Colored scanning electronmicrograph of Penicillium s.

fungus. The stalklike objects arecondiophores to which are attachednumerous round condia. The condiaare the fruiting bodies of the fun-gus. Inset: a model of amoxicillin.See Chemical Connections: "ThePenicillins and Cephalosporins:j3-Lactam Antibiotics."

OUTLINE

I n this chapter, we study five classes of organic compounds, each related to thecarboxyl group: acid halides, acid anhydrides, esters, amides, and nitriles.Under the general formula of each functional group is an illustration toshow you how the group is formally related to a carboxylic acid. Formal loss of-OH from a carboxyl group and H- from H-Cl, for example, gives an acidchloride. Similarly, loss of -OH from a carboxyl group and H- from ammoniagives an amide.

18.1 Structure andNomenclature

18.2 Acidity of Amides,Imides, and Sulfonamides

18.3 Characteristics Reactions18.4 Reaction with Water:

Hydrolysis18.5 Reaction with Alcohols18.6 Reactions with Ammonia

and Amines18.7 Reaction of Acid

Chlorides with Salts ofCarboxylic Acids

18.8 Interconversion ofFunctional Derivatives

18.9 Reactions withOrganometallicCompounds

18.10 Reduction

RC=N

HO HI I

RC=N

oII

RCNH2

oII

RC-OH H-NH2

oII

RCOR'

oII

RC-OH H-OR'

00II II

RCOCR'

An acid anhydride

I-H2oo 0II II

H-Cl RC-OH H -OCR'

oII

RCCl

An acid chloride

I-H2ooII

RC-OH

The enol ofan amide

Online homework for thischapter may be assignedin Organic OWL.

18.1 Structure and NomenclatureA. Acid HalidesThe functional group of an acid halide (acyl halide) is an acyl group (RCO-)bonded to a halogen atom. Acid chlorides are the most common acid halides.

Acyl groupAn RCO- or ArCO- group.

653

Connections tof ~~ Biological Chemistry

The Unique Structure of Amide Bonds

Amides have structural characteristics that are uniqueamong carboxylic acid derivatives. In the late 1930s,Linus Pauling discovered that the bond angles aboutthe nitrogen atom of an amide bond in proteins areclose to 120; the amide nitrogen is trigonal planarand sjJ hybridized. We know that amides are best rep-resented as a hybrid of three resonance contributingstructures (see Section 1.9C).

(7T' bond) in the resonance hybrid indicates the pres-ence of a restricted bond rotation about the C-Nbond. The measured C-N bond rotation barrier inamides is approximately 63-84 kJ (15-20 kcal)/mol,large enough so that, at room temperature, rotationabout the C-N bond is restricted. In addition, be-cause the lone pair on nitrogen is delocalized intothe 7T' bond, it is not as available for interacting with

This contributing structureplaces a double bond

between C and N

The fact that the six atoms of an amide bondare planar with bond angles of 120 means that theresonance structure on the right makes a significantcontribution to the hybrid, and that the hybrid looksvery much like this third structure. Inclusion of thethird contributing structure explains why the am-ide nitrogen is Sp2 hybridized and therefore trigonalplanar. Also, the presence of a partial double bond

protons and other Lewis acids. Thus, amide nitro-gens are not basic. In fact, in acid solution, amidesare protonated on the carbonyl oxygen atom, ratherthan on the nitrogen (review Example 4.2). Finally,delocalization of the nitrogen lone pair reduces theelectrophilic character (partial positive charge) onthe carbonyl carbon, thus reducing the susceptibilityof amides to nucleophilic attack.

18.2 Acidity of Amides, Imides, and SulfonamidesFollowing are structural formulas of a primary amide, a sulfonamide, and two cyclicimides, along with pK;, values for each.

~NH ~NHo 0

AcetamidepK" 15-17

BenzenesulfonamidepK" 10

SuccinimidepK" 9.7

PhthalimidepK" 8.3

Values of pK;, for amides of carboxylic acids are in the range of 15-17, whichmeans that they are comparable in acidity to alcohols. Amides show no evidence of

660 Chapter 18 Functional Derivatives of Carboxylic Acids

Amides Less electrophilic

protonate\=-~::eO::::bOnYISH ;1 / 41barrier due to partial

...... /Co~HI double bondH -C -oNH~ ~ 1~N atom is sp2 hybridized

H and non-basic'---------'

All of the atoms in the boxare in the same plane

The amide -NH group is a good hydrogen bonddonor, while the amide carbonyl is a good hydrogenbond acceptor, allowing both primary and secondaryamides to form strong hydrogen bonds.

As we will see in Chapter 27, the ability of amides toparticipate in both intermolecular and intramolecular hy-drogen bonding is an important factor in determining thethree-dimensional structure of polypeptides and proteins.

acidity in aqueous solution; that is, water-insoluble amides do not react with aque-ous solutions of NaOH or other alkali metal hydroxides to form water-soluble salts.

Imides (pJ(,. 8-10) are considerably more acidic than amides and readilydissolve in 5% aqueous NaOH by forming water-soluble salts. We account forthe acidity of imides in the same manner as for the acidity of carboxylic acids(Section 17.4), namely the imide anion is stabilized by delocalization of its nega-tive charge. The more important contributing structures for the anion formedby ionization of an imide delocalize the negative charge on nitrogen and the twocarbonyl oxygens.

.. .. ..

01:~ ~:p ~:oI :N:- I CN:- I N:~ ~ ~ ~0: (0: :0:.. .. ..

A resonance-stabilized anion

18.2 Acidity of Amides, Imides, and Sulfonamides 661

The weakest base in the series, and the best leaving group, is halide ion; acid ha-lides are the most reactive toward nucleophilic acyl substitution. The strongest base,and the poorest leaving group, is amide ion; amides are the least reactive towardnucleophilic acyl substitution. Acid halides and acid anhydrides are so reactive thatthey are not found in nature, but esters and amides are universally present.

The degree of partial positive charge on the carbonyl carbon increases inorder from amide to ester to acid anhydride to acid chloride. This increase isshown by the increasing amount of blue on the carbonyl carbon in the electro-static potential maps.

Amide < Ester < Acid anhydride < Acid halide

I' ' I leophilic acyl substitution

Given this trend, the carbonyl carbon of an acid chloride is most susceptible ofthe four functional groups to attack by a nucleophile; the carbonyl carbon of theamide is the least susceptible to nucleophilic attack.

Taken together, the combined effects ofleaving group ability and susceptibilityto nucleophilic attack reinforce each other. Acid chlorides are the most susceptibleto nucleophilic attack, and chloride is the best leaving group, making it clear thatacid chlorides have the highest reactivity of the four toward nucleophilic substitu-tion reactions. Amides are overall the least reactive.

oII

RCNH2Amide

oII

RCOR'

Ester

00II II

RCOCR'

Anhydride

oII

RCX

Acid halide

I : I . I

In addition, many reactions of the less reactive carboxyl derivatives occur byacid catalysis. In these reactions, the carbonyl group is protonated in the first step,which increases its electrophilicity and facilitates nucleophilic attack. In addition,the leaving group is protonated by the acid in a later step to decrease its basicityand make it a better leaving group. We will see detailed mechanisms for manyexamples of both acid- and base-catalyzed reactions in this chapter. We saw theacid-catalyzed reversible reaction of acids with alcohols in Section 17.7A.

18.4 Reaction with Water: HydrolysisA. Acid ChloridesLow-molecular-weight acid chlorides react very rapidly with water to form carboxylicacids and HeI.

o 0II II

CH3CCI + H20 - CH3COH + HCI

Acetyl chloride

Higher molecular-weight acid halides are less soluble and, consequently, reactless rapidly with water. Because the mechanisms for hydrolysis of acid chlorides

664 Chapter 18 Functional Derivatives of Carboxylic Acids

oII

(f) CH30~OCH3o

o

(C)~NHCH3

N,N-Dimethylacetamidemp -20C, bp 165C

o 0

(e) EtO~OEt

(b) Benzonitrile(d) Diethyloxalate(f) Butanoic anhydride(h) Ethyl 3-hydroxybutanoate(j) Diethyl cis-l,2-eydohexanedicarboxylate(1) p-Toluenesulfonyl chloride

o 0

(h)CI~CI

l.LiAlH4 ether2.H20

oII(b) Ph-S-NHII 2o

oII

CH3CNH2

Acetamidemp 82.3C, bp 221.2C

~CNVBr Br

o 0

(g) Ph~OCH"

(a) Dimethyl carbonate(c) Isopropyl 3-methylhexanoate(e) Ethyl (Z)-2-pentenoate(g) Dodecanamide(i) Octanoyl chloride(k) Methanesulfonyl chloride

19. Reduction of a Nitrile (Section 18.10CI Reduction of a cyano group by lithium alumi-num hydride gives a primary amino group.

rearranges electron pairs to eject an AI-O species to give an electrophilic iminium ion,which reacts with another equivalent of hydride to give the amine product.

o~ 1.LiAlH4~

NH2 2.H20 ) NH2

PROBLEMS

Physical Properties18.14 Both the melting point and boiling point of acetamide are higher than those of its

N;Ndimethyl derivative. How do you account for these differences?

18.13 Write the IUPAC name for each compound.

Structure and Nomenclature18.12 Draw a structural formulas for each compound.

","","",,",,",./,