Derivatives of Carboxylic Acids Lecture 18

Lecture 18 Derivatives of Carboxylic Acids

March 24, 2016 Chemistry 328N Important Information  Midterm Exam II – Wed March 30th – 7:00-9:00 PM – Room WEL 3.502 – Review Sessions:  Mon & Tue - 5-6 PM  room TBA – Know the reactions (cards) – Review your homework and the old exams – Practice synthesis problems – Know the acetal mechanism – Exam covers material through Thursday’s lecture – Do a good job…please get an A!! Chemistry 328N Practice

O O

Chemistry 328N Nucleophilic Acyl Substitution with an anion as nucleophile

•• - • • • O • •• •• • R • O • Y- O • - C X + X C C R X R Y Y

This is a very IMPORTANT general reaction.

Chemistry 328N Reactions of Acyl Chlorides O

RCCl O O

RCOCR' O RCOR' O

RCNR'2 O RCO– Chemistry 328N Chemistry 328N Reactions of Acyl Chlorides

Acyl chlorides react with carboxylic acids to give acid anhydrides:

O O O O

RCCl + R'COH RCOCR' + HCl H O O

via: R C OCR'

Cl Chemistry 328N Acid Anhydrides

 The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom – the anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups)  To name, replace acid of the parent acid by anhydride

O O O O O O

CH 3 COCCH 3 COC CH 3 COC- Acetic anhydride Benzoic anhydride Acetic benzoic anhydride

Chemistry 328N Reactions of Acyl Chlorides

Acyl chlorides react with alcohols to give esters:

O O

RCCl + R'OH RCOR' + HCl

Please review the nomenclature of esters

Chemistry 328N Reactions of Acyl Chlorides

Acyl chlorides react with water (or base) to give carboxylic acids (carboxylate ion in base): Hydrolysis

O O

RCCl + H2O RCOH + HCl

O O

– – – RCCl + 2HO RCO + Cl + H2O

Chemistry 328N Reactivity

 Acyl chlorides undergo nucleophilic acyl substitution much faster than the corresponding alkyl chlorides.

C6H5CCl C6H5CH2Cl Relative rates of 1,000 1 hydrolysis (25°C)

Chemistry 328N Reactions of Acyl Chlorides

Acyl chlorides react with ammonia and amines to give amides:

O O

+ – RCCl R'2NH RCNR'2 + Cl

via: R C NR'2

Cl Chemistry 328N Example

O O

CH3(CH2)5CCl + CH3(CH2)5COH

pyridine

O O

CH3(CH2)5COC(CH2)5CH3

Chemistry 328N Example of acyl chloride reaction with amines to make amides

O O NaOH C6H5CCl + HN C6H5CN H2O

Chemistry 328N Amides

 The functional group of an amide is an acyl group bonded to a nitrogen atom  IUPAC: drop -oic acid from the name of the parent acid and add -amide  If the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by N-

O O O

CH 3 CNH 2 CNH 2 CH 3 CNHCH 3 Acetamide Benzamide N-Methylacetamide (a 1° amide) (a 1° amide) (a 2° amide)

Chemistry 328N Amides

 Cyclic amides are called lactams  Name the parent carboxylic acid, drop the suffix -ic acid, and add -lactam

 O  2  O 3 1 2 1 3  4 NH  NH 5 6 H3 C   3-Butanolactam 6-Hexanolactam -Butyrolactam) -Caprolactam)

Chemistry 328N Reactions of Acid Anhydrides

 Acid anhydrides react with alcohols to give one mol of ester and one of carboxylic acid

O CH O 3 CH 3 COCHCH 2 CH 3 + O HOCHCH 2 CH 3 COH O O Phthalic 2-Butanol sec-Butyl hydrogen anhydride (sec-Butyl alcohol) phthalate

Chemistry 328N Reactions of Esters • Esters react with ammonia and amines to give amides:

O O + RCOR R'2NH RCNR'2 + ROH

H O

via: R C NR'2

OR Chemistry 328N Reaction of Esters with Grignard Reagents

O O H O + 2 - + RCOCH 3 NaOH RCO Na + CH 3 OH

Chemistry 328N Reaction of Esters with OH -

 Saponification

O O H O + 2 - + RCOCH 3 NaOH RCO Na + CH 3 OH

Chemistry 328N Saponification of Esters

 Hydrolysis of an esters is aqueous base is called saponification  Each mol of ester hydrolyzed requires 1 mol of base; for this reason, ester hydrolysis in aqueous base is said to be “base-promoted” (not catalyzed)

O O H O + 2 - + RCOCH 3 NaOH RCO Na + CH 3 OH

 Hydrolysis of an ester in aqueous base involves Nucleophilic acyl substitution

Chemistry 328N Saponification of Fat

O CH2 OH O O CH2 O C R NaOH R C O C H H C OH C - + R O Na CH OH CH2 O C R 2 O Fat glycerol Fatty Acid Salt "Soap"

R = CH3(CH2)16COOH Stearic Acid CH3(CH2)7CH CH(CH2)7COOH Oleic acid etc.

Chemistry 328N Physical Properties

 Water solubility decreases as the relative size of the hydrophobic portion of the molecule increases hydrophilic region; increases water solubility

hydrophobic region; decreases water solubility

Chemistry 328N Soaps and Detergents

Surface Active Agents = surfactants

- + CH3(CH2)16 COO N a Soap

O + CH3(CH2)11 S O'Na Anionic detergent O

CH3 Cl Cationic Detergent CH2 N (CH2)15CH3 CH3

Chemistry 328N Chemistry 328N Chemistry 328N Hydrolysis of Amides

Hydrolysis of amides is also irreversible. In acid solution the amine product is protonated to give an ammonium salt.

O O + + RCNHR' + H2O + H RCOH + R'NH3

Chemistry 328N Hydrolysis of Amides

• In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. • This makes the reaction irreversible!

O O – – RCNHR' + HO RCO + R'NH2

Chemistry 328N Hydrolysis of Amides in Acid

 Hydrolysis of amides in aqueous acid requires 1 mol of acid per mol of amide

O H2 O CH CH CHCNH + H O + HCl 3 2 2 2 heat Ph 2-Phenylbutanamide O + - CH 3 CH 2 CHCOH + NH 4 Cl Ph 2-Phenylbutanoic acid

Chemistry 328N Hydrolysis of Amides in Acid

 Acid-catalyzed hydrolysis of an amide is divided into three steps Step 1: protonation of the carbonyl oxygen

•• •• O + + •• •• •• •• •• OH OH R C NH + H O H + 2 •• •• •• R C NH R C NH + H O H 2 2 2 Resonance-stabilized cation

Chemistry 328N Hydrolysis of Amides in Acid

Step 2: addition of H2O to the carbonyl

carbon followed by proton transfer

•• •• •• •• •• •• OH OH proton transfer OH + •• •• •• from O to N + R C NH2 + O H R C NH2 R C NH3

+ •• H O OH H •• H •• Tetrahedral carbonyl addition intermediate

Chemistry 328N Hydrolysis of Amides in Acid

Step 3: collapse of the intermediate coupled with proton transfer to give the carboxylic acid and ammonium ion

+ OH O H O + R C NH + 3 R C NH3 + + R C OH NH4 OH OH

Chemistry 328N Hydrolysis of Amides in Base

 Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide

O O H2 O - + CH3 CNH + NaOH + H N heat CH3 CO Na 2 N-Phenylethanamide Sodium acetate Aniline

Chemistry 328N Hydrolysis of Amides in Base

 Hydrolysis of an amide in aqueous base is divided into three steps Step 1: addition of hydroxide ion to the carbonyl carbon

- O O - R C NH 2 + OH R C NH 2 OH Tetrahedral carbonyl addition intermediate

Chemistry 328N Hydrolysis of Amides in Base

Step 2: collapse of the intermediate to form a carboxylic acid and ammonia

•• •• •• •• •• - O O

•• •• •• - •• •• R C NH + H O H R C + NH + OH 2 •• 3 ••

•• •• OH OH •• •• Tetrahedral carbonyl addition intermediate A very rare event… Why???

Chemistry 328N Hydrolysis of Amides in Base

Step 3: proton transfer to form the carboxylate anion and water. Hydrolysis is driven to completion by this acid-base reaction

••

•• •• •• O O

•• •• -•• •• •• - •• R C O H + O-H R C O + H O H •• •• •• ••

Chemistry 328N Chemistry of Nitriles

 Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and both contain a  bond  Both both are electrophiles

Nitrile Carboxylic Acid

Chemistry 328N Naming Nitriles Name the parent alkane (include the carbon atom of the nitrile as part of the parent) followed with the word -nitrile. The carbon in the nitrile is given the #1 location position. It is not necessary to include the location number in the name because it is assumed that the functional group will be on the end of the parent chain.

Cycloalkanes are followed by the word -carbonitrile.

Cyclopropane carbonitrile Chemistry 328N Preparation of Nitriles

 Sandmeyer rection of diazonium salts  Sn2 reactions with Cyanide anion  Cyanohydrin formation  Dehydration of Amides  There are many more….

Chemistry 328N Preparation of Nitriles by Dehydration

 Reaction of primary amides RCONH2 with SOCl2 (or other dehydrating agents)

 Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with NaCN)

Chemistry 328N Mechanism of Dehydration of Amides

 Nucleophilic amide oxygen atom attacks SOCl2 followed by deprotonation and elimination

Chemistry 328N Addition of HCN to Carbonyls

 Mechanism of cyanohydrin formation

CH3 CH3 CH3

CH2 CH2 CH2 CH CH CH2 2 + 2 - - H3O +2 N C C O N C C O N C C OH + Mg THF dil. CH3 CH3 CH3

Chemistry 328N Cyanohydrins

 The value of cyanohydrins is for the new functional groups into which they can be converted – acid-catalyzed dehydration of the 2° alcohol gives a valuable monomer

OH acid catalyst CH 3 CHC N CH 2 =CHC N + H2 O 2-Hydroxypropanenitrile Propenenitrile (Acetaldehyde cyanohydrin) (Acrylonitrile)

Chemistry 328N Cyanohydrins – acid-catalyzed hydrolysis of the cyano group gives an -hydroxycarboxylic acid

OH acid HO O catalyst CHC N + H2 O CHCOH

Benzaldehyde cyanohydrin 2-Hydroxy-2-phenyl- (Mandelonitrile) ethanoic acid (Mandelic acid)

Chemistry 328N Cyanohydrins – catalytic reduction of the carbon-nitrogen triple bond converts the cyano group to a 1° amine

OH OH Ni CHC N + 2 H2 CHCH 2 NH 2

Benzaldehyde cyanohydrin 2-Amino-1-phenylethanol

LiAlH4 also works well...

But…what about Pd/C and H2

Chemistry 328N Hydrolysis: Conversion of Nitriles into Carboxylic Acids  Hydrolyzed in with acid or base gives a carboxylic acid and ammonia

Chemistry 328N Reaction of Nitriles with Organometallic Reagents

 Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone

Chemistry 328N Reduction: Conversion of Nitriles into Amines

– Reduction of a nitrile with LiAlH4 gives a primary amine

Chemistry 328N