Carboxylic Acids and Their Derivatives

Carboxylic Acids and Their Derivatives
Organic Chemistry Second Edition David Klein Chapter 21 Carboxylic Acids and Their Derivatives Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.14 Synthetic Strategies Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.3 Structure and Properties of Carboxylic Acids
In water, the equilibrium generally favors the acid pKa values mostly range between 4 and 5. What is pKa? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.3 Structure and Properties of Carboxylic Acids
How does the pKa value for a carboxylic acid compare to a strong acid like HCl or a very weak acid like ethanol? H-Cl pKa = -7 How can induction and resonance be used to explain the acidity of a carboxylic acid? Practice with conceptual checkpoints 21.4 through 21.7 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e

21.4 Preparation of Carboxylic Acids
In earlier chapters, we have already learned some methods to synthesize carboxylic acids Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Let’s examine two more ways to make carboxylic acids The hydrolysis of a nitrile can produce a carboxylic acid The mechanism will be discussed later Carboxylic acids can be made from alkyl halides using a two-step process Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Let’s examine two more ways to make carboxylic acids Carboxylation of a Grignard reaction can be achieved using CO2 The Grignard reagent and the H3O+ can not be added together. WHY? -MgBr Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

This gives us a second method to convert an alkyl halide into a carboxylic acid Practice with conceptual checkpoint 12.10 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.5 Reactions of Carboxylic Acids
LiAlH4 is a strong reducing agent that can convert an acid to a primary alcohol The LAH acts as a base first Then, an aldehyde is produced Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

LiAlH4 is a strong reducing agent that can convert an acid to a primary alcohol The aldehyde is further reduced to the alcohol Can the reduction be stopped at the aldehyde? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

The more mild borane reagent can also be used to promote the reduction Reduction with borane is selective compared to LAH reduction Practice with conceptual checkpoint 21.11 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.6 Introduction to Carboxylic Acid Derivatives
When Z is a heteroatom, the compound is called a carboxylic acid derivative Because it has the same oxidation state, a nitrile is also an acid derivative despite not having a carbonyl group Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.7 Reactivity of Carboxylic Acid Derivatives
Carboxylic acid derivatives have electrophilic sites Where? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Let’s examine the acid chloride The electronegative chlorine enhances the electrophilic character of the carbonyl. HOW? There are 3 resonance contributors to the acid chloride The chlorine does not significantly donate electron density to the carbonyl. HOW does that affect its quality as an electrophile Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Let’s examine the acid chloride Describe how the presence of the chloride affects the sterics of the nucleophilic attack on the carbonyl The chloride is a good leaving group, which also enhances its reactivity Considering all of the factors involved, the acid chloride is quite reactive Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Amides are the least reactive acid derivative Examine the factors below to explain amide reactivity Induction Resonance Sterics Quality of leaving group Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Aldehydes and ketones are also electrophilic, but they do not undergo substitution WHY? Consider induction, resonance, sterics, and quality of leaving group Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Nucleophilic acyl substitution is a two-step process Because C=O double bonds are quite stable, the “loss of leaving group” step should occur if a leaving group is present – H and –R do not qualify as leaving groups. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Do NOT draw the acyl substitution with an SN2 mechanism Sometimes a proton transfer will be necessary in the mechanism Under acidic conditions, (–) charges rarely form. WHY? Under basic conditions, (+) charges rarely form. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Neutral nucleophiles are generally less reactive, but they can still react if given enough time An intermediate with both (+) and (-) charge forms Intermediates with two (+) or two (-) charges are very unlikely to form. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Depending on reaction conditions, up to 3 proton transfers may be necessary in the mechanism Draw a complete mechanism for the reaction below Will the reaction be reversible? What conditions could be employed to favor products? Practice with SkillBuilder 21.1 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Give necessary reaction conditions and a complete mechanism for the reaction below Describe how conditions could be modified to favor the products as much as possible Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Acid chlorides can also be reduced using LAH The acid must be added after the LAH has given adequate time to react completely Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 organometallic reagent? The C-Cu bond is less ionic than the C-Mg bond. WHY? Gilman reagent R Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Figure 21.9 illustrates the reactions of acid chlorides we discussed Practice with conceptual checkpoints through 21.20 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.10 Preparation of Esters Fischer esterification combines a carboxylic acid and an alcohol using an acid catalyst Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.10 Preparation of Esters Fischer esterification mechanism continued
Each step is an equilibrium Under acidic conditions, (-) charges are avoided Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 and 21.23 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 and 21.25 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Amides can be hydrolyzed with H3O+, but the process is slow and requires high temperature The mechanism is very similar to that for the hydrolysis of an ester Show a complete mechanism WHY is the process generally slow? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Amides can be hydrolyzed with H3O+, but the process is slow and requires high temperature Should the equilibrium favor reactants or products? WHY? Where does the NH4+ come from? Amide hydrolysis can also be promoted with NaOH, although the process is very slow Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

LiAlH4 can reduce an amide to an amine The mechanism is quite different from the others we have seen in this chapter When the H- attacks, which is the best leaving group? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

The iminium is reduced with a second equivalent of hydride Practice with conceptual checkpoints 21.26 through 21.28 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.13 Preparation and Reactions of Nitriles
When a 1° or 2° alkyl halide is treated with a cyanide ion, the CN- acts as a nucleophile in an SN2 reaction Nitriles can also be made by dehydrating an amide using a variety of reagents including SOCl2 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

An aqueous strong acid solution can be used to hydrolyze a nitrile In the mechanism, the nitrogen is protonated multiple times and water acts as a nucleophile Draw a complete mechanism Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Basic hydrolysis of a nitrile can also be achieved Which group in the reaction acts as a nucleophile? Which group acts to protonate the nitrogen? Draw a complete mechanism Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Nitriles can also react with Grignards After the nitrile is consumed, H3O+ is added to form an imine, which can be hydrolyzed with excess H3O+ (aq) to form a ketone. SHOW a mechanism Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Similar to how carboxylic acids can be converted to alcohols using LAH (section 21.5), nitriles can be converted to amines Practice with conceptual checkpoints through 21.31 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.14 Synthetic Strategies When designing a synthesis, there are two general considerations that we make Is there a change in the carbon skeleton? Is there a change in functional groups? We have learned many new functional group transformations in this chapter – see next slide Practice with SkillBuilder 21.2 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

21.14 Synthetic Strategies Klein, Organic Chemistry 2e

21.14 Synthetic Strategies When forming new carbon-carbon bonds, it is critical to install functional groups in the proper location Give necessary reagents for the conversion below. More than one step will be necessary Practice with SkillBuilder 21.3 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Using induction, sterics, and resonance, explain why acid halides are especially electrophilic from a kinetic perspective. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Using the quality of the leaving group, explain why acid halides are especially reactive from a thermodynamic perspective. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Give reagents necessary for the synthesis below where all carbon atoms in the product come from a molecule of the reactant Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Carboxylic Acids and Their Derivatives

Similar presentations

Presentation on theme: "Carboxylic Acids and Their Derivatives"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Carboxylic Acids and Their Derivatives

Similar presentations

Presentation on theme: "Carboxylic Acids and Their Derivatives"— Presentation transcript:

Similar presentations

About project

Feedback