15-1 Chemistry 2060, Spring 2060, LSU Chapter 15: Functional Derivatives of Carboxylic Acids Sections 15.1-15.9.

15-1Chemistry 2060, Spring 2060, LSU

Chapter 15:Chapter 15:Functional Derivatives of Carboxylic Functional Derivatives of Carboxylic Acids Acids

Sections 15.1-15.9


SectionsSectionsChapter 15: Aldehydes and KetonesChapter 15: Aldehydes and Ketones

1.1. IntroductionIntroduction2.2. Structure and nomenclatureStructure and nomenclature3.3. Characteristic propertiesCharacteristic properties4.4. Reaction with water: hydrolysisReaction with water: hydrolysis5.5. Reaction with alcoholsReaction with alcohols6.6. Reactions with ammonia and aminesReactions with ammonia and amines7.7. Interconversion of functional derivativesInterconversion of functional derivatives8.8. Esters with Grignard reagentsEsters with Grignard reagents9.9. ReductionReduction


Carboxyl DerivativesCarboxyl DerivativesIn this chapter, we study four classes of organic In this chapter, we study four classes of organic

compoundscompounds• under the general formula of each is a drawing to help

you see how it is related to the carboxyl group

H-NH2H-Cl H-OR'RC-OHO

RC-OHO

H-OCR'O

RC-OHO

RC-OHO

-H2O -H2O -H2O -H2O

RCNH2

ORCClO

RCOR'O

RCOCR'O O

An acid chloride An esterAn acid anhydride An amide


Acid ChloridesAcid ChloridesThe functional group of an acid halide is an acyl The functional group of an acid halide is an acyl

group bonded to a halogengroup bonded to a halogen• the most widely used are the acid chlorides• to name, change the suffix --ic acid ic acid to --yl chlorideyl chloride

CH3CCl

OCCl

O

Benzoyl chlorideEthanoyl chloride(Acetyl chloride)


Acid AnhydridesAcid AnhydridesThe functional group of an acid anhydride is two The functional group of an acid anhydride is two

acyl groups bonded to an oxygen atomacyl groups bonded to an oxygen atom• the anhydride may be symmetrical (two identical acyl

groups) or mixed (two different acyl groups)• to name, replace acidacid of the parent acid by anhydrideanhydride

Acetic benzoic anhydride

Benzoic anhydrideAcetic anhydride

COCCH3COCCH3CH3COC

OOOO OO


Acid AnhydridesAcid AnhydridesA phosphoric acid anhydride contains two A phosphoric acid anhydride contains two

phosphoryl groups bonded to an oxygen atomphosphoryl groups bonded to an oxygen atom• shown here are two phosphoric anhydrides• each is shown on the right as it would be ionized at pH

7.4, the pH of blood

HO-P-O-P-OH

OH

O

OH

O-O-P-O-P-O

-

O-

O

O-

O

HO-P-O-P-O-P-OH

OH

O

OH

O

OH

O-O-P-O-P-O-P-O

-

O-

O

O-

O

O-

O

Triphosphoric acid

Diphosphate ion(Pyrophosphate ion)

Diphosphoric acid(Pyrophosphoric acid)

Triphosphate ion


EstersEstersThe functional group of an ester is an acyl group The functional group of an ester is an acyl group

bonded to -OR or -OArbonded 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-ic acid to -ate-ate

CH3COCH2CH3

OO

O

OO

Diethyl butanedioate(Diethyl succinate)

Ethyl Ethanoate(Ethyl acetate)


LactonesLactonesLactone:Lactone: a cyclic ester a cyclic ester

• IUPAC: name the parent carboxylic acid, drop the suffix -ic acid-ic acid, and add -olactone-olactone

• the location of the oxygen atom on the carbon chain is the location of the oxygen atom on the carbon chain is commonly indicated by a Greek lettercommonly indicated by a Greek letter

O

O

4-Butanolactone(A -lactone)

123 4


Phosphoric estersPhosphoric estersPhosphoric acid forms mono-, di-, and triestersPhosphoric acid forms mono-, di-, and triesters

• name by giving the name of the alkyl or aryl group(s) bonded to oxygen followed by the word phosphate

• in more complex phosphate esters, it is common to name the organic molecule followed by phosphate

CH3O-P-OH

O

OCH3CH2-O-P-O-

OHHOHHHHOOHH

CHO

O-

ON

HO

H3C

CH2O-P-O-CHO

O-

O

Dimethylphosphate

D-Glucose 6-phosphate

Pyridoxal phosphate


AmidesAmidesThe functional group of an amide is an acyl group The functional group of an amide is an acyl group

bonded to a trivalent nitrogenbonded to a trivalent nitrogen• IUPAC: drop -ic acidic acid from the name of the parent acid

and add -amide-amide• if the amide nitrogen is bonded to an alkyl or aryl

group, name the group and show its location on nitrogen by NN--

CH3CNH2

OCH3C-N

H

CH3

OH-C-N

CH3

CH3

O

N-Methylacetamide(a 2° amide)

Acetamide(a 1° amide)

N,N-Dimethyl-formamide (DMF)

(a 3° amide)


LactamLactamLactam:Lactam: a cyclic amide a cyclic amide

• name the parent carboxylic acid, drop the suffix -ic -ic acidacid and add -lactam-lactam

• the location of the nitrogen atom in the ring is commonly indicated by a Greek letter, , , etc.

• 6-hexanolactam is an intermediate in the synthesis of nylon 6 (Section 17.5A)

H3C

O

NH

O

NH

6-HexanolactamAn -lactone)

12 1

234

5 63

3-ButanolactamA-lactam)


The PenicillinsThe PenicillinsThe penicillins are a family of The penicillins are a family of -lactam antibiotics-lactam antibiotics

• one of the first discovered was penicillin G

N

S CH3

CH3

COOHO

NC

H

O

CH2

Penicillin G

H H

the penicillins differin the group bondedto the acyl carbon


The PenicillinsThe Penicillins• amoxicillin, a -lactam antibiotic

N

S

COOHO

HN

O

NH2

HH

HO


CephalosporinsCephalosporinsThe cephalosporins are also The cephalosporins are also -lactam antibiotics-lactam antibiotics

N

S

COOHO CH3

NH

NH2

OH H

Keflex(a -lactam antibiotic)

The cephalosporinsdiffer in the groupbonded to the carbonylcarbon...

...and the group bonded to this carbon of the six-membered ring


Characteristic ReactionsCharacteristic ReactionsNucleophilic acyl substitution:Nucleophilic acyl substitution: an addition-an addition-

elimination sequence resulting in substitution of elimination sequence resulting in substitution of one nucleophile for anotherone nucleophile for another• the reaction depends on having a suitable leaving

group bonded to the acyl carbon, here indicated Lv

Tetrahedral carbonyladdition intermediate

-

-

- ++ CNuR

CLv R

CNuR

O

Lv

O O

Nu Lv

Substitution product


Characteristic ReactionsCharacteristic Reactions• in the general reaction, we showed the nucleophile as

an anion; this need not be the case• neutral molecules such as water, alcohols, ammonia,

and amines can also serve as nucleophiles• in the general reaction, we showed the leaving group

as an anion to illustrate an important point about them: the weaker the base, the better the leaving group

NR2 OR OCR

O

X

Increasing basicity

Increasing leaving ability


Characteristic ReactionsCharacteristic Reactions• halide ion is the weakest base and the best leaving

group; acid halides are the most reactive toward nucleophilic acyl substitution

• amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution

RC-NH2

O

RC-OR'O

RC-OCRO O

RC-XO

Increasing reactivity toward nucleophilic acyl substitution

Amide Ester Anhydride Acid halide


Hydrolysis - Acid ChloridesHydrolysis - Acid Chlorides• low-molecular-weight acid chlorides react rapidly with

water • higher molecular-weight acid chlorides are less soluble

in water and react less readily

CH3CCl

O

H2O CH3COH

O

HCl++


Hydrolysis - Acid AnhydridesHydrolysis - Acid Anhydrides• low-molecular-weight acid anhydrides react readily

with water to give two molecules of carboxylic acid• higher-molecular-weight acid anhydrides also react

with water, but less readily

CH3COCCH3

O OH2O CH3COH

O O

HOCCH3++


Hydrolysis - EstersHydrolysis - EstersEsters are hydrolyzed only slowly, even in boiling Esters are hydrolyzed only slowly, even in boiling

waterwater

Hydrolysis becomes more rapid if they are heated Hydrolysis becomes more rapid if they are heated with either aqueous acid or aqueous basewith either aqueous acid or aqueous base

Hydrolysis in aqueous acid is the reverse of Fischer Hydrolysis in aqueous acid is the reverse of Fischer esterificationesterification

CR OCH3

O

H2OH+

CR

H3COOH

OHH+

CR OH

O

CH3OH+ +

Tetrahedral carbonyladdition intermediate


Hydrolysis - EstersHydrolysis - EstersHydrolysis of an ester in aqueous base is often Hydrolysis of an ester in aqueous base is often

called saponificationcalled saponification• each mole of ester hydrolyzed requires 1 mole of base;

for this reason, ester hydrolysis in aqueous base is said to be base promoted

• base-promoted ester hydrolysis involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse

O

RCOCH3 NaOHH2O

O

RCO- Na

+ CH3OH++


Hydrolysis - EstersHydrolysis - Esters• step 1: addition of hydroxide ion to the carbonyl

carbon

• step 2: collapse of the addition intermediate

• step 3: proton transfer completes the reaction

R-C

OH

O

OCH3 R-C OH

O

OCH3+

R-C-OCH3

OOH R-C

OH

OOCH3

+

R-C OO

H OCH3 R-C OO

H-OCH3+ +


Hydrolysis - EstersHydrolysis - EstersThere are two major differences between acid-There are two major differences between acid-

catalyzed and base-promoted ester hydrolysiscatalyzed and base-promoted ester hydrolysis1. for acid-catalyzed hydrolysis, acid is required in only

catalytic amounts; for base-promoted hydrolysis, base is required in equimolar amounts

2. hydrolysis of an ester in aqueous acid is reversible; base-promoted hydrolysis is irreversible


Hydrolysis - AmidesHydrolysis - AmidesHydrolysis of an amide requires much more Hydrolysis of an amide requires much more

vigorous conditions than hydrolysis of an estervigorous conditions than hydrolysis of an ester• hydrolysis in aqueous acid requires 1 mole of acid for

each mole of amide• the products are a carboxylic acid and an ammonium

or an amine salt

PhNH2

O

H2O HClH2O

PhOH

O

NH4+Cl

-

2-Phenylbutanoic acid2-Phenylbutanamide

++ +heat


Hydrolysis - AmidesHydrolysis - Amides• hydrolysis of an amide in aqueous base requires 1

mole of base per mole of amide• the products are a carboxylate salt and an amine

OCH3CNH NaOH

H2OCH3CO

- Na

+O

H2N

AnilineSodium acetateN-Phenylethanamide(N-Phenylacetamide, Acetanilide)

++heat


HydrolysisHydrolysisA summaryA summary

R-C-OR'O

R-C-O-C-RO O

R-C-ClO

H2O

H2O

NaOH

H2O H2SO4

R-C-NH2

OH2O

NaOH

HCl

R-C-OHO

R-C-OHO

R-C-OHO

R-C-OHO

R-C-O-Na+O

R-C-O-Na+O

HCl

R'OH

HO-C-RO

NH4+Cl-

NH3

R'OH

+ +

+ +

++

+

++

+


Reaction with AlcoholsReaction with AlcoholsAcid chlorides react with alcohols to give an ester Acid chlorides react with alcohols to give an ester

and HCland HCl

Butanoyl chloride

Cyclohexyl butanoate

+

Cyclohexanol

HO

HCl

Cl

O

+

O

O


Reaction with AlcoholsReaction with AlcoholsAcid anhydrides react with alcohols to give 1 mole Acid anhydrides react with alcohols to give 1 mole

of ester and 1 mole of carboxylic acidof ester and 1 mole of carboxylic acid

• aspirin is prepared by the following reaction:

O

CH3COCCH3

O

HOCH2CH3

O

CH3COCH2CH3 CH3COH

O

Acetic acidEthyl acetateEthanolAcetic anhydride++

OHCOOH

OO

CH3COCCH3

COOHO

OCH3COOH

Acetylsalicylicacid

(Aspirin)

2-Hydroxybenzoic acid

(Salicylic acid)

++

Acetic acid

Acetic anhydride


Reaction with AlcoholsReaction with AlcoholsEsters undergo an exchange reaction called Esters undergo an exchange reaction called

transesterificationtransesterification• the exchange is acid catalyzed• the original -OR group is exchanged for a new -OR

group

Ph OCH3

OHO

OHH2SO4

Ph O

OO Ph

O

2CH3OH+ +

1,2-Ethanediol(Ethylene glycol)

A diester of ethylene glycol)

Methylbenzoate


Reaction with AlcoholsReaction with AlcoholsAmides to not react with alcohols under any Amides to not react with alcohols under any

conditionsconditions

Summary of reactions with alcoholsSummary of reactions with alcohols

R-C-OR'O

R-C-O-C-RO O

R-C-ClO

R"OH

R"OH

HOR"

H2SO4

R-C-NH2

OR"OH

R-C-OR"O

R-C-OR"O

R-C-OR"O

HCl

R'OH

HO-C-RO

+ +

+ +

+ +

+ No Reaction


Reaction with NHReaction with NH33 and Amines and Amines

Acid halides react with ammonia, 1° amines, and 2° Acid halides react with ammonia, 1° amines, and 2° amines to form amidesamines to form amides• 2 moles of the amine are required per mole of acid

chloride; one to form the amide and one to neutralize the HCl formed

O

Cl 2NH3 NH2

O

NH4+Cl

-+ +

Hexanoylchloride

Ammonia Hexanamide Ammoniumchloride



Acid anhydrides react with ammonia, and with 1° Acid anhydrides react with ammonia, and with 1° and 2° amines to form amidesand 2° amines to form amides• 2 moles of ammonia or amine are required; one to form

the amide and one to neutralize the carboxylic acid byproduct

• here the reaction is broken into two steps

CH3COCCH3

O ONH3

CH3COHO

NH3

CH3COCCH3

O O2NH3

CH3CNH2

O

CH3CNH2

O

CH3CO-NH4+

OCH3COH

O

CH3CO-NH4+

O

+ +

+

+ +



Esters react with ammonia, and with 1° and 2° Esters react with ammonia, and with 1° and 2° amines to form amidesamines to form amides• esters are less reactive than either acid halides or acid

anhydrides

Amides do not react with ammonia, or with 1° or 2° Amides do not react with ammonia, or with 1° or 2° aminesamines

PhenylacetamideEthyl phenylacetate

+ +NH3Ph

O

O

PhNH2

O

HO

Ethanol


Reaction with NHReaction with NH33 & Amines & Amines

SummarySummary

R-C-ClO

2NH3

R-C-O-C-RO O

2NH3

R-C-OR'O

NH3

R-C-NH2

O

R-C-NH2

O

R-C-NH2

O

R-C-NH2

O

R'OH

NH4+Cl-

R-C-O-NH4+

O

+ +

+ +

+ +

No reaction with ammonia or amines


Interconversion Interconversion interconversion of functional groups interconversion of functional groups


Esters with Grignard ReagentsEsters with Grignard Reagents

a formic ester with 2 moles of Grignard reagent a formic ester with 2 moles of Grignard reagent followed by hydrolysis gives a 2° alcoholfollowed by hydrolysis gives a 2° alcohol

reaction of an ester other than a formate gives a 3° reaction of an ester other than a formate gives a 3° alcoholalcohol

O

HCOCH3 2RMgXH2O, HCl

R

HC-R

OH

CH3OH+magnesium alkoxide salt

A 2° alcohol An ester offormic acid

+

O

CH3COCH3 2RMgXH2O, HCl

CH3C-R

R

OH

CH3OHmagnesium alkoxide salt

+

A 3° alcohol An ester of any acidother than formic acid

+


Esters with Grignard ReagentsEsters with Grignard Reagents• Steps 1 and 2

• Steps 3 and 4

O

CH3-C-OCH3 R MgX

R

O

CH3-C OCH3

[MgX]+

CH3-C

R

O

CH3O - [ MgX]++

-

+

A magnesium salt A ketone1

1 2

2

CH3-C

R

O

MgXR CH3-C-R

R

O - [MgX]

+

H O H, HCl CH3-C-R

OH

RA ketone A 3° alcohol

3

+

3

Magnesium salt

4

4


ReductionReduction

• esters are reduced by LiAlH4 to two alcohols

• the alcohol derived from the carbonyl group is primary

• NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones

Methanol2-Phenyl-1-propanolMethyl 2-phenyl-

propanoate

+1. LiAlH4 , ether

2. H2O, HCl

CH3OHPhOCH3

O PhOH

OEt

O O NaBH4

EtOH OEt

OH O


ReductionReduction• LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine,

depending on the degree of substitution of the amide

NH2

O1. LiAlH42. H2O

1. LiAlH4

2. H2ONMe2

ONMe2

NH2

N,N-Dimethylbenzamide N,N-Dimethylbenzylamine

Octanamide 1-Octanamine


Some InterconversionsSome Interconversions• from Example 15.7

CH3OH, H2SO4

SOCl2

1. LiAlH4

2. H2O

PhOH

O

PhOH

PhOCH3

O

2. H2O1. LiAlH4

PhCl

O

CH3OH

NH3

PhNH2

NH3 (2 eq)

2. H2O

PhNH2

O

1. LiAlH4

Fischeresterification (a) (b)

(c)(d)

Phenylacetic acid

15-1 Chemistry 2060, Spring 2060, LSU Chapter 15: Functional Derivatives of Carboxylic Acids Sections 15.1-15.9.

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acid ic acidatechange

parent acid

lsu acid anhydrides

lsu acid chlorides

suffix ic acid

acid halide

phosphoric acid anhydride

parent carboxylic acid