Chapter 20 carboxylic acid derivatives nucleophilic acyl substitution
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Chapter 20 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution. 20.1 Nomenclature of Carboxylic Acid Derivatives. O. RC. X. Acyl Halides. name the acyl group and add the word chloride , fluoride , bromide , or iodide as appropriate

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Chapter 20 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution

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Chapter 20Carboxylic Acid DerivativesNucleophilic Acyl Substitution


20.1Nomenclature of Carboxylic Acid Derivatives


O

RC

X

Acyl Halides

  • 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


O

CH3CCl

O

H2C

CHCH2CCl

O

F

CBr

Acyl Halides

acetyl chloride

3-butenoyl chloride

p-fluorobenzoyl bromide


O

O

RCOCR'

Acid Anhydrides

  • 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


O

O

CH3COCCH3

O

O

C6H5COCC6H5

O

O

C6H5COC(CH2)5CH3

Acid Anhydrides

acetic anhydride

benzoic anhydride

benzoicheptanoic anhydride


O

RCOR'

Esters

  • 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


O

CH3COCH2CH3

O

CH3CH2COCH3

O

COCH2CH2Cl

Esters

ethyl acetate

methyl propanoate

2-chloroethyl benzoate


O

RCNH2

Amides having an NH2 group

  • identify the corresponding carboxylic acid

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


O

CH3CNH2

O

(CH3)2CHCH2CNH2

O

CNH2

Amides having an NH2 group

acetamide

3-methylbutanamide

benzamide


O

O

RCNHR'

RCNR'2

Amides having substituents on N

  • 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


O

CH3CNHCH3

O

CN(CH2CH3)2

O

CH3CH2CH2CNCH(CH3)2

CH3

Amides having substituents on N

N-methylacetamide

N,N-diethylbenzamide

N-isopropyl-N-methylbutanamide


RC

N

Nitriles

  • 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)


CH3C

N

C6H5C

N

CH3CHCH3

C

N

Nitriles

ethanenitrileor: acetonitrileor: methyl cyanide

benzonitrile

2-methylpropanenitrileor: isopropyl cyanide


20.2Structure of Carboxylic Acid Derivatives


The key to this chapter is the next slide.It lists the various carboxylic acids in order of decreasing reactivity toward their fundamental reaction type (nucleophilic acyl substitution).The other way to read the list is in order of increasing stabilization of the carbonyl group.


Mostreactive

Leaststabilized

O

O

O

O

O

O

CH3C

CH3C

CH3C

CH3C

CH3C

Cl

NH2

SCH2CH3

OCH2CH3

OCCH3

Leastreactive

Moststabilized


••

••

••

O

O

O

••

••

••

••

••

+

••

••

RC

X

RC

X

RC

X

+

Electron Delocalization and the Carbonyl Group

  • 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:


••

••

••

O

O

O

••

••

••

••

••

+

••

••

RC

X

RC

X

RC

X

+

Electron Delocalization and the Carbonyl Group

  • 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


Orbital overlaps in carboxylic acid derivatives

  • orbital of carbonyl group


Orbital overlaps in carboxylic acid derivatives

  • lone pair orbitalof substituent


Orbital overlaps in carboxylic acid derivatives

  • electron pair of substituent delocalized into carbonyl orbital


••

O

••

R

C

Cl

••

••

••

Acyl Chlorides

••

O

••

••

  • acyl chlorides have the least stabilized carbonylgroup

  • delocalization of lone pair of Cl into C=O group isnot effective because C—Cl bond is too long

R

C

+

Cl

••

••


O

RCCl

least stabilized C=O

most stabilized C=O


••

••

••

••

O

O

O

O

••

••

••

••

••

+

••

C

C

C

C

O

O

R

R

R

R

••

••

Acid Anhydrides

  • lone pair donation from oxygen stabilizes thecarbonyl group of an acid anhydride

  • the other carbonyl group is stabilized in ananalogous manner by the lone pair


O

RCCl

O

O

RCOCR'

least stabilized C=O

most stabilized C=O


••

••

O

O

••

••

••

+

••

C

C

SR'

SR'

R

R

••

••

Thioesters

  • Sulfur (like chlorine) is a third-row element.Electron donation to C=O from third-row elementsis not very effective.Resonance stabilization of C=O in thioesters isnot significant.


O

RCCl

O

O

RCOCR'

O

RCSR'

least stabilized C=O

most stabilized C=O


••

••

O

O

••

••

••

+

••

C

C

OR'

OR'

R

R

••

••

Esters

  • lone pair donation from oxygen stabilizes thecarbonyl group of an ester

  • stabilization greater than comparable stabilizationof an anhydride or thioester


O

RCCl

O

O

RCOCR'

O

O

RCOR'

RCSR'

least stabilized C=O

most stabilized C=O


••

••

O

O

••

••

••

+

••

C

C

NR'2

NR'2

R

R

Amides

  • lone pair donation from nitrogen stabilizes thecarbonyl group of an amide

  • N is less electronegative than O; therefore, amides are stabilized more than esters and anhydrides


••

••

O

O

••

••

••

+

••

C

C

NR'2

NR'2

R

R

Amides

  • amide resonance imparts significant double-bondcharacter to C—N bond

  • activation energy for rotation about C—N bondis 75-85 kJ/mol

  • C—N bond distance is 135 pm in amides versusnormal single-bond distance of 147 pm in amines


O

RCCl

O

O

RCOCR'

O

O

O

RCOR'

RCSR'

RCNR'2

least stabilized C=O

most stabilized C=O


••

••

O

O

••

••

••

••

C

C

O

O

R

R

••

••

••

••

Carboxylate ions

  • very efficient electron delocalization and dispersalof negative charge

  • maximum stabilization


O

RCCl

O

O

RCOCR'

O

O

O

RCOR'

RCSR'

RCNR'2

O

RCO–

least stabilized C=O

most stabilized C=O


Relative rateof hydrolysis

O

1011

RCCl

O

O

107

RCOCR'

O

1.0

RCOR'

O

< 10-2

RCNR'2

Reactivity is related to structure

Stabilization

  • The more stabilized the carbonyl group, the less reactive it is.

very small

small

moderate

large


••

••

O

O

••

••

C

C

R

R

X

Y

Nucleophilic Acyl Substitution

In general:

  • Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

+ HY

+ HX


O

RCCl

O

O

RCOCR'

O

O

O

RCOR'

RCSR'

RCNR'2

O

RCO–

most reactive

a carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table

least reactive


20.3General MechanismforNucleophilic Acyl Substitution


••

••

O

O

••

••

C

C

R

R

X

Nu

Nucleophilic Acyl Substitution

  • Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

+ HNu

+ HX


••

OH

••

O

O

HNu

-HX

••

••

R

C

C

C

Nu

R

X

R

Nu

X

General Mechanism for Nucleophilic Acyl Substitution

involves formation and dissociationof a tetrahedral intermediate

Both stages can involve several elementary steps.


••

OH

O

HNu

••

R

C

C

Nu

R

X

X

General Mechanism for Nucleophilic Acyl Substitution

first stage of mechanism (formation of tetrahedralintermediate) is analogous to nucleophilic additionto C=O of aldehydes and ketones


••

OH

••

O

O

HNu

-HX

••

••

R

C

C

C

Nu

R

X

R

Nu

X

General Mechanism for Nucleophilic Acyl Substitution

second stage is restoration of C=O by elimination

complicating features of each stage involveacid-base chemistry


••

OH

••

O

O

HNu

-HX

••

••

R

C

C

C

Nu

R

X

R

Nu

X

General Mechanism for Nucleophilic Acyl Substitution

Acid-base chemistry in first stage is familiar in thatit has to do with acid/base catalysis of nucleophilic addition to C=O.


••

OH

••

O

O

HNu

-HX

••

••

R

C

C

C

Nu

R

X

R

Nu

X

General Mechanism for Nucleophilic Acyl Substitution

Acid-base chemistry in second stage concernsform in which the tetrahedral intermediate existsunder the reaction conditions and how it dissociatesunder those conditions.


tetrahedral intermediate (TI)

H

H

••

••

O

O

••

••

••

••

••

••

R

R

O

••

••

C

C

C

R

Nu

Nu

••

Nu

X

X

Conjugate acid of tetrahedral intermediate (TI+)

Conjugate base of tetrahedral intermediate (TI–)

+

X

H

••

The Tetrahedral Intermediate


O

B

••

••

••

H

X

+

+B—H

+

••

C

R

Nu

••

Dissociation of TI—H+

••

O

H

••

R

X

C

H

+

Nu

••


••

O

H

O

••

R

B

••

X

C

••

••

Nu

••

••

+

X

+B—H

+

••

••

C

R

Nu

••

Dissociation of TI


••

O

O

••

••

R

X

C

••

••

Nu

••

••

+

X

••

••

C

R

Nu

••

Dissociation of TI–


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