Chapter 17 Carbonyl Compounds I Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

© 2011 Pearson Education, Inc.1

Chapter 17

Carbonyl Compounds I

Reactions of Carboxylic Acids and

Carboxylic Acid Derivatives

Organic Chemistry 6th Edition

Paula Yurkanis Bruice



Class I Carbonyl Compounds


Class II Carbonyl Compounds



Nomenclature of Carboxylic Acids


In systematic nomenclature, the carbonyl carbon is always C-1

In common nomenclature, the carbon next to the carbonyl is the -carbon


The functional group of a carboxylic acid is called acarboxyl group


Naming Cyclic Carboxylic Acid


Salts of Carboxylic Acids


Acyl Halides

Acid Anhydrides


Esters


Cyclic esters are known as lactones:


Amides

If a substituent is bonded to the nitrogen, the name of thesubstituent is stated first:


Cyclic amides are known as lactams:


Nitriles


Structures of Carboxylic Acids and Carboxylic Acid Derivatives


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


Carboxylic acids have relatively high boiling points because…

Amides have the highest boiling points:


Naturally Occurring Carboxylic Acids and Carboxylic Acid Derivatives



The reactivity of carbonyl compounds resides in thepolarity of the carbonyl group:


The tetrahedral intermediate is a transient species that eliminates the leaving group Y– or the nucleophile Z–:

This is a nucleophilic acyl substitution reaction


Z– will be expelled if it is a much weaker base than Y–; that is, Z– is a better leaving group than Y– (k–1 >> k2):


Y– will be expelled if it is a weaker base than Z–; that is, Y– is a better leaving group than Z– (k2 >> k–1):


Both reactant and product will be present if Y– and Z–

have similar leaving abilities:


(a) the Nu– is a weaker base

(b) the Nu– is a stronger base

(c) the Nu– and the leaving group have similar basicities

Reaction Coordinate Diagrams forNucleophilic Acyl Substitution Reactions


A Molecular Orbital Description of How Carbonyl Compounds React


The reactivity of a carboxylic acid derivative depends onthe basicity of the substituent attached to the acyl group:


Electron withdrawal increases the carbonyl carbon’ssusceptibility to nucleophilic attack:

The weaker the basicity of Y, the greater the reactivity:


Weak bases are easier to expel when the tetrahedral intermediate collapses:


A carboxylic acid derivative can be converted only into a less reactive carboxylic acid derivative:


The tetrahedral intermediate eliminates the weaker base:


If the nucleophile is neutral…


Reactions of Acyl Halides

A base is required to trap the HCl product

Suitable bases include triethylamine (TEA) and pyridine


TEA

Excess amine traps HCl




Formation of Amides from Acyl Halides

Tertiary amines cannot form amides


Reactions of Acid Anhydrides

Acid anhydrides do not react with sodium chloride or with sodium bromide because Cl– and Br– are weaker bases than acetate


Anhydride reactions are facilitated by acid or base catalysts


Mechanism for the conversion of an acid anhydride into an ester (and a carboxylic acid):

Addition facilitated by protonation

Elimination facilitated by protonation

In the absence of an acid catalyst, the reaction is sluggish, but the reaction speeds up as acid products are formed


Reactions of Esters



Phenyl esters are more reactive than alkyl esters becausephenolate ions are weaker bases than alkoxide ions:


Hydrolysis of an ester with primary or secondary alkylgroups can be catalyzed by an acid

The carbonyl oxygen is first protonated,

Because…


There are no negatively charged species in the reaction:


Excess water will force the equilibrium to the right

Alcohols that have low boiling points can be removed bydistillation as they are formed


Acid catalyzes the reaction by…


An acid catalyst can make a group a better leaving group:


Esters with tertiary alkyl groups undergo hydrolysis muchmore rapidly than do others:


Transesterification is also catalyzed by acid:


Hydroxide ion increases the rate of formation as well asthe collapse of the tetrahedral intermediate:


Elucidating the reaction mechanism of nucleophilic acylsubstitution:


Fats and Oils Are Triesters of Glycerol


Long-chain carboxylate ions form micelles:

• The nonpolar tails are buried in the hydrophobic interior.• The polar carboxylates are positioned at the aqueous exterior.


Reactions of Carboxylic Acids


Carboxylic acids do not undergo nucleophilic acylsubstitution reactions with amines at room temperature

Heating the ammonium carboxylate will afford the amide and water


Reactions of Amides

Amides are very unreactive carboxylative derivatives


Amides can react with water and alcohols if an acid catalyst is present:


Dehydration of an Amide

Dehydration reagents commonly used are SOCl2, P2O5,or POCl3


An acid catalyst can make the amine a better leaving group:


The need for an acid catalyst…

Ammonia is an excellent leaving group

Ammonia anion is a very poor leaving group


Hydrolysis of an Imide:The Gabriel Synthesis

This is a way to synthesize amines


The Hydrolysis of Nitriles

Mechanism:


Designing the Synthesis of Cyclic Compounds

Formation of lactones:


Preparation of a compound with a ketone group attachedto a benzene ring:


Preparation of a cyclic ether:


Activation of Carboxylic Acids


The goal is to convert the OH group into a better leavinggroup:


The acyl halide can be used to prepare other carboxylicacid derivatives:

TEA



Activated Carboxylic Acid Derivatives in Living Organisms



Attack of a nucleophile breaks a phosphoanhydride bond:



The carbonyl carbon of a thioester is more susceptible tonucleophilic attack than is the carbonyl carbon of an oxygen ester


Dicarboxylic acids readily lose water upon heating if they can form a five- or six-member cyclic anhydride


The two pKa values of a dicarboxylic acid are different:

Why? • The neighboring COOH group withdraws electrons

and lowers the first pKa.• Electrostatic interaction between like charges raises

the second pKa.


Preparation of Cyclic Anhydrides from Dicarboxylic Acids


Substitution Reactions of Acid Chlorides


Substitution Reactions of Anhydrides


Substitution Reactions of Esters


Substitution Reactions of Amides and Acids


Olestra

Sucrose esterified with fatty acids

Tastes like a fat, but the sterically hindered esters cannot be digested

Shown are esters of common fatty acids (actually, a variety of fatty ester combinations makes up Olestra)


AcetylcholinesteraseTerminates the cholinergic signal by hydrolyzing acetylcholine:

Mechanism involves acetyl transfer to a serine oxygen

Cholinergic activity = SLUDSalivationUrinationLacrimationDefecation


Nerve Gases• Nerve gases phosphorylate the active-site

serine oxygen of acetylcholinesterase.• Acetylcholine builds up, resulting in

“SLUD” and eventually death by convulsions.

• Nerve gases are actually high-boiling liquids that are used as aerosols.

The phosphorylation reaction requires the presence of a good leaving group


Bioactivation of Acetate

The –SCoA leaving group is highly functionalized so that acetyl transfer does not occur randomly


Biosynthesis of AcetylcholineThe choline from the acetylcholinesterase-mediated hydrolysis of acetylcholine is taken up by the presynaptic cholinergic neuron and reacetylated:

The acetylcholine is stored for the next nerve impulse


PenicillinThe strained lactam ring acylates a serine

hydroxyl of a transpeptidase,

resulting in the absence of peptidoglycan cross-links required for the bacterial cell wall synthesis


Bacteria can become resistant to penicillin by producing an enzyme that hydrolyzes the lactam ring:

Changing the R group can overcome resistance as well as increase the spectrum of activity:

Documents

Chapter 17 Carbonyl Compounds I Reactions of Carboxylic Acids and Carboxylic Acid Derivatives