21.8 Preparation and Reaction of Acid Chlorides Acid chlorides have great synthetic utility. WHY? An acid chloride may form when an acid is treated with SOCl2 Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides The mechanism is more favored in the presence of a non-nucleophilic base like pyridine. WHY? Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides: HYDROLYSIS To avoid an acid chloride being converted into an acid, it must be protected from moisture Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides: ALCOHOLYSIS Often acid chlorides are used to synthesize esters Give a complete mechanism showing how pyridine acts as a base in the mechanism Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides: AMINOLYSIS Often acid chlorides are used to synthesize amides Give a complete mechanism showing WHY two equivalents are used Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides Acid chlorides can also be reduced using LAH Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides Acid chlorides can also be reduced using LAH The acid must be added after the LAH has given adequate time to react completely Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides To stop the aldehyde from being reduced to the alcohol, a bulky reducing agent can be used HOW does lithium tri(t-butoxy) aluminum hydride allow the reduction to be stopped at the aldehyde? Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides Acid chlorides can also be attacked by Grignard nucleophiles Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides Two equivalents of the Grignard yield a 3° alcohol Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides The Gilman reagent is another nucleophilic organometallic reagent that reacts readily with acid chlorides How does the ionic character of the bond affect the reactivity of the organometalic reagent? The C-Cu bond is less ionic than the C-Mg bond. WHY? Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides Figure 21.9 illustrates the reactions of acid chlorides we discussed Practice with conceptual checkpoints 21.18 through 21.20 Copyright 2012 John Wiley & Sons, Inc.

21.8 Preparation and Reaction of Acid Chlorides Fill in necessary reagents for the reactions below Copyright 2012 John Wiley & Sons, Inc.

21.9 Preparation and Reactions of Acid Anhydrides Acetic anhydride can be synthesized by heating 2 moles of acetic acid Why is so much heat needed to drive the equilibrium forward? This process doesn’t work for most other acids, because their structures can not withstand such high temperatures Copyright 2012 John Wiley & Sons, Inc.

21.9 Preparation and Reactions of Acid Anhydrides A more practical synthesis occurs when an acid chloride is treated with a carboxylate The –R groups attached to the anhydride do not have to be equivalent Copyright 2012 John Wiley & Sons, Inc.

21.9 Preparation and Reactions of Acid Anhydrides Given that they both contain quality leaving groups, how do you think the reactions of anhydrides compare to the reactions we already saw for chlorides? Which has a better leaving group? WHY? Copyright 2012 John Wiley & Sons, Inc.

21.9 Preparation and Reactions of Acid Anhydrides Figure 21.10 shows how anhydrides can undergo many reactions analogous to those of acid chlorides Copyright 2012 John Wiley & Sons, Inc.

21.9 Preparation and Reactions of Acid Anhydrides A nonucleophilic weak base such as pyridine is not necessary when acid anhydrides react with a nucleophile. WHY? When a nucleophile reacts with an anhydride, there will be a carboxylic acid byproduct. WHY? Why is it often a disadvantage to have such a byproduct in a reaction? Copyright 2012 John Wiley & Sons, Inc.

21.9 Preparation and Reactions of Acid Anhydrides Acetic anhydride is often used to acetylate an amine or an alcohol Copyright 2012 John Wiley & Sons, Inc.

21.9 Preparation and Reactions of Acid Anhydrides Practice with conceptual checkpoint 21.21 Copyright 2012 John Wiley & Sons, Inc.

21.10 Preparation of Esters Fischer esterification combines a carboxylic acid and an alcohol using an acid catalyst Copyright 2012 John Wiley & Sons, Inc.

21.10 Preparation of Esters Fischer esterification mechanism continued Each step is an equilibrium Under acidic conditions, (-) charges are avoided Copyright 2012 John Wiley & Sons, Inc.

21.10 Preparation of Esters The overall Fischer esterification reaction is an equilibrium process How might you use Le Chatelier’s principle to favor products? How might you use Le Chatelier’s principle to favor reactants? Is there an entropy difference that might be exploited? Copyright 2012 John Wiley & Sons, Inc.

21.10 Preparation of Esters Esters can also be prepared by treating an acid chloride with an alcohol – see section 21.8 Practice with conceptual checkpoint 21.22 and 21.23 Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Esters can undergo hydrolysis in the presence of aqueous hydroxide (saponification) Predict the last steps in the mechanism To produce a carboxylic acid, H3O+ must be added at the end. WHY? Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Saponification is an equilibrium process Analyze the reversibility of each step in the mechanism How might you use Le Chatelier’s principle to favor products? How might you use Le Chatelier’s principle to favor reactants? Is there an entropy difference that might be exploited? Soap is made through the saponification of triglycerides. EXPLAIN HOW Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Ester hydrolysis can be catalyzed under acidic conditions The carbonyl of the ester is protonated, and then a water acts as a nucleophile attacking the carbonyl carbon Draw out the complete mechanism Show how regeneration of H3O+ makes it catalytic Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Esters can also undergo aminolysis The overall equilibrium favors the amide formation Because of enthalpy or entropy? The synthetic utility is limited, because the process is slow and because there are more efficient ways to synthesize amides Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Esters can be reduced using reagents such as LiAlH4 Two equivalents of reducing agent are required Two alcohols are produced Draw a reasonable mechanism Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters LiAlH4 is a strong reducing agent, so a full reduction beyond the aldehyde to the alcohol can not be avoided When performed at low temperature, reduction with DIBAH yields an aldehyde. HOW? Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Esters can also react with Grignard reagents Two moles can be used to make a tertiary alcohol Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Esters can also react with Grignard reagents Two moles can be used to make a tertiary alcohol Practice with conceptual checkpoint 21.24 and 21.25 Copyright 2012 John Wiley & Sons, Inc.

21.11 Reactions of Esters Give necessary reagents for the conversions below Copyright 2012 John Wiley & Sons, Inc.

Study Guide for Sections 21.8-21.11 DAY 22, Terms to know: Sections 21.8-21.11 pyridine, Gilman reagent, saponification, DAY 22, Specific outcomes and skills that may be tested on exam 4: Sections 21.8-21.11 Given reactants, be able to predict products and give complete mechanisms for nucleophilic substitution reactions on acids and acid derivatives Given a precursor, be able to give sets of reagents and reaction conditions that could yield a given carboxylic acid derivative Given a carboxylic acid derivative, be able to predict products and give complete mechanisms for any of the reactions we discussed that acid derivatives undergo

Extra Practice Problems for Sections 21.8-21.11 Complete these problems outside of class until you are confident you have learned the SKILLS in this section outlined on the study guide and we will review some of them next class period. 21.18 21.19 21.20 21.21 21.22 21.24 21.25 21.49

Prep for Day 23 Must Watch videos: Other helpful videos: https://www.youtube.com/watch?v=gMKtGulgGH8 (amide formation, Khan) https://www.youtube.com/watch?v=ZYaYUZLg6Hc (amide reactions, Holbrook) https://www.youtube.com/watch?v=qsajTAOd69w (amide hydrolysis, Holbrook) https://www.youtube.com/watch?v=Ari5PqeiJCc (nitrile hydrolysis, AK lectures) https://www.youtube.com/watch?v=CHT7keygh80 (enolates, FLC) watch the first 9:30 minutes Other helpful videos: https://www.youtube.com/watch?v=OMH6CubLVjE (amidenitrile, Holbrook) https://www.youtube.com/watch?v=VKiy9K3M-uY (reactions with amides and nitriles, UC-Irvine) https://www.youtube.com/watch?v=lhRfE13mM70 (enolates from ketones, Khan) https://www.youtube.com/watch?v=bhxo9Wwr4mA (enolates from aldehydes, Khan) Read Sections 21.12-21.15, 22.1