Reações de ácidos carboxilícos e

derivados

HN

N

Cl

O

N3

HO

N

NH

O

O

CH3

NH

HN

Br

O

O

Br

N

OO

N

H

H

H

H

HO

MeOO

OOMe

OMe

O

OMe

O

HO

O

O OOHO

N

CO2H

S

O

HN

NH

H

HHHO

N

N

CF3

CH3H2NSO2

Cl

Cl Cl

OH

Ácidos e derivados

Ésteres

Aminas

Anidridos

Haletos de ácidos

Anidridos cíclicos com anéis de 5 e 6 membros são preparados

pela desidratação de ácidos dicarboxilícos

Anidridos cíclicos são preparados a partir de

1,n-diácidos

OH

OH

O

O

tetracloroetilenosolvente

130 C

desidratação

O

O

O

Anidrido acético

Anidrido ftálico Anidrido malêico

Anidridos ácidos são precursores importantes

O

CH3OH3C

O

O

O

O

O

O

O

Acetato de 3-metilbutila

" acetato de isopentila" e “acetato de isoamila"

odor característico de bananas

O

OCH3 CH3

CH3

Frequentemente, os ésteres são encontrados como produtos

naturais

Ésteres

Triestearina: Gorduras animais e vegetais

O

O

O

CH3(CH2)16

O

O

(CH2)16CH3

(CH2)16CH3

O

Óleos e gorduras são misturas de triésteres de glicerila

(Z)-5-Tetradecen-4-olida

(feromônio sexual da fêmea do besouro japônes)

O

O

H

H

CH2(CH2)6CH3

As lactonas são ésteres cíclicos

Carboxylic Acids and Derivatives:

Nucleophilic Acyl Substitution

O

XR

O

NucR

Nuc-H

or

Nuc-

The extent to which the lone pair on X can be delocalized

into C=O depends on:

1) the electronegativity of X

2) how well the lone pair orbital of X interacts

with the orbital of C=O

Deslocalização eletrônica e o grupo

carboxila

O

XR

O

XR

O

XR

ESTERIFICAÇÃO

CH3C

O

Cl

CH3C

O

OCCH3

O

CH3C

O

SCH2CH3

CH3C

O

OCH2CH3

CH3C

O

NH2

Most

reactive

Least

reactive

Least

stabilized

Most

stabilized

Orbital Overlap in Carboxylic Acid

Derivatives

O

X

R

O

X

R

The p-* orbital interactioncan be represented in termsof resonance

O CX

R

Lone PairEmpty *

orbitial

Orbitals Overlap

1) the electronegativity of X

2) how well the lone pair orbital of X interacts with the

orbital of C=O

Orbital Overlap in Carboxylic Acid

Derivatives

NitrogenLone Pair

Empty *

Orbital of

CO group

Interaction of filled and empty orbitals lowers the energy of thesystem

New, lower

energy orbital

New, higher

energy orbital

O CX

R

Lone PairEmpty *

orbitial

Orbitals Overlap

Esterification

H+ (catalyst)

(a reversible

condenstation

reaction)

Ester

O

R OH

R OH

O

R O

R

AlcoholCarboxylic Acid

H2O

Fischer Esterification - A Reversible Process

Mechanism of Acid-Catalyzed Esterification

The mechanism involves two stages:

1) formation of tetrahedral intermediate

(3 steps)

2) dissociation of tetrahedral intermediate

(3 steps)

Mechanism of Fischer Esterification

tetrahedral intermediate in esterification

of benzoic acid with methanol

OCH3

HO OH

methanol adds to the

carbonyl group of the

carboxylic acid

the tetrahedral

intermediate is

analogous to a

hemiacetal

Stage One

Formation of Tetrahedral Intermediate

OCH3

HO OH

OH

O

HO CH3

H+

this stage corresponds

to an acid-catalyzed

dehydration

Stage Two

Collapse of Tetrahedral Intermediate to Ester

OCH3

HO OH

O

O

H+

CH3

H2O

Mechanism of formation

of

tetrahedral intermediate

Step 1

C

O

O H

••••

••

••

O ••+

H

CH3

H

••

C

O

O H

••

••

+ H ••O •

•

CH3

H

Step 1

••

C

O

O H

••

••

+ H

carbonyl oxygen is

protonated because

cation produced is

stabilized by electron

delocalization

(resonance)

C

O

O H

••••

+

H

••

Step 2

••

C

O

O H

••

••

+ H

••O •

•

CH3

H

C

OH

OH

••••

••

••

O ••

+CH3

H

Step 3

••

C

OH

OH

••••

••

O ••

CH3

H

+

••O •

•

CH3

H

O ••

CH3

H

H+

••

C

OH

OH

••••

••

O ••

CH3

••

Tetrahedral intermediate

to

ester stage

Step 4

O ••

CH3

H

H+••

C

OH

O

••••

••

OCH3••

••

H

••

C

OH

O

••••

OCH3••

••

H H

+ •• O •

•

CH3

H

Step 5

••

C

OH

O

••••

OCH3••

••

H H

+

O••H H

••+

C

OH••

••

OCH3

••

••

+

Step 5

C

OH••

••

OCH3

••

••

+

C

OH••

OCH3

••

••

+

Step 6

C

O••

OCH3

••

••

+ H

O••

H CH3••

+OH CH3••

H

C

O••

OCH3

••

••

••

Activation of carbonyl group by protonation of

carbonyl oxygen

Nucleophilic addition of alcohol to carbonyl group

forms tetrahedral intermediate

Elimination of water from tetrahedral intermediate

restores carbonyl group

Key Features of Mechanism

20.1

Nomenclature of Carboxylic Acid Derivatives

Name the acyl group and add the word chloride, fluoride, bromide, or iodide as appropriate.

Acyl chlorides are, by far, the most frequently encountered of the acyl halides

Nomenclature of Acyl Halides

O

XR

X = Halogen

acetyl chloride

3-butenoyl chloride

p-fluorobenzoyl bromide

Nomenclature of Acyl Halides - Examples

O

ClH3C

O

Cl

O

Br

F

When both acyl groups are the same, name the acid

and add the word anhydride

When the groups are different, list the names of the

corresponding acids in alphabetical order and add the

word anhydride

Nomenclature of Acid Anhydrides

O

OR R'

O

acetic anhydride

benzoic anhydride

benzoic heptanoic anhydride

Nomenclature of Acid Anhydrides - Examples

O

OH3C CH3

O

O

O

O

O

O

O

CH3

name as alkyl alkanoates

cite the alkyl group attached to oxygen first (R')

name the acyl group second; substitute the suffix

-ate for the -ic ending of the corresponding acid

Nomenclature of Acid Esters

O

ORR'

ethyl acetate

methyl propanoate

2-chloroethyl benzoate

Nomenclature of Acid Esters - Examples

O

OCH3CH3

O

OCH3 CH3

O

O

Cl

identify the corresponding carboxylic acid

replace the -ic acid or -oic acid ending by -amide

Nomenclature of Primary Amides

O

NH2R

acetamide

3-methylbutanamide

benzamide

Nomenclature of Primary Amides - Examples

O

NH2H3C

O

NH2H3C

H3C

NH2

O

name the amide as before

precede the name of the amide with the name of the

appropriate group or groups

precede the names of the groups by the letter N- (standing

for nitrogen and used as a locant)

and

Nomenclature of Secondary & Tertiary Amides

O

NH

RR

O

NRR

R'

N-methylacetamide

N-isopropyl-N-methylbutanamide

N,N-diethylbenzamide

Nomenclature of Secondary & Tertiary Amides

O

N CH3

CH3

H3C N

O

CH3

CH3

CH3

O

NH

H3CCH3

add the suffix -nitrile to the name of the parent hydrocarbon

chain (including the triply bonded carbon of CN)

or: replace the -ic acid or -oic acid name of the

corresponding carboxylic acid by -onitrile

or: name as an alkyl cyanide (functional class name

Nomenclature of Cyanides

R C N

CH3C N

ethanenitrile

or: acetonitrile

or: methyl cyanide

C6H5C N benzonitrile

NC

CH3CHCH3 2-methylpropanenitrile

or: isopropyl cyanide

Nomenclature of Cyanides

20.2

Structure and Reactivity

of

Carboxylic Acid Derivatives

The key to managing the information in

this chapter is the same as always:

structure determines properties.

---------------

The key structural feature is how well the

carbonyl group is stabilized.

---------------

The key property is reactivity in nucleophilic

acyl substitution.

Three Keys to Understanding the

Chemistry of Carboxylic Acids Derivatives

The main structural feature that distinguishes acyl

chlorides, anhydrides, thioesters, esters, and amides is

the interaction of the substituent with the carbonyl

group. It can be represented in resonance terms as:

Electron Delocalization and the Carbonyl Group

O

XR

O

XR

O

XR

lone pair orbital

of substituent

Orbital Overlap in Carboxylic Acid Derivatives

electron pair of substituent delocalized into

carbonyl orbital

Orbital Overlap in Carboxylic Acid Derivatives

Acyl chlorides have the least stabilized carbonyl

group

Delocalization of lone pair of Cl into C=O group is

not effective because C—Cl bond is too long

••

C

O

R

Cl••

••

••

••

••

C

O

R

Cl••

••

••

••

+

–

Orbital Overlap in Acyl Chlorides

RCCl

O

least stabilized C=O

most stabilized C=O

lone pair donation from oxygen stabilizes the

carbonyl group of an acid anhydride

the other carbonyl group is stabilized in an

analogous manner by the lone pair

••CR

O••

••

O••

C

O••

••

R

O••

••

••••

+

–

CR

O ••

O••

CR

Orbital Overlap in Acid Anhydrides

RCOCR'

O ORCCl

O

least stabilized C=O

most stabilized C=O

Sulfur (like chlorine) is a third-row element.

Electron donation to C=O from third-row elements

is not very effective.

Resonance stabilization of C=O in thioesters is

not significant.

••••

+

–

CR

O ••

SR'••

O••

••

••CR SR'

••

Orbital Overlap in Thioesters

RCOCR'

O ORCCl

O

least stabilized C=O

most stabilized C=O

RCSR'

O

lone pair donation from oxygen stabilizes the

carbonyl group of an ester

stabilization greater than comparable stabilization

of an anhydride or thioester

••••

+

–

CR

O ••

OR'••

O••

••

••CR OR'

••

Orbital Overlap in Esters

RCOCR'

O ORCCl

O

RCOR'

O

least stabilized C=O

most stabilized C=O

RCSR'

O

lone pair donation from nitrogen stabilizes the

carbonyl group of an amide

N is less electronegative than O; therefore,

amides are stabilized more than esters and

anhydrides

••••

+

–

CR

O ••

NR'2

O••

••

••CR NR'2

Orbital Overlap in Amides

amide resonance imparts significant double-bond

character to C—N bond

activation energy for rotation about C—N bond

is 75-85 kJ/mol

C—N bond distance is 135 pm in amides versus

normal single-bond distance of 147 pm in amines

••••

+

–

CR

O ••

NR'2

O••

••

••CR NR'2

Orbital Overlap in Amides

RCOCR'

O ORCCl

O

RCOR'

O

RCNR'2

O

least stabilized C=O

most stabilized C=O

RCSR'

O

very efficient electron delocalization and dispersal

of negative charge

maximum stabilization

O••

••

••CR

–O••

••

••••

–

CR

O ••

••••

O

Orbital Overlap in Carboxylate Ions

RCOCR'

O ORCCl

O

RCOR'

O

RCNR'2

O

RCO–

O

least stabilized C=O

most stabilized C=O

RCSR'

O

Stabilization

very small

small

large

moderate

Relative rate

of hydrolysis

1011

107

<10-2

1.0

The more stabilized

the carbonyl group,

the less reactive it

is.

Reactivity is Related to Structure

O

OR R

O

O

OR

R'

O

NR

R'

R'

O

ClR

In general:

O••

••

CR X

+ HY

O••

••

CR Y

+ HX

Reaction is feasible when a less stabilized

carbonyl is converted to a more stabilized

one (more reactive to less reactive).

Nucleophilic Acyl Substitution

RCOCR'

O ORCCl

O

RCOR'

O

RCNR'2

O

RCO–

O

RCSR'

O

most reactive

least reactive

a carboxylic acid

derivative can be

converted by

nucleophilic acyl

substitution to any other

type that lies below it in

this table

20.3

General Mechanism

for

Nucleophilic Acyl Substitution

O••

••

CR X

+ HNu

O••

••

CR Nu

+ HX

Reaction is feasible when a less stabilized

carbonyl is converted to a more stabilized

one (more reactive to less reactive).

Nucleophilic Acyl Substitution

involves formation and dissociation

of a tetrahedral intermediate

O••

••

CR X

HNu

C

ROH

X

Nu

O••

••

CR Nu

-HX

Both stages can involve several elementary steps.

Mechanism of Nucleophilic Acyl Substitution

first stage of mechanism (formation of tetrahedral

intermediate) is analogous to nucleophilic addition

to C=O of aldehydes and ketones

O••

••

CR X

HNu

C

ROH

X

Nu

Mechanism of Nucleophilic Acyl Substitution

second stage is restoration of C=O by elimination

O••

••

CR X

HNu

C

ROH

X

Nu

O••

••

CR Nu

-HX

complicating features of each stage involve

acid-base chemistry

Mechanism of Nucleophilic Acyl Substitution

O••

••

CR X

HNu

C

ROH

X

Nu

O••

••

CR Nu

-HX

Acid-base chemistry in first stage is familiar in that

it has to do with acid/base catalysis of nucleophilic

addition to C=O.

Mechanism of Nucleophilic Acyl Substitution

O••

••

CR X

HNu

C

ROH

X

Nu

O••

••

CR Nu

-HX

Acid-base chemistry in second stage concerns

form in which the tetrahedral intermediate exists

under the reaction conditions and how it dissociates

under those conditions.

Mechanism of Nucleophilic Acyl Substitution

tetrahedral intermediate (TI)

C

RO

X

Nu••

H••

••

••

C

RO

X

Nu••

H••

••

H +

Conjugate acid of tetrahedral

intermediate (TI+)

••

O••

••

C

R

X

Nu

••••

–

Conjugate base of tetrahedral

intermediate (TI–)

The Tetrahedral Intermediate

••

C

RO

X

Nu••

H ••

H+

+B—H +C

O

R Nu ••

••••

+ X H••

B••

Dissociation of Protonated Tetrahedral Inter.

B••

••

C

RO

X

Nu••

H ••

••

+B—H +C

O

R Nu ••

••••

+ X••

••–

Dissociation of Neutral Tetrahedral Inter.

C

O

R Nu ••

••••

+ X••

••–

••

C

RO

X

Nu••

••

••

••

–

Dissociation of Anionic Tetrahedral Inter.

Nucleophilic Substitution

in Acyl Chlorides

from carboxylic acids and thionyl chloride

(CH3)2CHCOH

OSOCl2

heat(CH3)2CHCCl

O

+ SO2 + HCl

(90%)

Preparation of Acyl Chlorides

RCOCR'

O ORCCl

O

RCOR'

O

RCNR'2

O

RCO–

O

Reactivity and Reactions of Acyl Chlorides

RCCl

O

+ R'COH

O

RCOCR'

O O

+ HCl

Acyl chlorides react with carboxylic acids to give

acid anhydrides:

via: CR

O

Cl

OCR'

HO

Reactions of Acyl Chlorides

Reactions of Acyl Chlorides - Example

H3C

Cl

O

H3C

OH

O

H3C

O

O

CH3

O

N

pyridine - solvent

(78-83%)

RCCl

O

+ RCOR'

O

+ HCl

Acyl chlorides react with alcohols to give esters:

R'OH

via: CR

O

Cl

OR'

H

Reactions of Acyl Chlorides with Alcohols

via: CR

O

Cl

OCR'

H

O

Reactions of Acyl Chlorides

via: CR

O

Cl

OR'

H

via: CR

O

Cl

NR'2

H

Acylation with Alcohols

N

pyridine - solvent

(80%)

Cl

O

H3C

CH3H3C

OH

O

O

CH3

CH3

CH3

RCCl

O

+ RCNR'2

O

+ H2O

Acyl chlorides react with ammonia and amines

to give amides:

R'2NH + HO–

+ Cl–

via: CR

O

Cl

NR'2

H

Acylation with Amines

Acylation with Amines - Example

N

pyridine - solvent

(90%)

Cl

O

N

O

NH