(21)Organic Chemistry - Carboxylic Acid Derivatives

Carboxylic Acid Derivatives

Introduction to Carboxylic Acid Derivatives

• Carboxylic acid derivatives are compounds with functional groups that can be converted to carboxylic acids via acidic or basic hydrolysis.
• Examples include penicillin V, cephalexin (Keflex®), and imipenem (Primaxin).
• Naturally occurring esters and amides include:
  • Isoamyl acetate (banana oil)
  • Geranyl acetate (geranium oil)
  • N,N-diethyl-meta-toluamide
  • Penicillin G

Structure and Nomenclature of Acid Derivatives

Esters

• Esters are carboxylic acid derivatives where the hydroxy group ($\text{--OH }$) is replaced by an alkoxy group ($\text{--OR}$).

Lactones

• Cyclic esters are called lactones.
• IUPAC names of lactones are derived by adding "lactone" to the end of the parent acid name.

Amides

• An amide is a composite of a carboxylic acid and ammonia or an amine.
• Ammonium salts can be converted to amides at high temperatures.
• Resonance representation of amides shows their structure with bond angles around the carbonyl carbon and nitrogen atoms:
  • C-O bond has partial double bond character due to resonance.
• Amide Substitution and Naming:
  • Primary amide: $\text{R-C(O)-NH}_2$
  • Secondary amide (N-substituted amide): $\text{R-C(O)-NHR' }$
  • Tertiary amide (N,N-disubstituted amide): $\text{R-C(O)-NR'R''}$
  • Examples:
    • N-ethylethanamide (N-ethylacetamide): $\text{CH}<em>3\text{-C(O)-NH-CH}</em>2\text{CH}_3$
    • Cyclopentanecarboxamide: $\text{C}<em>5\text{H}</em>9\text{-C(O)-NH}_2$
    • N,N-dimethylmethanamide (N,N-dimethylformamide): $\text{H-C(O)-N(CH}<em>3)</em>2$
    • N-ethyl-N,2-dimethylpropanamide (N-ethyl-N-methylisobutyramide)
    • N,N-dimethylcyclopropanecarboxamide
    • Acetanilide

Lactams

• Cyclic amides are called lactams.
• Lactams are named by adding "lactam" to the end of the IUPAC name of the parent acid.

Nitriles

• Nitriles contain the cyano group ($\text{-C≡N}$).
• Hydrolysis of nitriles leads to the formation of carboxylic acids.
• Reactions:
  • $\text{R-C≡N} + \text{H}<em>2\text{O} \xrightarrow{\text{H}^+} \text{R-C(O)-NH}</em>2$ (nitrile to primary amide)
  • $\text{R-C≡N} + 2\text{H}_2\text{O} \xrightarrow{\text{H}^+ \text{ or } ^-\text{OH}} \text{R-C(O)OH}$ (nitrile to acid)
• Synthesis of nitriles from acids:
  • $\text{R-C(O)OH} \xrightarrow{\text{NH}<em>3, \text{heat}} \text{R-C(O)NH}</em>2 \xrightarrow{\text{POCl}_3} \text{R-C≡N}$
• Examples:
  • Ethanenitrile (acetonitrile): $\text{CH}_3\text{-C≡N}$
  • 3-bromobutanenitrile ($\beta$-bromobutyronitrile): $\text{CH}<em>3\text{-CH(Br)-CH}</em>2\text{-C≡N}$
  • 5-methoxyhexanenitrile ($\delta$-methoxycapronitrile): $\text{CH}<em>3\text{O-CH}</em>2\text{CH}<em>2\text{CH}</em>2\text{CH}_2\text{-C≡N}$
• Electronic Structure of Nitriles
  • The atoms at the ends of the triple bonds are sp hybridized, and the bond angle is $180^\circ$.

Acid Halides

• Acid halides are also called acyl halides.
• They are activated derivatives used in the synthesis of other acyl compounds such as esters.
• Acid halides are named by replacing the -ic acid suffix with -yl and the halide name.

Acid Anhydrides

• An acid anhydride contains two molecules of acid, with the loss of a molecule of water.
• Acid anhydrides are activated derivatives of carboxylic acids.
• Naming Acid Anhydrides
  • Acid anhydrides are named by replacing the word acid with anhydride.

Nomenclature of Multifunctional Compounds

• Priority of functional groups (decreasing order):
  • acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene, alkyne

Summary of Functional Group Nomenclature

Physical Properties of Carboxylic Acid Derivatives

• The physical properties of acid derivatives largely depend on their polarity and their hydrogen-bonding properties.
• Resonance
  • The resonance picture of an amide shows its strongly polar nature.
• Esters, Amides, and Nitriles Commonly Used as Solvents for Organic Reactions
  • Acid derivatives (esters, acid chlorides, anhydrides, nitriles, and amides) are soluble in common organic solvents.

Spectroscopy of Carboxylic Acid Derivatives

Characteristic Carbonyl IR Stretching Absorptions

IR Spectra of Carbonyl Compounds

• Mentioned the IR spectra of carbonyl compounds and highlighted C-H stretch, and C=O stretch peaks.
• Most acid derivatives have C=O stretches between $1700 \text{ cm}^{-1}$ and $1800 \text{ cm}^{-1}$.

NMR Spectroscopy: 1H NMR

• The proton chemical shifts found in acid derivatives are close to those of similar protons in ketones, aldehydes, alcohols, and amines.

Nucleophilic Acyl Substitution

• Interconversion of acid derivatives occurs by nucleophilic acyl substitution.
• The nucleophile adds to the carbonyl, forming a tetrahedral intermediate.
• Elimination of the leaving group regenerates the carbonyl.
• This is an addition–elimination mechanism.
• Nucleophilic acyl substitutions are also called acyl transfer reactions because they transfer the acyl group to the attacking nucleophile.
• Mechanism of Acyl Substitution:
  • Step 1: Addition of the nucleophile forms the tetrahedral intermediate.
  • Step 2: Elimination of the leaving group regenerates the carbonyl group.

Reactivity of Acid Derivatives

• More reactive derivatives can be converted to less reactive derivatives.

Specific Conversions

• Acid Chloride to Anhydride
  • The carboxylic acid attacks the acyl chloride, forming the tetrahedral intermediate.
  • Chloride ion leaves, restoring the carbonyl.
  • Deprotonation produces the anhydride.
• Acid Chloride to Ester
  • The alcohol attacks the acyl chloride, forming the tetrahedral intermediate.
  • Chloride ion leaves, restoring the carbonyl.
  • Deprotonation produces the ester.
• Acid Chloride to Amide
  • Ammonia yields a 1° amide.
  • A 1° amine yields a 2° amide.
  • A 2° amine yields a 3° amide.
• Anhydride to Ester
  • Alcohol attacks one of the carbonyl groups of the anhydride, forming the tetrahedral intermediate.
  • The other acid unit is eliminated as the leaving group.
• Anhydride to Amide
  • Ammonia yields a 1° amide; a 1° amine yields a 2° amide; and a 2° amine yields a 3° amide.
• Ester to Amide: Ammonolysis
  • The nucleophile must be NH3 or 1° amine.
  • Prolonged heating is required.

Leaving Groups in Nucleophilic Acyl Substitution

• A strong base, such as an alkoxide ($\text{–OR}$), is not usually a leaving group, except in an exothermic step.
• Energy Diagram
  • In the nucleophilic acyl substitution, the elimination of the alkoxide is highly exothermic, converting the tetrahedral intermediate into a stable molecule.

Transesterification

• One alkoxy group can be replaced by another with acid or base catalyst.
• Use large excess of desired alcohol.

Acid-Catalyzed Transesterification Mechanism

• First half: Acid-catalyzed addition of the nucleophile.
  • Step 1: Protonation of the carbonyl.
  • Step 2: Nucleophile attack.
  • Step 3: Deprotonation.
• Second half: Acid-catalyzed elimination of the leaving group.
  • Step 1: Protonation of the leaving group.
  • Step 2: Elimination of the leaving group.
  • Step 3: Deprotonation.

Base-Catalyzed Transesterification Mechanism

• nucleophilic attack
• tetrahedral intermediate

Hydrolysis of Carboxylic Acid Derivatives

Hydrolysis of Acid Chlorides and Anhydrides

• Hydrolysis occurs quickly, even in moist air with no acid or base catalyst.
• Reagents must be protected from moisture.

Hydrolysis of Esters: Saponification

• The base-catalyzed hydrolysis of ester is known as saponification.
• Saponification means “soap-making.”
• Soaps are made by heating NaOH with a fat (triester of glycerol) to produce the sodium salt of a fatty acid—a soap.

Hydrolysis of Amides

• Amides are hydrolyzed to the carboxylic acid under acidic or basic conditions.

Basic Hydrolysis of Amides

• Similar to the hydrolysis of an ester.
• The hydroxide ion attacks the carbonyl, forming a tetrahedral intermediate.
• The amino group is eliminated and a proton is transferred to the nitrogen to give the carboxylate salt.

Acid Hydrolysis of Amides

• First half: Acid-catalyzed addition of the nucleophile (water).
  • Step 1: Protonation of the carbonyl.
  • Step 2: Addition of the nucleophile.
  • Step 3: Loss of a proton.
• Second half: Acid-catalyzed elimination of the leaving group.
  • Step 1: Protonation of the leaving group.
  • Step 2: Elimination of the leaving group.
  • Step 3: Deprotonation.

Hydrolysis of Nitriles

• Heating with aqueous acid or base will hydrolyze a nitrile to a carboxylic acid.

Base-Catalyzed Hydrolysis of a Nitrile

• enol tautomer of amide

Reduction of Acid Derivatives

Reduction of Esters to Alcohols

• Lithium aluminum hydride ($\text{LiAlH}_4$) reduces esters, acids, and acyl chlorides to primary alcohols.
• Mechanism of Reduction of Esters:
  • Step 1: Addition of the nucleophile (hydride).
  • Step 2: Elimination of alkoxide.
  • Step 3: Addition of a second hydride ion.
  • Step 4: Add acid in the workup to protonate the alkoxide.

Reduction of Acyl Halides to Aldehydes

• Lithium tri-tert-butoxyaluminum hydride is a milder reducing agent.
• Reacts faster with acyl chlorides than with aldehydes.

Reduction to Aldehydes with DIBAL

• Di-isobutylaluminum hydride, commonly called DIBAL or DIBAL-H, is another mild reducing agent that can reduce esters to aldehydes.

Reduction of an Amide to an Amine

• Amides will be reduced to the corresponding amine by $\text{LiAlH}_4$.
• Reduction of an Amide:
  • Step 1: Addition of hydride.
  • Step 2: Oxygen leaves.
  • Step 3: Second hydride adds.

Reduction of Nitriles to Primary Amines

• Nitriles are reduced to primary amines by catalytic hydrogenation or by lithium aluminum hydride reduction.

Reactions of Acid Derivatives with Organometallic Reagents

Organometallic Reagents

• Grignard and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.
• Mechanism of Grignard Addition
  • Esters react with two moles of Grignards or organolithium reagents to produce an alcohol.
  • The ketone intermediate will react with a second mole of organometallic to produce the alcohol.

Dialkylcuprate Reagents

• Acid chlorides react just once with dialkylcuprates (Gilman reagents) to give ketones.

Reaction of Nitriles with Grignards

• A Grignard reagent or organolithium reagent attacks the cyano group to form an imine, which is hydrolyzed to a ketone.

Summary of the Chemistry of Acid Chlorides

Synthesis of Acid Chlorides

• Thionyl chloride ($\text{SOCl}2$) and oxalyl chloride ($\text{COCl}2$) are the most convenient reagents because they produce only gaseous side products.
• Acid Chloride Reactions:

Friedel-Crafts Acylation

• Example
  • Using anisole and propionyl chloride

Summary of the Chemistry of Anhydrides

General Anhydride Synthesis

• The most generalized method for making anhydrides is the reaction of an acid chloride with a carboxylic acid or a carboxylate salt.
• Pyridine is sometimes used to deprotonate the acid and form the carboxylate.
• Reaction of Anhydrides:
  • Hydrolysis to form carboxylic acids.
  • Alcoholysis to form esters.
  • Aminolysis to form amides.

Friedel-Crafts Acylation Using Anhydrides

• Using a cyclic anhydride allows for only one of the acid groups to react, leaving the second acid group free to undergo further reactions.

Acetic Formic Anhydride

• Acetic formic anhydride, made from sodium formate and acetyl chloride, reacts primarily at the formyl group.
• The formyl group is more electrophilic because of the lack of alkyl groups.

Summary of the Chemistry of Esters

Synthesis of Esters

• Various methods to synthesize esters, including:
  • Reaction of carboxylic acids with alcohols under acidic conditions (Fischer esterification).
  • Reaction of acid chlorides with alcohols.
  • Reaction of anhydrides with alcohols.
  • Transesterification.
  • Reaction of acids with diazomethane to form methyl esters.
• Reactions of Esters

Formation of Lactones

• Formation is favored for five- and six-membered rings.
• For larger rings, remove water to shift equilibrium toward products.

Summary of the Chemistry of Amides

Reactions of Amides

• Hydrolysis under acidic or basic conditions to form carboxylic acids.
• Reduction with $\text{LiAlH}_4$ to form amines.
• Dehydration of primary amides to form nitriles.

Dehydration of 1o Amides to Nitriles

• Strong dehydrating agents can eliminate the elements of water from a primary amide to give a nitrile.
• Phosphorus oxychloride ($\text{POCl}3$) or phosphorus pentoxide ($\text{P}2\text{O}_5$) can be used as dehydrating agents.

Formation of Lactams

• Five-membered lactams ($\gamma$-lactams) and six-membered lactams ($\delta$-lactams) often form on heating or adding a dehydrating agent to the appropriate $\gamma$-amino acid or $\delta$-amino acid.

$\beta$-Lactams

• Unusually reactive, four-membered ring amides are capable of acylating a variety of nucleophiles.
• They are found in three important classes of antibiotics: penicillins, cephalosporins, and carbapenems.

Mechanism of $\beta$-Lactam Acylation

• The nucleophile attacks the carbonyl of the four-membered ring amide, forming a tetrahedral intermediate.
• The nitrogen is eliminated and the carbonyl reformed.
• Protonation of the nitrogen is the last step of the reaction.

Action of $\beta$-Lactam Antibiotics

• The $\beta$-lactams work by interfering with the synthesis of bacterial cell walls.
• The acylated enzyme is inactive for synthesis of the cell wall protein.

Summary of the Chemistry of Nitriles

Synthesis of Nitriles

• Dehydration of primary amides.
• Reaction of alkyl halides with sodium cyanide.
• From diazonium salts using copper cyanide.
• Addition of hydrogen cyanide to ketones or aldehydes to form cyanohydrins.
• Reactions of Nitriles

Reactions of Nitriles

• Hydrolysis to amides and carboxylic acids.
• Reduction to amines.
• Reaction with Grignard reagents to form ketones.
• Reduction with DIBAL-H to form aldehydes.

Thioesters

• A thioester is formed from a carboxylic acid and a thiol.
• Thioesters are also called thiol esters to emphasize that they are derivatives of thiols.

Resonance Overlap in Esters and Thioesters

• The resonance overlap in a thioester is not as effective as that in an ester.
• Thioesters are more reactive toward nucleophilic acyl substitution than are normal esters (poorer resonance and better leaving group).

Esters and Amides of Carbonic Acid

Synthesis of Carbamate Esters from Isocyanates

• Reaction of an isocyanate with an alcohol to form a carbamate ester (urethane).
• Reaction of an isocyanate with water to form an amine and carbon dioxide.

Polycarbonate Synthesis

• Polycarbonates are polymers bonded to the carbonate ester linkage.
• The diol used to make Lexan® is a phenol called bisphenol A, a common intermediate in polyester and polyurethane synthesis.

Synthesis of Polyurethanes

• Reaction of toluene diisocyanate with ethylene glycol produces one of the most common forms of polyurethanes.