Carboxylic acids and derivatives Dr. Sheppard CHEM 2412 Summer 2015 Klein (2nd ed.) sections: 21.1, 21.2, 21.6, 21.3, 21.15, 21.4, 21.5, 21.10, 21.7, 21.8, 21.9, 21.11, 21.12, 21.13, 21.14

Carboxylic Acids and Derivatives Found in nature Carboxylic acid derivatives:

Carboxylic Acids and Derivatives Nomenclature Review Physical Properties Acidity of Carboxylic Acids Spectroscopy Preparation of Carboxylic Acids Reactions of Carboxylic Acids Nucleophilic Acyl Substitution

I. Nomenclature (Review) Carboxylic acids Parent chain contains carbon of –CO2H Suffix is “-oic acid” –CO2H is carbon 1 Cyclic molecules with –CO2H substituents –CO2H is bonded to carbon 1 of ring Add “carboxylic acid” to end of ring parent name

Examples Structure Name

Naming Acid Chlorides Name corresponding carboxylic acid Change “-ic acid” to “-yl chloride” Examples: Structure Name

Naming Acid Anhydrides If R = R’, name carboxylic acid RCO2H. Replace “acid” with “anhydride” If R ≠ R’, list the two acids alphabetically and add the word “anhydride” Examples: Structure Name

Naming Esters Name alkyl group bonded to oxygen (R’) Name carboxylic acid RCO2H Change “-ic acid” to “-ate” Examples: Structure Name

Naming Amides Name corresponding carboxylic acid Change “-oic acid” to “-amide” Examples: Structure Name

Naming Nitriles Two methods Nitrile carbon is carbon 1 of parent chain. Add “-nitrile” to end of alkane name. Name as carboxylic acid derivative. Replace “-ic acid” with “-onitrile”

II. Physical Properties Carboxylic acids form a hydrogen bond dimer Boiling points Carboxylic acids are very high CA > alcohols > aldehyde/ketones > hydrocarbons Carboxylic acid derivatives are less predictable Generally amides > carboxylic acids > acid halides/esters Tertiary amides < primary and secondary amides no H-bonding in liquid phase (neat)

II. Physical Properties Solubility in water Low MW CAs and CADs are soluble Solubility decrease as MW increases Salts of carboxylic acids are more soluble CADs also react with water (to form carboxylic acids) Odor Esters = sweet or floral Carboxylic acids = unpleasant

III. Acidity of Carboxylic Acids Weak acids (pKa ~ 4-5) Stronger than alcohols because conjugate base is resonance-stabilized

III. Acidity of Carboxylic Acids Conjugate base can be further stabilized if electronegative atom is present Inductive effect Position of en atom affects pKa

III. Acidity of Carboxylic Acids Substituted benzoic acids If Z = electron-donating group, acid is weaker If Z = electron-withdrawing group, acid is stronger

IV. Spectroscopy of CAs: IR Absorption at 2500-3300 cm-1 for COOH Absorption at 1710-1760 cm-1 for C=O

IV. Spectroscopy of CAs: NMR 13C-NMR: 1H-NMR: COOH signal d11-12

IV. Spectroscopy of CADs: IR Absorption at 1650-1820 cm-1 for C=O

IV. Spectroscopy of CADs: NMR 13C-NMR: Carbonyl carbon slightly upfield from aldehydes and ketones 1H-NMR: H adjacent to C=O around d2, but doesn’t always help you determine functional group Look for OH (CA), NH (amide), or OR (ester)

V. Preparation of Carboxylic Acids Oxidation of primary alcohols and aldehydes (section 13.10)

V. Preparation of Carboxylic Acids Oxidative cleavage of alkenes or alkynes (section 10.9)

V. Preparation of Carboxylic Acids Oxidation of alkylbenzenes We will see this in the aromatic chapters

V. Preparation of Carboxylic Acids Hydrolysis of nitriles Requires aqueous acid and heat

V. Preparation of Carboxylic Acids Carboxylation of Grignard reagents Addition of CO2, followed by H3O+ Mechanism: Example:

Show two methods that could be used to make butanoic acid from 1-bromopropane

VI. Reactions of Carboxylic Acids Types of reactions Deprotonation a-Substitution Oxidation? Reduction? Conversion to CADs

Reduction Need a strong reducing agent Reduce to primary alcohol LAH Remember reducing agent chart from alcohol chapter

Conversion to CADs Fischer esterification Carboxylic acid + alcohol → ester + water Needs acid catalyst (H2SO4 or HCl) Reaction is reversible Push to the right with excess alcohol or remove water

Conversion to CADs Formation of acid chlorides Reagent = SOCl2 Where have we seen this reagent before?

Conversion to CADs Formation of acid anhydrides Anhydride = without water Apply heat to carboxylic acids to remove water

Conversion to CADs Formation of amides Reaction is difficult with N nucleophile because the N (base) reacts with the carboxylic acid (acid)

VII. Nucleophilic Acyl Substitution Include all of the CA → CAD reactions Also used to make CAs from CADs and convert between CADs Z is leaving group Compare to nucleophilic addition (aldehydes/ketones)

VII. Nucleophilic Acyl Substitution Mechanism Acid or base catalyst typically needed Acid makes electrophile more electrophilic Base makes nucleophile more nucleophilic

VII. Nucleophilic Acyl Substitution Reactivity: Less substituted molecules are more reactive

VII. Nucleophilic Acyl Substitution Reactivity: Molecules with better leaving groups are more reactive Less reactive compounds need heat or catalyst to react and are limited in the number of reactions they will undergo Example: amides only undergo hydrolysis and reduction

VII. Nucleophilic Acyl Substitution Reactivity: More reactive compounds can be converted to less reactive compounds Can an ester be converted into an amide? Can an amide be converted into an ester?

VII. Nucleophilic Acyl Substitution Types of reactions

VII. Nucleophilic Acyl Substitution Types of reactions: Reaction Nucleophile Product Special Notes Hydrolysis H2O Carboxylic acid Alcoholysis ROH Ester Aminolysis NH3 1° amine 2° amine 1° amide 2° amide 3° amide With acid chlorides, 2 eq. of amine are needed: the nucleophile neutralizes HCl byproduct Reduction Hydride from LAH CA → 1° ROH Ester → 1° ROH Anhydride → 1° ROH Acid chloride → 1° ROH Amides → amines Hydride from DIBALH aldehyde Ester only Grignard RMgX 3° alcohol Ester and acid halide only

VII. Nucleophilic Acyl Substitution Summary of reactions: acid halide Also Grignard Anhydride formation:

VII. Nucleophilic Acyl Substitution Summary of reactions: anhydrides Example: commercial preparation of aspirin

VII. Nucleophilic Acyl Substitution Summary of reactions: esters Hydrolysis Alcoholysis Aminolysis Reduction (to 1° alcohols and aldehydes) Grignard Alcoholysis of esters = transesterification

VII. Nucleophilic Acyl Substitution Summary of reactions: amides Hydrolysis Acid or base catalyst Heat Reduction

VII. Nucleophilic Acyl Substitution Summary of reactions: nitriles Hydrolysis Acid or base catalyst Heat Reduction

VII. Nucleophilic Acyl Substitution Complete the chart with the functional group that will form from the following reactions.   H2O ROH NH3 LAH Grignard Carboxylic acid Acid halide Acid anhydride Ester Amide Nitrile

VII. Nucleophilic Acyl Substitution Specific reactions: Saponification (soap-making) Hydrolysis of ester in base Irreversible reaction

VII. Nucleophilic Acyl Substitution Condensation polymerization A step-growth reaction Example: polyamide What is a polyester? How could a polyester be synthesized?

VII. Nucleophilic Acyl Substitution Step-growth polymerization Compare Fischer esterification… …to polymerization

VII. Nucleophilic Acyl Substitution Step-growth polymerization Biodegradable polymers

What is the order of decreasing activity (most reactive = 1, least reactive = 4) toward nucleophilic acyl substitution for the following carboxylic acid derivatives?

Draw the products of these reactions.

Synthesis Propose a synthesis for ethyl acetate from ethanol.

Provide reagents to complete the reaction scheme

Provide reagents for the following reactions: