Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • The functional group of a carboxylic acid is a carboxyl group • the general formula of an aliphatic carboxylic acid is RCOOH • that of an aromatic carboxylic acid is ArCOOH

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • IUPAC names: drop the -e from the parent alkane and add the suffix -oic acid • if the compound contains a carbon-carbon double bond, change the infix -an- to -en-

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • The carboxyl group takes precedence over most other functional groups

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • dicarboxylic acids: add -dioic acid to the name of the parent alkane containing both carboxyl groups • there is no need to use numbers to locate the carboxyl groups; they can only be on the ends of the chain

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • if the carboxyl group is bonded to a ring, name the ring compound and add the suffix -carboxylic acid • benzoic acid is the simplest aromatic carboxylic acid • use numbers to show the location of substituents

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • when common names are used, the lettersetc. are often used to locate substituents • in common nomenclature, keto indicates the presence of a ketone, and CH3CO- is named an aceto group

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • Carboxylic acids have significantly higher boiling points than other types of organic compounds of comparable molecular weight • they are polar compounds and form very strong intermolecular hydrogen bonds • Carboxylic acids are more soluble in water than alcohols, ethers, aldehydes, and ketones of comparable molecular weight • they form hydrogen bonds with water molecules through their C=O and OH groups • water solubility decreases as the relative size of the hydrophobic portion of the molecule increases

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • Carboxylic acids are weak acids • values of pKa for most aliphatic and aromatic carboxylic acids fall within the range 4 to 5 • the greater acidity of carboxylic acids relative to alcohols, both of which contain an OH group, is due to resonancestabilization of the carboxylate anion • electron-withdrawing substituents near the carboxyl group increase acidity through their inductive effect

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • the acid-strengthening effect of a halogen substituent falls off rapidly with increasing distance from the carboxyl group

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates • Carboxylic acids, whether soluble or insoluble in water, react with NaOH, KOH, and other strong bases to give water-soluble salts • They also form water-soluble salts with ammonia and amines

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates Higher reactivity of carbonyl!!!

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates Mechanism:

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates Leaving groups:

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates Synthesis of anhydrides

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile • The functional group of an ester is an acyl group bonded to -OR or -OAr • name the alkyl or aryl group bonded to oxygen followed by the name of the acid • change the suffix -ic acid to -ate Acid + Alcohol -> Ester Excess

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile Acid + Alcohol -> Ester Excess

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile Acid + Alcohol -> Ester base-catalysed esterfication -> does not work with acid + alcohol Pyridine as proton catcher

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile Acid + Alcohol -> Ester Transesterfication

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile Hydroxyacid -> Lactone • Lactone: a cyclic ester • IUPAC: name the parent carboxylic acid, drop the suffix -ic acid, and add -olactone • the location of the oxygen atom on the carbon chain is commonly indicated by a Greek letter

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile Hydroxyacid -> Lactone

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile Hydrolysis of carboxylic acid derivates

Nucleophilic substitution on carbonyl groups – Oxygen as nucleophile Hydrolysis of carboxylic acid derivates Amides (Peptides and Proteins)

Nucleophilic substitution on carbonyl groups – Sulfur as nucleophile • Thiols + Carboxylic acid derivates -> Thioacids and Thioesters • Reactivity increased (compared to formation of ester): • Sulfur better nucleotide than oxygen • RS- better leaving group than RO-

Nucleophilic substitution on carbonyl groups – Sulfur as nucleophile Thiols + Carboxylic acid derivates -> Thioacids and Thioesters

Nucleophilic substitution on carbonyl groups – Nitrogen as nucleophile Amines (1º, 2º, 3º) + Carboxylic acid (derivates) -> Amides -> with Carboxylic acid

Nucleophilic substitution on carbonyl groups – Nitrogen as nucleophile Amines (1º, 2º, 3º) + Carboxylic acid (derivates) -> Amides -> with Carboxylic acid derivates

Nucleophilic substitution on carbonyl groups – Nitrogen as nucleophile Amines (1º, 2º, 3º) + Carboxylic acid (derivates) -> Amides -> with esters

Nucleophilic substitution on carbonyl groups – Nitrogen as nucleophile Amines (1º, 2º, 3º) + Carboxylic acid (derivates) -> Amides

Nucleophilic substitution on carbonyl groups – Nitrogen as nucleophile Aminoacids -> Lactams (cyclic amides) • name the parent carboxylic acid, drop the suffix -ic acid and add lactam • the location of the nitrogen atom in the ring is commonly indicated by a Greek letter, α, β, etc.

Nucleophilic substitution on carbonyl groups – Nitrogen as nucleophile Aminoacids -> Lactams (cyclic amides) Penicillins and Cephalosporins are member of a family of β-lactam antibiotics

Nucleophilic substitution on carbonyl groups – Hydride as nucleophile Reduction of carboxylic acid derivates -> Alkohols Lithium aluminium hydride (LAH) -> strong hydrid donor Sodium borohydride (NaBH4) -> weaker hydrid donor LAH reduces -> acyl halides, anhydrides, esters, and acids -> primary alcohol

Nucleophilic substitution on carbonyl groups – Hydride as nucleophile Reduction of carboxylic acid derivates -> Alkohols Lithium aluminium hydride (LAH) -> strong hydrid donor -> reduces almost all carboxylic acid derivates Sodium borohydride (NaBH4) -> weaker hydrid donor -> reduces acyl halides, ketons, aldehydes

Nucleophilic substitution on carbonyl groups – Hydride as nucleophile Reduction of Amides -> Amines ->different mechanism!!!

Nucleophilic substitution on carbonyl groups – Carbon as nucleophile Carboxylic acid derivates + Grignard -> Alcohols

Nucleophilic substitution on derivates of sulfuric and phosphoric acids

Nucleophilic substitution on derivates of sulfuric and phosphoric acids Sulfuric acid derivates

Nucleophilic substitution on derivates of sulfuric and phosphoric acids Phosphoric acid derivates

Nucleophilic substitution on carbonyl groups – Carboxylic acid derivates