initially and Ether Formation A Relatively low HH from 2-Propanol temperature is then trapped by an alcohol (SN1). H 75% Secondary and tertiary ethers can also be made by acid treatment of secondary and 2-Propanol 2-(1-Methylethoxy)propane tertiary alcohols. However, in these cases, a carbocation is formed initially and is then (Diisopropyl ether) trapped by an alcohol (S 1), as described in Section 9-2. H ϩ H O N ½ÂO 2 The major side reaction follows the E1 pathway (Sections 9-2, 9-3, and 11-7), which, again, becomes dominant at higher temperatures. Symmetrical Ether Synthesis from a Secondary Alcohol ϩ It is harder to synthesize ethers containing two different alkyl groups, because mixing S 1 Mechanism for OH two alcohols in the presence of an acid usually results in mixtures of all three possible N products. However, mixed ethers containing one tertiary and one primary or secondary alkyl the Acid-Catalyzed A H SO , 40ºC 2 4 ϩ substituent can be prepared in good yield in the presence of dilute acid. Under these condi- 2 CH3CCH3 (CH3)2CHOCH(CH3)2 ϩ HOH ϩ H Ether Formation Relatively low H tions, the much more rapidly formed tertiary carbocation is trapped by the other alcohol. A temperature from 2-Propanol H 75% ϩ šO 2-Propanol 2-(1-Methylethoxy)propane (Diisopropyl ether) Synthesis of a Mixed Ether from a Tertiary Alcohol H CH3 CH3 ½ÂO A A The major side reaction follows the E1 pathway (Sections 9-2, 9-3, and 11-7), which, again, 15% aqueous H2SO4, 40ºC CH3COHϩ CH3CH2OH (excess) CH3COCH2CH3 becomes dominant at higher temperatures. A Ϫ HOH A ϩ It is harder to synthesize ethers containing two different alkyl groups, because mixing šOð ϩ Hϩ CH3 CH3 two alcohols in the presence of an acid usually results in mixtures of all three possible 95% 2-Ethoxy-2-methylpropane products. However, mixed ethers containing one tertiary and one primary or secondary alkyl 5 substituent can be prepared in good yield in the presence of dilute acid. Under these condi- H tions, the much more rapidly formed tertiary carbocation is trapped by the other alcohol. ϩ šO

Synthesis of a Mixed Ether from a Tertiary Alcohol

In this reaction, the strongest nucleophile present in solution is the unprotonated starting alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, the ultimate products being an ether and water. Mechanism

Mechanism of Ether Synthesis from Primary Alcohols: Protonation and SN2

CH3CH2šOH H CH3CH2 CH3CH2 ϩ ϩ š ϩ H ϩf SN2 f ϩ Ϫ H f ϩ ϩϩCH3CH2OO O OH H2šO šO ϩ H3Oð ϩ " " ϩ " Ϫ H i i š ϩ H i CH3CH2šOH H CH3CH2 CH3CH2 š CH3CH2šOH š

E2 Mechanism for Only symmetric ethers can be prepared by this method. the Acid-Catalyzed At even higher temperatures (see footnote on p. 329), elimination of water to generate Dehydration of an alkene is observed. This reaction proceeds by an E2 mechanism (Sections 7-7 and 11-7), 1-Propanol in which the neutral alcohol serves as the base that attacks the alkyloxonium ion (margin). H ½ÂO Alkene Synthesis from a Primary Alcohol and Strong Acid at Elevated Temperature: E2 H A H A H2SO4, 180ЊC CH3CHCH2OH CH3CHPCH2 ϩ HOH Â Relatively high O 1-Propanol temperature Propene ϩ HH Secondary and tertiary ethers can also be made by acid treatment of secondary and tertiary alcohols. However, in these cases, a carbocation is formed initially and is then trapped by an alcohol (SN1), as described in Section 9-2. ϩ H2O

Symmetrical Ether Synthesis from a Secondary Alcohol

SN1 Mechanism for OH the Acid-Catalyzed A H SO , 40ºC 2 CH CCH 2 4 (CH ) CHOCH(CH ) ϩ HOH ϩ Hϩ Ether Formation 3 3 Relatively low 3 2 3 2 A temperature from 2-Propanol H 75% The major side2-Propanolreaction follows the 2-(1-Methylethoxy)propaneE1 pathway, which becomes dominant at higher (Diisopropyl ether) H temperatures. ½ÂO The major side reaction follows the E1 pathway (Sections 9-2, 9-3, and 11-7), which, again, It is harderbecomesto synthesize dominant atethers higher containingtemperatures.two different alkyl groups, because mixing two ϩ alcohols in theIt presenceis harder to ofsynthesizean acid ethersusually containingresults twoin mixturesdifferent alkylof allgroups,three becausepossible mixingproducts . two alcohols in the presence of an acid usually results in mixtures of all three possible Mixed ethersproducts.containing However,one mixedtertiary ethers andcontainingone primaryone tertiaryor andsecondary one primaryalkyl or secondarysubstituent alkyl can be prepared insubstituentgood yieldcan bein preparedthe presence in good yieldof indilute the presenceacid. Underof dilute theseacid. Underconditions, these condi-the much H more rapidlytions,formed the muchtertiary more carbocationrapidly formed istertiarytrapped carbocationby the isother trappedalcohol by the. other alcohol. ϩ šO

Synthesis of a Mixed Ether from a Tertiary Alcohol

CH3 CH3 A A 15% aqueous H2SO4, 40ºC CH3COHϩ CH3CH2OH (excess) CH3COCH2CH3 A Ϫ HOH A šOð ϩ Hϩ CH3 CH3 95% 2-Ethoxy-2-methylpropane

6 9-8 Reactions of Ethers CHAPTER 9 349

Ethers also form by alcoholysis Exercise 9-16 H3C Cl Tertiary and secondary ethers may also form by the alcoholysis of 1 Write mechanismsthe corresponding for the followinghaloalkanes two reactions. (a)or 1,4-Butanediolalkyl sulfonates 1 H y. oxacyclopentane (tetrahydrofuran); (b) 5-methyl-1,5-hexanediol 1 H1 y 2,2-dimethyloxacyclohexane (2,2- dimethyltetrahydropyran). The starting material is simply dissolved in an alcohol until the 1-Chloro-1-methylcyclohexane SN1 process is complete. Ethers also form by alcoholysis CH3CH2OH

As we know, tertiary and secondary ethers may also form by the alcoholysis of the cor- H3C OCH2CH3 responding haloalkanes or alkyl sulfonates (Section 7-1). The starting material is simply dissolved in an alcohol until the S 1 process is complete (see margin). N ϩϩHϩ ClϪ

Exercise 9-17 86% 1-Ethoxy- You now know several ways of constructing an ether from an alcohol and a haloalkane. Which 1-methylcyclohexane approach would you choose for the preparation of (a) 2-methyl-2-(1-methylethoxy)butane; (b) 1-methoxy-2,2-dimethylpropane? [Hint: The product for (a) is a tertiary ether, that for (b) is Reminder a neopentyl ether.] Free H1 does not exist in solution but is attached to any 7 available electron pair, such In Summary Ethers can be prepared by treatment of alcohols with acid through SN2 and S 1 pathways, with alkyloxonium ions or carbocations as intermediates, and by alcoholysis as (in the structure above) the N oxygen of ethanol or ethoxy, of secondary or tertiary haloalkanes or alkyl sulfonates. and chloride ion.

9-8 REACTIONS OF ETHERS

A more useful reaction is cleavage by strong acid. The oxygen in ethers, like that in alcohols, may be protonated to generate alkyloxonium ions. The subsequent reactivity of these ions depends on the alkyl substituents. With primary groups and strong nucleophilic acids such as HBr, SN2 displacement takes place. Primary Ether Cleavage with HBr ReactionR HBr CH3CH2OCH2CH3 CH3CH2Br ϩ CH3CH2OH Ethoxyethane Bromoethane Ethanol

Mechanism of Primary Ether Cleavage: SN2

H Ϫ Hϩ ðBr"šð fϩ CH3CH2"šOCH2CH3 CH3CH2OšO CH3CH2Br ϩ HOCH"š 2CH3 i Mechanism CH2CH3 Alkyloxonium ion

The alcohol formed as the second product may in turn be attacked by additional HBr to give more of the bromoalkane. 9-8 Reactions of Ethers CHAPTER 9 349

Exercise 9-16 H3C Cl

Write mechanisms for the following two reactions. (a) 1,4-Butanediol 1 H1 y oxacyclopentane (tetrahydrofuran); (b) 5-methyl-1,5-hexanediol 1 H1 y 2,2-dimethyloxacyclohexane (2,2- dimethyltetrahydropyran). 1-Chloro-1-methylcyclohexane

Ethers also form by alcoholysis CH3CH2OH

Exercise 9-17 86% 1-Ethoxy- You now know several ways of constructing an ether from an alcohol and a haloalkane. Which 1-methylcyclohexane approach would you choose for the preparation of (a) 2-methyl-2-(1-methylethoxy)butane; (b) 1-methoxy-2,2-dimethylpropane? [Hint: The product for (a) is a tertiary ether, that for (b) is Reminder a neopentyl ether.] Free H1 does not exist in solution but is attached to any available electron pair, such 9.8 REACTIONSIn SummaryOF EthersETHERS can be prepared by treatment of alcohols with acid through SN2 and S 1 pathways, with alkyloxonium ions or carbocations as intermediates, and by alcoholysis as (in the structure above) the N oxygen of ethanol or ethoxy, of secondary or tertiary haloalkanes or alkyl sulfonates. Ethers are normally rather inert. and chloride ion.

They do, however,9-8 REACTIONSreact slowly OFwith ETHERSoxygen by radical mechanisms to form hydroperoxides and peroxides. As mentioned earlier, ethers are normally rather inert. They do, however, react slowly with Becauseoxygenperoxides by radicalcan mechanismsdecompose to explosively, form hydroperoxidesextreme and care peroxides.should Becausebe taken peroxideswith samples of etherscanthat decomposehave been explosively,exposed extremeto air carefor shouldseveral be daystaken .with samples of ethers that have been exposed to air for several days. Peroxides from Ethers A A A A 2 ROCH ϩ O2 2 ROCOOOOH ROCOOOO OCOR A A A A An ether An ether peroxide hydroperoxide

A more useful reaction is cleavage by strong acid. The oxygen in ethers, like that in alcohols, may be protonated to generate alkyloxonium ions. The subsequent reactivity of these ions depends on the alkyl substituents. With primary groups and strong nucleophilic 8 acids such as HBr, SN2 displacement takes place. Primary Ether Cleavage with HBr ReactionR HBr CH3CH2OCH2CH3 CH3CH2Br ϩ CH3CH2OH Ethoxyethane Bromoethane Ethanol

Mechanism of Primary Ether Cleavage: SN2

H Ϫ Hϩ ðBr"šð fϩ CH3CH2"šOCH2CH3 CH3CH2OšO CH3CH2Br ϩ HOCH"š 2CH3 i Mechanism CH2CH3 Alkyloxonium ion

The alcohol formed as the second product may in turn be attacked by additional HBr to give more of the bromoalkane. 9-8 Reactions of Ethers CHAPTER 9 349

Exercise 9-16 H3C Cl

Ethers also form by alcoholysis CH3CH2OH

Exercise 9-17 86% 1-Ethoxy- You now know several ways of constructing an ether from an alcohol and a haloalkane. Which 1-methylcyclohexane approach would you choose for the preparation of (a) 2-methyl-2-(1-methylethoxy)butane; (b) 1-methoxy-2,2-dimethylpropane? [Hint: The product for (a) is a tertiary ether, that for (b) is Reminder a neopentyl ether.] Free H1 does not exist in solution but is attached to any available electron pair, such In Summary Ethers can be prepared by treatment of alcohols with acid through SN2 and S 1 pathways, with alkyloxonium ions or carbocations as intermediates, and by alcoholysis as (in the structure above) the N oxygen of ethanol or ethoxy, of secondary or tertiary haloalkanes or alkyl sulfonates. and chloride ion.

9-8 REACTIONS OF ETHERS

As mentioned earlier, ethers are normally rather inert. They do, however, react slowly with oxygen by radical mechanisms to form hydroperoxides and peroxides. Because peroxides can decompose explosively, extreme care should be taken with samples of ethers that have been exposed to air for several days. Peroxides from Ethers A more useful reactionA is cleavage byAstrong acid. The oxygenA in ethers,A like that in 2 ROCH ϩ O2 2 ROCOOOOH ROCOOOO OCOR alcohols, may be Aprotonated to generate Aalkyloxonium ions. A A An ether An ether peroxide The subsequent reactivity of these ionshydrodependsperoxide on the alkyl substituents. With primary groups and strong nucleophilic acids such as HBr, S 2 displacement takes place. A more useful reaction is cleavage by strong acid.N The oxygen in ethers, like that in alcohols, may be protonated to generate alkyloxonium ions. The subsequent reactivity of The alcoholthese formedions dependsas the on secondthe alkyl productsubstituents.may Within primaryturn be groupsattacked and strongby additional nucleophilicHBr to give more of acidsthe bromoalkane such as HBr, S.N2 displacement takes place. Primary Ether Cleavage with HBr ReactionR HBr CH3CH2OCH2CH3 CH3CH2Br ϩ CH3CH2OH Ethoxyethane Bromoethane Ethanol

Mechanism of Primary Ether Cleavage: SN2

H Ϫ Hϩ ðBr"šð fϩ CH3CH2"šOCH2CH3 CH3CH2OšO CH3CH2Br ϩ HOCH"š 2CH3 i Mechanism CH2CH3 Alkyloxonium ion 9 The alcohol formed as the second product may in turn be attacked by additional HBr to give more of the bromoalkane. 350 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

Exercise 9-18 Treatment of methoxymethane with hot concentrated HI gives two equivalents of iodomethane. Suggest a mechanism.

Exercise 9-19

O Reaction of oxacyclohexane (tetrahydropyran; shown in the margin) with hot concentrated HI gives Oxacyclohexane 1,5-diiodopentane. Give a mechanism for this reaction. (Tetrahydropyran) Oxonium ions derived from secondary ethers can transform by either SN2 or SN1 (E1) reactions, depending on the system and conditions.

Oxonium ions derived from secondary ethers can transform by either SN2 or SN1 (E1) For example,reactions,2- ethoxypropanedepending on the systemis protonated and conditionsby (Sectionaqueous 7-9HI andand Tablesthen 7-2 andconverted 7-4). For into 2- propanolexample,and iodoethane 2-ethoxypropaneby selective is protonatedattack by byaqueousiodide HIat andthe thenless convertedhindered into primary2-propanolcenter . and iodoethane by selective attack by iodide at the less hindered primary center.

Primary-Secondary Ether Cleavage with HI: SN2 at Primary Center Protecting-Group Strategy Less hindered OH HI, H O 2 ϩ O R Function I 2-Ethoxypropane 2-Propanol Iodoethane

Protection step Tertiary butyl ethers function to protect alcohols Ethers containing tertiary alkyl groups transform even in dilute acid to give intermediate tertiary carbocations, which are either trapped by SNl processes, when good nucleophiles are present, or deprotonated in their absence: 10 Protected R function Primary-Tertiary Ether Cleavage with Dilute Acid: SN1 and E1 at Tertiary Center

H SO , H O, 50ЊC O 2 4 2 OH ϩ

Chemical transformation Because tertiary ethers are made under similarly mild conditions from alcohols (Section 9-7), of R they act as protecting groups for the hydroxy function. A protecting group renders a spe- ci! c functionality in a molecule unreactive with respect to reagents and conditions that would normally transform it. Such protection allows chemistry to be carried out elsewhere in a molecule without interference. Subsequently, the original function is restored (deprotection). A protecting group has to be reversibly installed, readily and in high yield. Such Protected is the case with tertiary ethers, in which the original alcohol is protected from base, organo- R function metallic reagents, oxidants, and reductants. Another method of alcohol protection is esteri- ! cation (Section 9-4; Real Life 9-2).

Protection of Alcohols as Tertiary Butyl Ethers

Deprotection Carry out reactions on R by using Grignard reagents, step ϩ ϩ (CH3)3COH, H oxidizing agents, etc. H , H2O ROH ROC(CH3)3 R؅OC(CH3)3 R؅OH ϪH2O Protection step Protected R changed into RЈ Deprotection alcohol R Function Using protecting groups is a common procedure in organic synthesis, which enables chemists to carry out many transformations that would otherwise be impossible. We shall see other protecting strategies in conjunction with other functional groups later in the course. 350 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

Exercise 9-18 Treatment of methoxymethane with hot concentrated HI gives two equivalents of iodomethane. Suggest a mechanism.

Exercise 9-19

O Reaction of oxacyclohexane (tetrahydropyran; shown in the margin) with hot concentrated HI gives Oxacyclohexane 1,5-diiodopentane. Give a mechanism for this reaction. (Tetrahydropyran)

Oxonium ions derived from secondary ethers can transform by either SN2 or SN1 (E1) reactions, depending on the system and conditions (Section 7-9 and Tables 7-2 and 7-4). For example, 2-ethoxypropane is protonated by aqueous HI and then converted into 2-propanol and iodoethane by selective attack by iodide at the less hindered primary center.

Primary-Secondary Ether Cleavage with HI: SN2 at Primary Center Protecting-Group Strategy Less hindered OH HI, H O 2 ϩ O R Function I 2-Ethoxypropane 2-Propanol Iodoethane Tertiary butyl ethers function to protect alcohols

Protection step Ethers containingTertiary butyltertiary ethersalkyl groups functiontransform to protecteven alcoholsin dilute acid to give intermediate Ethers containing tertiary alkyl groups transform even in dilute acid to give intermediate tertiary carbocations, which are either trapped by SN1 processes, when good nucleophiles are present,tertiaryor deprotonated carbocations, whichin their are eitherabsence trapped: by SNl processes, when good nucleophiles are present, or deprotonated in their absence: Protected R function Primary-Tertiary Ether Cleavage with Dilute Acid: SN1 and E1 at Tertiary Center

H SO , H O, 50ЊC O 2 4 2 OH ϩ

Chemical transformation Because tertiary ethers are made under similarly mild conditions from alcohols (Section 9-7), of R Becausetheytertiary act asethers protectingare groupsmade forunder the hydroxysimilarly function.mild Aconditions protecting groupfrom rendersalcohols, a spe-they act as protectingci! cgroups functionalityfor the in ahydroxy molecule function unreactive. with respect to reagents and conditions that would normally transform it. Such protection allows chemistry to be carried out elsewhere in a molecule without interference. Subsequently, the original function is restored (depro- A protectingtection).group A protectingrenders groupa specific has to befunctionality reversibly installed,in a moleculereadily and unreactivein high yield. withSuch respect to Protectedreagentsisand the caseconditions with tertiarythat ethers,would in normallywhich the originaltransform alcoholit. is protected from base, organo- R function metallic reagents, oxidants, and reductants. Another method of alcohol protection is esteri- ! cation (Section 9-4; Real Life 9-2). 11 Protection of Alcohols as Tertiary Butyl Ethers

Exercise 9-18 Treatment of methoxymethane with hot concentrated HI gives two equivalents of iodomethane. Suggest a mechanism.

Exercise 9-19

O Reaction of oxacyclohexane (tetrahydropyran; shown in the margin) with hot concentrated HI gives Oxacyclohexane 1,5-diiodopentane. Give a mechanism for this reaction. (Tetrahydropyran)

Primary-Secondary Ether Cleavage with HI: SN2 at Primary Center Protecting-Group Strategy Less hindered OH HI, H O 2 ϩ O R Function I 2-Ethoxypropane 2-Propanol Iodoethane

Protection step Tertiary butyl ethers function to protect alcohols Ethers containing tertiary alkyl groups transform even in dilute acid to give intermediate tertiary carbocations, which are either trapped by SNl processes, when good nucleophiles are present, or deprotonated in their absence: Protected R function Primary-Tertiary Ether Cleavage with Dilute Acid: SN1 and E1 at Tertiary Center

H SO , H O, 50ЊC Such protection allows chemistryO to2 4 be2 carried out elsewhereOH ϩ in a molecule without interference. Subsequently, the original function is restored (deprotection). Chemical Using protecting groups is a common procedure in organic synthesis, which enables transformation Because tertiary ethers are made under similarly mild conditions from alcohols (Section 9-7), of chemists to carry out many transformations that would otherwise be impossible. R they act as protecting groups for the hydroxy function. A protecting group renders a spe- ci! c functionality in a molecule unreactive with respect to reagents and conditions that A protectingwould groupnormallyhas transformto be reversiblyit. Such protectioninstalled, allowsreadily chemistryand toin behigh carriedyield out. elsewhereSuch is the case with tertiaryin a moleculeethers, withoutin which interference.the original Subsequently,alcohol theis originalprotected functionfrom is restoredbase, (depro-organometallic reagents,tection).oxidants, A protectingand reductants group has to. be reversibly installed, readily and in high yield. Such Protected is the case with tertiary ethers, in which the original alcohol is protected from base, organo- R function metallic reagents, oxidants, and reductants. Another method of alcohol protection is esteri- Another! cationmethod (Sectionof alcohol 9-4; Realprotection Life 9-2).is esterification.

Protection of Alcohols as Tertiary Butyl Ethers

Deprotection Carry out reactions on R by using Grignard reagents, step ϩ ϩ (CH3)3COH, H oxidizing agents, etc. H , H2O ROH ROC(CH3)3 R؅OC(CH3)3 R؅OH ϪH2O Protection step Protected R changed into RЈ Deprotection alcohol R Function Using protecting groups is a common procedure in organic synthesis, which enables 12 chemists to carry out many transformations that would otherwise be impossible. We shall see other protecting strategies in conjunction with other functional groups later in the course. 352 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

nucleophiles. Carbocation formation follows protonation when secondary and tertiary groups are present, leading to SN1 and E1 products. The hydroxy group of alcohols can be protected in the form of a tert-butyl ether. 9.9 REACTIONS OF OXACYCLOPROPANES 9-9 REACTIONS OF OXACYCLOPROPANES Although ordinary ethers are relatively inert, the strained structure of the oxacyclopropanes makes possibleAlthoughnucleophilic ordinary ethersring are-opening relatively reactionsinert, the strained. structure of the oxacyclopropanes makes possible nucleophilic ring-opening reactions. This section presents details of these Nucleophilicprocesses.ring opening of oxacyclopropanes by SN2 is regioselective and stereospecific Nucleophilic ring opening of oxacyclopropanes by SN2 is Oxacyclopropaneregioselectiveis subject andto bimolecular stereospeciﬁring copening by anionic nucleophiles. Because of the symmetry of the substrate, substitution occurs to the same extent at either carbon. Oxacyclopropane is subject to bimolecular ring opening by anionic nucleophiles. Because of the symmetry of the substrate, substitution occurs to the same extent at either carbon. The reactionThe reactionproceeds proceedsby nucleophilic by nucleophilicattack, attack,with with the the ether oxygenoxygen functioningfunctioning as anas an intramolecularintramolecularleaving leavinggroup .group.

>Op D G ϪϪ HO>pOH CH2 OCH2 ϩ CH3>S) )>OCH2CH2O>SCH3 Ϫ HOCH> 2CH2>SCH3 p p p ϪHO>p) p p Oxacyclopropane 2-Methylthioethanol

This SN2 transformation is unusual for two reasons. First, alkoxides are usually very poor 13 leaving groups. Second, the leaving group does not actually “leave”; it stays bound to the molecule. The driving force is the release of strain as the ring opens. What is the situation with unsymmetric systems? Consider, for example, the reaction of 2,2-dimethyloxacyclopropane with methoxide. There are two possible reaction sites: at the primary carbon (a), to give 1-methoxy-2-methyl-2-propanol, and at the tertiary carbon (b), to yield 2-methoxy-2-methyl-1-propanol. Evidently, this system transforms solely through path a.

Nucleophilic Ring Opening of an Unsymmetrically Substituted Oxacyclopropane

@ @ G

H GOH O HO CH3

& Ϫ

H CH O , CH OH Ϫ G

3 3 O O CH3O , CH3OH CH3 C C C C

G C C COC C C G Model Building a b ( CH3 H ( ( CH3 H ( CH3O CH3 H CH3 H OCH3 ab 1-Methoxy- 2,2-Dimethyloxacyclopropane 2-Methoxy- 2-methyl-2-propanol 2-methyl-1-propanol (Not formed)

Is this result surprising? No, because, as we know, if there is more than one possibility, SN2 attack will be at the less substituted carbon center (Section 6-10). This selectivity in the nucleophilic opening of substituted oxacyclopropanes is referred to as regioselectivity, because, of two possible and similar “regions,” the nucleophile attacks only one. In addition, when the ring opens at a stereocenter, inversion is observed. Thus, we ! nd that the rules of nucleophilic substitution developed for simple alkyl derivatives also apply to strained cyclic ethers.

Hydride and organometallic reagents convert strained ethers into alcohols The highly reactive lithium aluminum hydride is able to open the rings of oxacyclopropanes, a reaction leading to alcohols. Ordinary ethers, lacking the ring strain of oxacyclopropanes, do not react with LiAlH4. The reaction also proceeds by the SN2 mechanism. Thus, in unsymmetric systems, the hydride attacks the less substituted side; when the reacting carbon constitutes a stereocenter, inversion is observed. 352 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

9-9 REACTIONS OF OXACYCLOPROPANES

Although ordinary ethers are relatively inert, the strained structure of the oxacyclopropanes makes possible nucleophilic ring-opening reactions. This section presents details of these processes.

Nucleophilic ring opening of oxacyclopropanes by SN2 is regioselective and stereospeciﬁ c Oxacyclopropane is subject to bimolecular ring opening by anionic nucleophiles. Because of the symmetry of the substrate, substitution occurs to the same extent at either carbon. The reaction proceeds by nucleophilic attack, with the ether oxygen functioning as an intramolecular leaving group.

>Op D G HO>pOH This SN2 transformationCH OCH isϩ unusualCH >S ϪϪfor two>OreasonsCH CH O:>S(CH1) alkoxidesHOCHare> usuallyCH >SCHvery poor 2 2 3p) )p 2 2 p 3 Ϫ p 2 2p 3 leaving groups, (2) the leaving group does not actually “leave”ϪHO>p) ; it stays bound to the Oxacyclopropane 2-Methylthioethanol molecule.

This SN2 transformation is unusual for two reasons. First, alkoxides are usually very poor The driving forceleavingis groups.the release Second, ofthe strainleaving asgroupthe doesring notopens actually. “leave”; it stays bound to the molecule. The driving force is the release of strain as the ring opens. What is the situation with unsymmetric systems? Consider, for example, the reaction of 2,2-dimethyloxacyclopropane with methoxide. There are two possible reaction sites: at the primary carbon (a), to give 1-methoxy-2-methyl-2-propanol, and at the tertiary carbon (b), to What is the situationyield 2-methoxy-2-methyl-1-propanol.with unsymmetric systems? Evidently, this system transforms solely through path a.

Nucleophilic Ring Opening of an Unsymmetrically Substituted Oxacyclopropane

@ @ G

H GOH O HO CH3

& Ϫ

H CH O , CH OH Ϫ G

3 3 O O CH3O , CH3OH CH3 C C C C

G C C COC C C G Model Building a b ( CH3 H ( ( CH3 H ( CH3O CH3 H CH3 H OCH3 ab 1-Methoxy- 2,2-Dimethyloxacyclopropane 2-Methoxy- 2-methyl-2-propanol 2-methyl-1-propanol (Not formed)

Is this result surprising? No, because, as we know, if there is more than one possibility, 14 SN2 attack will be at the less substituted carbon center (Section 6-10). This selectivity in the nucleophilic opening of substituted oxacyclopropanes is referred to as regioselectivity, because, of two possible and similar “regions,” the nucleophile attacks only one. In addition, when the ring opens at a stereocenter, inversion is observed. Thus, we ! nd that the rules of nucleophilic substitution developed for simple alkyl derivatives also apply to strained cyclic ethers.

Hydride and organometallic reagents convert strained ethers into alcohols The highly reactive lithium aluminum hydride is able to open the rings of oxacyclopropanes, a reaction leading to alcohols. Ordinary ethers, lacking the ring strain of oxacyclopropanes, do not react with LiAlH4. The reaction also proceeds by the SN2 mechanism. Thus, in unsymmetric systems, the hydride attacks the less substituted side; when the reacting carbon constitutes a stereocenter, inversion is observed. If there is more than one possibility, SN2 attack will be at the less substituted carbon center.

This selectivity in the nucleophilic opening of substituted oxacyclopropanes is referred to as regioselectivity, because, of two possible and similar “regions,” the nucleophile attacks only one.

In addition, when the ring opens at a stereocenter, inversion is observed.

The rules of nucleophilic substitution can be developed9-9 Reactionsfor simple of Oxacyclopropanesalkyl derivatives alsoCHAPTER 9 353 apply to strained cyclic ethers.

Ring Opening of an Oxacyclopropane

by Lithium Aluminum Hydride

O 1. LiAlH4, (CH3CH2)2O H GOH

ϩ &

O O 2. H , H2O H G C C C COC GC C H ( ( H ( H H R H R Less hindered

Inversion on Oxacyclopropane Opening 15 OH

O 1. LiAlD4 ϩ 2. H , H2O CH3 ã ) CH3 H H Model Building D 99.4% D and OH are trans, not cis

Working with the Concepts: A Retrosynthetic Solved Exercise 9-21 Analysis of an Oxacyclopropane Applying the principles of retrosynthetic analysis, as described in Section 8-9, which oxacyclopropane would be the best precursor to racemic 3-hexanol after treatment with LiAlH4, followed by acidic aqueous work-up? Strategy The ! rst thing to do is write the structure of 3-hexanol. Then look to see how many pathways lead to this structure from oxacyclopropanes and examine each path for feasibility. Solution • We recognize two possible retrosynthetic paths to 3-hexanol from oxacyclopropanes: removal of an anti H:2 with simultaneous ring closure either to the “left” side or the “right” side. In our drawing, these two pathways are indicated by a and b, respectively. anti anti ab

H H H H O O /∑ /∑ 0 OH 3-Hexanol Via a Via b • Now that we have drawn the two possible precursors to 3-hexanol, let us see which one is better at making the desired product when it is reacted with LiAlH4. (Caution: Remember that both carbons of an oxacyclopropane are electrophilic, so attack by hydride can occur in two possible ways.) • Inspection of the precursor derived from retrosynthetic path a shows that it is unsymmetrical. Because both ring carbons are equally hindered, ring opening by hydride will give the two isomers, 2- and 3-hexanol. • On the other hand, retrosynthetic path b furnishes a symmetric oxacyclopropane in which the regiochemistry of hydride opening is immaterial. Hence this precursor is best. O O

HðϪ HðϪ Unsymmetric: Symmetric: will give 2- and will give only 3-hexanol 3-hexanol 9-9 Reactions of Oxacyclopropanes CHAPTER 9 353 Hydride and organometallic reagents convert strained ethers into alcohols

The highly reactive lithium aluminum hydride is able to open the rings of oxacyclopropanes, Ring Opening of an Oxacyclopropane a reaction leading to alcohols.

by Lithium Aluminum Hydride

O 1. LiAlH4, (CH3CH2)2O H GOH

Ordinary ethers, lacking the ring strain of oxacyclopropanesϩ , do not &react with LiAlH .

G 4

O O 2. H , H2O H C C C COC GC C H ( ( H ( H The reaction also proceeds by theHSN2 mechanismR . Thus, in unsymmetricH R systems, the hydride attacks the less substitutedLess sidehindered; when the reacting carbon constitutes a stereocenter, inversion is observed. Inversion on Oxacyclopropane Opening OH

O 1. LiAlD4 ϩ 2. H , H2O CH3 ã ) CH3 H H Model Building D 99.4% D and OH are trans, not cis 16 Working with the Concepts: A Retrosynthetic Solved Exercise 9-21 Analysis of an Oxacyclopropane Applying the principles of retrosynthetic analysis, as described in Section 8-9, which oxacyclopropane would be the best precursor to racemic 3-hexanol after treatment with LiAlH4, followed by acidic aqueous work-up? Strategy The ! rst thing to do is write the structure of 3-hexanol. Then look to see how many pathways lead to this structure from oxacyclopropanes and examine each path for feasibility. Solution • We recognize two possible retrosynthetic paths to 3-hexanol from oxacyclopropanes: removal of an anti H:2 with simultaneous ring closure either to the “left” side or the “right” side. In our drawing, these two pathways are indicated by a and b, respectively. anti anti ab

HðϪ HðϪ Unsymmetric: Symmetric: will give 2- and will give only 3-hexanol 3-hexanol 354 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

In contrast withExercisehaloalkanes, 9-22 Tryoxacyclopropanes It Yourself are sufficiently reactive electrophiles to be

attacked by organometallic(2R)-Butanol can compoundsbe made by LiAlH. 4 reduction of an oxacyclopropane. Which one?

Grignard reagentsIn contrastand alkyllithium with haloalkanescompounds (Section 8-8),undergo oxacyclopropanes2-hydroxyethylation are suf! ciently by reactiveether ring opening, followingelectrophilesthe S toN 2 bemechanism attacked by . organometallic compounds. Thus, Grignard reagents and alkyllithium compounds undergo 2-hydroxyethylation by ether ring opening, following the This reactionSNconstitutes2 mechanism. aThistwo reaction-carbon constituteshomologation a two-carbonof anhomologationalkyl chain, of an asalkylopposed chain, as to the one-carbon homologationopposed to the one-carbonof alkyl organometallichomologation of alkylreagents organometallicby formaldehyde reagents by formaldehyde. (Sections 8-8 and 8-9).

Oxacyclopropane Ring Opening by a Grignard Reagent: 2-Hydroxyethylation

O 1. THF ϩ O O 2. H , H2O H2CO CH2 ϩ CH3CH2CH2CH2MgBr CH3CH2CH2CH2CH2 2OHCH 62% Oxacyclopropane Butylmagnesium bromide 1-Hexanol: “2-hydroxyethylated butyl”

Exercise 9-23 Propose an ef! cient synthesis of 3,3-dimethyl-1-butanol from starting materials containing no more than four carbons. (Hint: Consider the product retrosynthetically as a 2-hydroxyethylated tert-butyl.) 17

REAL LIFE: CHEMISTRY 9-3 Hydrolytic Kinetic Resolution of Oxacyclopropanes

As we pointed out in Real Life 5-5, nature is “handed” In our example, the most obvious feature is that members of and shows great, if not exclusive, preference for reactions the respective groups are shaped completely differently and with only one of two enantiomers of a chiral compound. could be separated by an achiral device, such as a sieve. This preference is of particular signi! cance in drug devel- From the resulting two piles, the right hands would be opment, because usually only one enantiomer of a chiral recovered and recycled, leaving the right shoes separated drug is effective (Real Life 5-4). Therefore, the pre- from the left ones. paration of single enantiomers is an important “green” A much better machine would be a ! shing device, in challenge for the synthetic chemist (Real Life 3-1). which the hook would be shaped like a right (or left) foot. The classic way of meeting this challenge has been the This machine would pull out only right shoes from the pile, resolution of racemates via the (readily reversible) reaction allowing their selective tagging, for example by attaching a with an optically pure compound generating diastereomers weight. Left and right shoes could then be separated by an that can be separated by chromatography or fractional crys- achiral device on the basis of their differing weights. Such a tallization (Section 5-8). The approach is equivalent to using process at the molecular level is called catalytic kinetic reso- a collection of right hands to separate a collection of pairs lution. An example is the hydrolysis of methyloxacyclopro- of shoes. Once all hands are “on,” the resulting collection pane with basic water. Normally, starting with a racemate, is divided into two groups, namely, the combinations right the result is racemic 1,2-propanediol. This is to be expected, hand/right shoe and right hand/left shoe. These groups are not as the two respective transition states for the reactions of related by mirror symmetry, hence they are diastereomeric. R and S starting ether are enantiomeric (Section 5-7).

OH OH O O Ϫ H2O, HO % ´ ϩ OH ϩ OH ) } H3C R H3C S R S Racemic Racemic methyloxacyclopropane 1,2-propanediol

However, in the presence of an enantiomer of a chiral propanediol (our “selective tagging”), leaving behind pure cobalt catalyst (the “right foot” in our device above), water (S)-oxacyclopropane. The reason is the chiral nature of the attacks the R form of starting material much more rapidly catalyst, rendering the two respective transition states of the than the S counterpart, converting it selectively to (2R)-1,2- reaction diastereomeric. Thus, they are of unequal energy, 9-9 Reactions of Oxacyclopropanes CHAPTER 9 355 Acids catalyze oxacyclopropane ring opening9-9 Reactions of Oxacyclopropanes CHAPTER 9 355

Ring openingAcidsof catalyzeoxacyclopropanes oxacyclopropaneis also catalyzed ring openingby acids. The reaction in this case proceedsAcidsRingthrough catalyze openinginitial of oxacyclopropane oxacyclopropanescyclic alkyloxonium is also ring catalyzedion openingformation by acids. followed The reactionby inring this caseopening as a resultRingof proceedsnucleophilic opening ofthrough oxacyclopropanesattack initial. cyclic isalkyloxonium also catalyzed ion byformation acids. Thefollowed reaction by ring in this opening case as a proceedsresult through of nucleophilic initial cyclic attack. alkyloxonium ion formation followed by ring opening as a result of nucleophilic attack. Acid-Catalyzed Ring Opening of Oxacyclopropane Acid-CatalyzedO Ring Opening of Oxacyclopropane ReactionR O O H2SO4 OH2CO CH2 ϩ CH3OH HOCH2CH2OCH3 ReactionR H SO O O 2 4 2-Methoxyethanol H2CO CH2 ϩ CH3OH HOCH2CH2OCH3 Mechanism of Acid-Catalyzed2-Methoxyethanol Ring Opening MechanismH of Acid-Catalyzed Ring Opening A Oš H Oϩ ðšOH # ϩ # H , CH3šOH A A Mechanism O O # ϩ O O ðšOH OšH CO CH ϩ O COCHH CH OCH HOCHš CH šOCH # 2 22ϩ # 2 2 2 ϩ # 2 2# 3 H , CH3#šOHϪH A ϪH Mechanism O O O O Cyclic A H2CO CH222COCHH CH2OCH2 ϩ ϩ HOCHš 2CH2šOCH ϩ O # # 3 ϪH alkyloxonium A E#HϪH Cyclic H#šOCH3 ion OHϩ CH3 alkyloxonium HšOCH E#H ion # 3 H CH The anionic nucleophilic opening of oxacyclopropanes just discussed3 is regioselective 18 Theand anionic stereospeci nucleophilic! c. What openingabout acid-catalyzed of oxacyclopropanes ring opening—is just discussed that also is regioselective regioselective and and stereospecistereospeci! !c. c? What Yes, about but the acid-catalyzed details are different. ring opening—is Thus, acid-catalyzed that also regioselective methanolysis and of 2,2- stereospecidimethyloxacyclopropane! c? Yes, but the details proceeds are different. by exclusive Thus, ring acid-catalyzed opening at the methanolysis more hindered of 2,2- carbon. dimethyloxacyclopropane proceeds by exclusive ring opening at the more hindered carbon.

allowing one enantiomer of oxacyclopropane to hydrolyze by the substituted cyclohexane scaffold. The cobalt attacks allowingfaster one than enantiomer the other. of oxacyclopropane to hydrolyze by theselectively substituted the cyclohexane lone pairs onscaffold. the (R The)-oxacyclopropane cobalt attacks sub- faster thanThe the structureother. of the catalyst enantiomer is shown below. selectivelystrate theas alone Lewis pairs acid on (Sectionthe (R)-oxacyclopropane 2-3), thus facilitating sub- ring TheYou structure can see theof thechiral catalyst environment enantiomer around is shownthe metal, below. provided strate openingas a Lewis by acidwater. (Section 2-3), thus facilitating ring You can see the chiral environment around the metal, provided opening by water.

H2O, chiral Co2ϩ OH O O O H2O, catalyst % ϩϩchiral Co2ϩ OH OH O ) O } catalyst % O } H3C R ϩϩH3C S ROH H3C S ) } } H C R RacemicH C S R S 3 methyloxacyclopropane3 H3C Racemic methyloxacyclopropane

) RR H @ (~H ) RRN N H @ (~H N NCo CoO O O O

Cobalt catalyst

Cobalt catalyst Using the mirror image of the catalyst shown gives the of medicines and other ! ne chemicals and therefore in great Usingcomplementary the mirror image results of the to catalystour example: shown Only gives ( Sthe)-methyloxa- of medicinesdemand andby syntheticother ! ne chemists. chemicals As and a result,therefore the inabove great kinetic complementarycyclopropane results is attacked to our example: to furnish Only (S)-diol, (S)-methyloxa- leaving behind demandresolution by synthetic has been chemists. re! ned As to a require result, lessthe abovethan 1 kinetic kg of cata- cyclopropaneunreacted is Rattacked starting to material. furnish (SuchS)-diol, highly leaving functionalized behind resolutionlyst tohas make been 1 re ton! ned of toproduct require and less is thanbeing 1 usedkg of by cata- Daiso Co. unreactedsmall R chiral starting building material. blocks Such are highly of great functionalized value in the synthesis lyst toin make Japan 1 onton aof 50-ton/year product and scale. is being used by Daiso Co. small chiral building blocks are of great value in the synthesis in Japan on a 50-ton/year scale. 356 CHAPTERAcid- catalyzed9 Furthermethanolysis Reactions ofof Alcohols2,2-dimethyloxacyclopropane and the Chemistry ofproceeds Ethers by exclusive ring opening at the more hindered carbon.

Acid-Catalyzed Ring Opening of 2,2-Dimethyloxacyclopropane

Nucleophile attacks

ReactionR this carbon @

O HO G CH3

O O H2SO4 , CH3OH & CH3 H2COC~ CH2 G C G ( CH3 CH3 OCH3 2,2-Dimethyloxacyclopropane 2-Methoxy-2-methyl-1-propanol

Why is the more hindered position attacked? Protonation at the oxygen of the ether Protonationgeneratesat the aoxygen reactive intermediateof the ether alkyloxoniumgenerates iona reactive with substantiallyintermediate polarizedalkyloxonium oxygen– ion carbon bonds. This polarization places partial positive charges on the ring carbons. Because with substantiallyalkyl groupspolarized act as electronoxygen donors–carbon (Sectionbonds 7-5),. more positive charge is located on the tertiary than on the primary carbon. You can see this difference in the electrostatic potential This polarizationmap in theplaces margin,partial in whichpositive the moleculecharges is viewedon the fromring thecarbons perspective. of the attacking nucleophile. The tertiary carbon at the bottom is more positive (blue) than the primary neighbor above (green). The proton in the back is strongly blue. The color-energy scale of Protonated this map was changed to make this subtle gradation in shading visible. 2,2-dimethyloxacyclopropane 19 Mechanism of Acid-Catalyzed Ring Opening of 2,2-Dimethyloxacyclopropane by Methanol Oxacyclopropane: Primary Tertiary carbocation-like: less hindered carbocation-like: more hindered The Warhead of Drugs H H

A ϩϩ A ϩϩ ␦ ␦ ðOð O O O

ϩ ϩ ϩ

O O O O H ␦ O O ␦ C C C C C C C COC C CCO COC or COC H ( ( H H ( ( CH3 H ( ( CH3 H ( ( CH3 OPP CH H CH H CH H CH OOH 3 3 3 3

O ϩ ϩ HO ϪH CH3OH ϪH CH3OH Fosfomycin 1-Methoxy-2-methyl-2-propanol 2-Methoxy-2-methyl-1-propanol H ½ (Not formed) SÂ H This uneven charge distribution counteracts steric hindrance: Methanol is attracted by cou- N Cysteine lombic forces more to the tertiary than to the primary center. Although the result is clear-cut H ( in this example, it is less so in cases in which the two carbons are not quite as different. O For example, mixtures of isomeric products are formed by acid-catalyzed ring opening of 2-methyloxacyclopropane. Enzyme Why do we not simply write the isomeric free carbocations as intermediates in the acid- catalyzed ring openings? The reason is that the cyclic oxonium ion has an octet structure, The antibiotic fosfomycin whereas the carbocation isomer has a carbon with an electron sextet. Indeed, experimentally, works by interfering with inversion is observed when reaction takes place at a stereocenter. Like the reaction of bacterial cell-wall synthesis oxacyclopropanes with anionic nucleophiles, the acid-catalyzed process includes backside through oxacyclopropane ring displacement—in this case, on a highly polarized cyclic alkyloxonium ion. opening. Thus, the enzyme crucial for wall construction is deactivated by reaction of the Exercise 9-24 SH group of one of its cysteine Predict the major product of ring opening of 2,2-dimethyloxacyclopropane on treatment with amino acids (for structure, see 1 1 Problem 45 of Chapter 2) with each of the following reagents. (a) LiAlH4, then H , H2O; (b) CH3CH2CH2MgBr, then H , H2O; the strained ether function. (c) CH3SNa in CH3OH; (d) dilute HCl in CH3CH2OH; (e) concentrated aqueous HBr.

In Summary Although ordinary ethers are relatively inert, the ring in oxacyclopropanes can be opened both regioselectively and stereospeci! cally. For anionic nucleophiles, the usual rules of bimolecular nucleophilic substitution hold: Attack is at the less hindered carbon center, which undergoes inversion. Acid catalysis, however, changes the regioselectivity (but not the stereospeci! city): Attack is at the more hindered center. Hydride and organometallic reagents behave like other anionic nucleophiles, furnishing alcohols by an SN2 pathway. 356 CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers

Acid-Catalyzed Ring Opening of 2,2-Dimethyloxacyclopropane

Nucleophile attacks

ReactionR this carbon @

O HO G CH3

O O H2SO4 , CH3OH & CH3 H2COC~ CH2 G C G ( CH3 CH3 OCH3 2,2-Dimethyloxacyclopropane 2-Methoxy-2-methyl-1-propanol

Why is the more hindered position attacked? Protonation at the oxygen of the ether Becausegeneratesalkyl groups a reactiveact as intermediateelectron alkyloxoniumdonors, more ionpositive with substantiallycharge is polarizedlocated on oxygen–the tertiary than on carbonthe primary bonds. carbonThis polarization. places partial positive charges on the ring carbons. Because alkyl groups act as electron donors (Section 7-5), more positive charge is located on the tertiary than on the primary carbon. You can see this difference in the electrostatic potential This unevenmap in chargethe margin,distribution in which thecounteracts molecule is viewedsteric fromhindrance the perspective: Methanol of theis attackingattracted by coulombicnucleophile.forces more The to tertiarythe tertiary carbon than at theto bottomthe primary is morecenter positive. (blue) than the primary neighbor above (green). The proton in the back is strongly blue. The color-energy scale of Protonated Inversionthisis mapalso wasobserved changedwhen to makereaction this subtletakes gradationplace atin ashadingstereocenter visible. . 2,2-dimethyloxacyclopropane Mechanism of Acid-Catalyzed Ring Opening of 2,2-Dimethyloxacyclopropane by Methanol Oxacyclopropane: Primary Tertiary carbocation-like: less hindered carbocation-like: more hindered The Warhead of Drugs H H

A ϩϩ A ϩϩ ␦ ␦ ðOð O O O

ϩ ϩ ϩ

O O O O H ␦ O O ␦ C C C C C C C COC C CCO COC or COC H ( ( H H ( ( CH3 H ( ( CH3 H ( ( CH3 OPP CH H CH H CH H CH OOH 3 3 3 3

O ϩ ϩ HO ϪH CH3OH ϪH CH3OH Fosfomycin 1-Methoxy-2-methyl-2-propanol 2-Methoxy-2-methyl-1-propanol H ½ (Not formed) 20 SÂ H This uneven charge distribution counteracts steric hindrance: Methanol is attracted by cou- N Cysteine lombic forces more to the tertiary than to the primary center. Although the result is clear-cut H ( in this example, it is less so in cases in which the two carbons are not quite as different. O For example, mixtures of isomeric products are formed by acid-catalyzed ring opening of 2-methyloxacyclopropane. Enzyme Why do we not simply write the isomeric free carbocations as intermediates in the acid- catalyzed ring openings? The reason is that the cyclic oxonium ion has an octet structure, The antibiotic fosfomycin whereas the carbocation isomer has a carbon with an electron sextet. Indeed, experimentally, works by interfering with inversion is observed when reaction takes place at a stereocenter. Like the reaction of bacterial cell-wall synthesis oxacyclopropanes with anionic nucleophiles, the acid-catalyzed process includes backside through oxacyclopropane ring displacement—in this case, on a highly polarized cyclic alkyloxonium ion. opening. Thus, the enzyme crucial for wall construction is deactivated by reaction of the Exercise 9-24 SH group of one of its cysteine Predict the major product of ring opening of 2,2-dimethyloxacyclopropane on treatment with amino acids (for structure, see 1 1 Problem 45 of Chapter 2) with each of the following reagents. (a) LiAlH4, then H , H2O; (b) CH3CH2CH2MgBr, then H , H2O; the strained ether function. (c) CH3SNa in CH3OH; (d) dilute HCl in CH3CH2OH; (e) concentrated aqueous HBr.