Carboxyl Derivatives

8/11/2019 Carboxyl Derivatives

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An acid

chloride An ester

An acid

anhydride

OO

RCCl RCOR'RCOCR'

O

RC-OH H-Cl

O

RC- OH H- OCR'

O

RC- OH H- OR'

O

O O

An amide A nitrile

O

RC NRCNH2

O

RC- OH H- NH2 RC= N

HO H

The enol of

an amide



RC-

O

RCCl

O

CH3CCl

O

CCl

O

ClC(CH2 )4 CCl

OO

Benzoylchloride

Ethanoyl chloride(Acetyl chlorid e)

An acyl chloride

(An acid chlorid e)

An acyl

group

Hexanedioyl chloride (Adipoyl chloride)



replacement of -OH in a sulfonic acid by -Cl givesa sulfonyl chloride

SOHH3 C

O

O

CH3SOH

O

O

SClH3 C

O

O

CH3 SCl

O

O

Methanesulfonicacid

p-Toluenesulfonic acid

Methanesulfonyl chloride(Mesyl chloride, MsCl)

p-Toluenesulfonyl chloride (Tosyl chlorid e, TsCl)



The functional group of an acid anhydride is twoacyl 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 enzoicanhydride

Benzoic anhydrideAcetic anhydride

COCCH3 COCCH3 CH3 COC

OOOO OO



Cyclic anhydrides are named from thedicarboxylic acids from which they are derived

Maleic

anhydride

O

O

O!hthalic

anhydride"uccinic

anhydride

O

O

O

O

O

O



The functional group of an ester is an acylgroup bonded to -O or -O!r name the al"yl or aryl group bonded to oxygen

followed by the name of the acid

change the suffix -ic acid-ic acid to -ate-ate

Ethyl ethanoate(Ethyl acetate)

#iethyl utanedioate(#iethyl succinate)

O

O

O O

O

O

O

O

$sopropylenzoate



Cyclic esters are called lactones name the parent carboxylic acid, drop the suffix -ic-ic

acidacid, and add -olactone-olactone

%&Hexanolactone δ

&Caprolactone)

'&Butanolactone

γ

&Butyrolactone)

&Butanolactone

β

&Butyrolactone)

δ

β

α

γ

α

β

α

γ

O OO

O O O

H3 C CH3

23 1

2 2

1

3

1

3 4 4 5



The functional group of an amide is an acylgroup bonded to a nitrogen atom #$%!C& drop -oic acidoic acid from the name of the parent

acid and add -amide-amide

if the amide nitrogen is bonded to an al"yl or arylgroup, name the group and show its location onnitrogen by '-'-

&Methylacetamide(a *+ amide)

Acetamide(a + amide)

CH3 CNH2 CH3 CNHCH3 HCN(CH3 ) 2

,&#imethyl&formamide (#M-)

(a + amide)

O O O



Cyclic amides are called lactams

'ame the parent carboxylic acid, drop thesuffix -ic acid-ic acid and add -lactam-lactam

γ

δ

ε

.&Hexanolacta ε&Caprolactam

H3 C

O

NH

O

NH

12 1

23

45 6

3

&Butanolactam β&Butyrolactam)



The functional group of a nitrile is a cyanogroup

#$%!C& name as an al"anenitrileal"anenitrile

Common& drop the -ic acid-ic acid and add -onitrile-onitrile

CH3 C N C N CH2 C N

Ethanenitrile(Acetonitrile)

Benzonitri le !henylethanenitri le(!henylacetonitrile)



!mides are comparable in acidity to alcohols water-insoluble amides do not react with 'aOH or

other al"ali metal hydroxides to form water solublesalts

ulfonamides and imides are more acidic thanamides

CH3 CNH2

O

NH

O

O

NH

O

OO

SNH2

O

p/ a 01p/ a 213p/ a 4

!hthalimide"uccinimideBenzenesulfonamideAcetamide

p/ a %&3



#mides are more acidic than amides because

* the electron-withdrawing inductive of the twoad+acent CO groups wea"ens the '-H bond, and

* the imide anion is stabili.ed by resonancedelocali.ation of the negative charge

!hthalimide A resonance&stailized anion

+N-H

O

O O

O

N - N

O-

O

H3 O++ H2 O



imides such as phthalimide readily dissolve ina/ueous 'aOH as water-soluble salts

(strongeracid)

(5ea6eracid)

(5ea6erase)

(strongerase)

p/ a %13p/ a 01

77

O

O

NH N- Na

+

O

O

NaOH H2 O



Additional"tretchings (cm&)

8&H at *'44&'44C&8 at *4&*4

(*+ ha9e one &H pea6)

(+ ha9e t5o &H pea6s)

&H at *44 and '44

C&8 at 244&44

C&8 at 444&44and *44&*%4

(cm&)

C:8 "tretch

3'4&3.4and

044&0%4

.4&.04

3%&044

344&3*%

O

O

O

O

RCOH

RCOCR

RCOR

RCNH2

Cmpd

O



)H-'0 H on the α-carbon to a CO group are slightly

deshielded and come into resonance at δ *-*1

H on the carbon of the ester oxygen are more

strongly deshielded and come into resonance at δ 2*3-4*3

)2C-'0 the carbonyl carbons of esters show characteristic

resonance at δ 15-65

Methyl p ropanoate

1.0(s) *1(;)O

CH3 -CH2 -C-O-CH3



'ucleophilic acyl substitution&'ucleophilic acyl substitution& an addition-elimination se/uence resulting in substitutionof one nucleophile for another

Tetrahedral caronyladdition intermediate

-- ++ CNuR

C

Y R

Y

O O-

Nu Y

"ustitution product

:

:

:

RC

Nu

O



in this general reaction, we have shown the leavinggroup as an anion to illustrate an important pointabout them& the wea"er the base, the better theleaving group

$ncreas ing as icity

$ncreasing lea9ing aility

X-RO-R2 N - RCO-

O



halide ion is the wea"est base and the best leavinggroup7 acid halides are the most reactive towardnucleophilic acyl substitution

amide ion is the strongest base and the poorest

leaving group7 amides are the least reactive towardnucleophilic acyl substitution

O

RCXRCOCR'RCOR'RCNH2

$ncreas ing reacti9ity to5ard nucleophilic acyl sustitution

Amide Ester Anhydride Acid halide

OO OO



low-molecular-weight acid chlorides react rapidlywith water

higher molecular-weight acid chlorides are lesssoluble in water and react less readily

++

O O

CH3 CCl H2 O CH3 COH HCl



low-molecular-weight acid anhydrides react readilywith water to give two molecules of carboxylic acid

higher-molecular-weight acid anhydrides also reactwith water, but less readily

CH3COCCH3

O O

H2 O CH3COH

O O

HOCCH3++



8sters are hydroly.ed only slowly, even inboiling water

Hydrolysis becomes more rapid if they areheated with either a/ueous acid or base

Hydrolysis in a/ueous acid is the reverse of9ischer esterification the role of the acid catalyst is to protonate the

carbonyl oxygen and increase its electrophilic

character toward attac" by water to form atetrahedral carbonyl addition intermediate collapse of this intermediate gives the carboxylic

acid and alcohol



!cid-cataly.ed ester hydrolysis

R OCH3C

O

H2 O H

+ OH

CR

OCH3

OH

H+

R OHC

O

CH3 OH7 7

Tetrahed ral caronyladdition intermediate



Hydrolysis of an amide in a/ueous acid re/uires mole of acid per mole of amide

*&!henylutanoic acid*&!henylutanamide

++ +heat

H2 O HCl H2 O NH4+ Cl-

Ph

NH2

O

Ph

OH

O



Hydrolysis of an amide in a/ueous basere/uires mole of base per mole of amide

CH3CNH

8

NaOH H2O

CH3 CO-Na

+

O

H2N

Aniline"odium acetate

&!henylethanamide(&!henylacetamide, Acetanilide)

+

+heat



The cyano group is hydroly.ed in a/ueous acidto a carboxyl group and ammonium ion

Ammoniumhydrogen sulfate

!henylacetic acid

!henylacetonitrile

+

heat

++CH2

C

CH2 COH

N 2 H2 O H

2 SO

4

H2 O

NH4+

HSO4-

O



protonation of the cyano nitrogen gives acation that reacts with water to give an imidicacid

"eto-enol tautomerism of the imidic acid givesthe amide

R-C N H2O H

+

R-C

OH

NH

O

R-C-NH2

An imidic acid(en ol of an amide)

+

An amide



hydrolysis of a cyano group in a/ueous basegives a carboxylic anion and ammonia7acidification converts the carboxylic anion tothe carboxylic acid

<ndecanenitrileheat

++CH3 ( CH2 ) 9 C H2 O NaOHH2 O

<ndecanoic acid"odium undecanoateCH3 ( CH2 ) 9 CO

-

Na

+ HCl

H2 O CH3 ( CH2 ) 9 COH

OO

N



Hydrolysis of nitriles is a valuable route tocarboxylic acids

heat

Benzaldehyde

Benzaldehydecyanohydrin

(Mandelonitrile)

*&Hydroxyphenyl&acetic acid

(Mandelic acid)

CH

HO

CC

H

N CHCOHH2 SO4 , H2 O

etha!l, "ate#

HCN, $CN

HO

O

O



!cid halides react with alcohols to give esters acid halides are so reactive toward even wea"

nucleophiles such as alcohols that no catalyst isnecessary

where the alcohol or resulting ester is sensitive toHCl, reaction is carried out in the presence of a 2:amine to neutrali.e the acid

Butanoylchloride

Cyclohexyl utanoate

+

Cyclohexanol

HO

HCl

Cl

O

+

O

O



sulfonic acid esters are prepared by the reaction ofan al"ane- or arenesulfonyl chloride with analcohol or phenol

S-ClH3 C

O

O

C OH

C6 H1 3

H

H3 C

O

OCH3O-SC

C6 H1 3

H

H3 C

+

(=)&*&8ctanol p-Toluenesulfonylchloride

(Tos yl chloride> TsCl)

%&#'('e

(=)&*&8ctyl p-t oluenesulfonate

?(=)&*&8ctyl tosylate@



!cid anhydrides react with alcohols to give onemole of ester and one mole of carboxylic acid

Acetic acidEthyl acetate

EthanolAcetic anhydride

+

+

O

OO

CH3 COCCH3 HOCH2 CH 3

CH3 COCH2 CH3 CH3 COH

O



cyclic anhydrides react with alcohols to give oneester group and one carboxyl group

&Methylpropyl hydrogen phthalate(s ec&Butyl hydrogen phthalate)

*&Butanol( sec- Butyl alcohol)

+

!hthalicanhydride

O

O

O

O

O

O

OH

HO



aspirin is synthesi.ed by treatment of salicylic acidwith acetic anhydride

Acetylsalicylic acid (Aspirin)

*&Hydroxyenzoicacid

("alicylic acid)

+

+

Acetic acid

Aceticanhydride

CH3 COH

CH3 COCCH3

OO

COOH

CH3

O

OH

COOH

O O



8sters react with alcohols in the presence of anacid catalyst in a reaction calledtransesterification, an e/uilibrium reaction

Butyl propenoate(Butyl acrylate)

(p '3+C)

&Butanol(p 3+C)

Methyl propenoate(Methyl acrylate)

(p 0+C)

+

+ HCl

CH3 OH

Methanol(p .%+C)

OCH3

O

HO

O

O



!cid halides react with ammonia, : amines,and : amines to form amides moles of the amine are re/uired per mole of acid

chloride

+ +

Hexanoyl

chloride

Ammonia Hexanamide Ammonium

chloride

2 NH3 NH4+

Cl-

Cl

O

NH2

O



!cid anhydrides react with ammonia, and :and : amines to form amides* moles of ammonia or amine are re/uired

Ammonia

+

Ammoniumacetate

Ethanamide(Acetamide)

+

Aceticanhydride

O O O

CH3 COCCH3 2 NH3 CH3 CNH2 CH3 CO-NH4

+

O



!cid chlorides react with salts of carboxylicacids to give anhydrides most commonly used are sodium or potassium salts

+

Acetyl

chloride

"odium enzoate Acetic enzoic

anhydride

+CH3 CCl -

OC CH3 COC Na+ Cl -Na+

O O O O



treatment of a formic ester with moles of;rignard reagent followed by hydrolysis witha/ueous acid gives a : alcohol

+

magnesium

al6oxide salt

A secondaryalcohol

An ester of formic acid

OH

=

HCOCH3 2 R*X

H2 O, HCl

HC-R + CH3 OH

O



treatment of an ester other than formic with a;rignard reagent followed by hydrolysis in a/ueousacid gives a 2: alcohol

magnesium

al6oxide s alt

+

A tertiary

alcohol

An es ter other

than a formate

O

R

OH

CH3 COCH3 2 R*X

H2 O, HClCH3 C- R + CH3 OH



* addition of mole of 0g< to the carbonyl carbongives a TC!#

* collapse of the TC!# gives a "etone (an aldehydefrom a formic ester)

CH3 -C-OCH3 R *#

O *#. +

CH3 -C OCH3

R

O

R

CH3 -C CH3 O- *#. +

+

+

A magnesium salt(a TCA$)

A 6etone

O



2* reaction of the "etone with a nd mole of 0g<gives a second TC!#

4* treatment with a/ueous acid gives the alcohol

R

O

CH3 -C R *#

R

O- *#. +

CH3 -C-R

H2 O, HClOH

RCH3 -C-R

Magnesium salt

A 6etone

+

A tertiary alcohol



Organolithium compounds are even morepowerful nucleophiles than ;rignard reagents they react with esters to give the same types of :

and 2: alcohols as do ;rignard reagents

and often in higher yields

RCOCH3

1 / 2 R' 0

2 / H2 O, HCl

R- C-R'

O

R'

OH

7 CH3 OH



!cid chlorides at -36:C react with ;ilman reagentsto give "etones* under these conditions, the TC!# is stable, and it is not

until acid hydrolysis that the "etone is liberated

1 / (CH3 ) 2 Cu0, ether, &30+C

2 / H2 O

!entanoyl chloride *&Hexanone

Cl

O O



;ilman reagents react only with acid chlorides

they do not react with acid anhydrides, esters,amides, or nitriles under the conditions described

1 / (CH3 ) 2 Cu0, ether, &30+C

2 / H2 OO

H3COCl

O

O

H3CO

O



0ost reductions of carbonyl compounds nowuse hydride reducing agents

esters are reduced by =i!lH4 to two alcohols

the alcohol derived from the carbonyl group isprimary

Methanol*&!henyl&&

propanolMethyl *&phenyl&

propanoate

+1/ 0lH4 , et he#

2 / H2 O, HCl

CH3 OHPhOCH3

O PhOH



eduction occurs in three steps plus wor"up

:H- R-C-H

H

(3)

:H2O

R- C-H

H

OH

A primaryalcohol

R- C

H

O

+(4 )

O-

O

R- C-OR' :H- R- C-OR'

H

O

R- C

H

O-:OR'+

An ester A tetrahedral caronyladdition intermediate

+(1) (2)

Analdehyde

:



'a>H4 does not normally reduce esters, but it

does reduce aldehydes and "etones

elective reduction is often possible by the

proper choice of reducing agents andexperimental conditions

NaH4

tOHO

O O

O

OH O



?iisobutylaluminum hydride (?#>!lH) at -36:Cselectively reduces an ester to an aldehyde at -36:C, the TC!# does not collapse and it is not

until hydrolysis in a/ueous acid that the carbonyl

group of the aldehyde is liberated

Hexanal

Methyl hexanoate

+

1 / 0H, toluene, &30+C

2 / H2 O, HCl

CH3 OH

OCH3

O

H

O



=i!lH4 reduction of an amide gives a :, :, or

2: amine, depending on the degree ofsubstitution of the amide

8ctanamide &8ctanamine

1/ 0'lH4

2 / H2 ONH2

O

NH2

,&#imethylenzamide ,&#imethylenzylamine

1/ 0'lH4

2 / H2 O

N

O

N



The mechanism is divided into 4 steps tep & transfer of a hydride ion to the carbonyl

carbon

tep & formation of an oxygen-aluminum bond

C

R NH2

O

CR

NH2

O

H

lH3-

CR

NH2

O-

lH3

H

H

lH3-

:() (*)



tep 2& redistribution of electrons gives an iminiumion

tep 4& transfer of a second hydride ion completesthe reduction to the amine

:

CR

N

O

H

lH3-

H H

CR

N

H

H H

H: -

CR

N

H

H

H HAn iminium ion

() (')

:



The cyano group of a nitrile is reduced by=i!lH

4 to a : amine

.&8ctenenitrile

.&8cten&&amine

CH3 CH= CH( CH2 ) 4 C 1 / 0lH

42 / H2 O

CH3 CH=CH(CH2 ) 4 CH2 NH2

N



tage & acid-base reaction gives an amide anion,which reacts as a nucleophile with >r

tage & a nd acid-base reaction followed byelimination of >r- gives a nitrene, an electron-

deficient species, that rearranges to an isocyanate

:

: +-

An &romoamideAn amide anion

R C N H

H

O

N

H

CR# #

O

N

H

# CRHO-

:# -: : O

HO-

- H2 O

An acylnitrene

-:# -R-C-N-#

H

O B

R-C-N-#

O B

B R-C-N

O B

B

An isocy anate

R-N=C=O B



The penicillins are a family of β-lactamantibiotics

N

S CH3

CH3

COOH

O

NC

H

O

CH2

!enicillin

H H

the penicillins differ

in the group ondedto the acy l caron



!moxicillin

N

S

COOHO

HN

O

NH2

HH

HO



The cephalosporins are also β-lactam antibiotics

NO

NC

H

N

S

COOH

CH3

S

NH2N

Cefetamet

H

CH3 O

H

the cephalo sporins differin the group onded to the

acy l caron and the side chainonded to the thiaz ine ring



NO

NC

H

N

S

COOH

CH3

S

NH2N

H

OCH3

H



http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/crbacid2.htm

Brown Foote Ierson ! "r#anic $hemistryFourth %dition

Carboxyl Derivatives

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