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Section 20.7 REACTIONS OF ESTERS: A PREVIEW Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Substitution of Esters • Esters react with amines and ammonia to form amides • Under acidic or basic conditions, esters react with water to form acids and alcohols Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Section 20.8 ACID-CATALYZED ESTER HYDROLYSIS Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Acid-catalyzed Hydrolysis of Esters • We have seen acid-catalyzed (Fischer) esterification previously. Recall that esterification is reversible! • The reverse reaction is called hydrolysis, since water cleaves an ester into an acid and an alcohol • A large excess of water is used to promote hydrolysis Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Mechanism of Hydrolysis • Step 1: protonation of the carbonyl oxygen of the ester • Protonation at the other oxygen does not lead to a stabilized intermediate Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Mechanism of Hydrolysis • Step 2: nucleophilic attack by water at the carbonyl carbon • Step 3: deprotonation of intermediate Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Mechanism of Hydrolysis • Step 4: re-protonation at the “alkoxy” oxygen • Step 5: elimination of alcohol Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Mechanism of Hydrolysis • Step 6: deprotonation of the protonated acid by water, regenerating acid catalyst Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Section 20.9 ESTER HYDROLYSIS IN BASE: SAPONIFICATION Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Saponification of Esters • Basic hydrolysis of esters (saponification) is irreversible due to the formation of carboxylate anions • A separate acidification step is used to isolate the carboxylic acid • Two mechanisms can be envisioned: SN2 at the alkyl group (CH3) or nucleophilic acyl substitution Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Evidence for Acyl Substitution • Labeled “alkoxy” oxygen ends up faithfully in the alcohol product, not the carboxylate • Configuration at the “alkoxy” carbon is retained, ruling out an SN2 mechanism Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Mechanism of Saponification • Step 1: nucleophilic addition of OH– to C=O • Rate-determining (slow) step Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Mechanism of Saponification • Step 2: elimination of alkoxide • Step 3: proton transfers to give carboxylate and alcohol Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Section 20.10 REACTIONS OF ESTERS WITH AMMONIA AND AMINES Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Esters and Ammonia/Amines • Ammonia reacts with esters to give primary amides; aqueous ammonia may be used • Amines react in an analogous way; only primary and secondary amines may be used (tertiary amines have no H to lose) • Mechanism similar to the nucleophilic acyl substitutions we’ve seen previously Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Section 20.11 REACTIONS OF ESTERS WITH GRIGNARD AND ORGANOLITHIUM REAGENTS AND LITHIUM ALUMINUM HYDRIDE Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Double Addition of RM to Esters • Esters react with two equivalents of strong organometallic nucleophiles to give tertiary alcohols • This double addition mechanism involves nucleophilic acyl substitution followed by nucleophilic addition • The ketone intermediate formed after substitution is more reactive than the ester starting material Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Reduction of Esters with LAH • Lithium aluminum hydride reacts similarly with esters—the products are primary alcohols via double addition • The intermediate aldehyde is more reactive than the ester starting material Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Section 20.12 AMIDES Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Physical Properties and Acidity • Amides are highly polar; secondary and primary amides can engage in strong hydrogen bonding • Amide N–H is about as acidic as water (pKa = 16); doubly activated imides have pKa around 10 Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Synthesis of Amides • Amides can be prepared from RCOCl, anhydrides, and esters • In reactions with acid chlorides and anhydrides, two equivalents of amine are used to consume generated acid (HCl or RCO2H) • Externally added base (e.g., hydroxide) can be used to reduce the amine to 1 equivalent Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Synthesis of Amides • Amides can be prepared from RCOCl, anhydrides, and esters • Mechanisms all follow the basic pattern of nucleophilic acyl substitution Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education.
