Carboxylic Acids and Their Derivatives

Carboxylic Acids and Their Derivatives
Chapter 21 Carboxylic Acids and Their Derivatives Suggested Problems –

Introduction to Carboxylic Acids
Carboxylic acids are abundant in nature and in pharmaceuticals

Introduction to Carboxylic Acids
The US produces over 2.5 million tons of acetic acid per year, which is primarily used to produce vinyl acetate Vinyl acetate is used in paints and adhesives Carboxylic acid derivatives such as vinyl acetate are very common and play a central role in organic chemistry

Nomenclature of Carboxylic Acids
Monocarboxylic acids are named with the suffix “oic acid” The carbon of the carboxylic acid moiety is assigned locant position 1

When the carboxylic acid group is attached to a ring, it is named as an alkane carboxylic acid There are also many common names for carboxylic acids

Dicarboxylic acids are named with the suffix “dioic acid” There are also many common names for dicarboxylic acids Practice with conceptual checkpoints 12.1 through 12.3

Structure and Properties of Carboxylic Acids
The carbon atom of the carboxylic acid has a trigonal planar geometry. WHY? The acid moiety is capable of strong hydrogen bonding including H-bonding between acid pairs As a result, carboxylic acids generally have high boiling points – consider the BPs of acetic acid (118 °C) and isopropanol (82 °C)

Carboxylate ions end in the suffix “oate” Compounds that end in the suffix “oate” are often found in food ingredient lists as preservatives NaOH is a strong base, so it is capable of reacting ≈100% with a carboxylic acid NaOH

In water, the equilibrium generally favors the acid pKa values mostly range between 4 and 5.

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

Let’s examine the equilibrium between the carboxylic acid and the carboxylate at physiological pH (7.3) The acid and the conjugate base make a buffer. HOW? Recall that the Henderson-Hasselbalch equation can be used to calculate the pH of a buffer Assuming the pKa is 4.3, calculate the ratio of carboxylate/acid

Many biomolecules exhibit carboxylic acid moieties Biomolecules such as pyruvic acid exist primarily as the carboxylate under physiological conditions Practice with conceptual checkpoint 21.8

Electron withdrawing substituents have a great effect on acidity

Electron withdrawing substituents affect benzoic acid as well Practice with conceptual checkpoint 21.9

Preparation of Carboxylic Acids
In earlier chapters, we have already learned some methods to synthesize carboxylic acids

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

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

This gives us a second method to convert an alkyl halide into a carboxylic acid Practice with conceptual checkpoint 12.10

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

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?

The milder 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

Introduction to Carboxylic Acid Derivatives
The reduction of acids with LAH or borane result in a decrease in the oxidation number for carbon. HOW? There are also many reactions where carboxylic acids don’t change the oxidation state

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

Acid halides and anhydrides are relatively unstable, so they are not common in nature – we will discuss their instability in detail later in this chapter Some naturally occurring esters are known to have pleasant odors

Amides are VERY common in nature What type of molecule in nature includes amide linkages? Many other compounds feature amides including some natural sedatives like melatonin

To name an acid halide, replace “ic acid” with “yl halide”

Alternatively, the suffix, “carboxylic acid” can be replaced with “carbonyl halide”

Acid anhydrides are named by replacing “acid” with “anhydride”

Asymmetrical acid anhydrides are named by listing the acids alphabetically and adding the word anhydride

Esters are named by naming the alkyl group attached to the oxygen followed by the carboxylic acid’s name with the suffix “ate”

Amides are named by replacing the suffix “ic acid” or “oic acid” with “amide”

If the nitrogen atom of the amide group bears alkyl substituents, their names are placed at the beginning of the name with N as their locant

Nitriles are named by replacing the suffix “ic acid” or “oic acid” with “onitrile” Practice with conceptual checkpoints and 21.13

Reactivity of Carboxylic Acid Derivatives
Carboxylic acid derivatives have electrophilic sites Where?

Reactivity can be affected by Induction Resonance Sterics Quality of leaving group

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

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

Amides are the least reactive acid derivative Examine the factors below to explain amide reactivity Induction Resonance Sterics Quality of leaving group

Aldehydes and ketones are also electrophilic, but they do not undergo substitution WHY? Consider induction, resonance, sterics, and quality of leaving group

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?

Let’s analyze a specific example The highest quality leaving group leaves the tetrahedral intermediate

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?

Under acidic conditions, (-) charges rarely form The first step will NOT be nucleophilic attack The electrophile and nucleophile are both low in energy

H3O+ is unstable and drives the equilibrium forward by starting the reaction mechanism Now that the electrophile carries a (+) charge, it is much less stable (higher in energy. Complete the rest of the mechanism

Under basic conditions, (+) charges rarely form The OH- is the most unstable species in the reaction and drives the equilibrium forward Continue the rest of the mechanism

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?

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

Draw a complete mechanism for the reaction below Will the reaction be reversible? Yes What conditions could be employed to favor products? A base can be added to remove the HCl and drive the equilibrium forward.

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

Give necessary reaction conditions and a complete mechanism for the reaction below. A more facile process would require base promotion or acid catalyst, and excess ethanol also aids kinetically and thermodynamically

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

The mechanism is more favored in the presence of a non-nucleophilic base like pyridine. WHY?

Preparation and Reaction of Acid Chlorides: HYDROLYSIS
To avoid an acid chloride being converted into an acid, it must be protected from moisture

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

Preparation and Reaction of Acid Chlorides: ALCOHOLYSIS
Give a complete mechanism showing how pyridine acts as a base in the mechanism

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

Acid chlorides can also be reduced using LAH

Acid chlorides can also be reduced using LAH The acid must be added after the LAH has given adequate time to react completely

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?

Acid chlorides can also be attacked by Grignard nucleophiles

Two equivalents of the Grignard yield a 3° alcohol

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. Gilman reagent

Figure 21.9 illustrates the reactions of acid chlorides we discussed Practice with conceptual checkpoints through 21.20

Fill in necessary reagents for the reactions below

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

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

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?

Figure shows how anhydrides can undergo many reactions analogous to those of acid chlorides

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?

Acetic anhydride is often used to acetylate an amine or an alcohol

Practice with conceptual checkpoint 21.21

Preparation of Esters Fischer esterification combines a carboxylic acid and an alcohol using an acid catalyst

Preparation of Esters Fischer esterification mechanism continued
Each step is an equilibrium Under acidic conditions, (-) charges are avoided

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?

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

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?

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

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

Reactions of Esters Ester hydrolysis can be catalyzed under acidic conditions Draw out the complete mechanism

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

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

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?

Reactions of Esters Esters can also react with Grignard reagents
Two moles can be used to make a tertiary alcohol

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

Reactions of Esters Give necessary reagents for the conversions below

Preparation and Reactions of Amides
Nylon is a polyamide Polyester is made similarly. HOW?

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?

The reaction is slow because there are many high energy transition states and the attack of the first water molecule in step two should be mostly favoring the reactant side of the equilibrium due to entropy

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

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?

The iminium is reduced with a second equivalent of hydride Practice with conceptual checkpoints through 21.28

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

What base might you use?

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

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

Draw a complete mechanism

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.

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

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

Synthetic Strategies

Synthetic Strategies Give necessary reagents for the conversion below. Multiple steps will be necessary

Synthetic Strategies There are 2 categories of bond-forming reactions

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

Spectroscopy of Carboxylic Acids and Their Derivatives
Recall that C=O stretching is a prominent peak in IR spectra Recall that conjugated carbonyl signals appear at lower wavenumbers (about 40 cm-1 less)

The O-H stretch of an acid gives a very broad peak ( cm-1) The CΞN triple bond stretch appears around 2200 cm-1 Carbonyl 13C peaks appear around ppm Nitrile 13C peaks appear around ppm The 1H peak for a carboxylic acid proton appears around 12 ppm Practice with conceptual checkpoint 21.38

Predict the number and chemical shift of all 13C peaks for the molecule below Predict the number, chemical shift, multiplicity, and integration of all 1H peaks for the molecule below

Predict the number and chemical shift of all 13C peaks for the molecule below

Predict the number, chemical shift, multiplicity, and integration of all 1H peaks for the molecule below

Additional Practice Problems
2,5-di(3,3-dichloropropyl)-1,6-hexanedioic acid

Rank the following molecules by increasing pKa values. Using ARIO and solvation, C should have the lowest pKa due to the stabilization of the S atom. B should be next because its conjugate base should be easily solvated. Next, is A, and finally, D should have the highest pKa due to negative forming in the conjugate base not being stabilized by resonance as the others are.

Predict the products for the reactions below.

Give an appropriate name for the amide below 3,5-dimethyl-N-ethyl-N-methylbenzamide

Using induction, sterics, and resonance, explain why acid halides are especially electrophilic from a kinetic perspective. A kinetic perspective takes into account among other things, how often molecules collide and how stable the transition state is during the collision. Inductively, the halide attracts electron density from the carbonyl carbon giving it a greater partial positive to attract a nucleophile more often. That also raises the potential energy of the reactant giving a lower activation energy. Because the halide does not donate nearly as much electron density through resonance as an oxygen or nitrogen would, that gives the carbonyl carbon more of a partial positive as well. Because a halide is one single atom rather than a group of atoms, it is relatively small and does not create a lot of sterics. Such sterics would increase the energy during the collision also giving a higher activation energy.

Using the quality of the leaving group, explain why acid halides are especially reactive from a thermodynamic perspective. Because the halide is so stable with a negative charge, it is an excellent leaving group. That means that the products are relatively low in free energy shifting the equilibrium toward the products side of the equation.

Give reagents necessary for the synthesis below where all carbon atoms in the product come from a molecule of the reactant

Carboxylic Acids and Their Derivatives

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