© 2011 Pearson Education, Inc. 1 Chapter 17 Carbonyl Compounds I Reactions of Carboxylic Acids and Carboxylic Acid Derivatives Organic Chemistry 6 th Edition Paula Yurkanis Bruice

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3 Class I Carbonyl Compounds

© 2011 Pearson Education, Inc. 4 Class II Carbonyl Compounds

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6 Nomenclature of Carboxylic Acids

© 2011 Pearson Education, Inc. 7 In systematic nomenclature, the carbonyl carbon is always C-1 In common nomenclature, the carbon next to the carbonyl is the  -carbon

© 2011 Pearson Education, Inc. 8 The functional group of a carboxylic acid is called a carboxyl group

© 2011 Pearson Education, Inc. 9 Naming Cyclic Carboxylic Acid

© 2011 Pearson Education, Inc. 10 Salts of Carboxylic Acids

© 2011 Pearson Education, Inc. 11 Acyl Halides Acid Anhydrides

© 2011 Pearson Education, Inc. 12 Esters

© 2011 Pearson Education, Inc. 13 Cyclic esters are known as lactones:

© 2011 Pearson Education, Inc. 14 Amides If a substituent is bonded to the nitrogen, the name of the substituent is stated first:

© 2011 Pearson Education, Inc. 15 Cyclic amides are known as lactams:

© 2011 Pearson Education, Inc. 16 Nitriles

© 2011 Pearson Education, Inc. 17 Structures of Carboxylic Acids and Carboxylic Acid Derivatives

© 2011 Pearson Education, Inc. 18 Two major resonance contributors in esters, carboxylic acids, and amides:

© 2011 Pearson Education, Inc. 19 Carboxylic acids have relatively high boiling points because… Amides have the highest boiling points:

© 2011 Pearson Education, Inc. 20 Naturally Occurring Carboxylic Acids and Carboxylic Acid Derivatives

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© 2011 Pearson Education, Inc. 22 The reactivity of carbonyl compounds resides in the polarity of the carbonyl group:

© 2011 Pearson Education, Inc. 23 The tetrahedral intermediate is a transient species that eliminates the leaving group Y – or the nucleophile Z – : This is a nucleophilic acyl substitution reaction

© 2011 Pearson Education, Inc. 24 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 >> k 2 ):

© 2011 Pearson Education, Inc. 25 Y – will be expelled if it is a weaker base than Z – ; that is, Y – is a better leaving group than Z – (k 2 >> k –1 ):

© 2011 Pearson Education, Inc. 26 Both reactant and product will be present if Y – and Z – have similar leaving abilities:

© 2011 Pearson Education, Inc. 27 (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 for Nucleophilic Acyl Substitution Reactions

© 2011 Pearson Education, Inc. 28 A Molecular Orbital Description of How Carbonyl Compounds React

© 2011 Pearson Education, Inc. 29 The reactivity of a carboxylic acid derivative depends on the basicity of the substituent attached to the acyl group:

© 2011 Pearson Education, Inc. 30 Electron withdrawal increases the carbonyl carbon’s susceptibility to nucleophilic attack: The weaker the basicity of Y, the greater the reactivity:

© 2011 Pearson Education, Inc. 31 Weak bases are easier to expel when the tetrahedral intermediate collapses:

© 2011 Pearson Education, Inc. 32 A carboxylic acid derivative can be converted only into a less reactive carboxylic acid derivative:

© 2011 Pearson Education, Inc. 33 The tetrahedral intermediate eliminates the weaker base:

© 2011 Pearson Education, Inc. 34 If the nucleophile is neutral…

© 2011 Pearson Education, Inc. 35 Reactions of Acyl Halides A base is required to trap the HCl product Suitable bases include triethylamine (TEA) and pyridine

© 2011 Pearson Education, Inc. 36 TEA Excess amine traps HCl

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© 2011 Pearson Education, Inc. 39 Formation of Amides from Acyl Halides Tertiary amines cannot form amides

© 2011 Pearson Education, Inc. 40 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

© 2011 Pearson Education, Inc. 41 Anhydride reactions are facilitated by acid or base catalysts

© 2011 Pearson Education, Inc. 42 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

© 2011 Pearson Education, Inc. 43 Reactions of Esters

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© 2011 Pearson Education, Inc. 45 Phenyl esters are more reactive than alkyl esters because phenolate ions are weaker bases than alkoxide ions:

© 2011 Pearson Education, Inc. 46 Hydrolysis of an ester with primary or secondary alkyl groups can be catalyzed by an acid The carbonyl oxygen is first protonated, Because…

© 2011 Pearson Education, Inc. 47 There are no negatively charged species in the reaction:

© 2011 Pearson Education, Inc. 48 Excess water will force the equilibrium to the right Alcohols that have low boiling points can be removed by distillation as they are formed

© 2011 Pearson Education, Inc. 49 Acid catalyzes the reaction by…

© 2011 Pearson Education, Inc. 50 An acid catalyst can make a group a better leaving group:

© 2011 Pearson Education, Inc. 51 Esters with tertiary alkyl groups undergo hydrolysis much more rapidly than do others:

© 2011 Pearson Education, Inc. 52 Transesterification is also catalyzed by acid:

© 2011 Pearson Education, Inc. 53 Hydroxide ion increases the rate of formation as well as the collapse of the tetrahedral intermediate:

© 2011 Pearson Education, Inc. 54 Elucidating the reaction mechanism of nucleophilic acyl substitution:

© 2011 Pearson Education, Inc. 55 Fats and Oils Are Triesters of Glycerol

© 2011 Pearson Education, Inc. 56 Long-chain carboxylate ions form micelles: The nonpolar tails are buried in the hydrophobic interior. The polar carboxylates are positioned at the aqueous exterior.

© 2011 Pearson Education, Inc. 57 Reactions of Carboxylic Acids

© 2011 Pearson Education, Inc. 58 Carboxylic acids do not undergo nucleophilic acyl substitution reactions with amines at room temperature Heating the ammonium carboxylate will afford the amide and water

© 2011 Pearson Education, Inc. 59 Reactions of Amides Amides are very unreactive carboxylative derivatives

© 2011 Pearson Education, Inc. 60 Amides can react with water and alcohols if an acid catalyst is present:

© 2011 Pearson Education, Inc. 61 Dehydration of an Amide Dehydration reagents commonly used are SOCl 2, P 2 O 5, or POCl 3

© 2011 Pearson Education, Inc. 62 An acid catalyst can make the amine a better leaving group:

© 2011 Pearson Education, Inc. 63 The need for an acid catalyst… Ammonia is an excellent leaving group Ammonia anion is a very poor leaving group

© 2011 Pearson Education, Inc. 64 Hydrolysis of an Imide: The Gabriel Synthesis This is a way to synthesize amines

© 2011 Pearson Education, Inc. 65 The Hydrolysis of Nitriles Mechanism:

© 2011 Pearson Education, Inc. 66 Designing the Synthesis of Cyclic Compounds Formation of lactones:

© 2011 Pearson Education, Inc. 67 Preparation of a compound with a ketone group attached to a benzene ring:

© 2011 Pearson Education, Inc. 68 Preparation of a cyclic ether:

© 2011 Pearson Education, Inc. 69 Activation of Carboxylic Acids

© 2011 Pearson Education, Inc. 70 The goal is to convert the OH group into a better leaving group:

© 2011 Pearson Education, Inc. 71 The acyl halide can be used to prepare other carboxylic acid derivatives: TEA

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© 2011 Pearson Education, Inc. 73 Activated Carboxylic Acid Derivatives in Living Organisms

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© 2011 Pearson Education, Inc. 75 Attack of a nucleophile breaks a phosphoanhydride bond:

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© 2011 Pearson Education, Inc. 77 The carbonyl carbon of a thioester is more susceptible to nucleophilic attack than is the carbonyl carbon of an oxygen ester

© 2011 Pearson Education, Inc. 78 Dicarboxylic acids readily lose water upon heating if they can form a five- or six-member cyclic anhydride

© 2011 Pearson Education, Inc. 79 The two pK a values of a dicarboxylic acid are different: Why? The neighboring COOH group withdraws electrons and lowers the first pK a. Electrostatic interaction between like charges raises the second pK a.

© 2011 Pearson Education, Inc. 80 Preparation of Cyclic Anhydrides from Dicarboxylic Acids

© 2011 Pearson Education, Inc. 81 Substitution Reactions of Acid Chlorides

© 2011 Pearson Education, Inc. 82 Substitution Reactions of Anhydrides

© 2011 Pearson Education, Inc. 83 Substitution Reactions of Esters

© 2011 Pearson Education, Inc. 84 Substitution Reactions of Amides and Acids

© 2011 Pearson Education, Inc. 85 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)

© 2011 Pearson Education, Inc. 86 Acetylcholinesterase Terminates the cholinergic signal by hydrolyzing acetylcholine: Mechanism involves acetyl transfer to a serine oxygen Cholinergic activity = SLUD Salivation Urination Lacrimation Defecation

© 2011 Pearson Education, Inc. 87 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

© 2011 Pearson Education, Inc. 88 Bioactivation of Acetate The – SCoA leaving group is highly functionalized so that acetyl transfer does not occur randomly

© 2011 Pearson Education, Inc. 89 Biosynthesis of Acetylcholine The 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

© 2011 Pearson Education, Inc. 90 Penicillin The 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

© 2011 Pearson Education, Inc. 91 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: