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Chapter 17
Carbonyl Compounds I
Reactions of Carboxylic Acids and
Carboxylic Acid Derivatives
Organic Chemistry 6th Edition
Paula Yurkanis Bruice
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Class I Carbonyl Compounds
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Class II Carbonyl Compounds
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Nomenclature of Carboxylic Acids
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In systematic nomenclature, the carbonyl carbon is always C-1
In common nomenclature, the carbon next to the carbonyl is the -carbon
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The functional group of a carboxylic acid is called acarboxyl group
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Naming Cyclic Carboxylic Acid
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Salts of Carboxylic Acids
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Acyl Halides
Acid Anhydrides
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Esters
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Cyclic esters are known as lactones:
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Amides
If a substituent is bonded to the nitrogen, the name of thesubstituent is stated first:
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Cyclic amides are known as lactams:
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Nitriles
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Structures of Carboxylic Acids and Carboxylic Acid Derivatives
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Two major resonance contributors in esters, carboxylic acids, and amides:
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Carboxylic acids have relatively high boiling points because…
Amides have the highest boiling points:
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Naturally Occurring Carboxylic Acids and Carboxylic Acid Derivatives
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The reactivity of carbonyl compounds resides in thepolarity of the carbonyl group:
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The tetrahedral intermediate is a transient species that eliminates the leaving group Y– or the nucleophile Z–:
This is a nucleophilic acyl substitution reaction
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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):
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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):
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Both reactant and product will be present if Y– and Z–
have similar leaving abilities:
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(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
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A Molecular Orbital Description of How Carbonyl Compounds React
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The reactivity of a carboxylic acid derivative depends onthe basicity of the substituent attached to the acyl group:
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Electron withdrawal increases the carbonyl carbon’ssusceptibility to nucleophilic attack:
The weaker the basicity of Y, the greater the reactivity:
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Weak bases are easier to expel when the tetrahedral intermediate collapses:
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A carboxylic acid derivative can be converted only into a less reactive carboxylic acid derivative:
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The tetrahedral intermediate eliminates the weaker base:
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If the nucleophile is neutral…
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Reactions of Acyl Halides
A base is required to trap the HCl product
Suitable bases include triethylamine (TEA) and pyridine
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TEA
Excess amine traps HCl
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Formation of Amides from Acyl Halides
Tertiary amines cannot form amides
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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
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Anhydride reactions are facilitated by acid or base catalysts
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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
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Reactions of Esters
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Phenyl esters are more reactive than alkyl esters becausephenolate ions are weaker bases than alkoxide ions:
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Hydrolysis of an ester with primary or secondary alkylgroups can be catalyzed by an acid
The carbonyl oxygen is first protonated,
Because…
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There are no negatively charged species in the reaction:
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Excess water will force the equilibrium to the right
Alcohols that have low boiling points can be removed bydistillation as they are formed
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Acid catalyzes the reaction by…
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An acid catalyst can make a group a better leaving group:
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Esters with tertiary alkyl groups undergo hydrolysis muchmore rapidly than do others:
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Transesterification is also catalyzed by acid:
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Hydroxide ion increases the rate of formation as well asthe collapse of the tetrahedral intermediate:
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Elucidating the reaction mechanism of nucleophilic acylsubstitution:
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Fats and Oils Are Triesters of Glycerol
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Long-chain carboxylate ions form micelles:
• The nonpolar tails are buried in the hydrophobic interior.• The polar carboxylates are positioned at the aqueous exterior.
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Reactions of Carboxylic Acids
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Carboxylic acids do not undergo nucleophilic acylsubstitution reactions with amines at room temperature
Heating the ammonium carboxylate will afford the amide and water
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Reactions of Amides
Amides are very unreactive carboxylative derivatives
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Amides can react with water and alcohols if an acid catalyst is present:
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Dehydration of an Amide
Dehydration reagents commonly used are SOCl2, P2O5,or POCl3
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An acid catalyst can make the amine a better leaving group:
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The need for an acid catalyst…
Ammonia is an excellent leaving group
Ammonia anion is a very poor leaving group
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Hydrolysis of an Imide:The Gabriel Synthesis
This is a way to synthesize amines
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The Hydrolysis of Nitriles
Mechanism:
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Designing the Synthesis of Cyclic Compounds
Formation of lactones:
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Preparation of a compound with a ketone group attachedto a benzene ring:
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Preparation of a cyclic ether:
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Activation of Carboxylic Acids
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The goal is to convert the OH group into a better leavinggroup:
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The acyl halide can be used to prepare other carboxylicacid derivatives:
TEA
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Activated Carboxylic Acid Derivatives in Living Organisms
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Attack of a nucleophile breaks a phosphoanhydride bond:
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The carbonyl carbon of a thioester is more susceptible tonucleophilic attack than is the carbonyl carbon of an oxygen ester
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Dicarboxylic acids readily lose water upon heating if they can form a five- or six-member cyclic anhydride
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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.
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Preparation of Cyclic Anhydrides from Dicarboxylic Acids
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Substitution Reactions of Acid Chlorides
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Substitution Reactions of Anhydrides
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Substitution Reactions of Esters
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Substitution Reactions of Amides and Acids
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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)
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AcetylcholinesteraseTerminates the cholinergic signal by hydrolyzing acetylcholine:
Mechanism involves acetyl transfer to a serine oxygen
Cholinergic activity = SLUDSalivationUrinationLacrimationDefecation
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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
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Bioactivation of Acetate
The –SCoA leaving group is highly functionalized so that acetyl transfer does not occur randomly
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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
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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
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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: