Chapter 21
Carboxylic Acid Derivatives
21-00-09UN

Labeled
Title
 Protonation of an Amide
Caption
 A concentrated strong acid is required to protonate an amide, and protonation occurs on the carbonyl oxygen atom rather than on nitrogen.
Notes
 As can be seen from the resonance forms, the carbon nitrogen bond has double bond character.
Keywords
 protonation, amide
21-01

Labeled
Title
 Electronic Structures of Acetonitrile and Propyne
Caption
 Figure 21-1 Comparison of the electronic structures of acetonitrile and propyne (methylacetylene). In both compounds, the atoms at the ends of the triple bonds are sp hybridized, and the bond angles are 180o. In place of the acetylenic hydrogen atom, the nitrile has a lone pair of electrons in the sp orbital of nitrogen.
Notes
 The nonbonding electrons on the nitrogen are not basic.
Keywords
 acetonitrile, propyne
21-02

Labeled
Title
 Boiling Points of Carboxylic Acid Derivatives
Caption
 Figure 21-2 Boiling points of acid derivatives plotted against their molecular weights. Alcohols and unbranched alkanes are included for comparison.
Notes
 Amides have higher boiling points than acid, nitriles, esters, and acyl chlorides.
Keywords
 acid, nitriles, esters, acyl chlorides
21-03

Labeled
Title
 Intermolecular Forces of Amides
Caption
 Figure 21-3 The resonance picture of an amide shows its strong polar nature. Hydrogen bonds and dipolar attraction stabilize the liquid phase, resulting in higher boiling points.
Notes
 Amides have higher boiling points than carboxylic acids of similar molecular weights.
Keywords
 liquid phase
21-03-03T03

Labeled
Title
 Characteristic IR Stretching Absorptions of Acid Derivatives
Caption
 IR spectroscopy is often the best method to detect and differentiate these carboxylic acid derivatives.
Notes
 Acid chlorides, anhydrides, nitriles and esters have C=O frequencies above 1710 cm-1.
Keywords
 IR spectroscopy
21-04a

Labeled
Title
 IR Spectrum of Ethyl Octanoate
Caption
 Infrared spectra of ethyl octanoate. The carbonyl stretching frequency of simple esters is around 1735 cm-1.
Notes
 Conjugated esters have lower C=O stretching frequencies.
Keywords
 ethyl octanoate
21-05

Labeled
Title
 IR Frequencies of Lactones and Lactams
Caption
 Figure 21-5 Ring strain in a lactam increases the carbonyl stretching frequency.
Notes
 High strained systems have higher C=O frequencies.
Keywords
 lactams, lactones, ring strain
21-06

Labeled
Title
 IR Spectrum of Propionic Anhydride
Caption
 Figure 21-6 IR spectrum of propionic anhydride, showing C=O stretching absorptions at 1818 and 1751 cm-1.
Notes
Keywords
 propionic anhydride
21-07

Labeled
Title
 Typical Proton NMR Absorptions of Acid Derivatives
Caption
 Figure 21-7 Typical absorptions of acid derivatives in the proton NMR spectrum.
Notes
 The absoption of an amide proton is variable and depend on the sample concentration and the solvent used.
Keywords
 absorption
21-08-08UN

Labeled
Title
 Reactivity of Acid Derivatives
Caption
 The reactivity of acid derivatives toward nucleophilic attack depends on their structure and on the nature of the attacking nucleophile.
Notes
 Acid chlorides are the most reactive derivatives, while the carboxylate ion is the less reactive of the derivatives.
Keywords
 carboxylate ion
21-09

Labeled
Title
 Interconversion of Acid Derivatives
Caption
 Figure 21-9 More reactive acid derivatives are easily converted to less reactives.
Notes
 Only a carboxylic acid can be converted into a more reactive intermediate (the acyl chloride) by reaction with thionyl chloride.
Keywords
 thionyl chloride
21-09-02UN

Labeled
Title
 Synthesis of Anhydrides
Caption
 Conversion of an acyl chlroride to an anhydride.
Notes
 The reaction of an acyl chloride with an acid gives the anhydride.
Keywords
21-09-03UN

Labeled
Title
 Synthesis of Esters
Caption
 Conversion of an acid chloride to an ester.
Notes
 Nucleophilic attack of the alcohol on the acid chloride produces the ester.
Keywords
21-09-04UN

Labeled
Title
 Synthesis of Amides
Caption
 Conversion of an acid chloride to an amide.
Notes
 Addition of two equivalent of amine to the acid chloride will produce the amide.
Keywords
21-09-06UN

Labeled
Title
 Synthesis of Esters
Caption
 Conversion of an acid anhydride to an ester.
Notes
 Attack of the alcohol on either carbonyl will produce one molecule of ester and a molecule of the carboxylic acid.
Keywords
21-09-07UN

Labeled
Title
 Synthesis of Amides
Caption
 Conversion of an acid anhydride to an amide.
Notes
 Depending on the amine used, the product can be a secondary or a tertiary amine.
Keywords
21-09-08UN

Labeled
Title
 Ammonolysis of an Ester
Caption
 Conversion of an ester to an amide.
Notes
 The reaction of ammonia or a primary amine with an ester gives an equivalent of amide and an equivalentof alcohol.
Keywords
21-10

Labeled
Title
 SN2 versus Acyl Addition-Elimination
Caption
 Figure 21-10 Comparison of SN2 and acyl addition-elimination reactions with methoxide as the leaving group.
Notes
 The SN2 reaction has a concerted mechanism, while the acyl substitution has two step mechanism with an exothermic second step.
Keywords
 leaving group
21-10-08UN

Labeled
Title
 Transesterification Reaction
Caption
 When an ester is treated with a different alcohol in the presence of an acid catalyst, the two alcohol groups can interchange. An equilibrium results, and the equilibrium can be driven toward the desired ester by using a large excess of the desired alcohol or by removing the other alcohol.
Notes
 Transesterification can also occur under basic conditions using an alkoxide.
Keywords
 transesterification
21-10-15UN

Labeled
Title
 Hydrolysis of Acid Halides
Caption
 Hydrolysis of an acid halide or anhydride is usually an annoying side reaction that takes place on exposure to moist air.
Notes
 Water attack the carbonyl displacing the halide and giving, after deprotonation, the carboxylic acid.
Keywords
 hydrolysis, side reaction
21-10-17UN

Labeled
Title
 Hydrolysis of Esters: Saponification
Caption
 Soap is made by the basic hydrolysis of fats, which are esters of long-chain carboxylic acids with the triol glycerol.
Notes
 Sodium hydroxide, also called "lye", is used for the reaction.
Keywords
 triol, glycerol, fats
21-10-20UN

Labeled
Title
 Basic Hydrolysis of Amides
Caption
 Amides are the most stable acid derivatives, and stronger conditions are required for their hydrolysis than for hydrolysis of an ester.
Notes
 The hydroxide ion attacks the carbonyl forming a tetrahedral intermediate. Displacement of the amino group gives the carboxylic acid. The amine acts as a base and deprotonates the acid.
Keywords
 hydrolysis
21-10-21UN

Labeled
Title
 Acid Hydrolysis of an Amide
Caption
 Hydrolysis of an amide under acidic conditions typically requires prolonged heating in 6 M HCl.
Notes
 Under acidic conditions the mechanism of amide hydrolysis resembles that of acid-catalyzed hydrolysis of an ester.
Keywords
 hydrolysis
21-10-24UN

Labeled
Title
 Hydrolysis of Nitriles
Caption
 Nitriles are hydrolyzed to amides, and further to carboxylic acids, by heating with aqueous acid or base. Mild conditions can hydrolyze a nitrile only as far as the amide. Stronger conditions can hydrolyze it all the way to the carboxylic acid,
Notes
 The hydroxide attack the carbon of the nitrile.
Keywords
 nitriles
21-10-25UN

Labeled
Title
 Acid Hydrolysis of Nitriles
Caption
 Nitriles are hydrolyzed to amides, and further to carboxylic acids, by heating with aqueous acid or base. Mild conditions can hydrolyze a nitrile only as far as the amide. Stronger conditions can hydrolyze it all the way to the carboxylic acid,
Notes
 Under acidic conditions, the nitrile is first protonated, activating it toward attack by water.
Keywords
 hydrolysis
21-10-29UN

Labeled
Title
 Mechanism of LiAlH4 Reduction of Esters
Caption
 Both esters and acid chlorides react through an addition-elimination mechanism to give an aldehyde, which is quickly reduced to the alkoxide. Dilute acid is added in a second step to protonate the alkoxide.
Notes
 The reduction of carboxylic acids, esters, and acid chlorides with LiAlH4 produces primary alcohols
Keywords
 reduction, alkoxide
21-10-47UN

Labeled
Title
 General Anhydride Synthesis
Caption
 The most generalized method for making anhydrides is the reaction of an acid chloride with a carboxylic acid or a carboxylate salt.
Notes
 Pyridine is sometimes used to deprotonate the acid and form the carboxylate. The carboxylate attacks the carbonyl carbon, forming the tetrahedral intermediate. Expulsion of the chloride gives the anhydride.
Keywords
 pyridine, tetrahedral intermediate
21-10-51UN

Labeled
Title
 Friedel-Crafts Acylation Using Anhydrides
Caption
 Like acid chlorides, anhydrides participate in Friedel-Crafts acylation. Catalyst may be aluminum chloride, polyphosphoric acid (PPA), or other acidic reagents.
Notes
 Using a cyclic anhydride allows for only one of the acid groups to react, leaving the second acid group free to undergo further reactions.
Keywords
 cyclic anhydride, Friedel-Crafts acylation, catalyst
21-10-52UN

Labeled
Title
 Acetic Formic Anhydride
Caption
 Acetic formyl anhydride, made from sodium formate and acetyl chloride, reacts primarily at the formyl group.
Notes
 The formyl groups is more electrophilic because of the lack of alkyl groups.
Keywords
 acetic formyl anhydride, formyl group
21-10-60UN1-2

Labeled
Title
 L-Ascorbic Acid and Erythromycin
Caption
 Lactones are common among natural products. In acidic solutions, ascorbic acid is an equilibrium mixture of the cyclic and acyclic forms, but the cyclic form predominates.
Notes
 For example, L-ascorbic acid (vitamin C) is necessary in the human diet to avoid the connective tissue disease known as scurvy.
Keywords
 ascorbic acid, lactones, erythromycin
21-10-68UN

Labeled
Title
 Dehydration of Amides to Nitriles
Caption
 Strong dehydrating agents can eliminate the elements of water from a primary amide to give a nitrile.
Notes
 Phosphorus oxychloride (POCl3) or phosphorus pentoxide (P2O5) can be used as dehydrating agents.
Keywords
 dehydration, dehydrating agent, nitrile
21-10-70UN

Labeled
Title
 Formation of Lactams
Caption
 Five memebred lactams (g-lactams) and six-membered lactams (d-lactams) often form on heating or adding a dehydrating agent to the apporpriate g-amino acid or d-amino acid.
Notes
 The formation of five or six-memebred rings is favored.
Keywords
 lactams, g-lactam, d-lactam, g-amino acid, d-amino acid
21-10-71UN

Labeled
Title
 b-Lactams
Caption
 b-Lactams are unusually reactive amides capable of acylating a variety of nucleophiles. The considerable strain in the four memebered ring appears to be the driving force behind the unusual reactivity of b-lactams.
Notes
 The b-lactam ring is found in penicillins, cephalosporins, and carbapenems.
Keywords
 b-lactam, penicillins, cephalosporins, carbapenems
21-10-72UN1-3

Labeled
Title
 Penicillin V, Keflex and Primaxin
Caption
 The b-lactam ring is found in penicillins, cephalosporins, and carbapenems.
Notes
 These antiobiotics are believed to interfere with the synthesis of bacterial cell walls.
Keywords
 antiobiotics, b-lactam, penicillins, cephalosporins, carbapenems
21-11

Labeled
Title
 Function of the b-Lactams
Caption
 Figure 21-11 b-Lactams antiobiotics function by acylating and inactivating one of the enzymes needed to make the bacterial cell wall.
Notes
 The acylated enzyme is inactive.
Keywords
 acylation, enzyme
21-12

Labeled
Title
 Resonance Overlap in Ester and Thioesters
Caption
 Figure 21-12 The resonance overlap in a thioester is not as effective as that in an ester.
Notes
 The different sized of the p orbitals or sulfur and oxygen prevent an effective overlap.
Keywords
 resonance overlap, overlap, pi overlap
21-13

Labeled
Title
 Structure of Coenzyme A (CoA)
Caption
 Figure 21-13 Coenzyme A (CoA) is a thiol whose thioesters serve as a biochemical acyl transfer reagents. Acetyl CoA transfers an acetyl group to a nucleophile, with coenzyme A serving as the leaving group.
Notes
 Thioesters are not so prone to hydrolysis, yet they are excellent selective acylating reagents; therefore, thioesters are common acylating agents in living systems.
Keywords
 coenzyme A , acylating agent, thioester
21-13-04UN

Labeled
Title
 Synthesis of Carbamate Esters from Isocyanates
Caption
 Another way of making urethanes is to treat an alcohol or a phenol with an isocyanate, which is an anhydride of carbamic acid. Although the carbamic acid is unstable, the urethane is stable.
Notes
 The insecticide Sevin is synthesized this way.
Keywords
 isocyanates, carbamate esters, carbamic acid
21-13-14UN

Labeled
Title
 Polycarbonate Synthesis
Caption
 Polycarbonates are polymers bonded to the carbonate ester linkage.
Notes
 The diol used to make Lexan is a phenol called bisphenol A, a common intermediate in polyester and polyurethane synthesis.
Keywords
 polycabonate, polyurethanes, bisphenol, diol, polyester
21-13-15UN

Labeled
Title
 Synthesis of Polyurethanes
Caption
 A polyurethane results when a diol reacts with a diisocyanate, a compound with two isocyanate groups.
Notes
 Reaction of toluene diisocyanate with ethylene glycol produces one of the most common forms of polyurethanes.
Keywords
 polyurethanes, diisocyanate, isocyanate, ethylene glycol
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