Carboxylic Acids & Derivatives - ChemConnections

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Carboxylic Acid Derivatives. Nucleophilic Substitution: 1) Addition & 2) Elimination. GUAR: A General Utilitarian Approach for Reactions of. Acid Derivatives ...

Systematic Names of Functions

Carboxylic Acid Derivatives Nucleophilic Substitution: 1) Addition & 2) Elimination GUAR: A General Utilitarian Approach for Reactions of Acid Derivatives (Carbon,Sulfur & Phosphorous)

Systematic Names of Acid Functions

Malonic Acid / Condensations and Barbiturates

Barbiturates / Condensations

Malonic Acid

Urea + Malonic Acid & Derivatives

HO

O

O

C

C

H

C

1864

Present

H

Anesthetics / “ Sleeping

OH

H

Malonic ester is hydrolyzed to malonic acid, which reacts with urea to produce barbituric acid.

Pills” Pills” / “Truth Serum” Serum”

>2,500 Compounds

O N

N

O

H

“bluebirds, downers,

O R5 R 5

DEA Schedule II, III & IV:

goofballs, tooties, yellow jackets”” jackets

Nembutal Veronal

Esters Salts of Carboxylic Acids

Question

Cyclic Esters:Lactones Which compound cannot form a lactone? A)

B)

C)

D)

Cyclic Amides: Lactams

Amides O

α

O

α

H N

β

O

H N

δ γ

2-azacyclohexanone δ-valerolactam

β

H N

γ 2-azacyclopentanone γ-butyrolactam

2-azacyclobutanone β-propiolactam

Recognizing Functions

Recognizing Functions

Generic Reaction: Nucleophilic Substitution

In general: ••

Chemical Reactivity of Carboxylic Acid Derivatives

••

O •• R

C

O •• + X

HY HY R

C

+ Y

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

HX HX

most reactive

Generic Steps for Nucleophilic Substitution

O RCCl RCCl

O O

involves formation and dissociation of a tetrahedral intermediate

RCO RCOCR' O A carboxylic acid RCO RCOR' O derivative can be converted by RCN RCNR'2 O nucleophilic acyl substitution to any other RCO RCO– type that lies below it in this table. least reactive

OH

••

O •• R

C

HY

C

X

••

O ••

-HX -HX

R Y

R

C

Y

X

Question When benzoic acid reacts with 18O-enriched methanol (CH318OH) and an acid catalyst, which product will be obtained?

A)

B)

C)

D)

Most reactive

O CH3C O CH3C

Cl

Least stabilized

Reactivity, Electron Delocalization & Relative Acidity-Basicity

The extent of delocalization depends on:

O

1) The electronegativity of X

OCCH3

2) the interaction of X with the π orbital of C=O

O CH3C

OCH2CH3

O Least reactive

CH3C

NH2

•• – •O• • •

••

O •• Most stabilized

RC

••

X

RC +

•• – •O • • • ••

X

RC

+ X

least stabilized C=O

Carboxylate Ions O •• R

C

O

– •• ••O ••

••

•• –

O •• ••

R

C

RCCl RCCl O •• ••

Very efficient electron delocalization and dispersal of negative charge Maximum stabilization

O O RCO RCOCR' O RCO RCOR'

O RCN RCNR'2

O RCO RCO–

most stabilized C=O

Reactivity is Related to Structure Stabilization

Relative rate of hydrolysis

RCCl RCCl O O

very small

1011

RCO RCOCR' O

small

107

RCO RCOR' O

moderate

1.0

RCN RCNR'2

large

< 10-2

O

Relative Acidity-Basicity

Z– will be eliminated if it is a much weaker base than Y– (k–1 >> k2) The more stabilized the carbonyl group, the less reactive it is.

Reaction Coordinate Diagrams for Nucleophilic Acyl Substitution Reactions

(a) the Nu– is a weaker base (b) the Nu– is a stronger base (c) the Nu– and the leaving group have similar basicities

Y– will be eliminated if it is a much weaker base than Z– (k2 >> k–1)

Molecular Orbitals Describe How Compounds React

Malathion Module: Exploration 3

http://chemconnections.org/organic/chem227/chem-risk/explore-3.html

Two major resonance contributors in esters, carboxylic acids, and amides

β-Lactams & Antibiotic Resistance

β-Lactams & Antibiotic Resistance

Preparation of Acyl Chlorides from carboxylic acids and thionyl chloride

O (CH3 )2CHCOH CHCOH

O SOCl2 heat

(CH3 )2CHCCl CHCCl + SO2 + HCl (90%)

http://chemconnections.org/organic/chem227/Staph-infection/index.html

Reactions of Acyl Chlorides O RCCl RCCl

O O RCOCR'

O RCOR'

O RCNR' RCNR'2

O RCO–

Reactions of Acyl Chlorides

Reactions of Acyl Chlorides

Acyl chlorides react with carboxylic acids to give acid anhydrides: O

O

RCCl RCCl + R'CO R'CO H

O O RCO RCOCR'

Acyl chlorides react with carboxylic acids to give acid anhydrides: O

+

HCl

O O

O

RCCl RCCl + R'COH

RCOCR' H

via:

R

O

O

C

OCR'

Cl

+

HCl

Example

Reactions of Acyl Chlorides O

O

CH3(CH2)5CCl +

Acyl chlorides react with alcohols to give esters:

CH3(CH2)5COH O

O

pyridine

RCCl R'OH RCCl + R'O

RCO RCOR'

+

HCl

O O CH3(CH2)5COC(CH2)5CH3 (78-83%)

Reactions of Acyl Chlorides

Example

Acyl chlorides react with alcohols to give esters:

RCCl R'OH RCCl + R'O

RCO RCOR' H

via:

R

O

C6 H5CCl + (CH3 )3COH

O

O

O

+

pyridine

C6 H5CO C(CH3)3 (80%)

HCl

O C

OR'

Cl

Reactions of Acyl Chlorides

Reactions of Acyl Chlorides

Acyl chlorides react with ammonia and amines to give amides: O RCCl RCCl + R'2NH + HO–

O

Acyl chlorides react with ammonia and amines to give amides: O

O

RCN RCNR'2 + H2 O

RCCl + R'2NH + HO– H

+ Cl– via:

R

RCNR'2 + H2 O + Cl–

O C Cl

NR'2

Example

Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base):

O

O NaOH

C6 H5CCl + HN

C 6 H 5C N

H2 O

O

O

(87-91%)

RCCl RCCl + H2 O

RCO RCOH

+

HCl

+

Cl–

O

O RCCl 2HO– RCCl + 2HO

RCO RCO–

+ H2 O

Reactions of Acyl Chlorides

Example

Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base):

O C6 H5CH2 CCl + H2 O

O

O RCCl RCCl + H2 O

RCO RCOH H

via:

R

+

O C6 H5CH2 COH + HCl

HCl

O C

OH

Cl

Activation of Carboxylic Acids

Reactivity Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. O

Relative rates of hydrolysis (25°C)

C6 H5CCl

C6 H5CH2 Cl

1,000

1

Activated Carboxylic Acid Derivatives in Living Organisms