21.1 Introduction Carboxylic Acids 21.1 Introduction Carboxylic Acids

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• Carboxylic acids are abundant in nature and in • The US produces over 2.5 million tons of acetic acid per pharmaceuticals. 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 they play a central role in organic chemistry.

21.2 Nomenclature of Carboxylic 21.2 Nomenclature of Carboxylic Acids Acids • Monocarboxylic acids are named with the suffix • When the carboxylic acid group is “oic acid.” attached to a ring, it is named as an alkane carboxylic acid. • There are also many common names for carboxylic acids.

• The carbon of the carboxylic acid moiety is assigned the locant position 1.

21.2 Nomenclature of Carboxylic 21.3 Structure and Properties of Acids Carboxylic Acids • Dicarboxylic acids are named with • The carbon atom of the carboxylic acid the suffix “dioic acid.” has a trigonal planar geometry. WHY? • There are also many common names for dicarboxylic • The acid moiety is capable of strong hydrogen (H‐) acids: bonding including H‐bonding between acid pairs.

• As a result, carboxylic acids generally have high boiling points. • Practice with CONCEPTUAL CHECKPOINTs – Consider the BPs of acetic acid (118 °C) and 12.1 through 12.3. isopropanol (82 °C). Copyright 2012 John Wiley & Sons, Inc. 21-5 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-6 Klein, Organic Chemistry 1e

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21.3 Structure and Properties of 21.3 Structure and Properties of Carboxylic Acids Carboxylic Acids • Carboxylate ions end in the suffix “oate.” • In water, the equilibrium generally favors the acid .

• pKa values mostly range btbetween 4 and 5. Wha t is pKa?

• 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.

21.3 Structure and Properties of 21.3 Structure and Properties of Carboxylic Acids Carboxylic Acids

• How does the pKa value for a carboxylic acid compare to • Let’s examine the equilibrium between the carboxylic a strong acid like HCl, or a very weak acid like ethanol? acid and the carboxylate at physiological pH (7.3). • The acid and the conjugate base make a buffer. HOW? H–Cl • Recall that the Henderson‐Hasselbalch equation can be

pKa = -7 used to calculate the pH of a buffer:

• How can induction and resonance be used to explain the acidity of a carboxylic acid? • Assuming the pK is 4.3, calculate the ratio of • Practice with CONCEPTUAL CHECKPOINTs 21.4 through a carboxylate/acid. 21.7.

21.3 Structure and Properties of 21.3 Structure and Properties of Carboxylic Acids Carboxylic Acids • Many biomolecules exhibit carboxylic acid moieties. • Electron withdrawing substituents have a great effect • Biomolecules such as pyruvic acid exist primarily as the on acidity. carboxylate under physiological conditions.

• Practice with CONCEPTUAL CHECKPOINT 21.8. • WHY?

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21.3 Structure and Properties of 21.4 Preparation of Carboxylic Acids Carboxylic Acids • Electron withdrawing substituents affect benzoic acid as • In earlier chapters, we already learned some methods well. to synthesize carboxylic acids.

• Practice with CONCEPTUAL CHECKPOINT 21.9.

21.4 Preparation of Carboxylic Acids 21.4 Preparation of Carboxylic Acids • Let’s examine two more ways to make carboxylic acids: • In earlier chapters, we already learned some methods 1. The hydrolysis of a nitrile can produce a carboxylic acid. to synthesize carboxylic acids.

– The mechanism will be discussed later. – Carboxylic acids can be made from alkyl halides using a two‐ step process.

21.4 Preparation of Carboxylic Acids 21.4 Preparation of Carboxylic Acids

• Let’s examine two more ways to make carboxylic acids: • This gives us a second method to convert an alkyl halide 2. Carboxylation of a Grignard reaction can be achieved using into a carboxylic acid:

CO2.

• Practice with CONCEPTUAL CHECKPOINT 12.10. + – The Grignard reagent and the H3O cannot be added together. WHY?

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21.5 Reactions of Carboxylic Acids 21.5 Reactions of Carboxylic Acids

• LiAlH4 (LAH) is a strong reducing agent that can convert • LiAlH4 (LAH) is a strong reducing agent that can convert an acid to a primary alcohol: an acid to a primary alcohol: – The LAH acts as a base first. – The aldehyde is further reduced to the alcohol.

– Then, an aldehyde is produced.

21.6 Introduction to Carboxylic Acid 21.5 Reactions of Carboxylic Acids • The milder borane reagent can also be used to promote Derivatives the reduction. • The reduction of acids with LAH or borane result in a decrease in the oxidation number for carbon. HOW?

• • Reduction with borane is selective compared to LAH There are also many reactions where carboxylic acids reduction. don’t change their oxidation state.

• Practice with CONCEPTUAL CHECKPOINT 21.11. • What criteria must Z fulfill so that there is no change in the oxidation state?

21.6 Introduction to Carboxylic Acid 21.6 Introduction to Carboxylic Acid Derivatives Derivatives • When Z is a heteroatom, the compound is called a • Acid halides and anhydrides are relatively unstable, so carboxylic acid derivative. 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: • Because it has the same oxidation state, a nitrile is also an acid derivative despite not having a carbonyl group.

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21.6 Introduction to Carboxylic Acid 21.6 Introduction to Carboxylic Acid Derivatives Derivatives • Amides are VERY common • To name an acid halide, replace “ic acid” with “yl in nature. halide.” • What type of molecule in nature includes amide lin kages ? • Many other compounds feature amides, including some natural sedatives like melatonin.

21.6 Introduction to Carboxylic Acid 21.6 Introduction to Carboxylic Acid Derivatives Derivatives • Alternatively, the suffix, “carboxylic acid” can be • Acid anhydrides are named by replacing “acid” with replaced with “carbonyl halide.” “anhydride.”

21.6 Introduction to Carboxylic Acid 21.6 Introduction to Carboxylic Acid Derivatives Derivatives • Asymmetric acid anhydrides are named by listing the • Esters are named by naming the alkyl group attached to acids alphabetically and adding the word anhydride. the oxygen followed by the carboxylic acid’s name with the suffix “ate.”

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21.6 Introduction to Carboxylic Acid 21.6 Introduction to Carboxylic Acid Derivatives Derivatives • Amides are named by replacing the suffix “ic acid” or • If the nitrogen atom of the amide group bears alkyl “oic acid” with “amide.” substituents, their names are placed at the beginning of the name with N as their locant.

21.6 Introduction to Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives • Nitriles are named by replacing the suffix “ic acid” or • In general, carboxylic acid “oic acid” with “onitrile.” derivatives are good electrophiles. • WHY?

• Practice with CONCEPTUAL CHECKPOINTs 21.12 and 21.13.

21.7 Reactivity of Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives • Reactivity can be • Let’s examine the acid chloride: affected by – The electronegative chlorine enhances the electrophilic – Induction character of the carbonyl. HOW? – Resonance – There are 3 resonance contributors to the acid chloride: – SiSterics – Quality of leaving group

– The chlorine does not significantly donate electron density to the carbonyl. HOW does that affect its quality as an electrophile. Copyright 2012 John Wiley & Sons, Inc. 21-35 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-36 Klein, Organic Chemistry 1e

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21.7 Reactivity of Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives • Let’s examine the acid chloride: • Amides are the least reactive acid derivative. – Describe how the presence of the chloride affects the sterics • Examine the factors below to explain amide reactivity: of the nucleophilic attack on the carbonyl. – Induction – The chloride is a good leaving group, which also enhances its – Resonance reactivity. • Considering all of the factors involved, the acid chloride is quite reactive.

– Sterics – Quality of leaving group

21.7 Reactivity of Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives • Aldehydes and ketones are also electrophilic, but they • Nucleophilic acyl substitution is a two‐step process. do not undergo substitution.

• WHY? Consider induction, resonance, sterics, and – Because C=O double bonds are quite stable, the “loss of quality of leaving group. leaving group” step should occur if a leaving group is present. – –H and –R do not qualify as leaving groups. WHY?

21.7 Reactivity of Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives

• Let’s analyze a specific example: • Do NOT draw the acyl substitution with an SN2 mechanism.

– The highest quality leaving group leaves the tetrahedral intermediate. • Sometimes a proton transfer will be necessary in the mechanism: – Under acidic conditions, (–) charges rarely form. WHY? – Under basic conditions, (+) charges rarely form. WHY?

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21.7 Reactivity of Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives + • Under acidic conditions, (–) charges rarely form. • H3O is unstable and drives the equilibrium forward by starting the reaction mechanism. • Now that the – The first step will NOT be nucleophilic attack. electrophile carries a – The electrophile and (+) charge, it is much nucleophile are both low in less stable (higher in energy. energy). Complete the rest of the mechanism. Copyright 2012 John Wiley & Sons, Inc. 21-43 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-44 Klein, Organic Chemistry 1e

21.7 Reactivity of Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives • Under basic • Neutral nucleophiles are generally less reactive, but conditions, (+) charges they can still react if given enough time. rarely form. • An intermediate with both (+) and (‐) charges forms. • The OH– is the most unstable species in the reaction and drives the equilibrium forward. • Continue the rest of the mechanism. • Intermediates with two (+) or two (–) charges are very unlikely to form. WHY?

21.7 Reactivity of Carboxylic Acid 21.7 Reactivity of Carboxylic Acid Derivatives Derivatives • Depending on reaction conditions, UP TO THREE proton • Give necessary reaction conditions and a complete transfers may be necessary in the mechanism: mechanism for the reaction below.

• Draw a complete mechanism for the reaction below.

– Will the reaction be reversible? • Describe how conditions could be modified to favor the – What conditions could be employed to favor products? products as much as possible. • Practice with SKILLBUILDER 21.1.

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21.8 Preparation and Reaction of 21.8 Preparation and Reaction of Acid Chlorides 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?

21.8 Preparation and Reaction of 21.8 Preparation and Reaction of Acid Chlorides: HYDROLYSIS Acid Chlorides: ALCOHOLYSIS • To avoid an acid chloride being converted into an acid, it • Often acid chlorides are used to synthesize esters. must be protected from moisture.

• Give a complete mechanism showing the role of pyridine in the mechanism.

21.8 Preparation and Reaction of 21.8 Preparation and Reaction of Acid Chlorides: AMINOLYSIS Acid Chlorides • Often acid chlorides • Acid chlorides can also be reduced using LAH: are used to synthesize amides. • Give a complete mechihanism shhiowing why TWO equivalents are used.

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21.8 Preparation and Reaction of 21.8 Preparation and Reaction of Acid Chlorides Acid Chlorides • Acid chlorides can also be reduced using LAH: • To stop the aldehyde from being reduced to the alcohol, – The acid must be added after the LAH has given adequate a bulky reducing agent can be used. time to react completely.

• HOW does lithium tri(t‐butoxy) aluminum hydride allow the reduction to be stopped at the aldehyde?

21.8 Preparation and Reaction of 21.8 Preparation and Reaction of Acid Chlorides Acid Chlorides • Acid chlorides can also be attacked by Grignard • Two equivalents of the Grignard yield a 3° alcohol. nucleophiles:

21.8 Preparation and Reaction of 21.8 Preparation and Reaction of Acid Chlorides Acid Chlorides • The Gilman reagent is another nucleophilic • Figure 21.9 organometallic reagent that reacts readily with acid illustrates the chlorides. reactions of acid • The C–Cu bond is less chlorides that we iiionic than the C–Mg discussed. bond. WHY? • Practice with • How does the ionic character of the bond affect the CONCEPTUAL reactivity of the organometallic reagent? CHECKPOINTs 21.18 through 21.20. Copyright 2012 John Wiley & Sons, Inc. 21-59 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-60 Klein, Organic Chemistry 1e

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21.8 Preparation and Reaction of 21.9 Preparation and Reactions of Acid Chlorides Acid Anhydrides • Fill in necessary reagents for the reactions below. • 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 cannot withstand such high temperatures.

21.9 Preparation and Reactions of 21.9 Preparation and Reactions of Acid Anhydrides Acid Anhydrides • A more practical synthesis occurs when an acid chloride • Given that they both contain good quality leaving is treated with a carboxylate. 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? • The –R groups attached to the anhydride do not have to be equivalent.

21.9 Preparation and Reactions of 21.9 Preparation and Reactions of Acid Anhydrides Acid Anhydrides • A non‐nucleophilic weak base such as pyridine is not • Figure 21.10 necessary when acid anhydrides react with a shows how nucleophile. WHY? anhydrides can • When a nucleophile reacts with an anhydride, there will undergo many be a carbblioxylic acid bbdyproduct. WHY? reactions analogous to • Why is it often a disadvantage to have such a byproduct those of acid in a reaction? chlorides.

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21.9 Preparation and Reactions of 21.9 Preparation and Reactions of Acid Anhydrides Acid Anhydrides • Acetic anhydride is often used to acetylate an amine or an alcohol.

21.10 Preparation of Esters 21.10 Preparation of Esters • Each step of the Fischer esterification mechanism is • Fischer esterification combines a carboxylic acid and an equilibrium. alcohol using an acid catalyst. • Under acidic conditions, (–) charges are avoided.

21.10 Preparation of Esters 21.10 Preparation of Esters

• The overall Fischer esterification reaction is an • Esters can also be prepared by treating an acid chloride equilibrium process. with an alcohol—see Section 21.8.

• How might you use Le Châtelier’s principle to favor products? • What is the role of pyridine? – How might you use Le Châtelier's principle to favor reactants? • Why doesn’t pyridine act as a nucleophile? • Is there an entropy difference that might be exploited? • Practice with CONCEPTUAL CHECKPOINTs 21.22 and 21.23.

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21.11 Reactions of Esters 21.11 Reactions of Esters

• Esters can undergo hydrolysis in the presence of • SAPONIFICATION is an equilibrium process. aqueous hydroxide (SAPONIFICATION). – Analyze the reversibility of each step in the mechanism. – How might you use Le Châtelier’s principle to favor products? – How might you use Le Châtelier’s principle to favor reactants? – Is there an entropy difference that mihight be expliloite d?

• Soap is made through the saponification of triglycerides. EXPLAIN HOW. • 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. 21-73 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-74 Klein, Organic Chemistry 1e

21.11 Reactions of Esters 21.11 Reactions of Esters

• Ester hydrolysis can be catalyzed under acidic • Esters can also undergo aminolysis. conditions. • The carbonyl of the ester is protonated, and then a water acts as a nucleophile attacking the carbonyl carbon. • The overall equilibrium favors the amide formation. • Draw out the complete mechanism. – Because of enthalpy or entropy?

• The synthetic utility is limited because the process is • + Show how regeneration of H3O makes it catalytic. slow and because there are more efficient ways to synthesize amides. Copyright 2012 John Wiley & Sons, Inc. 21-75 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-76 Klein, Organic Chemistry 1e

21.11 Reactions of Esters 21.11 Reactions of Esters

• Esters can be reduced using reagents such as LAH: • LAH is a strong reducing agent, so a full reduction beyond the aldehyde to the alcohol cannot be avoided. • When performed at low temperature, reduction with DIBAH yields an aldehyde. HOW?

– Two equivalents of reducing agent are required. – Two alcohols are produced. • Draw a reasonable mechanism.

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21.11 Reactions of Esters 21.11 Reactions of Esters

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

• Practice with CONCEPTUAL CHECKPOINTs 21.24 and 21.25. Copyright 2012 John Wiley & Sons, Inc. 21-79 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-80 Klein, Organic Chemistry 1e

21.12 Preparation and Reactions of 21.11 Reactions of Esters Amides • Give necessary reagents for the conversions below. • Nylon is a polyamide. O HO O O HO O

OH OH OH OH

HO HO

• Polyester is made similarly. HOW?

21.12 Preparation and Reactions of 21.12 Preparation and Reactions of Amides Amides + + • Amides can be hydrolyzed with H3O , but the process is • Amides can be hydrolyzed with H3O , but the process is slow and requires high temperature. slow and requires high temperature.

• The mechanism is very similar to that for the hydrolysis • Should the equilibrium favor reactants or products? of an ester. WHY? + • Show a complete mechanism. • Where does the NH4 come from? • Amide hydrolysis can also be promoted with NaOH, • WHY is the process generally slow? although the process is very slow.

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21.12 Preparation and Reactions of 21.12 Preparation and Reactions of Amides Amides • LAH can reduce an amide to an amine. • The iminium is reduced with a second equivalent of hydride.

• The mechanism is quite different from the others we have seen in this chapter. • When the H‐ attacks, which is the best leaving • group? Practice with CONCEPTUAL CHECKPOINTs 21.26 through 21.28. Copyright 2012 John Wiley & Sons, Inc. 21-85 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 21-86 Klein, Organic Chemistry 1e

21.13 Preparation and Reactions of 21.13 Preparation and Reactions of Nitriles Nitriles • When a 1° or 2° alkyl halide is treated with a cyanide • What base might you use? – 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.

21.13 Preparation and Reactions of 21.13 Preparation and Reactions of Nitriles Nitriles • An aqueous strong acid solution can be used to • Basic hydrolysis of a nitrile can also be achieved. hydrolyze a nitrile.

• Which group in the reaction acts as a nucleophile? • In the mechanism, the nitrogen is protonated multiple • Which group acts to protonate the nitrogen? times and water acts as a nucleophile. • Draw a complete mechanism. • Draw a complete mechanism.

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21.13 Preparation and Reactions of 21.13 Preparation and Reactions of Nitriles Nitriles • Nitriles can also react with Grignards. • Similar to how carboxylic acids can be converted to alcohols using LAH (Section 21.5), nitriles can be converted to amines.

+ • 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. • Practice with CONCEPTUAL CHECKPOINTs 21.29 through 21.31.

21.14 Synthetic Strategies 21.14 Synthetic Strategies

• When designing a synthesis, there are two general considerations that we make: 1. Is there a change in the CARBON SKELETON? 2. Is there a change in FUNCTIONAL GROUPS? • We have learned many new FUNCTIONAL GROUP TRANSFORMATIONs in this chapter.

• Practice with SKILLBUILDER 21.2.

21.14 Synthetic Strategies 21.14 Synthetic Strategies

• Give necessary reagents for the conversion below. • There are 2 categories of bond‐forming reactions: Multiple steps will be necessary.

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21.15 Spectroscopy of Carboxylic 21.14 Synthetic Strategies Acids and Their Derivatives • When forming new carbon‐carbon bonds, it is critical to • Recall that C=O stretching is a prominent peak in IR install functional groups in the proper location. spectra. • Give necessary reagents for the conversion below. More than one step will be necessary.

• Recall that conjugated carbonyl signals appear at lower wavenumbers (about 40 cm‐1 less). • Practice with SKILLBUILDER 21.3.

21.15 Spectroscopy of Carboxylic 21.15 Spectroscopy of Carboxylic Acids and Their Derivatives Acids and Their Derivatives • The O–H stretch of an acid gives a very broad peak • Predict the number and chemical shift of all 13C peaks (2500‐3300 cm‐1). for the molecule below. • The C≡N triple bond stretch appears around 2200 cm‐1. • Predict the number, chemical shift, multiplicity, and • Carbonyl 13C peaks appear around 160‐185 ppm. integration of all 1H peaks for the molecule below. • Nitrile 13C peaks appear around 115‐130 ppm. • The 1H peak for a carboxylic acid proton appears around 12 ppm. • Practice with CONCEPTUAL CHECKPOINT 21.38.