chapter 21 carboxylic acid derivativesfaculty.sdmiramar.edu/choeger/chap 21 carbox acids derivs...4...

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Chapter 21Carboxylic Acid Derivatives

Chapter 21 Carboxylic Acids Derivs Slide 21-2

Acid Derivatives

• All can be converted to the carboxylic acid by acidic or basichydrolysis.

• Esters and amides common in nature.

2


Naming Esters

• Esters are named as alkyl carboxylates.• Alkyl from the alcohol, carboxylate from the carboxylic acid

precursor.

CH3CH2 OH HO C

O

CH3

H+

+ + H2OCH3CH2 O C

O

CH3

ethanol

ethyl alcohol

ethanoic acid

acetic acid

ethyl ethanoate

ethyl acetate

=>


Cyclic Esters: Lactones

• Reaction of -OH and -COOH on same molecule produces acyclic ester, lactone.

• To name, add word lactone to the IUPAC acid name orreplace the -ic acid of common name with -olactone.

O

O

H3C

CH3

4-hydroxy-2-methylpentanoic acid lactoneα-methyl-γ-valerolactone

=>

3


Amides

• Product of the reaction of a carboxylic acid and ammoniaor an amine.

• Not basic because the lone pair on nitrogen is delocalizedby resonance.

• Good water solubility

H

C

O

N

H

H

H

C

O

N

H

H

_

+

Bond angles around Nare close to 120°. =>


Classes of Amides

• 1° amide has one C-N bond (two N-H).• 2° amide or N-substituted amide has two C-N bonds (one

N-H).• 3° amide or N,N-disubstituted amide has three C-N bonds

(no N-H).

4


Naming Amides

• For 1° amide, drop -ic or -oic acid from the carboxylic acidname, add -amide.

• For 2° and 3° amides, the alkyl groups bonded to nitrogen arenamed with N- to indicate their position.

CH3CHC N

O

CH2CH3

CH3

CH3

N-ethyl-N,2-dimethylpropanamideN-ethyl-N-methylisobutyramide

=>


Cyclic Amides: Lactams

• Reaction of -NH2 and -COOH on same molecule produces acyclic amide, lactam.

• To name, add word lactam to the IUPAC acid name or replacethe -ic acid of common name with -olactam.

N

O

CH3

H4-aminopentanoic acid lactam

γ-valerolactam

=>

5


Nitriles

• -C≡N can be hydrolyzed to carboxylic acid, so nitriles areacid derivatives.

• Nitrogen is sp hybridized, lone pair tightly held, so not verybasic (pKb about 24).

=>


Naming Nitriles

• For IUPAC names, add -nitrile to the alkane name.• Common names come from the carboxylic acid. Replace -ic

acid with -onitrile.

CH3CHCH2CH2CH2CN

Br

5-bromohexanenitrile∂-bromocapronitrile

C N

Cyclohexanecarbonitrile =>

6


Acid Halides

• More reactive than acids; the halogen withdraws e- density fromcarbonyl.

• Named by replacing -ic acid with -yl halide.

C

O

Cl CH3CHCH2C

Br O

Br

benzoyl chloride3-bromobutanoyl bromideβ-bromobutyryl bromide =>


Acid Anhydrides

• Two molecules of acid combine with the loss of water to formthe anhydride.

• Anhydrides are more reactive than acids, but less reactivethan acid chlorides.

• A carboxylate ion is the leaving group in nucleophilic acylsubstitution reactions.

• Symmetric vs. Asymmetric anhydrides

R C

O

O H RC

O

OH R C

O

O C

O

R

=>

7


Naming Anhydrides

• The word acid is replaced with anhydride.• For a mixed anhydride, name both acids.• Diacids may form anhydrides if a 5- or 6-membered ring is

the product.

CH3 C

O

O C

O

CH3

ethanoic anhydrideacetic anhydride

O

O

O

1,2-benzenedicarboxylic anhydridephthalic anhydride =>


Multifunctional Compounds

• The functional group with the highest priority determines theparent name.

• Acid > ester > amide > nitrile > aldehyde > ketone > alcohol >amine > alkene > alkyne.

C

CN

O

OCH2CH3ethyl o-cyanobenzoate

=>

8


Boiling Points

Even 3° amides have strongattractions.

=>


Melting Points

• Amides have very high melting points.• Melting points increase with increasing number of N-H bonds.

m.p. -61°C m.p. 28°C m.p. 79°C

=>

9


Solubility

• Acid chlorides and anhydrides are too reactive to be used withwater or alcohol.

• Esters, 3° amides, and nitriles are good polar aprotic solvents.• Solvents commonly used in organic reactions:

Ethyl acetateDimethylformamide (DMF)Acetonitrile


IR Spectroscopy

=>

10


1H NMR Spectroscopy

=>


13C NMR Spectroscopy

=>

11


Interconversion of Acid Derivatives

• Nucleophile adds to the carbonyl to form a tetrahedralintermediate. (Nothing new!)

• Leaving group leaves and C=O regenerates. (Nucleophilicaddition-elimination reaction)


Reactivity

Reactivity decreases as leaving group becomes more basic.

=>

12


Interconversion of Derivatives

More reactive derivatives canbe converted to lessreactive derivatives.


Acid Chloride to Anhydride

• Acid or carboxylate ion attacks the C=O.• Tetrahedral intermediate forms.• Chloride ion leaves, C=O is restored, H+ is abstracted.

+ HClC

O

R OC

O

R'

_

C

O

R Cl

OH C

OR'

C

O

R ClR' C

O

O H

+

- H+

13


Acid Chloride to Ester

• Alcohol attacks the C=O.• Tetrahedral intermediate forms.• Chloride ion leaves, C=O is restored, H+ is abstracted.

+ HClC

O

R OR'

_

C

O

R Cl

OH R'

C

O

R Cl+

- H+

R' O H


Acid Chloride to Amide

• Ammonia yields a 1° amide• A 1° amine yields a 2° amide• A 2° amine yields a 3° amide

=>

14


Anhydride to Ester

• Alcohol attacks one C=O of anhydride.• Tetrahedral intermediate forms.• Carboxylate ion leaves, C=O is restored, H+ is abstracted.• See a theme here????


Anhydride to Amide

• Ammonia yields a 1° amide• A 1° amine yields a 2° amide• A 2° amine yields a 3° amide

=>

15


Ester to Amide

• Nucleophile must be NH3 or 1° amine.• Prolonged heating required.• More reactive esters will do this better!


Leaving Groups

A strong base is not usually a leaving group unless it’s in anexothermic step (reason RO- leaves)

=>

16


Transesterification

• One alkoxy group can be replaced by another with acid or basecatalyst.

• Use large excess of preferred alcohol.• Later: reason that reactions done on esters using alkoxide

bases are done as they are.


Hydrolysis of Acid Chlorides and Anhydrides

• Hydrolysis occurs quickly, even in moist air with no acid or basecatalyst.

• Reagents must be protected from moisture.• Best: make, then use immediately

17


Acid Hydrolysis of Esters

• Reverse of Fischer esterification (previously discussed).• Reaches equilibrium (remember: esterification is an

equilibrium process!)• Use a large excess of water to drive reaction (LeChat!).

+CH3 C

O

OCH3 HOH CH3 C

O

OH + CH3OH

H+


Saponification

• Base-catalyzed hydrolysis of ester.• “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 - asoap.

• Products (before neutralization) are alcohol andcarboxylate salt

• One example of a soap is sodium stearate,Na+ -OOC(CH2)16CH3.

18


Hydrolysis of Amides

Due to their increased stability, prolonged heating in 6 M HCl or40% aqueous NaOH is required.

=>


Hydrolysis of Nitriles

• Under mild conditions, nitriles hydrolyze to an amide.• Heating with aqueous acid or base will hydrolyze a nitrile

to an acid.

=>

19


Reduction to Alcohols

Lithium aluminum hydride reduces acids, acid chlorides, andesters to primary alcohols.

=>


Reduction to Aldehydes

Acid chlorides will react with a weaker reducing agent to yield analdehyde.

=>

20


Reduction to Amines

• Lithium aluminum hydride reduces amides and nitriles toamines.

• Nitriles and 1° amides reduce to 1° amines.• A 2° amide reduces to a 2° amine.• A 3° amide reduces to a 3° amine.

=>


Organometallic Reagents

Grignard reagents and organolithium reagents add twice to acidchlorides and esters to give alcohols after protonation(previously discussed).

=>

21


Grignard Reagents and Nitriles

A Grignard reagent or organolithium reagent attacks the cyanogroup to yield an imine which is hydrolyzed to a ketone.

=>


Acid Chloride Synthesis

• Previously discussed.• Use thionyl chloride, SOCl2, or oxalyl chloride, (COCl)2.• Other products are gases.• Make in situ and use immediately

=>

22


Acid Chloride Reactions (1)

acid

ester

amide

acid anhydride =>


Acid Chloride Reactions (2)

3° alcohol

ketone

1° alcohol

aldehyde

acylbenzene =>

AlCl3

23


Industrial Synthesis of Acetic Anhydride

• Four billion pounds/year produced.• Use high heat (750°C) and triethyl phosphate catalyst to

produce ketene.

CH3 C

O

OH(EtO)3P O

heat

CH

HC O

CH

HC O + CH3 C

O

OH CH3 C

O

O C

O

CH3

=>


Lab Synthesis of Anhydrides

• React acid chloride with carboxylic acid or carboxylate ion.

C

O

Cl+ CH3 C

O

O_ C

O

O C

O

CH3

• Heat dicarboxylic acids to form cyclic anhydrides.

C

O

OH

C

O

OH

O

O

O =>

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Anhydride Reactions

acid

ester

amide

=>acylbenzene

AlCl3


Anhydride vs. Acid Chloride

• Acetic anhydride is cheaper, gives a better yield than acetylchloride (reactivity and conditions issues).

• Use acetic formic anhydride to produce formate esters andformamides.

• Use cyclic anhydrides to produce a difunctional molecule.

C

O

OCH2CH3

C

O

OH

O

O

O

CH3CH2OH =>

25


Synthesis of Esters

R C

O

OR'R C

O

OH + R'OHH

+

+ HOH

acid

R C

O

OR'R C

O

Cl + R'OH + HCl

acid chloride

R C

O

OR'R C

O

O C

O

R + R'OH

H+

+ RCOOH

acid anhydride

R C

O

OH CH2N2+ R C

O

OCH3 N2+

methyl ester =>


Reactions of Esters

acid

ester

amide

1° alcohol

3° alcohol=>

26


Lactones

• Formation favored for five- and six-membered rings.

O

OCOOH

OH H+

H2O+

• For larger rings, remove water to shift equilibrium towardproducts

H+

H2O+

O

O

OH

COOH

=>


Polyesters

• Dacron® thread• Mylar® tape

• Glyptal resin• PET bottles

=>

27


Synthesis of Amides

R C

O

OH + HOH+ R'NH2

heatR C

O

NHR'

acid

R C

O

O C

O

R + RCOOHR'2NH R C

O

NR'2+

acid anhydride

R C

O

OR'' + R''OHR'NH2 R C

O

NHR'+

ester

R C

O

NH2R C N + H2O

H+ or OH

-

nitrile =>

acid chlorideR'2NH2

+Cl

-+R C

O

NR'2R'2NH+ 2R C

O

Cl


Reactions of Amides

acid and amine

amine

1° amine

=>

nitrile

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Lactam Formation

• Five- and six-membered rings can be formed by heating γ-and δ-amino acids.

• Smaller or larger rings do not form readily.


β-Lactams

• Highly reactive, 4-membered ring.• Found in antibiotics isolated from fungi.

Amide → ester !!

=>

29


Synthesis of Nitriles

R C

O

NH2 R C NPOCl3

1° amide

R C N +R XNaCN

Na+X-

alkyl halide

+Ar N N+ CuCN

Ar CN N2diazonium salt

R C

O

R'HCN

KCNR C R'

HO CN

aldehyde or ketone

cyanohydrin =>


Reactions of Nitriles

ketone

=>

amide acid

1° amine

30


Thioesters

More reactive than esters because: -S-R is a better leaving group than -O-RResonance overlap is not as effective.

=>


Carbonic Acid Esters

• CO2 in water contains some H2CO3.• Diesters are stable.• Synthesized from phosgene.

+C

O

ClCl CH3CH2OCOCH2CH3

O

2 CH3CH2OH

diethyl carbonate

=>

phosgene

31


Urea and Urethanes

• Urea is the diamide of carbonic acid.• Urethanes are esters of a monoamide of carbonic acid.

+C

O

ClCl C

O

NH2H2N2 NH3urea

N C O

H2O

NH C OH

O

a carbamic acid

ROHNH C OR

O

a urethane =>


Polycarbonates

Long-chain esters of carbonic acid

=>

32


Polyurethanes

A diol reacts with a diisocyanate.

=>


End of Chapter 21

Homework: 48-50, 54, 57, 59, 60, 64, 65

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Name These

CH3CHCH2OCCH3

CH3 O

HCOCH2

O

isobutyl acetate2-methylpropyl ethanoate

benzyl formatebenzyl methanoate

=>


Polyamides

Nylon 6.6

=>

chapter 21 carboxylic acid derivativesfaculty.sdmiramar.edu/choeger/chap 21 carbox acids derivs...4...

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