Carboxylic Acids Introduction • The functional group of carboxylic acids COOH consists of a C=O with -OH bonded to the same carbon • Aliphatic acids have an alkyl group bonded to -COOH • Aromatic acids have an aryl group bonded to -COOH • Fatty acids are long-chain aliphatic acids => Some Important Acids • CH3COOH is in vinegar and other foods, used industrially as solvent, catalyst, and reagent for synthesis • Fatty acids from fats and oils • C6H5COOH-Benzoic acid in drugs, preservatives • Adipic acid used to make nylon 66 • Phthalic acid used to make polyesters => Nobel Prize 1982 lessens pain, anti inflammation BiochemistSune K.Bergstrom, Bengt I.Samuelsson John R.Vane Plant Hormone Gibberellin (GA) IBA-Indol butyric Phenyl acetic IAA-Indol Acetic Biosynthesis of Shikimic acid Tamiflu L-Ascorbic acid (Vitamin C) Antioxidant Common Names • Aliphatic acids have historical names • Positions of substituents on the chain are labeled with Greek letters Cl O CH3CH2CHC OH α-chlorobutyric acid Ph CH3CH2CH2CHCH2COOH β-phenylcaproic acid => IUPAC Names • Remove -e from alkane (or alkene) name, add -oic acid • The carbon of the carboxyl group is #1 Cl O CH3CH2CHC OH 2-chlorobutanoic acid Ph H H C C COOH trans-3-phenyl-2-propenoic acid (cinnamic acid) => Naming Cyclic Acids • Cycloalkanes bonded to -COOH are named as cycloalkanecarboxylic acids • Aromatic acids are named as benzoic acids COOH CH(CH3)2 COOH OH 2-isopropylcyclopentanecarboxylic acid o-hydroxybenzoic acid (salicylic acid) => Reaction with Grignard Reagents Treating a formic ester with two moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2° alcohol O HCOCH3 + RMgX An ester of formic acid OH magn esium H2 O, HCl alkoxide HC-R + CH3 OH salt R A 2° alcohol Reaction with Grignard Reagents Treating an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol O CH3 COCH3 + RMgX An ester of an y acid other than formic acid magnesiu m H2 O, HCl alk oxid e salt OH CH3 C-R + CH3 OH R A 3° alcohol Reaction with Grignard Reagents Reaction of the ketone with a second mole of RMgX gives a second TCAI Treatment with aqueous acid gives the alcohol O CH -C 3 R A k eton e + R MgX - O [MgX] + OH H2 O, HCl CH -C-R (4) R R Magnesiu m salt A 3° alcohol CH3 -C-R Reactions with RLi • Organolithium compounds are even more powerful nucleophiles than Grignard reagents They react with esters to give the same types of 2° and 3° alcohols as Grignard reagents and often in higher yields O RCOCH3 R' Li H2 O, HCl OH R- C-R' + CH3 OH R' Reduction Ester to 1° Alcohols • Most reductions of carbonyl compounds now use hydride reducing agents Esters are reduced by LiAlH4 to two alcohols The alcohol derived from the carbonyl group is primary O Ph OCH Methyl 2-phenylpropanoate (racemic) LiA lH4 , e t he r H2 O, HCl Ph OH + CH OH 2-Phenyl-1propanol (racemic) Methanol Reduction Ester to 1° Alcohols • Use strong reducing agent, LiAlH4 • Borane, BH3 in THF, reduces carboxylic acid to alcohol, but does not reduce ketone => Reduction Ester to 1° Alcohols • Reduction occurs in three steps plus workup:  Steps and reduce the ester to an aldehyde O R C OR' + H (1) O R C OR' H (2) O R C A tetrahedral carbonyl addition intermediate + OR' H  Step 3: Reduction of the aldehyde followed by work-up gives a 1° alcohol derived from the carbonyl group O R C H + H (3) O R C H H OH (4) R C H H A 1° alcohol Reduction - Esters by NaBH4 • NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones • Selective reduction is often possible by the proper choice of reducing agents and experimental conditions O O OEt NaBH4 EtOH OH O OEt (racemic) Reduction - Esters by DIBALH • Diisobutylaluminum hydride at -78°C selectively reduces an ester to an aldehyde At -78°C, the TCAI does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated O OCH3 Methyl hexanoate DIBALH , toluen e, -78°C H2 O, HCl O H + CH3 OH Hexanal Reduction - Amides by LiAlH4 • LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide O NH2 Octanamide LiAlH4 H2 O NH2 1-Octanamine O NMe2 LiAlH4 H2 O N,N -D imethylben zamide NMe2 N ,N-D imeth ylb enzylamine Reduction - Amides by LiAlH4 • The mechanism is divided into steps: Step 1: Transfer of a hydride ion to the carbonyl carbon Step 2: A Lewis acid-base reaction and formation of an oxygen-aluminum bond O R C NH2 + H AlH3 (1) O R C NH2 + AlH3 H (2) AlH3 O R C NH2 H Reduction - Amides by LiAlH4 Step 3: Redistribution of electrons and ejection of H3AlO- gives an iminium ion Step 4: Transfer of a second hydride ion to the iminium ion completes the reduction to the amine O H AlH3 R C N H H H (3) R C N H H H An iminium ion (4) R-CH2 -NH2 A 1° amine Reduction - Nitriles by LiAlH4 The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine LiA lH4 CH3 CH= CH( CH ) C N H2 O 6-Octenenitrile CH3 CH= CH ( CH2 ) CH2 N H2 6-Octen-1-amine Reduction to Aldehyde • Difficult to stop reduction at aldehyde • Use a more reactive form of the acid (an acid chloride) and a weaker reducing agent, lithium aluminum tri(t-butoxy)hydride O O CCl LiAl[OC(CH3)3]3H C H => Interconversions Problem: Show reagents and experimental conditions to bring about each reaction O Ph Cl (a) O Ph OH Ph enylacetic acid (d ) (c) (b ) O O Ph (e) Ph OMe (g) (f) Ph OH NH2 (h ) Ph NH2