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Carboxylic Acids: Synthesis

Na2Cr2O7 H2SO4 conc. KMnO4 or 1. O3 2. H2O

Ag2O NH3, H2O H3O+

1. CO2 2. H3O+

or

Carboxylic Acid Derivatives

acid anhydride

ester

acyl halide (chloride) ( hl id )

O R O N R'

an "activated" ester

carboxylic acid thioester

N H

R'

carbodiimide adduct

amides

Stability (to hydrolysis)

Exchanging Carboxylic Acid Derivatives

Groups on the right can be interchanged by equilibrium (although sometimes harsh conditions are required). Example: Fischer Esterification

thioester

ester

carboxylic acid

+

H+ catalyzed (but inhibited by -OH)

+

H 2O

amides

Kinetic Barriers Inhibit Exchange of Carboxylic Acid Derivatives

or, "Why we don't melt into a puddle of amino acid goo."

O OH

+

H2N

amino acid/protein fragments

Conditions that catalyze the synthesis of protein and fat... a protein

O N H

...also catalyze their di th i digestion! ti !

+ H2O

So, how does our body selectively degrade the biopolymers we eat, and then synthesize the biopolymers we need?

Nature's Solution to Equilibration of Acid Derivatives

Answer: Isolate different reactions in different places, and/or with different catalysts. In the gut...

O N H O

Inside cells...

+ H2O

H+ catalysis

N H

+ H2O

+ ADP + Pi

ribosome

O

O OH

+

H2N

OH

+

H2N

+ ATP

...proteolysis is driven by water and equilibrium.

...protein synthesis is driven by energy (ATP).

Exchanging Carboxylic Acid Derivatives

Often impractical to synthesize carboxylic acid derivatives by equilibrium reactions. y q Solution: "Activate" acyl group first, by converting acid to a more reactive derivative.

acyl halide (chloride)

carboxylic acid

amide

Stability (to hydrolysis)

Acyl Halides as Acylating Agents

thionyl chloride

OR

O Cl

O Cl

oxalyl l l chloride

Acyl halides are so reactive, no catalyst necessary.

Reactivity of Acyl Halides

SOCl2 or (COCl)2 1.

or

2. H2O H2O R'2CuLi

1. LiAlH4 2. H2O AlCl3 LiAlH(OtBu)3

Acid Anhydrides

SOCl2 or (COCl)2

Useful applications

· Formylation. (Formyl chloride unstable.)

an acid anhydride

undergo same reactions as acyl halides.

· Cyclic anhydrides. (COCl)2

(1 equiv)

Acylation in Polar Media

For molecules that are only soluble in H2O, can't use acyl halides.

NH2 how?

+

interferon -2b (a protein pharmaceutical)

poly(ethylene glycol) carboxylic acid

PegIntron (treatment for hepatitis C)

(Connecting polymer to protein increases circulation time of injected protein in blood.)

Carbodiimide Coupling of Nucleophiles and Carboxylic Acids

dicyclohexylcarbodiimide (DCC)

OR

(also reacts with directly y ethyl-dimethylaminopropylcarbodiimide (HCl salt; EDC·HCl) )

Reading: Wade 24.11A.

Indirect Coupling via NHS Esters

DCC

or

EDC·HCl EDC HCl

Key feature: Carbodiimide adduct and NHS ester prefer stronger (amine, alcohol) nucleophiles over H2O.

indirectly i di tl

N-hydroxy succinimide i i id (NHS)

O O R O N O

an NHS ester

Lactones and Lactams

DCC

(or just ) rate of ring closure (lo k) g og

5-, 6-membered rings are easiest to make.

2 0 -2 -4 3 5 7 9 11 13

ring size (atoms)

a lactone (a cyclic ester)

(or just )

DCC

a lactam (a cyclic amide) ring strain

entropy cost of joining ends

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