CH 9. Carboxylic Acids & Derivatives

A. Carboxylic Acid Properties

1. Structures, nomenclature, acidity and synthesis

a. Carboxylic acid framework

• A carboxylic acid contains a carbonyl group directly bonded to a hydroxyl group: R–C(=O)–OH.

• The carboxyl group combines a polarized C=O bond with an O–H bond; its two oxygen atoms share electron density in the conjugate base.

• Acyl compounds have the general framework R–C(=O)–Z, where Z identifies the functional-group family.

b. Parent chain and substituents

• Select the longest parent chain containing the carboxyl carbon; this carbon is C1.

• Replace the parent alkane suffix with -oic acid. For a carboxyl group attached to a ring, use -carboxylic acid.

• Two acid groups may be described with the suffix -dioic acid.

c. Intermolecular association

• Carboxylic acids can donate and accept hydrogen bonds. They often form hydrogen-bonded pairs in nonpolar environments.

• Small carboxylic acids are readily soluble in water; increasing the hydrocarbon portion reduces water solubility.

• Carboxylate salts are ionic and frequently show much greater water solubility than their neutral parent acids.

d. Resonance of a carboxylate

• Loss of H⁺ produces a carboxylate ion (RCO₂⁻) in which the negative charge is delocalized over two oxygen atoms.

• The two major resonance contributors have the same atomic connectivity, while the C–O π bond and negative charge are interchanged.

• This resonance stabilization contributes to the greater acidity of carboxylic acids relative to ordinary alcohols.

e. Inductive electron withdrawal

• Electron-withdrawing substituents stabilize the carboxylate conjugate base and generally increase acidity.

• The inductive effect is stronger when the substituent is closer to the carboxyl group and diminishes with separation.

• For example, chloroacetic acid is appreciably more acidic than acetic acid because the chlorine substituent withdraws electron density.

f. Oxidative conversion

• Primary alcohols can be oxidized to carboxylic acids using sufficiently strong oxidation conditions.

• Aldehydes are readily oxidized to carboxylic acids; secondary alcohols ordinarily oxidize to ketones instead.

• Side-chain oxidation of suitable alkylbenzenes can produce benzoic-acid derivatives.

g. Nitriles and organometallic reagents

• Acidic or basic hydrolysis of a nitrile ultimately produces a carboxylic acid (after acidic workup where needed).

• Reaction of an appropriate Grignard reagent with CO₂, followed by acidic workup, gives a carboxylic acid with one additional carbon.

• Grignard reagents must be kept away from water and other protic reagents until the workup step.

h. Solubility and salts

• Carboxylic acids form strong hydrogen-bond associations. Small acids are water soluble; a large hydrocarbon framework reduces solubility.
• Base converts an acid to a carboxylate salt; subsequent acidification regenerates the acid. Bicarbonate can deprotonate ordinary carboxylic acids with CO₂ evolution.

B. Nucleophilic Acyl Substitution

1. Addition–elimination and acyl reactivity

a. Acyl family comparison

• An acyl halide has Z = halogen (commonly Cl); an anhydride has Z = OC(=O)R; an ester has Z = OR; an amide has Z = NR₂.

• Thioesters contain Z = SR. Nitriles (R–C≡N) are related in synthesis and hydrolysis but do not possess an acyl carbonyl.

• The atoms directly attached to the acyl carbon strongly influence reactivity and leaving-group ability.

b. Addition and elimination

• The acyl carbon is electrophilic because the C=O bond is polarized toward oxygen.

• A nucleophile attacks the carbonyl carbon to form a tetrahedral intermediate; re-formation of C=O can then expel a leaving group.

• This differs from aldehyde/ketone nucleophilic addition: an acyl derivative has a group Z that can leave.

c. Relative tendencies

• A commonly useful reactivity order is acyl chloride > anhydride > ester ≈ carboxylic acid > amide for nucleophilic acyl substitution under comparable conditions.

• Leaving-group ability, resonance donation, reagent identity and reaction conditions all affect whether a conversion is practical.

• Converting a less reactive derivative into a more reactive one generally needs activation rather than a simple exchange.

Acyl derivative	Common reaction	Typical product
Acyl chloride	Water / alcohol / amine	Acid / ester / amide
Anhydride	Alcohol / amine	Ester / amide
Ester	Hydrolysis / hydride / Grignard	Acid / alcohol / tertiary alcohol
Amide	Hydrolysis / strong hydride	Acid / amine

• Leaving-group basicity affects the driving force for acyl substitution.

• Protonation and basic conditions can change the practical reactivity ordering.

d. Recognizing the family

• Acid chlorides, anhydrides, esters and amides contain a substituent attached to an acyl carbon that can act as a leaving group under suitable conditions.
• A lactone is a cyclic ester; a lactam is a cyclic amide. Nitriles are related acid precursors but do not contain a carbonyl group.

e. Addition–elimination

• Nucleophile addition forms a tetrahedral intermediate. Collapse restores C=O and expels a leaving group; proton transfers depend on the conditions.
• A common neutral derivative reactivity trend is acid chloride > anhydride > ester > amide. Carboxylic acids require separate attention because bases often deprotonate them first.

Derivative	Group on acyl carbon	General reactivity
Acid chloride	Cl	High
Anhydride	OCOR	High
Ester	OR	Intermediate
Amide	NR₂	Lower; strong resonance donation

C. Acyl Chlorides, Anhydrides, Esters and Amides

1. Preparation, interconversion and reduction

a. Activation and coupling

• A carboxylic acid can be activated before reaction with ammonia or an amine to form an amide.

• Directly mixing an amine with a carboxylic acid often gives an ammonium carboxylate salt; activation or dehydrating conditions are typically needed for efficient amidation.

b. Hydride reduction

• Strong hydride reagents such as LiAlH₄ can reduce carboxylic acids to primary alcohols, followed by careful workup.

• Selectivity differs from the milder NaBH₄ reagent, which ordinarily does not reduce simple carboxylic acids under standard conditions.

c. Substitution chemistry

• Acyl chlorides react readily with water to form acids, with alcohols to form esters, and with ammonia or amines to form amides.

• When amines are used, a suitable base or excess amine can neutralize the hydrogen chloride formed.

d. Acyl transfer

• Anhydrides transfer an acyl group to nucleophiles, producing a carboxylic-acid-related by-product.

• Anhydrides are often used for esterification or amide formation when direct reaction of the carboxylic acid is inefficient.

• For anhydride hydrolysis, identify both acyl fragments when determining the products.

e. Resonance and reduction

• The nitrogen lone pair strongly donates into the carbonyl system, making ordinary amides relatively unreactive toward substitution.

• Strong hydride reduction of many amides can furnish amines, rather than alcohols.

• Under sufficiently vigorous acidic or basic conditions, amides can undergo hydrolysis to carboxylic-acid-related products.

Reagent or conditions	Starting group	Typical change
H₃O⁺, heat	Ester	Carboxylic acid + alcohol
OH⁻, heat; then H₃O⁺	Ester	Carboxylate, then acid
LiAlH₄; workup	Ester	Primary alcohol from acyl fragment
Excess RMgX; workup	Ester	Tertiary alcohol (often)
LiAlH₄; workup	Amide	Amine

f. Step-growth bonds

• Polyesters contain repeated ester linkages and can be prepared from suitable bifunctional monomers.

• Polyamides contain repeated amide linkages, as in many synthetic fibers and biological peptide bonds.

• The nature of the monomers and reaction conditions controls chain growth, side products and material properties.

g. Fischer esterification

• An acid and alcohol form an ester and water under acid catalysis. Each mechanistic step is reversible; excess alcohol or water removal can favor ester.
• The acid carbonyl oxygen is activated by protonation, alcohol adds, proton transfers prepare water departure, and loss of water restores the carbonyl.

• The alcohol supplies the ester alkoxy oxygen, while the carboxylic acid supplies the acyl carbon skeleton.

h. Activated derivatives

• An acid chloride can give an anhydride, ester or amide with an appropriate nucleophile. A carboxylic acid can be converted to an acid chloride using SOCl₂ or related activating reagents.
• Directly converting a less reactive derivative into a more reactive one usually requires activation rather than simple nucleophile exchange.

i. Ester and amide hydrolysis

• Acidic ester hydrolysis is reversible. Basic ester hydrolysis gives carboxylate plus alcohol; formation of carboxylate helps drive saponification.
• Amide hydrolysis generally requires stronger acid/base conditions and heat. Acidic workup gives the acid after basic hydrolysis. Transesterification exchanges OR groups under suitable catalysis and equilibrium control.

j. Hydride products

• LiAlH₄ reduces carboxylic acids and esters to primary alcohols; the alcohol-derived portion of an ester is also released after workup. Amides reduce to amines.
• Selected bulky hydrides can stop acid chloride reduction at an aldehyde; controlled DIBAL conditions can convert suitable esters or nitriles to aldehydes after workup. The exact conditions matter.

• Beta-keto acids can decarboxylate readily on heating.

k. Carbon–carbon formation

• Esters and acid chlorides commonly react twice with excess Grignard reagent: initial acyl substitution gives a ketone, followed by a second addition to give a tertiary alcohol after workup.
• An organocuprate can convert an acid chloride to a ketone without the usual second addition. Carboxylic acids consume strongly basic organometallic reagents by proton transfer first.

• For an ester, LiAlH₄ gives an alcohol from the acyl portion and releases the alkoxy-derived alcohol after workup. The ketone formed after the first Grignard addition is generally more reactive than the starting ester.

l. Intramolecular acyl substitution

• A hydroxy acid can form a lactone and an amino acid derivative can form a lactam when ring size and conditions permit. Five- and six-membered products are often favorable.
• Ring formation remains an equilibrium and reactivity problem; not every chain cyclizes efficiently. Distinguish carbonyl addition from acyl substitution by whether the final C=O remains.

D. Nitrile Chemistry

1. Hydrolysis, reduction and carbon count

a. Nitrile structure, SN2 homologation and carbon count

• Nitriles contain a C≡N functional group with a linear sp-hybridized carbon.

• A primary alkyl halide can react with cyanide by an SN2 pathway to form a nitrile with one additional carbon.

• Cyanide-related transformations require particularly careful chemical safety controls.

• SN2 substitution with CN⁻ adds one carbon to the alkyl chain; subsequent acidic or basic nitrile hydrolysis gives the carboxylic acid after the appropriate workup.

b. Nitrile chemistry

• A nitrile contains C≡N. Hydrolysis gives a carboxylic acid; strong hydride reduction gives a primary amine.
• Grignard addition to a nitrile forms an imine-derived intermediate; hydrolysis produces a ketone. A methyl/primary halide can undergo SN2 with cyanide to extend its carbon skeleton.

E. Claisen Condensation

1. Ester enolates, condensation and decarboxylation

a. Mechanism and product

• An ester enolate attacks another ester, then alkoxide elimination restores the carbonyl and yields a β-keto ester framework.
• For the usual self-Claisen process, deprotonation of the β-dicarbonyl product helps drive the equilibrium; acidic workup gives the neutral product.

• A matching alkoxide helps avoid transesterification, and suitable α-hydrogens are required for the usual equilibrium-driven process.

b. Matching conditions

• Use an alkoxide base matching the ester OR group to reduce unwanted transesterification. A typical ester donor needs two α-H atoms for the usual driven condensation.
• Crossed Claisen selectivity is improved when the electrophilic ester has no α-H. Intramolecular Claisen condensation is the Dieckmann reaction.

Reaction	Electrophile	Main initial product
Aldol addition	Aldehyde/ketone	β-Hydroxy carbonyl
Aldol condensation	Aldehyde/ketone	α,β-Unsaturated carbonyl
Claisen	Ester	β-Keto ester

• In crossed reactions, identify the enolate donor and ester electrophile; when both partners can enolize, a single clean product should not be assumed.

c. Comparing alpha substitution, aldol and Claisen carbon accounting

• Alpha substitution retains the original carbonyl group while replacing an alpha substituent.
• An aldol coupling joins the carbon skeletons of two carbonyl partners; for example, two C2 units give a C4 aldol product.
• Claisen condensation of suitable esters also creates a C–C bond, whereas subsequent hydrolysis or decarboxylation can change the product carbon count.

Reaction	Typical change	Product
Alpha halogenation	Alpha C–H → C–X	Alpha-halo carbonyl
Enolate alkylation	Alpha C–H → C–C bond	Alpha-alkyl carbonyl
Aldol addition	Two carbonyl partners join	Beta-hydroxy carbonyl
Aldol condensation	Aldol product loses water	Alpha,beta-unsaturated carbonyl
Claisen condensation	Ester enolate acylation	Beta-keto ester

Species	Nucleophilic site	Typical role
Enol	Alpha carbon of C=C–OH	Electrophilic substitution
Enolate	Alpha carbon / oxygen (ambident)	C–C formation; O-protonation
Aldehyde or ketone	Carbonyl carbon (electrophilic)	Aldol acceptor
Ester	Carbonyl carbon with leaving group	Acyl substitution

• The following comparisons connect CH 8 enolate/aldol chemistry with the ester acyl-substitution chemistry developed here. They compare different transformations; the same mechanism should not be assigned to every row.

d. Malonic ester synthesis

• Deprotonate malonic ester, alkylate with a suitable SN2 electrophile, hydrolyze the esters, then heat to decarboxylate.
• The sequence provides substituted acetic-acid derivatives. Count the retained carbonyl carbon and the carbon lost as CO₂ separately.

e. Acetoacetic ester synthesis

• Alkylation of a β-keto ester followed by hydrolysis and decarboxylation gives a substituted methyl ketone.
• Suitable substrates may undergo more than one alkylation before hydrolysis. Ring synthesis requires appropriate chain length and leaving-group placement.