Solution(a) Diphenylamine(b) trans-2-Aminocyclohexanol(c) Its systematic name is (S)-1-phenyl-2-propanamine. Its common name is am-

phetamine. The dextrorotatory isomer of amphetamine (shown here) is acentral nervous system stimulant and is manufactured and sold under severaltrade names. The salt with sulfuric acid is marketed as Dexedrine sulfate.

Problem 23.4Write the IUPAC and, where possible, a common name for each compound.

(){OOH

(a) I NH:::::::,.. 2

Quaternary 14) ammonium ionAn ion in which nitrogen isbonded to four carbons and bearsa positive charge.

An ion containing a nitrogen atom bonded to any combination of four alkylor aryl groups is classified as a quaternary (4) ammonium ion. Compounds con-taining such ions have properties characteristic of salts. Cetylpyridinium chlorideis used as a topical antiseptic and disinfectant.

Tetramethylammoniumchloride

CI-

< ICH2(CH2h2CH3Tetradecylpyridinium chloride

(Cetylpyridinium chloride)Benzyltrimethylammonium

hydroxide

iiciill."

.l!~

.~~

L...- ~ ____' JQ

23.3 Chirality of Amines and QuaternaryAmmonium Ions

The geometry of a nitrogen atom bonded to three other atoms or groups of atoms istrigonal pyramidal (Section 1.4). The sp3-hybridized nitrogen atom is at the apex ofthe pyramid, and the three groups bonded to it extend downward to form the triangu-lar base of the pyramid. Ifwe consider the unshared pair of electrons on nitrogen asa fourth group, then the arrangement of "groups" around nitrogen is approximatelytetrahedral. Because of this geometry, an amine with three different groups bonded tonitrogen is chiral and can exist as a pair of enantiomers, as illustrated by the nonsuper-posable mirror images of ethylmethylamine. In assigning configuration to these enan-tiomers, the group of lowest priority on nitrogen is the unshared pair of electrons.

In principle, a chiral amine should be resolvable; that is, it should be separableinto a pair of enantiomers. Except for special cases, however, the enantiomers can-

Several over-tlu7-countermouthwashes contain anN-alkylpyridinium chlorideas an antibacterial agent.

884 Chapter 23 Amines

(S)-Ethylmethylamine (R)-Ethylmethylamine

not be resolved because they undergo rapid interconversion by a process knownas pyramidal inversion. Pyramidal inversion is the rapid oscillation of a nitrogenatom from one side of the plane of the three atoms bonded to it to the other sideof that plane.

To visualize this process, imagine the sp3-hybridized nitrogen atom lyingabove the plane of the three atoms to which it is bonded. In the transition statefor pyramidal inversion, the nitrogen atom and the three groups to which itis bonded become coplanar, and the molecule becomes achiral. In this planartransition state, nitrogen is sp2 hybridized, and its lone pair of electrons lies inits unhybridized 2p orbital. Nitrogen then completes the inversion, becomes Sp3hybridized again, and now lies below the plane of the three atoms to which itis bonded.

Unhybridized2porbital

H

!H3C~/ /CH2CH3

sfJl hybrid

""

SEnantiomer Planar transition state REnantiomer

As a result of pyramidal inversion, a chiral amine quite literally turns itselfinside out, like an umbrella in a strong wind, and in the process becomes a race-mic mixture. The activation energy for pyramidal inversion of simple amines isabout 25 kJ (6 kcal)/mol. For ammonia at room temperature, the rate of nitrogeninversion is approximately 2 X lOll S-l. For simple amines, the rate is less rapidbut nonetheless sufficient to make resolution impossible.

Pyramidal inversion is not possible for quaternary ammonium ions, and theirsalts can be resolved.

23.4 Physical PropertiesAmines are polar compounds, and both primary and secondary amines form inter-molecular hydrogen bonds (Figure 23.1).

Phosphorus, in the same family as nitrogen, forms trivalent compounds calledphosphines, which also have trigonal pyramidal geometry. The activation energyfor pyramidal inversion of trivalent phosphorus compounds is considerably greaterthan it is for trivalent compounds of nitrogen, with the result that a number of chi-ral phosphines have been resolved.

hydrogen bonding

....~ll+ RH '"

""I> ll+ ll-vRN:H-N

R'\\\'J .~""R

Figure 23.1Intermolecular associationby hydrogen bonding in pri-mary and secondary amines.Nitrogen is approximatelytetrahedral in shape with theaxis of the hydrogen bondalong the fourth position ofthe tetrahedron.

R Enantiomer

(')c~

+~N~IEtMe

SEnantiomer

23.4 Physical Properties 885

ChemicalConnections

The Poison Dart Frogs of South America

The Noanama and Embra peoples of the jungles ofwestern Colombia have used poison blow darts for cen-turies, perhaps millennia. The poisons are obtainedfrom the skin secretions of several brightly coloredfrogs of the genus Phyllobates (neara and kokoi in thelanguage of the native peoples). A single frog containsenough poison for up to 20 darts. For the most poison-ous species (Phyllobates terribilis), just rubbing a dartover the frog's back suffices to charge the dart withpoison.

Scientists at the National Institutes of Health inthe United States became interested in studying thesepoisons when it was discovered that they act on cellu-lar ion channels, which would make them useful toolsin basic research on mechanisms of ion transport. Afield station was, therefore, established in western Co-lombia to collect the relatively common poison dartfrogs. From 5000 frogs, 11 mgs of two toxins, giventhe names batrachotoxin and batrachotoxinin A, wereisolated. These names are derived from batrachos, theGreek word for frog. A combination of NMR spec-troscopy, mass spectrometry, and single-crystal x-ray

channels in nerve and muscle cells to be blocked in theopen position, which leads to a huge influx of Na+ ionsinto the affected cell.

The batrachotoxin story illustrates several com-mon themes in drug discovery. First, information

H

Batrachotoxin

diffraction was used to determine the structures ofthese compounds.

Batrachotoxin and batrachotoxinin A are among themost lethal poisons ever discovered. It is estimated thatas little as 200 p,g of batrachotoxin is sufficient to induceirreversible cardiac arrest in a human being. It has beendetermined that they act by causing voltage-gated Na+

H

Batrachotoxinin A

about the kinds of biologically active compounds andtheir sources is often obtained from the native peo-ples of a region. Second, tropical rain forests are arich source of structurally complex, biologically ac-tive substances. Third, the entire ecosystem, not justthe plants, is a potential source of fascinating organicmolecules.

An N-H .. N hydrogen bond is weaker than an O-H"'O hydrogenbond because the difference in electronegativity between nitrogen andhydrogen (3.0 - 2.1 = 0.9) is less than that between oxygen and hydrogen(3.5 - 2.1 = 1.4). The effect of intermolecular hydrogen bonding can be illus-trated by comparing the boiling points of methylamine and methanol. Both arepolar molecules and interact in the pure liquid by hydrogen bonding. Because

886 Chapter 23 Amines

Connections toBiological Chemistry

The Planarity of-NH2 Groups on Aromatic Rings

An important aspect of the molecular structure of bio-molecules is that amino groups bonded to an aromatic

ring are sp2 hybridized and planar. As described for ani-line in the preceding section, this structure is the result

sp2-like andnear planar

-/~Aniline Aniline (viewed through an edge)

of resonance delocalization of the amino group lone pairinto the aromatic ring. Resonance delocalization requiresthe nitrogen to be sf hybridized with the lone pair in a2p orbital to allow overlap with the aromatic 7T system.

The planarity of amino groups on aromatic ringshas a profound influence on the properties and fold-ing of nucleic acids. Three of the four common hetero-cyclic aromatic amine bases of nucleic acid bases haveplanar amino groups (Figure 1). Not only does the sfhybridization of the amino group allow for a relativelyflat overall base structure (perfect for stacking), but thegeometry of the planar amino group is ideal for mak-ing specific, highly directional hydrogen bonds with thecomplementary base.

Two hydrogen sp2 hybridized

:~~~,~;j;:~~~o-t~o~N-H 'N~N\yoN----( "=~\--n :0:o ,( Ad.rune .-J 1

oI

-o-p=oIo1

Sp2 hybridized Three hydrogenand planar bonds

~ Guanine (G) ~- K,--H---':K-J\y-:1~o

N----( )=~\1 :O:---H-No 0 j\H 0

o sp2 hybridized lI and planar

-O-p=OIo1

Figure 1The structures of the T-A and C-G base pairs showing the locations of planar -NH2 groups bonded to the aromatic basesas well as the specific patterns of hydrogen bonds responsible for recognition between complementary strands of DNA.

For aniline and other arylamines, the resonance stabilization is the result of theinteraction of the unshared pair on nitrogen with the 7T system of the aromaticring. The resonance energy of benzene is approximately 151 kJ (36 kcal)/mol. Foraniline, it is 163 kJ (39 kcal)/mol. Because of this resonance interaction, the elec-tron pair on nitrogen is less available for reaction with acid. No such resonancestabilization is possible for alkylamines. Therefore, the electron pair on the nitro-gen of an alkylamine is more available for reaction with an acid; alkylamines arestronger bases than arylamines.

The second factor contributing to the decreased basicity of aromatic amines isthe electron-withdrawing inductive effect of the sp2-hybridized carbons of the aro-matic ring compared with the sp3-hybridized carbons of aliphatic amines. The

890 Chapter 23 Amines

The DNA duplex (Chapter 28) stores genetic in-formation, based largely on patterns of specific hy-drogen bonds. Adenine (A)-thymine (T) base pairshave two hydrogen bonds between them; guanine(G)-cytosine (C) base pairs have three hydrogenbonds (Figure 1). Moreover, the pattern of hydro-gen bond donors and acceptors is different for thetwo base pairs. These two distinct patterns of hydro-

gen bonding make possible the recognition of DNAstrands of the complementary sequence. In addition,the hydrogen bonds help hold two complementaryDNA strands together in the familiar double helix(Figure 2). If the amino groups on the DNA baseswere not sp2 hybridized and planar, the DNA basepairs would not be flat enough to stack in the in-terior of the assembled helix.

Figure 2A section of a DNA double helix illustrating the planarity of thebases, including the planarity of the -NH2 groups. Base-pairhydrogen bonds are shown as green broken lines.

unshared pair of electrons on nitrogen in an aromatic amine is pulled toward thering and, therefore, is less available for protonation to form the conjugate acid ofthe amine. These factors are the same two that operate to make phenoxide ion lessbasic than alkoxide ions (Section 21.4B).

Electron-releasing groups (for example, methyl, ethyl, and other alkyl groups)increase the basicity of aromatic amines, whereas electron-withdrawing groups (forexample, nitro, and carbonyl groups) decrease their basicity. The decrease in basicityon halogen substitution is the result of the electron-withdrawing inductive effect ofthe electronegative halogen. The decrease in basicity on nitro substitution is causedby a combination of inductive and resonance effects as can be seen by comparingthe pK;. values for the conjugate acids of 3-nitroaniline and 4-nitroaniline.

23.5 Basicity 891

Online homework for this Chapter may be assigned in Organic OWL. indicates problems assignable in Organic OWL.Red numbers indicate applied problems.

(a) N;NDimethylaniline (b) Triethylamine(c) ten~Butylamine (d) 1,4-Benzenediamine(e) 4-Aminobutanoic acid (f) (R)-2-Butanamine(g) Benzylamine (h) trans-2-Aminocyclohexanol(i) I-Phenyl-2-propanamine (amphetamine) (j) Lithium diisopropylamide (LDA)(k) Benzyltrimethylammonium hydroxide (Triton B)

0-

0- I+ 100-150C 0CH2-~-CH3----' CH2 + (CH3hNOHCH3

~ClY

Cl

18. Cope Elimination: Pyrolysis of a Tertiary Amine Oxide (Section 23.10) Elimination issyn stereoselective and involves a cyclic flow of six electrons in a planar transition state.

17. Hofmann Elimination (Section 23.9) Anti stereoselective elimination of quaternary am-monium hydroxides occurs preferentially to form the least substituted carbon-carbondouble bond (Hofmann's rule). The mechanism involves the simultaneous deproton-ation of a fj-hydrogen by base and loss of the amino group in an anti geometry.

14. Sandmeyer Reaction (Section 23.8E) Treatment ofan arenediazonium saltwith CuCl, CuBr,or CuCN results in replacement of the diazonium group by -Cl, -Br, or -eN, respectively.

15. Reaction of an Arenediazonium Salt with KI (Section 23.8E) Treatment of an arene-diazonium salt with KI is the most convenient method for introducing iodine onto anaromatic ring.

16. Reduction of an Arenediazonium Salt with Hypophosphorous Acid (Section 23.8E)An -N02 or -NH2 group can be used to control orientation of further substitutionand then removed after it has served its purpose.

PROBLEMS

Structure and Nomenclature23.16 Draw a structural formula for each amine and amine derivative.

914 Chapter 23 Amines Assignable in OWL

crCOOH(h) I~N

Chloroquine(an antimalarial racemic)

H(d)/N~

(R)-Albuterol

OH

HO~'t_BUHoN

Benzocaine(a topical anesthetic)

oIf,OEt(b)HN ~2

(R)-Epinephrine(Adrenaline)

OH

Hoif~""""I MeHO ~

Serotonin(a neurotransmitter)

R = H; MorphineR= CH3; Codeine

Classity each amine as primary, secondary, or tertiary and as aliphatic or aromatic.EtHN~~""""EtDJ~(c) ICI ~ N h

23.18

(a) Classity each amine as a primary, secondary, or tertiary.(b) Compare the similarities and differences between their structural formulas.

23.20 Draw the structural formula for a compound with the given molecular formula.(a) A 2 0 arylamine, C7HgN (b) A 30 arylamine, CsHnN(c) Al 0 aliphatic amine, C7H gN (d) A chiral1 0 amine, C4H n N(e) A 30 heterocyclic amine, C6H n N (f) A trisubstituted 10 arylamine, C9H 13N(g) A chiral quaternary ammonium salt, C6H 16NCI

23.21 Morphine and its ().methylated derivative codeine are among the most effective pain-killers known. However, they possess two serious drawbacks: they are addictive, and re-peated use induces a tolerance to the drug. Many morphine analogs have been pre-pared in an effort to find drugs that are equally effective as painkillers but that haveless risk of physical dependence and potential for abuse. Following are several of these.

23.19 Epinephrine is a hormone secreted by the adrenal medulla. Among its actions, it isa bronchodilator. Albuterol, sold under several trade names, including Proventil andSalbumol, is one of the most effective and widely prescribed antiasthma drugs. TheR enantiomer of albuterol is 68 times more effective in the treatment of asthma thanthe Senantiomer.

23.17 Give an acceptable name for these compounds.

HOQJNH2(a) I I

~ NI

H

Assignable in OWL Problems 915