bpo c chapter 23

7/29/2019 Bpo c Chapter 23

1/72

23ORGANON TROGENCOMPOUNDS

A wide variety of organic compounds contain nitrogen. In fact, the types ofnitrogen compounds are so numerous and diverse that we shall be unable toconsider them all. We shall give most attention to the chemistry of amines andamides in this and the following chapter, because these represent the twolargest classes of nitrogen compounds.

23-1 AMINES COMPARED WITH ALCOHOLSAs you read the chapter you will recognize a similarity between the chemistryof amines and the chemistry of alcohols, which we discussed in Chapter 15.Primary amines (RNH,) and secondary amines (R,NH) are much weakeracids than alcohols (ROH) and form strongly basic anions:Acids - -


2/72

d096 23 Organonitrogen Compounds I. AminesAmines, ]like alcohols, have nonbonding electrons that impart basic and nucleo-philic properties.

Bases

Nucleophiles

Also, amines and alcohols both can behave as carbon electrophiles underappropriate reaction conditions such that cleavage of C-N and C-O bonds

so so so sooccurs in the sense C j IN and C :O. However, because -NH2 and-OH both are poor leaving groups, each must be suitably activated to makethis kind of reaction possible (see Section 8-7C). The OH group can be acti-vated by addition of a proton or conversion to a sulfonate ester, R03SR1, utthese processes generally are ineffective for RNH,. The most effective activa-

0tion for RNH, is through conversion with nitrous acid, HONO, to R-N=N;then N, is the leaving group (this reaction is described in more detail inSection 23-1OA):

0 -H@R-NH2 *ON' > [R-N=N] + 2H20- -OH + N2 + H 2 0H@HBrR-OH - -Br + H,OThere is, though, a major difference in the way that amines and alcohols behavetoward oxidizing agents. Amines generally show more complex behavior onoxidation because, as we shall see, nitrogen has a larger number of stableoxidation states than oxygen.


3/72

23-2 Some Naturally Occurring Amines. Alkaloids and Related Compounds23-2 SOME NATURALLY OCCURRING AMINES.ALKALOIDS AND RELATED COMPOUNDSA large and widespread class of naturally occurring amines is known asalkaloids.T he se a re basic organic nitrogen comp ounds, mostly of plant origin.T h e stru ctures of the plant alkaloids a re extraordinarily complex, yet they arerelated to the simple amines in being weak nitrogen bases. In fact, the firstinvestigator to isolate an alkaloid in pu re form was F. W . A. Sertiirner who , in18 16, described morph ine (Figu re 23-1) as basic, salt-forming, and ammonia-like. He used th e term "organic alkali" from which is derived the n ame nlkaloid.

HO\R

0R HO-C-H0 /CI? -cH3O

R = H, strychnine R = H, morphineR =OCH,, brucine R = CH,, codeine(analgesic)cH

quinine(antimicrobial)(antimalarial)

cocaine(local anaesthetic)(stimulant)

atropine(stimulant)

0I

c H 3 0 ~ c " ~ z ~CH,O

OCH,H mescaline

lysergic a cid diethylamide (LSD) (hallucinogen)(hallucinogen)

caffeine(stimulant)

Figure 23-1 Some naturally occurring basic nitrogen compounds (alkaloids)


4/72

1098 23 Organonit rogen Com pounds I. Amines

amphetamine ~ ( ~ 2 ~ 5 ) 2(st imulant, decongestant) N,N-diethyl-(Benzedrine) meta-toluamide(mos quito repellant)

phenobarbi tal secobarbi tal(sedative, anticonvulsant) (seconal, sopo rif ic)

CH3pr imaquine(antimalarial)

sodium pentothal(anaesthetic)

chlorpromazine chlord iazepoxide procaine(tranquil izer) (tranquil izer) ( local anaesthetic)(Li br ium) (Novocaine)Figure 23-2 Synthetic drugs that are either basic or acidic nitrogen compounds

T he structure s of som e of the be tter known plant alkaloids are shown inFigure 23- 1.You will recog nize som e of them by n am e even if you have ne verseen their structures before. Many of the alkaloids are polycyclic structuresand have other functional groups in addition to basic nitrogen. You will seethat the nitrogens of alkaloids frequently are tertiary amine functions.All of the alkaloids s how n in Fig ure 23-1 ar e substances with very pro-nounced physiological action. Indee d, alkaloids in general have b een used andabused fo r centuries as m edicinals, drugs, and poisons. Ho we ver, only in thiscen tury hav e their structu res becom e known, and we a re still a long way fromunderstanding the chemistry that leads to their pronounced physiologicaleffects. I t is not even understood what function, if any, these com pounds hav ein the h ost plant.As you can see from Figure 23-1, alkaloids include compounds thatmay be classified a s antimicrobial (quinine), as analgesics (m orphine, code ine),as hallucinogens (mescaline, LSD), a s stimulants (coc aine, atropine , caffeine),


5/72

23-2 Some Naturally Occurring Amines. Alkaloids and Related Compoundsas topical anaesthetics (cocaine). With the possible exception of caffeine, allmay be described as potentially poisonous enough to warrant great care in theiruse. Although som e of these com pounds a re used as natural medicinals, an en-tire industry has developed in an effort to produce synthetic analogs withsimilar, but safer, medicinal pro perties. So m e of the be tter known of these sy n-thetic drugs are shown in Figure 23-2. They include a group of narcoticsubstances known as barbiturates, which are used widely as sedatives, anti-convulsants, and sleep-inducing drugs. Several representative nitrogen-containing tranquilizing drugs, synthetic stimulants, and antibiotics also areshown.Basic nitrogen compounds similar to the plant alkaloids also occur inanimals, although the description animal alkaloid seldom is used. Certainam ines and amm onium com pounds play key roles in the function of the centralnervous system (Figure 23-3) and the b alance of amines in the brain is criticalfor normal brain functioning. Also, many essential vitamins and hormonesar e basic nitrogen com pounds. N itrogen b ases also ar e vital constituents ofnucleic acid polymers ( D N A and R N A ) and of proteins (C hapter 25).

0I I CH3lo @CH3-C-0-CH2CH2-N-CH3 CIICH3acetylchol ine chlor ide(neurotransmitter) adrena lin (epineph rine) serotonin

(amine components of nerve action)

vitamin B, (thiam ine chlo ride ) nicot in ic ac id(antipellagra vitamin B)(niacin)

pyridoxamine(one of the co mp lexof B, vitam ins) riboflavin(vitamin 6,)Figure 23-3 Some biologically important amines


6/72

4 6 0 0 23 Organoni trogen Com pounds I. Amines23-3 TYPES AND NOMENCLATURE OF AMINESAmine bases are classified according to the number of alkyl or aryl groupsattached to nitrogen. This number is important in determining the chemicalreactions that a re possible at the nitrogen atom :

pr imary secondary tertiary quaternaryamine amine amine ammonium sal t

A further classification exists if the nitrogen is multiply bonded tocarbon, as in imines and arom atic nitrogen co mpo unds:R,C=NH R,C=R;IRimines (Schiff bases)

.aromatic ni t rogen bases

T he n omen clature of amines w as co nsidered briefly in Section 7-8. Weshall give only a short review here to focus on the main points. Am ino com-pounds can be named either as derivatives of amm onia o r as amino-substitutedcompounds:HOCH,CH,NH, 2-hydroxyethanam ine (2-hydroxyethylam ine) or2-aminoethanol (preferred because -01-1 takesprecedence over -NH,; Section 7- 1A )T o be consistent and logical in naming amines as substituted am monias, theystrictly should be called allcanamines and arenamines, according.to the natureof the hydrocarbon grouping. Unfortunately, the term alkylamine is used ve rycomm only in place of alkana min e, while a host of trivial nam es a re used forarenamines. We shall try to indicate both th e trivial and the system atic name swn ere possible. Som e typical amines, their names, and their physical propertiesar e listed in Table 23-1. Th e completely system atic names given in Table 23-1illustrate in a poignant way the difficulty one gets into by using completelysystematic nam es, and why simpler but less systematic nam es continue to beused for common compounds. A good example is N,N-dibutylbutanamineversus tributylamine. The special ways of naming heterocyclic amines werementioned previously (Sectio n 15- 1 1A).


7/72

23-3 Types and Nomenclature of Amines 1101Table 23-1Typical Amines and Their Properties

Am ine NameWater

BP, M p, s olubility, Kb"C "C gI100 ml in watera pKa b

ammonia -33methanamine -6.5(methylamine)ethanamine(ethylamine)1 I dimethylethanamine 46(tert-butylamine)N-ethylethanamine 55.5(diethylamine)N,N-diethylethanamine 89.5(triethylamine)N,N-dibu tyl butanamine 214(tri butylam ine)

azacyclohexane 106(piperidine)

sI. sol.

azabenzene 115 -42 00 1.7 x 5.23(pyrid ne)

cyclohexanamine 134 -18 sl .s ol . 4.4 x 10-4 10.64

benzenamine(aniline)H2NCH2CH2NH2 1,2-ethanediamine 116 8.5 sol. 8.5 x I O - ~ 9.93

(ethylenediamine)

aUsually at 20-25". bThe pKa values refer to the diss ociation of the conjugate ac id RNH3@Ka+ H,O tl. NH, + H30@, here pK, = log Ka= 14 + og K b (see Sections 8-1 a nd 23-7).


8/72

1"12 23 Organoni t rogen Com pounds I . AminesSalts of amines with inorganic or organic acids are named as substituted

ammon ium salts, except when the nitrogen is part of a ring system. Exam-ples are

methylamm onium 2-propenyldimethylammon ium ethanoate 4-methylazoniacyclo-ch lorid e hexane nitrate'

Exercise 23-1 Name the fo l lowing subs tances by an accepted sys tem (Section7 - 8 ) :

23-4 PHYSICAL PROPERTIES OF AMINESThe physical properties of amines depend in an important way on the extentof substitution at nitrogen. Thus primary amines, RNH,, and secondaryam ines, R, N H , ar e less volatile than hydroca rbons of similar size, weight, andshape, as the following exam ples show:

pentanamineMW 87 ; bp 130" hexaneMW 86; bp 69"

pentaneMW 72 ; bp 36"'Note the use of azonia to denote the cationic nitrogen in the ring, whereas aza is usedfor neutral nitrogen (see Section 15- 11A).


9/72

23-4 Physical Propert ies of Amines 1This is because the amines are associated through hydrogen bonding of thetype N- ---- N . Generally, N-H---- :N bonds are somewhat weaker thanthose of the corresponding types, 0- H -- -- :0 and F-H----:F, because theelectronegativity of nitrogen is less than that of oxygen or fluorine therebymaking nitrogen a po ore r hydrogen do nor. Eve n so, association through hydro-gen bonding is significant in am ines of the type R N H , or R 2 N H as the boiling-point comparison shows. With tertiary amines, where N- H ----: N bonding isnot possible, the boiling points are much lower and are similar to those ofhydrocarbons of similar branching and molecular weights:

propanamineMW 59; b p 49"

The water solubilities of the lower-molecular-weight amines are appre-ciable, as can be seen from the solubility data in Table 23-1. In fact, am inesar e more water-soluble than alcohols of similar molecular w eights. T his is theresult of hydrogen bonding, with amine molecules as the hydrogen acceptorsand w ater m olecules as the hydrogen donors:

\Hydrogen bonds of this type are stronger than 0 : - -H - 0 -H b on ds./Amines, especially those with significant volatility, have unpleasantodors. Some of them smell like ammonia, others smell fishy, while othersare indescribably revolting. The alkanediamines of structure H,N (CH ,) , ,N H 2are notably wretched and two are aptly called putrescine (n = 4) and cadav-erine (n = 5 ) . A s you m ay guess from the names, these compounds are amongthe amines produced by bacterial decay of organic animal matter (putrefac-tion of protein) and ar e poisonous compo nents (ptomaines) thereof.


10/72

23 Organonitrogen Compounds I. Amines23-5 SPECTROSCOPIC PROPERTIES OF AMINES23-5A lnfrared an d Ultraviolet Sp ectraA characteristic feature of the infrared spectra of primary and secondaryamines is the moderately weak absorption at 3500 cm-l to 33 00 cm-l, whichcorresponds to N-H stretching vibrations. Primary amines have two suchband s in this region, wh ereas second ary am ines generally sho w only one band.Absorption is shifted to lower frequencies by hydrogen bonding, but becauseN H - - - - :N bonding is weaker than OH-- - - : 0 bonding, the shift is not as greatand the bands are not as intense as are the absorption bands of hydrogen-bonded O-H groups (see Table 9-2). Bands corresponding to N-H bendingvibrations ar e observed around 1600 cm-l. Absorptions corresponding toC-N vibrations a re less easily identifiable, exce pt in the case of arenam ines,which ab sorb fairly strongly nea r 1300 cm-I. Sp ectr a that illustrate theseeffects are shown in Figure 23-4.

frequency, cm- 'Figure 23-4 lnfrared spectra of cyclohexanamine and N-methylbenzenamine (N-methylaniline)


11/72

23-5 S pectrosc opic P roperties of AminesThe ultraviolet absorptions of simple saturated amines occur at rather

short wavelengths (- 220 nm) and are not particularly useful for identification.These are n -+ c* ransitions that correspond to excitation of an electron ofthe unshared pair on nitrogen to the antibonding o-orbital of a C-N bond.

23-5B NMR SpectraThe proton nmr spectra of amines show characteristic absorptions for H-C-Id protons around 2.7 ppm. The positions of the resonances of N-H pro-tons show considerable variability as the result of differences in degree ofhydrogen bonding (Section9- 10E). Sometimes the N-H resonance has nearlythe same chemical shift as the resonances of CIA3---C protons (as with N-ethylethanamine, Figure 23-5).

A further complication associated with N-H and H-C-N reso-nances is their variable chemical shift and line width in the presence of acidicsubstances because of a chemical exchange process of the type illustrated inEquation 23-1:

H'!& ICH,-N-H + H'A CH3-N-H + A@ CH3-N: + HA (23-1)I ICH3 ICH3 CH3Depending on the rate at which the proton transfers of Equation 23-1 occurand the concentrations of the reactants, the chemical shift of the N-H proton

Figure 23-5 Nmr spectrum of N-ethylethanamine (diethylamine) at 60MHz relative to TMS at 0 ppm . Rapid exchange of the N-H protonsbetween different amine molec ules causes the N-H resonance to bea single peak (Section 9-101).


12/72

23 Organonitrogen Compounds I. Amineswill come somewhere be tween tha t of pure (CH ,) ,NH and pure H A . Exceptat high acid con centrations, this exchan ge eliminates any observable couplingbetween the N-H proton and the N-methyl protons (H-C-N-H); seeSection 9-101.

Exercise 23-2 How could one show with certainty that the peak at 47 Hz with refer-ence to TMS in the nmr spectrum of N-ethylethanamine (Figure 23-5) is due to theN-H resonance?Exercise 23-3 Show how structures can be ded uce d for the isom eric substances ofm ole cu lar form ula C,H,,N, whose n mr and infrared spe ctra are shown in Fig ure 23-6.

In Section 9-10L, we discussed 13C nmr and its many applications to struc-tural problems. The nmr of 15N nuclei has similar possibilities but, because 15Nis only 0.37% of natural nitrogen and has an even smaller nuclear magneticmoment than 13C, it is very difficult to detect I5N resonances at the natural-abundance level.2 Indeed, natural 15N has to be observed for about a 6 x 101longer time than protons to achieve the same signal-to-noise ratio! Despitethis difficulty, natural-abundance 15N spectra can be obtained for many com-pounds (even enzymes) and, in some cases, provide very useful chemical in-formation (see Figure 24-4).

23-5C Mass Sp ectra of AminesThe most prominent cleavage of the parent molecular ion M+ derived fromam ines occurs a t the C B-C, bond to give an imminium ion which, for ethana-mine, has mle = 30:

electron a @CH~CH,NH, impact > CH ,CH ,N H , + e@m le = 45

It is helpful in identifying the molecular ion of an organonitrogen com-pound to remember that the mle value of M+ will be a n uneven n um ber if the2The abundant nitrogen nucleus, 14N,has a magnetic moment but generally gives verypoor nmr spectra with very broad lines. The reason is that 14N usually "relaxes"rapidly, which means that its nuclear magnetic states have short lifetimes (see Sec-tion 27-1).


13/72


14/72

6608 23 Organonitrogen Compounds I. AminesTable 23-2m le Values of Odd- and Even-Electron Ions from Organic Compounds

CompositionOdd-electron parent Even-electron ions,M+ molecular from fragmentationions, m le of M+ ,m ie

C, H,0,ven or zero N evenC, H, 0, odd N odd

oddeven

ion contains one or an othe r odd number of nitrogen atoms. Th us ethanamine,C,H,N , gives an M + of m / e = 45. For all other elemental compositions ofC , H , 0 , or with an even number of nitrogens, the molecular ion will have aneven m / e value.The cleavage reaction of Equation 23-2 reveals other useful general-izations. Whatever its source, a parent molecular ion, M+ , has one unpairedelectron and is properly described as an odd-electron ion (a radical cation).When a parent molecular ion fragments, it does so hornolytically,as shown inEquation 23-2, and produces a radical and an ion in which the electrons arepaired- an even-electron ion. T h e m / e value of an eve n-electron ion is an evennum ber for any elem ental composition of C, H , 0 in combination with an oddnum ber of nitrogens. T he se generalizations are summarized in Tab le 23-2 andcan be useful in the interpretation of m ass spec tra, as illustrated by Exercises23-4 and 23-5.

Exercise 23-4 The highest mass peak in the mass spectrum of a certain compoundis m /e 73. The most abund ant pea k has m le 58. Suggest a structure for the co mp oundand explain how it could form an ion of m le 58.Exercise 23-5 Prominent peaks in the m ass spectrum of a basic nitrogen co mp oundhave m le values of 87, 72, 57, and 30. The nmr spectrum shows only three protonresonances, having intensity rat ios of 9:2:2 at 0.9, 1.3, and 2.3 p pm . Ass ign a structureto the compound and account for the fragment ions m le 72, 57, and 30.

23-6 STEREOCHEMISTRY O F AMINESIn amm onia and am ines, the bon ds to nitrogen a re pyramidal with bond anglescloser to the tetrahedral value of 109.5" than to th e 90" value ex pected for the


15/72

23-6 Stereochemistry of Amines 1189use of pure p orbitals of nitrogen in bond formation. We consider that thenitrogen in amines is formulated best with hybrid spxtype orbitals; three ofthese orbitals ar e used in cr-bond form ation while the fourth con tains the non-bonding electron pair:

pyramidal configurat ion at n i trogen

A consequ ence of the pyramidal configuration a t nitrogen is that, whenthe attached groups R,, R, and R, are nonidentical, the nitrogen becomes achiral atom. Under these circumstances, we would expect two enantiomericconfigurations :mirror p lane

I

Ienantiomers of a chira l amineT h e resolution of an acyclic chiral amine into its sep arate enantiomers has notbeen achieved yet, and it appears that the enantiomers are very rapidly inter-converted by a n inversion process involving a planar transition state :

planar transitionstateWith ammonia, inversion of this type occurs about 4 x 101 times per secondat room temperature, which corresponds to the planar state being less stablethan the pyramidal sta te by abo ut 6 kcal mo lep1. W ith aliphatic tertiary am ines,the inversion rate is more on the order of lo3 o lo5 imes per second. Suchrates of inversion are m uch to o great to permit resolution of an amine into itsenantiomers by presently available techniques.W hen the am ine nitrogen is incorpo rated in a small ring, as in azacyclo-propanes, 1, the rate of inversion at nitrogen is markedly slower than in open-chain amines. In fact, with some oxazacyclopropanes, such as 2, inversion


16/72

1110 23 Organoni t rogen C om pou nds I . Aminesdoes not occur rapidly at ordinary temperatures, which means that the con-figuration at the nitrogen persists long enough for resolution into enantiomersto be possible:

I ethylazacyclopropane 2-tert-butyloxazacyclopropaneAG' ( inversion) = 19.4 kcal mole- ' A G ' ( inversion) = 33 kcal mole- 'The stereochemistry of azacyclohexanes is complicated by the fact that thereis a conformational change in the ring as well as inversion at the pyramidalnitrogen. Therefore it is difficult to say whether the axial-equatorial equilibriumof, for example, l-methylazacyclohexane is achieved by ring inversion, or bynitrogen inversion, or both:

inversionring 11 inversionI1 ringinversion at nitrogen

Exercise 23-6* Explain why the configuration of the nitrogen in l-ethylaz acy clo-propane, 1, is more stable than in triethylamine. Why is the configuration of oxaza-cyclopropanes, such as 2, exceptionally stable? (Consider the T molecular orbitalsof an ethene bo nd , Figure 21-3, as a m ode l for orbitals of the adja ce nt 0 nd N atomsin the planar transition state for inv ersion in 2.)Exercise 23-7 The proton nmr spectrum of 1,2,2-tr imethylazacyclopropane, 3, atroom temperature is shown in Figure 23-7. When the m aterial is heated to 1 o 0 , hetwo lines at 63 Hz and 70 Hz are found to have coale sced to a sing le line. At the sametime, the l ines at 50 Hz and 9 2 Hz coalesce to a single l ine.


17/72

23-7 Amines as Bases

Figure 23-7 Proton nmr sp ectrum of 1,2,2-trimethylazacyclopropane a t60 MHz relative to TMS at 0.0 ppm. See Exe rcise 23-7.

When the sam ple is cooled the spectrum change s b ack to that of Figure 23-7. Accou ntfor all the nmr lines of 3 and exp lain the e ffect of temperature on the spectrum. ReviewSe ction 9-1 OC.3Exercise 23-8* The 19F spectrum of 4,4-difluoroazacyclohexane in acetone solutionat 25" is a sharp, narrowly sp ace d 1 4:6:4:1 quintet; at -60" it is a broad quartet witha chem ical-shift difference of 960 Hz and J of 235 Hz, and at -90" it is a pa ir of over-lapping quartets with chemical-shift differences and relative intensities of 1050 Hz(75%) and 700 H z (25%), both with J of 235 Hz. Ac cou nt for these cha nge s in the 19Fspectra w ith temperature, R eview Section 9-1O C 3

23-7 AMINES AS BASES23-7A Standard Expressions of Base StrengthPerhaps the most characteristic property of amines is their ability to act asbases by accepting protons from a variety of acids:

3 Y o ~lso may wish to read ahead in Section 27-2.


18/72

$112 23 Organoni trogen Com pounds I. AminesW hen the reference acid, H A , is water, we can set up a scale of base strengthsfrom the equilibrium cons tant, K,, measured for the proton-transfer reactionshown in Equation 23-3:

In many reference works, it is customary to express the strengths oforganic bases not a s K, values but a s the acid-dissociation constants, K, (orpK,'s) for the corresponding conjugate acids. The se K a values are then theacid cons tants of the corresponding ammonium ions in aqueous solution(Equation 23-4):0 Ka 0R N H 3 + H 2 0 R N H , + H 3 0 (23-4)

With this convention, the stronger the base, RNH,, the more the equi-librium in Equation 23-4 will lie to the left, and the smaller will be K,. T h erelationship between Ka and K b in w ater solution is

and in terms of pK values, because by definition pK = log K,

23-7B Base Strengths of Alkanamines an d C ycloalkanaminesThe base strengths of simple alkanamines usually are around K, =( K , = 10-lo) in w ater solution, and vary within perha ps a fac tor of 10 fromamm onia to primary, secondary, and tert iary am ines, as can be seen from thedata in Table 23-1. Cyclohexanamine has about the same base strength asmethanamine, whereas the effect on the basic nitrogen of being in a saturatedring, as in azacyclohexane, increases the base strength somewhat.The trends that are evident, especially from basicities of amines mea-sured in the gas phase, point to increasing basicity with the nu m ber and size ofalkyl groups on th e nitrogen atom.Order of basicity (gas phase): (cH,),N > (cH,),NH > CH,NH, > NH,

0Th is is reasonable beca use the conjugate acids, R,N H, are likely to be stabi-lized by electron-donating and polarizable alkyl groups, thereby making R3Na stronger base. Th at the sam e trend is not evident in aqueous solution againshows the influence of the solvent on thermochemical properties (see Section11-8A).


19/72

23-7C Base Strengths of ArenaminesGene rally, substituents located o n sa turated groups attached to nitrogeninfluence base strengths through their inductive effects in the same way thatthe se sub stituents influence the streng ths of carboxylic acids (see Section 18-2).

Exercise 23-9 Acc ount for the fol lowing observations:a. The proton nmr spectrum of trimethylamine in nitromethane-d, (C D 3N 02 )shows asingle resonance near 2.7 ppm . On ad ding an e quivalent of f luoroboric a cid, HBF,,the singlet at 2 7 pp m is replace d by a doublet at 3.5 ppm.b. On adding trace amounts of tr imethylamine to the solution described in Part a,the do ublet at 3.5 ppm col lapses to a singlet centere d at 3.5 ppm . As m ore tr imethyl-amine is ad ded , the singlet resonance moves progress ively upfield.Exercise 23-10 Decide which member in each of the fol lowing pairs of compoundsis the stronger base. Give your reasoning.a. CH3CH2NH2 r (CH,CH,),N 0 0b. (CH,),NH or (CH,),NH d. (CH,),NCH,CH,NH, or 02CCH2CH2NH2c. CF3CH2CH2NH2r CH3CH2CH2NH2

23-7C Base S trengths of ArenaminesAlkenamines, or enamines, R-C H= CH NH ,, usually are not stable andrearrange readily to imines (Section 16-4C ). A n im portant excep tion isbenzena mine (aniline), C,H,NH,, which has an amino group attached to abenzene ring. T h e imine stru cture is less favorable by virtue of the considerablestabilization energy of the aromatic ring:

From the heat of combustion of benzenamine we know that i t has a 3 kcalmo le-l larger stabilization energy th an ben zene (Table 2 1 1). Th is differencein stabilization energies can be ascribed in either valence-bond or molecular-orbital theory to delocalization of the unshared pair of electrons on nitrogenover the b enzen e r ing. Th e valence-bond structures are


20/72

I 1 14 23 Organonit rogen C ompo unds I. AminesT h e extra 3-kcal mole- ' stabilization energy of benzene amine c an be accountedfor in terms of the structures 4 a to 4 c.Benzena mine is only 11 1,000 ,000 a s strong a base a s cyclohexanamine.Most, if not all, of the difference can be accounted for by the decrease instabilization w hen the unsh ared electron pair of nitrogen is localized in formingan N-H bond. H enc e, benzenamine is stabil ized more in the un-ionized stateby electron delocalization, relative to cyclohexanamine, than in the ionizedstate, as expressed by the following equilibrium which lies far to the right:

K = 10"+ 0 . H . --SE = 38 kcal mole- ' SE = 0

SE = 41 kcal mole- ' SE =0

Exercise 23-11 Draw atomic-orbital m odels for benzenamine and its conjugate acidand describe the features of these models that account for the low base strength ofbenzenamine relative to saturated amines.

FHExercise 23-12 Amidines, R-C , are stronger bases than saturated amines.\NH*Explain why this should be so, paying special attention to which nitrogen the protonadds to.

According to the valence-bond structures, 4a, 4b, and 4c , benzenaminehas some degree of double-bond c hara cter between th e nitrogen and the ring,and some d egree of negative charge a t the ortho and para positions. Accord-ingly, the ability of the amine nitrogen to add a proton should be particularlysensitive to the electrical effects produced by the presence of substituentgroups o n the aroma tic ring. Fo r exam ple, carbonyl, nitro, cyano, and ethoxy-carbonyl substituents, which can delocalize an electron pair on an adjacentcarbon (see Sections 17-l A, 17-3E, and 18-8B), are exp ected to reduce thebase strength of the amine nitrogen when substituted in the ortho or parapositions. The reason is that stabilization by the substituent, as shown by


21/72

23-7C Base Strengths of Arenamines 4 4 4 5structure 5 for 4-nitrobenzenamine, is important for the free base and not forthe conjugate acid, 6:

6(unfavora ble VB structure)

It is sirnpler and common practice to discuss substituent effects on basestrength in terms of the dissociation equilibria of the conjugate acids, ArNH,@-I- H,O ArNH, -I- H300. Substituents that can stabilize the free base byelectron delocalization or induction, as in 5, will tend to increase the aciddissociation of ArNH,@ (decrease base strength of ArNH,). We see this inthe data of Table 23-3 for electron-withdrawing groups (NO,, CN, CF,,CH3CO-) , which increase acid strengths, and for electron-donating groups(CH,, NH,), which decrease acid strengths. The effect is most pronouncedwhen the groups are at the ortho or para (2 or 4) positions.

Table 23-3Strengths of Conjug ate Acids of Monosubst i tu ted Benzenam ines in AqueousSolution at 25"

Su bstitu ent Formu la PKa


22/72

1116 23 Organonitrogen Compounds I. AminesTable 23-3 (continued)Strengths of C onjugate Acid s of Mono substi tuted Benzenamines in AqueousSolution at 25"

Su bstituent Formula PKa

Exercise 23-13 3-Nitrobenzenamine is less than 1 I00 as strong a base as benzen-amine, but is 23 times stronger than 4-nitrobenzenamine. Remembering that theinductive effect falls off rapidly with the number of intervening bonds, why should3-nitrobenzenamine be a mu ch weaker bas e than benzenam ine itself, but substantiallystronger than 4-nitrobenzenamine?


23/72

23-713 Unsaturated Amines. AzarenesExercise 23-14 Ind icate whether the fo l lowing equi l ibr ia would have K greater, orless, than uni ty . This is equivalent to asking w hich amine is the st ronger b ase. Give areason for your answer.

23-7D Unsaturated Amines. AzarenesSubstantial differences in base strength are found between alkanamines and

\unsaturated amines that have the group c=G-. An example is azabenzene/(pyridine, C,H,N), which is a nitrogen analog of benzene:azabenzene(pyrid ine)

Azabenzene is quite a weak base- n fact, it is 11100,000 as strong abase as typical alkanamines. This low basicity can be ascribed to the hybridiza-


24/72

1138 23 Organoni t rogen Compounds I. Aminestion of the nitrogen orbitals (sp2) in azabenzene. As we indicated in Section11-8B in connection with C-H acidity, the more s character in the C-H

,bonding orbital, the higher the acidity. The same arguments hold for N-H0bonds in the conjugate acids, C=NH-, as the following data show:/

@ Ka 0(CH3CH2)3NH+ H 2 0 (CH3CH2),N:+ H 3 0sp3 hybridization K, = 2.3 X l o - "at nitrogen (K, = 4.4 x

'sp2 hybridization K, = 6.0 xat nitrogen (K, = 1.7 x l o p 9 )

Other examples include:

.1,3-diaza-2,4-cyclopentadene 1-azanaphthalene 1,3-d azabenzene( imidazo le) (quinol ine) (pyr imidine )K,= 1.2 x l o - ' K b= 6.3 X K,= 2 x 10- j3

It is incorrect to assume that the bascity of unsaturated nitrogen in aC=N- group is always low. Consider, for example, the base strength of2,2-diaminoazaethene (guanidine):

This substance is the strongest electrically neutral organonitrogen base known.The basic nitrogen is the imino (sp2) nitrogen, which on protonation forms aparticularly stable conjugate acid in which the three NH, groups becomeidentical because of electron delocalization:


25/72

23-7D Unsaturated Amines. Azarenes

Exercise 23-15 Offer plau sib le explanations of the following facts:a. Aza-2,4-cyclopentadiene (pyrrole) is unstable in acid solut ion and polymerizes.(Co nside r the effect of ad din g a proton to this m olecule at the nitrogen and at carbon.)

b. 1,3-Diaza-2,4-cyclopentad iene (imida zole) is a m uch stronger base than 1,3-diazabenzene (pyrimidine).

0c. The triamino me thyl cation , (NH,),C, is an excep tion ally weak ac id .Exercise 23-16 The pKa of the con jugate a ci d of caffeine (Figure 23-1) is 10.61.Calc ulate the K, of caffeine. Write structures for the poss ible con jugate ac ids ofcaffeine in which the added proton is attached to one or the other of the nitrogens ofthe f ive-mem bered ring. Use the resonance method to determine which of these twonitrogens will be the preferred protonation site of caffeine. Give your reasoning.Exercise 23-17* 2-Amino- l ,3-d iazabenzene (2-aminopyrimidine) undergoes N-methylation with methyl iodide to give two isomeric products, A and B, of formulaC5H,N3 (Section 23-9D ). At hi gh pH , the m ajor me thylation produ ct is A, which is aweakly ba sic com pound with pKa=3.82. N-M ethylat ion in neutral condit ions producesthe more strongly basic compound B with pKa= 10.75. Draw structures for the twoisomers, A and B, and explain why A is a weak base and B is a much stronger base.Why is A the predominant product under basic condit ions? Give your reasoning.Exercise 23-18 * The conjuga te ac id of N,N-dimethyl benzenam ine has pKa= 5.06,whereas the conjug ate a cid of di phe nyldiaz ene (azobenzene, C6H5N=NC,H5) haspKa= 2.5. Yet for many years there was cons ide rab le co ntroversy abou t where a pro-ton adds to 4-(CH,),N-C,H,N=NC,H,. Why is it not an op en -and -shu t ca se that aproton wo uld a dd most favorably to the (CH,),N- nitro ge n? W hich of the two -N=N- nitrogens would you expect to be the more bas ic? Give your reasoning. (Con-side r the effect of the -N=N- gro up on the bas icity of the (CH,),N- nitro ge n andals o the effec t of the (CH,),N- grou p on the bas ici ty of ea ch of the -N=N-nitrogens.)


26/72

1120 23 Organoni t rogen Compounds I. Amines23-8 AMINES AS ACIDSPr imary and secondary am ines are very weak ac ids . Th e l ithium sa lt s of suchamines can be prepared in ether solut ion by t reatment of the amine withphenyl l i thium:

e the r 0 0HM ( c 2 H S ) ,+ C,H,Li - i :N ( C 2 H 5 ) ,+ C,H,l i thium diethylamideT h e li thium sa lt of N -eth yleth ana m ine (diethylamine) is called l ithiumd i e t h ~ l a m i d e , ~ut th i s nomencla ture can lead to confus ion wi th comp ounds ofthe t ype RC O,N H,, which are der ived from carboxyl ic acids and also are..@ 0called amides. W e ch oo se to avoid using the name "alkali amide" for R N H L Iand accordingly will refer to th em as m etal sal ts of the pa rent am ine.Alkanam ines have ac id s t rengths cor responding to K , values of aboutlo-", which means that their conjugate bases are powerful ly basic reagents .Therefore they are very effect ive in causing el iminat ion react ions by the E2mechanism (Sect ion 8-8) and aromatic subst i tut ion by the aryne mechanism(Sect ion 14-6C). The fol lowing example i l lust rates this property in a usefulsynthes i s of a benzenamine f rom bromobenzene:

N ,N-diethyl benzenamine(N, N-diethylani l ine)Sal ts of alkanam ines also a re useful for generat ing enolate sal ts of car-

bony1 compound s (Se ct ions 17-4A and 18-8C) .

Exercise 23-19 a. Exp lain why 1,3-d azacyc lopentadiene ( imidazole) is a muchstronger acid than azacyc lopentadiene (pyrrole).

b. Would you expect benzenamine to be a stronger or weaker ac id than cyclo-hexanamine? Give your reasoning.

"he system used here names these salts as substitution products of NH,? Clearly, togive LiN(C,H,), the name "lithium N-ethylethanamide" would be totally incorrectbecause N-ethylethanamide is CH,CONHC,H,. Perhaps a better name would belithium diethylazanide or N,N-diethylaminolithium.


27/72

23-9 Amines as Nucleophi les23-9 AMINES AS NUCLEOPHILES23-9A Acylation of Amines. Synthesis of AmidesT h e unshared electrons o n nitrogen play a key role in the reactions of amines.In fact, almost all reactions of amines at the nitrogen atom have, as a firststep , the form ation of a bond involving the unshared electron pair on nitrogen.A typical ex am ple is acylaticsn, which is amide formation through the reactionof an acyl chloride, an anhy dride, or an este r with an am ine. T h e initial step inthese reactions with benzenecarbonyl derivatives and rnethanamine as illus-trative reactants is as follows:

IX = halogen, -0-C-C,F15, or -OR

The reaction is completed by loss of a proton and elimination of X @ :

0I1The reaction is called acylation because an acyl group, R-C-, istransferred to the amine nitrogen. I t will be seen that these reactions are verysimilar to th e form ation of esters by acylating age nts, whereby the acyl groupis transferred to the oxygen of an alcohol (Section 15-4D):0 0I1 11R-C-X + R'OH --+ R-C-OR' + FIXA serious disadvantag e to the preparation of amide s through the reactionof an am ine with a n acyl chloride (or anhydride) is the form ation of on e moleof amine salt for each mole of amide:


28/72

23 Organonitrogen Compounds I. AminesTh is is especially seriou s if the am ine is the ex pensive ingredient in the reac-tion. In such circum stances, the reaction usually is carried on in a two-ph asesystem with the acyl chloride and amine in the nonaqueous p hase and sodiumhydroxide in the aqueous phase. As the amine salt is formed and dissolves inthe w ater, i t is con verted back to amine by the sodium hydroxide and extractedback into the nonaqueous phase:0 0 0 0 0 0R N H 3 C l + N a O H - N H , + N a C l + H,OTh is procedure requires an exc ess of acid chloride because som e of it is wastedby hydrolysis.

23-9B lmine an d Enamine FormationAmines also add to the carbonyl carbon of aldehydes and ketones, but thereactions take a different cou rse from acylation and, with amm onia or a primary\amine, yield imines, C= N-R , as previously discussed in Section 16-4C./Imines formed f rom ammonia and a ldehydes ( R C H = N H ) a re veryunstable and readily polym erize (Section 16-4C). H ow eve r, substitution of analkyl or aryl group on the nitrogen increases the stability, and N-substituted

\imines, C = N - R , ar e familiarly know n a s Sch i f b a s e s . Th ey a re key inter-/mediates' in a num ber of synthetic and biological reactions (see, for examp le,Section 17 -3F ) and ar e capable of rearrangem ent by reversible proton transferthat, in some respects, resembles the rearrangement of ketones to enols:

C-N/ / /Secondary amines c anno t form imines with aldehydes and k etones but

\ Imay react instead to form enamines , C=C-NR,. T h e formation and/synthetic uses of these compounds were discussed previously (Sections16-4C, 17-4B, and 18-9D).

23-9C Sulfonam ide Formation from AminesWe have seen that amines react with acyl chlorides to give amides. A verysimilar reaction occurs with sulfonyl chlorides to give sulfonamides. A n


29/72

23-9C Sulfonamide Formation from Aminesexample is benzenesulfonyl chloride reacting with methanamine to giveN-methylbenzenesulfonamide:

N-methyl benzenesulfonamide

Sulfonylation of amines can be a useful way of differentiating (chemi-cally) between primary, secondary, and tertiary amines by what is known asthe Hinsberg test. Primary and secondary amines both react with a sulfonylchloride, but only the sulfonamide from the primary amines has an N-Hhydrogen. The sulfonyl group makes this hydrogen relatively acidic and thesulfonamide therefore d issolves readily in sodium hydroxide so lutions. T h esecondary amine does not give a base-soluble amide, whereas the tertiaryamine gives no sulfonamide:

N a O H____3 insoluble

\ o sulfonamideSulfonamides have medicinal value as antibacterial agents. In fact, 4-amino-benzenesulfonamide was the first synthetic antibacterial drug in clinical use,and is effective against a large number of bacterial infections:

This substance inhibits the growth of bacteria by interfering with the synthesisof folic acid, 7, which is an essential substance for bacteria and animals alike.However, animals acquire folic acid from a normal diet, whereas bacteria haveto synthesize it. Biosynthesis of folic acid is blocked by 4-aminobenzenesulfon-amide, probably because of the structural similarity of the sulfonamide to4-aminobenzoic acid, which is a normal ingredient in the biosynthesis of folicacid. The enzyme system involved apparently substitutes the sulfonamide for


30/72

23 Organoni trogen C ompounds I. Aminesthe aminobenzoic acid and creates a sulfonamide-type folic acid instead of thecarboxamide derivative (compare structures 7 and 8):

0II iC H 2 t N o C T N H - C H C 0 2 HH - I fo~i c cidCH2I( 3 -32IC 0 2 H

derived from4-aminobenzoicacid

sulfonamideanalogof folic acidH2N 8CH2IC 0 2 H

derived from4-aminobenzene-sulfonic acid

Some 10,000 structurally different sulfonamides have been synthesized as aresult of the discovery of the antibacterial properties of sulfanilamide. Thepractice of synthesizing numerous structurally related compounds in an effortto find some that are more efficient or have fewer side effects than those alreadyavailable is very important to the pharmaceutical industry. However, as isusually the case, of the many known sulfonamides only about thirty have theproper balance of qualities to be clinically useful.

Exercise 23-20 Show the products you would expect to be obtained in each of thefollowin g reactions:

NaOHa. ( )-NH, (2 moles) + COCI, (1 mole)-NaOHb. H,N(CH,),NH, (1 mole) -t ,H,SO,CI (2 mole s)-

0 - C H,NCH, NaOH. CH,


31/72

23-9D Alkylation. Synthesis of AlkanaminesExercise 23-21 2,4-Pentanedione reacts with methanamine to g ive a product ofcom pos ition C6HllN0 that is an eq uil ib rium mixture of three isomers. The nmr spe c-trum of the mixture indicates that all three isomers have strong hydrogen bonding.Draw the structures of the three isomers and indicate the nature of the hydrogenbonding.Exercise 23-22 Write a structural formula (one for each part) that fi ts the followingdescript ions. (These descript ions can apply to more than one structural formula.)Write equ ations for the reactions involved.a. A li qu id ba sic n itrog en co m pou nd of formula C,H,N with C,H,SO,CI and excessNaOH solution gives a clear solution. This solution when acidified gives a sol id prod-uct of formula C,Hl,02NS.b. A l iq ui d dia m ine of form ula C5H,,N2 with C6H5S0,CI and NaO H give s an insolublesol id. This s ol id dissolves when the mixture is acidi f ied with di lute hydroch loric acid.

23-9D Alkylation. Synthesis of Alkanam inesAm monia and amines can function a s nucleophiles in S,2 displacement reac-tions of alkyl halides (Section 8-7E). Such processes provide syntheses ofalkanamines only with those halides tha t are reactive in S,2 but not E2 reac-tions. F o r example,

The product formed according to Equation 23-5 is an ammonium salt fromwhich t he paren t am ine can be recovered by neutralization w ith a strong base,such as sodium hydroxide:

Acid-base equilibria similar to Equation 23-6 also occur between anammonium salt and a neutral amine (Equation 23-7). This c an have seriouscons eque nces in amine alkylations because it can lead t o m ixtures of products,whereby mo re than one alkyl group is bonded to nitrogen:

The refore w e m ay expe ct the reaction of amm onia with methyl iodide togive four possible alkylation products, mono-, di-, and trimethylamines, aswell a s tetramethylamm onium iodide:

De spite the fa ct that alkylation reac tions of am ines generally give mixtures ofproducts, they are of practical value on an industrial scale. The commercialsynthesis of methanam ines uses methanol as the methylating agent and alumi-


32/72

23 Organonitrogen Compounds I. Aminesnum oxide as an acidic catalyst; all three amines are formed, and are sepa-rated by distillation a nd extraction (see Exercise 23-24). Th e function of thecatalyst is to make O H a better leaving group (Section 8-7D):

> C H 3 N H 2+ ( C H 3 ) , N H + ( C H 3 ) , N + H 2 0CH30H + NH3 450, 200 psiThe tetraalkylammonium halides formed by complete alkylation of aminesar e ionic com pounds that resemble alkali-metal salts. When silver oxide is usedto precipitate the halide ion, tetraalkylammonium halides are converted totetraalkylammonium hydroxides, which are strongly basic substances similarto sodium or potassium hydroxide:

Higher-molecular-weight alkylammonium hydroxides decompose on heatingto give alkenes. The reaction is a standard method for the preparation of al-kenes and is known as the Hofmann elimination (see Section 8-8B):

Exercise 23-23 Show how the fol lowing comp ounds may be prepared from amm oniaand the given starting materials:a. 1,2-ethanediamine from etheneb. 2-aminoethanol from ethenec. benzenamine from chlorobenzeneExercise 23-24 Show how a mixture of amines prepared from 1-bromobutane andan excess of butanamine may be reso lved into its compone nts by reaction with thean hyd ride of 1,4 -bu tan ed ioic ac id, (CH,),(CO),O, separa tion of the produ cts thro ughadvantage of their solubil ity properties in acid or base, and regeneration of the cor-responding am ines (Section 18-IOC). Write equations for the reactions involved.

In principle, conv ersion of a primary o r seconda ry amine into its conju-gate base, RNH@o r R ~ N @ ,hould m ake the nitrogen powerfully nucleophilictoward alkylating agents:

In practice, the sam e problems of polyalkylation and E 2 elimination exist withthe am ine anion as with the neutral amine-and as far as E 2 goes, muchmore so.


33/72

23-9D Alkylation. Synthesis of Alkanamines 1127There are nitrogen anions that are useful in alkylation reactions, but they arederived from carboxamides and sulfonamides rather than amines. Two exam-ples are given here to illustrate the synthesis of a primary and a secondaryamine (also see Section 18-10C):Gabriel synthesis of primary amines

The success of the Gabriel synthesis depends on N-alkylation being favoredover 0-alkylat ion and SN 2being favored ov er E2. Polar, aprotic solvents suchas methylsulfinylmethane, (C H,),S O, are useful for the Gab riel synthesis.Hydrolysis of the alkylation product often is difficult and "amide interchange"(analogous to es ter interchange, Section 1$-?A)with hydrazine c an be an effec-t ive way t o free the am ine from the imide.Sulfonam ide synthesis of secondary amines

0+

0 O l N a O H

In this sy nthesis, the acidic prop erties of sulfonamides of the type C,H,SO,NHRare utilized to form anion s capable of alkylation by the SN 2mechanism.


34/72

4428 23 Organoni trogen Compoun ds I. Amines

Exercise 23-25* Assess the p oss ibi l i ty of 0-alk ylat ion in the reaction of CH2=CH-CH,Br with C,H,SO,NH@Na@. G iv e your reason ing.

23-9E Arylation. Synthesis of ArenaminesIn previous discussions (Section 14 -6A) we stated tha t it is not possible todisplace halogen from simple aryl halides such as bromobenzene by simpleS,2 reactio ns using am ines or oth er weakly basic nucleophiles at ordina rytemperatures :

However, arylation with such systems will occur with strong bases by thebenzyn e m echanism (Sections 14-6C and 23-8).Ary lation of amin es by th e direct displacem ent of aryl halides is possiblewhen the halogen is activated by strong electron-withdrawing groups in theortho and para positions. For example, 2,4-dinitrobenzenamine can be pre-pared by heating 2,4-dinitrochlorobenzene with ammonia:

The reasons why this reaction proceeds are discussed in detail in Section14-6B.

23-9F Arenamines as N uc leo ph i es. Electroph l c AromaticSubstitutionT h e nitrogen of arenamine s is less basic a nd less nucleophilic than the nitrogenof alkanamines because of electron delocalization of the nitrogen lone pair, asshown for benzenam ine in Section 23 -7C. T h e polar valence-bond structuresemphasize that the ring atoms, particularly the ortho and para positions,should be more nucleophilic than in benzene. Accordingly, the amino groupstrongly activates the ring toward attack by electrophiles. In fact, brominereacts rapidly with benzenamine in aqueous solution to introduce three


35/72

23-10 Amines with Nitrous Ac idbromine substituents and form 2,4,6-tribromobenzenamine; no catalystis required:

2,4,6-tri brom obe nzen am ine(2,4,6-tribromoanil ine)Weakly electrophilic reagents that do not normally attack benzene will attackthe ring carbons of arenamines. Some of those reactions are described laterin the chapter (Sections 23- 10C and 23-10D).

23-10 AMINES WITH NITROUS ACID23-10A Alkanamines with Nitrous AcidSome of the most important reactions of amines are brought about by nitrousacid (HONO). The character of the products depends very much on whetherthe amine is primary, secondary, or tertiary. In fact, nitrous acid is a usefulreagent to determine whether a particular amine is primary, secondary, ortertiary. With primary amines nitrous acid results in evolution of nitrogengas; with secondary amines insoluble yellow liquids or solid N-nitroso com-pounds, R2N N=O, separate; tertiary alkanamines dissolve in and reactwith nitrous acid solutions without evolution of nitrogen, usually to givecomplex products :RNH, + HONO - ROH + H,O + N, 1' (evolution of nitrogen)R,NH + HONO ---+ R,N-N=O + H,O (separation of insoluble yellow

N-nitroso compound)R,N + WON0 --+complex products, but no N, evolution)

Nitrous acid is unstable and always is prepared as needed, usually bymixing a solution of sodium nitrite, NaNO,, with a strong acid at 0". These con-ditions provide a source of @NO,which is transferred readily to the nucleo-philic nitrogen of the amine:


36/72

1130 23 Organoni t rogen Com pounds I. AminesWith this common key step, why do amines react differently with nitrous aciddepending on their degree of substitution? The answer can be seen from the

1 0reactions that are most easily possible for the-N-NO intermediate. Clearly,Iif the re is a hydrogen on t he po sitive nitrogen, it can be lost as a proto n and aN-nitrosamine formed:

W ith a secondary amine , the reaction stops here, with formation of R,N -N O ,and because these substances are very weak bases, they are insoluble in diluteaqueous acids. They are characteristically yellow or orange-yellow solidsor oils.

0 0A ter tiary am ine.N O complex, R,N-NO, canno t lose a proton fromnitrogen, but instead may lose a proton from carbon and go on to form complexproducts (see Exercise 23-26).With a primary amine, th e initially formed N-nitrosamine can undergoa proton shift by a sequence analogous to interconversion of a ketone to an

enol. The product is called a diazoic acid:

Ha N-ni trosamine a d iazoic ac id

Some diazoic acids form salts that are quite stable, but the acids themselvesusually d ecom pose rapidly to diazonium ions:

Diazonium salts can be regarded as combinations of carbocations R@withN, an d, becau se of the con sidera ble stability of nitrogen in the form of N,, w ewould exp ect diazonium salts to decom pose readily with evolution of nitrogenand formation of carbocations. This expectation is realized, and diazoniumsalts normally decompose in this manner in water solution. The aliphaticdiazonium ions decom pose so rapidly th at their pres enc e can only be inferred


37/72

23-10 Amines with Nitrous Acidfrom the fact tha t the products ar e typically tho se of reactions of carbocations:

HONO @ rapidRNH, HO, Oo f R - N = N :b - > R @ + N,

H 2 Q/ ROH

R@ -----+ alkeneRCl

With propanamine, loss of nitrogen from the diazonium ion gives thevery poorly stabilized propyl cation, which then undergoes a variety of reac-tions that are consistent with the carbocation reactions discussed previously(see Sections 8-9B and 15-5E):

CH3CH2CH20H alkylation of solvent/-'/ xu alkylation of anions present,/-' CH3CH2CH2X NO,@- - - - I -La3H=CH2 EI elimination

rearrangement

The isopropyl cation formed by rearrangement undergoes substitution andelimination like the propyl cation. About half of the products arise fromisopropyl cations.There is one exceptional reaction of the propyl cation that involves 1,3-elimi-nation and formation of about 10% of cyclopropane:

Clearly, the plethora of products to be expected, particularly those resultingfrom rearrangement (see Exercise 23-3 l ) , prevents the reaction of the simpleprimary amines with nitrous acid from having any substantial synthetic utility.


38/72

11132 23 Organoni t rogen Compounds I. Amines

Exercise 23-26 The tertiary a m ine , C,H5CH2N(CH3),, reacts w ith nitrous a c id togive benzenecarbaldehyde and N-nitroso-N-methylmethanamine (N-nitrosodimethyl-amine):

A possible reaction sequence that explains the formation of benzenecarbaldehydeinvolves nitrosation, E2 elimination, hydrolysis, and finally nitrosation. Write each ofthe steps involved in this sequence. Formation of N20 appears to take plac e by dimer-ization of the hypothetical substance HNO (2HNO --+ N 2 0+ H 2 0 ) .Exercise 23-27 a. Write two va lence -bond structures for N-nitroso-N-methylmethan-amine and show how these structures explain the fact that the N-nitrosamine is amuch weaker base than N-methylmethanamine.b. N-Nitroso-N-methylmethanamine shows two separate methyl resonances in itsproton nmr spectrum. These collapse to a single resonance when the material isheated to 190" and reapp ear on cooling . Studies of the chang es in the line shapes withtemperature show that the process involved has an energy barrier of about 23 kcalmole-'. Ex plain why there should be separate m ethyl peaks in the nmr and why theyshould coale sce on he ating. (Review Section 9-10C. You also may wish to readSection 27-2.)Exercise 23-28 a. When ethyl aminoethanoate (H2NCH2C02C2H5)s treated withnitrous acid in the presence of a layer of diethyl ether, a yellow compound known asethyl diazoethanoate (N2CHC02C2H5)s ex tracted into the ether layer. What is theprob able structure of this compou nd and what is the m echanism by which i t is formed?b. Would you e xpe ct the same type of reaction sequence to occ ur with ethyl 3-amino-propanoate? Explain.Exercise 23-29 Predict the products expected from the reactions of the followingamines with nitrous ac id (prepared from NaNO, + HCI in aqueous solution):a. 2-methylpropanamine c. 2-butenamineb. azacyclopentane d. 3-amino-2,3-dimethyl-2-butanolExercise 23-30 The following sequence is very useful for expanding the ring sizeof a cycl ic ketone:

List reagents, conditions, and the important intermediates for the sequence, notingthat several in div idu al synthetic steps may be req uired. (Refer to Table 23-6 for am inesynthesis.)Exercise 23-31* The reaction of nitrous ac id with 3-butenamine, CH2=CHCH2C H2NH2,has been found to give the following mixture of alcohols: 3-buten-1-01 (45%),3-buten-


39/72

23-106 Arenamines with Nitrous Acid. Arenediazonium Salts 11332-01 (21% ), 2-b ute n-I -01 (7%) cyclobutanol (12% ) , and cyclopropylmethanol (15%).Show how each of these prod ucts may be formed from the 3-butenyl cat ion.Exercise 23-32* How cou ld one determine e xperimen tally how mu ch of the pro peneformed in the reaction of propan amine with nitrous ac id arises from the propyl cat ionand how much from the isopropyl cat ion?

23-108 Arenamines with Nitrous Acid. Arenediazonium SaltsUnlike primary alkylamines, primary arenamines react with nitrous acid at 0'to give diazonium ions that, in m ost c ases, are stable enough to be isolated ascrystalline BF,O salts. Other salts can be isolated, but som e of these, su ch asbenzenediazonium chloride, in the solid state may decompose with explosiveviolence:

benzenediazoniumchlor ide(water soluble)

benzenediazoniumfluoroborate(water insoluble)

The reason for the greater stability of arenediazonium salts comparedwith alkanediazonium salts appears to be related to the difficulty of formingaryl carbocations (Section 14-6A). Even the gain in energy associated withhaving nitrogen as th e leaving group is no t sufficient to mak e aryl cations formreadily, although th e solvolysis of arened iazonium ions in wa ter does proceedby an S,1 mech anism (see Ex ercise 23-33):

Th is reaction h as g eneral utility for rep lacement of aromatic am ino groups byhydroxyl groups. In contrast to the behavior of alkylamines, no rearrange-ments occur.Generally, diazonium salts from arenamines are much more usefulintermediates than diazonium salts from alkanamines. In fa ct, arenediazoniumsalts provide the only substances that undergo nucleophilic substitution


40/72

23 Organonit rogen Compounds I. Aminesreactions on the aromatic ring under mild conditions, without the necessityof having activating group s, such as nitro o r cyano, in the o rtho o r para position.The most important reactions of this type include the replacement of thediazonium group by nucleophiles such as Cla, Bra, Ia, C N a, NO 2@ , nd thesereactions lead t o the form ation of aryl halogen, cyano, and nitro com pounds.M ost of these reactions require cuprous ions, Cu(I ), as catalysts. T h e methodis known as the Sandrneyer reaction. The following examples illustrate how aprimary arenamine can be converted to a variety of different groups by wayof its diazonium salt:

4-bromo-1 -methyl-benzenec u e 1H C l

H 2 S 0 4 ,N aN O ,, H 2 0 4-iodo-1 -me thyl-0-5" (n o catalyst benzenenecessary)

CH3 CH3 \ CH34-methyl-benzenamine(para- to lu id ine)

4-methyl benzen ediazoniumhydrogen sulfate(not isolated)

I \6-cyano-Ienzenemethyl-

hypophosphorousacid , H 3 P 0 2 ,and Cu(1) sal ts

methyl benzene


41/72

23-108 Arenamines with Nitrous Acid. Arenediazonium SaltsAryl fluorides also may be prepared from arenamines by way of dia-zonium salts if th e pro ced ure is slightly modified. T h e ,amine is diazotizedwith nitrou s acid in the usual w ay; then fluoroboric acid or a fluoroborate saltis added, which usually causes precipitation of a sparingly soluble diazoniurnfluoroborate. The salt is collected and thoroughly dried, then carefully heatedto the decomposition point- he prod ucts being an aryl fluoride, nitrogen, andboron trifluoride:

@ @ heatC 6 H 5 N 2 B F 4 c 6 H 5 FS- N 2 3- B F 3This reaction is known as the Schiemann reaction. A n ex amp le (which gives abetter than usual yield) follows:

4-b romo- l -naphthalenamine 4-bromo-I-napthalene- 1 bromo-4-fluoro 'diazonium fluoroborate naphthalene (97%)T h e utility of all these transform ations may beco m e clearer if you workExercise 23-34. It will give you practice in seeing how various benzenederivatives can be prepared from primary benzenam ines. Late r in the chapterwe shall see that amines can be p repared by th e reduction of nitro com pound s,which permits the following sequence of reactions:

A rH HN03 > A r N O , H O N O + C u X> A r N H 2- ~N,' A rX-N2 >Th is sequence is especially useful to introduce groups o r produce orientationsof substituents that may not be possible by direct substitution.The Sandmeyer group of reactions is an example of the production of nucleo-phil ic su bs ti t~ l t io n y way of radical intermediates (see Section 14-1OA):

phenylradical

phenyl cation

This mechanism is supported by the fact that Cu(I1) is important in the forma-tion of C,H,X. If the concentration of Cu(I1) is kept very low so as to slow


42/72

23 Organonitrogen Compounds I. Aminesdown conversion of C6H,. to C,H5@, nd a compound with a reactive doublebond is present, then products are formed by attack of C,H,. on the doublebond. This is called the Meerwein reaction:

Iodide ion appears to be a good enough reducing agent to form C6H5.withoutthe intervention of Cu(1); considerable I, usually is formed in the reaction:

Secondary arenamines react with nitrous acid to form N-nitroso com-pounds while tertiary arenamines undergo electrophilic substitution with NO@if they have an unsubstituted para position:

Exercise 23-33 Benzenediazonium chlo ride solvolyzes in water to g ive a mixture ofbenzen ol and chloroben zene. Som e of the facts known about this and re lated reactionsare

1. The ratio C,H,CI/C,H,OH increases m arke dly w ith C I@ oncentra tion but therate ha rdly chang es at al l .

2. There is no rearrangement observed with 4-substituted benzenediazoniumions, and when the solvolysis is carried out in D,O, ins tea d of H,O, no C-D bonds areformed to the benzene ring.

3. 4-Methoxybenzenediazonium chloride solvolyzes about 30 t imes fasterthan 4-ni trobenzenediazonium chloride.

4. Benzenediazonium salts solvolyze in 98% H 2S 04 t almost the same rate asin 80% H,SO, and, in these solution s, the effective H,O conce ntra tion d iffe rs by afactor of 1000.Show how these observat ions support an S1 react ion of benzenediazonium chlor ide,and can be used to argue against a benzyne-type el imination-addit ion with wateractin g as the E2 base (Section 14-6C) or an S2 reaction with water as the nucleoph i le(Section 8-4, Mecha nism B, and Se ction 14-6).


43/72

23-10C D iazo Co upling Reactions23-10C Diazo Coupling ReactionsN o t all reaction s of diazonium ions involve cleavage of the C-N bond . A nimportant group of reactions of arenediazonium ions involves aromatic sub-stitution by the diazonium ion acting as an electrophilic agent to yield azocompounds, Ar-N=N-Ar:

Th is reaction is highly sensitive to the nature of the substituent X , and couplingto benzene derivatives normally occurs only when X is a strongly electron-donating group such as -0, -N (C H 3),, and -OW. Ho we ver, couplingwith X = -O CH 3 may take place with particularly active diazonium ions.Diazo coupling has considerable technical value, because the azo compoundsthat are produced are highly colored. Many are used as fabric dyes and forother coloring purposes. A typical example of diazo coupling is formation of4-N,N-dimethylaminoazobenzene from benzenediazonium chloride andN,N-dimethylbenzenamine:

4-N,N-dimethylaminoazobenzene(yellow)The product once was used to color edible fats and therefore was known as"Butter Yellow," but its use to color food is prohibited because it is reportedto be a potent liver carcinogen for rats.

The pH used for diazo coupling of amines is very important in determiningthe nature of the products. Under near-neutral conditions the diazonium ionmay attack the nitrogen of the arenamine rather than a ring carbon. In this eventa diazoamino compound, a triazene, -N=N-N-, is formed:

benzened azoam nobenzene(a triazene)The reaction is readily reversed if the pH is lowered sufficiently (see Exercise23-35).

As you see from this brief discussion of arenediazonium salts, their chemistryis complex. It is inappropriate to discuss all of their many reactions here, buta summary of the most important types of reactions is given in Table 23-4.


44/72

23 Organoni t rogen Com pounds I. AminesTable 23-4Summary of Reactions of Arenediazonium Salts

Reaction Comment

1. Rep lacem ent react ions: A~N,@ + X@- rX + N,a. a ryl hal id e formationA~N,@ + CI@ Cu(l) , rCI + N,A~N,@@BF, --@% ArF + N, + BF,

b. areneca rbonitr i le formationA~N,@ + OCN CU2(CN)2,ArCN + N,

c. aryl nitro compound formationA~N,@ + @NO, Cu(i) , rNO, + N,

d. benzenols by hydrolysis-.H@A~N,@ + H,O-ArOH + N,e. aryl azide formationA~N,@ + ON, -+ ArN, + N,

2. Addi t ion to conjuga ted alkenes

Cuprous-catalyzed replacement reac-t ions are cal led Sandm eyer react ions;aryl chlorides, bromides, cyanides, andni tro compo unds are prepared in thisway; formation of aryl iodide s requiresno catalyst, fluorides are obtained byheating diazonium fluoroborates (i.e.,Sch iema nn react ion) ; benzenols areobtained by warming aqueousdiazonium salt solut ions.

Cuprous-catalyzed addit ion of adiazonium salt to activated doublebonds of al kenes and related com-poun ds is known as the Mee rweinreaction; i t competes with theSandmeyer reaction.

3. Biaryl formation Decomposit ion of diazonium salts inpresence of Cu( l) and ammonia leadsa A~N,@+ Cu(l) NH> Ar-Ar + Cu(l l) + N, to biaryls.- @b. A~N,@@O,CCH, e rN=NO,CCH, Thermal dec om pos ition of dia zo

Ar'H ethanoates in an aromatic solvent lead sArN=NO,CCH, -N2 9 Ar-- r-Arr-CH,CO,. to biaryl formation by attack of arylradic als on solvent.4. Reduct ion of d iazonium salts

a. arene formationRe duc tive replac em ent of -N,@ byhydrogen is ef fected by hypophos-phorous acid; reduction is init iated

A~N,@+ H,O + H,PO, Cu(l) , rH + N, +H@+ H3P03 with Cu(l)b. hydrazine formation Sulfi te reduction of diazonium salts&N,@ + 2 ~ 0 ~ 2 0HO@ + H,O --+ ArNHNH, + 2 ~ 0 ~ 2 0eads to hydrazines.

5. Diazo -coupl ing react ionsa. formation of azo compounds- @A~N,@ + Ar'X O , r-N=N-Ar'X

Elec troph ilic a ttack of ArN,@ on A rrXleads to azo compounds; the substi t-uent X must be p owerful ly activating[e.g., -00, -N(CH,),] .


45/72

23-1OD R earrangem ents of N-Substituted A renaminesTable 23-4 (continued)Summary of Reactions of Arenediazonium Salts

Reaction Comment

b. formation o f tr iazenes (diazoamino) com pound s Electrophilic attack of ArN,@ onnitrogen of a prim- or sec-arylamineA~N,@ + ArtNH2 pH > Ar--N=N-NHAr1 + H@ in neutral or alkaline solution.

6. Diazotate formation Diazotate salts are formed reversibly0"A~N,@@CI+ @ OH -3 Ar-N=N-OH + GI@ from diazonium salts in basic solution.diazoic acid0"ArN=N-OH + @ O He ~N=N-O@ + H,Od azotate

Exercise 23-34 Indicate how you could prepare each of the fol lowing compounds,starting with benzene. One of the steps in each synthesis should involve format~on fa diazonium salt. (Review Sections 22-4 and 22-5 if necessary.)a. monodeuteriobenzene f. 3- iodobenzenecarboxylic acidb. 2-cyano-1 -isopro pyl benzene g. 4-chlorophenyl azidec. 4-tert-butyl benz eno l h. 4-methylphenylhydrazined. 3-hydroxyphenylethanone i. 2-amino-4'-methylazo benzenee. 3-chloronitrobenzene j. 2-chloro-1 -phenyIpropane

23-1OD Rearrangements of N-Substi tuted A renaminesA secondary arenamine behaves like a secondary alkanamine in reacting withnitrous acid to give an N-nitrosamine. However, when treated with an acid theN-nitrosamine rearranges:

N-nitroso-N-methyl benzen amine 4-nitroso-N-methyl benzena mine

This is one example of a group of formally related rearrangements in which asubstituent, Y, attached to the nitrogen of a benzenamine derivative migrates


46/72

23 Organonitrogen Compounds I . Aminesto the ortho or para position of the aromatic ring under the influence of acid:

Rearrangement occurs most readily when Y is a strongly electron-attractinggroup and the N-Y bond that is broken is not as strong as the C-Y bond thatis formed. A few of the many examples of this type of reaction follow:

hydrazobenzene 4,4'-diaminobiphenyl(benzidine)

4-aminobenzenol(para-aminophenol)

N-chloro-N-phenylethanamide N-(4-ch1orophenyl)ethanamide(N-chloroacetanilide) (para-chloroacetanil ide)

phenyldiazane 1,4-benzenediamine(phenylhydrazine) (para-diaminobenzene)

Exercise 23-35* Some of the rea rrange me nts of arenam ines, ArNHY, to Y-Ar-NH,shown above proceed by an intermolecular mechanism involving acid-catalyzedcleav age of the N-Y bon d follow ed by a norma l elec trophilic substitution of thearomatic ring. Show the steps in this mechanism for Y = NO and CI.


47/72

23-1 1 Oxidation of Amines 4141Exercise 23-36* Treatment of a mixture of 2,2'dim ethyl hydrazoben zene a nd hydrazo-benzene with acid gives only 4,4'-diaminobiphenyl and 4,4'-diamino-2,2'-dimethyl-biph eny l. What do es this tell you about the mec han ism of this type of rearrangemen t?Write a mechanism for the rearrangement of hydrazobenzene that is in accord withthe acid catalysis (the rate depends on the square of the H@ concentration) and thelack of mixing of groups as described above.Exercise 23-37* Show how the fol lowing substances could be prepared by a suit-able ArNRY-type rearrangement.

b. 4-amino-3-m ethyl benzeno l d. N-methyl- l ,4-benzenediamine

23-1 1 OXIDATION OF AMINES23-11A Oxidation States of Nitrogen in Organic CompoundsNitrogen has a wide range of oxidation states in organic compounds. We canarrive at an arbitrary scale for the oxidation of nitrogen in much the same wayas w e did fo r carbo n (Section 11- 1). W e simply define elem entary n itrogen a sthe zero oxidation state, and every atom bonded to nitrogen contributes -1 tothe oxidation state if it is more electropositive than nitrogen (e.g., H, C , Li,B, Mg) and +1 if i t is more electronega tive (e.g., 0 , F, Cl). Doubly bondedatom s are co unted twice, an d a formal positive charge associated with nitro-gen counts as +l.T o illustrate, the oxidation states of several representative com poun dsare as follows:

- lC H3 - 'C6H5 - 'CH3 - lCH 3- IH-N: I+ l N @ N: I+ I N @Ill I oO/ \oON + 20 + 1 +2

Oxidationstate: -3 -3 0 (for each N) + +3Several types of nitrogen compounds are listed in Table 23-5 to illustrate therange of oxidation states that are possible.


48/72

23 Organonitrogen Compounds I. AminesTable 23-5Oxidation States of Nitrogen

Compound orclass of comp ound Example Oxidation state

amine CH3NH2 -3imine CH2=NH (unstable) -3nitrile CH,C=N -3azanol CH3NHOH -1(hydroxylamine)

nitrogen :N=N:nitroso CH3N=0nitr ic oxide .N=O

nitro

nitrite ester CH3-0-N=O +3nitrogen dioxide -NO2 4-4

Exercise 23-38 What is the oxidation state of each nitrogen in each of the followingsubstances?

0 00IIa. HO-C-NH, I /T2f . CH3-N=N-CH, j. N-N0


49/72

23-116 Oxidation of Tertiary Amines. Amine Oxides 114323-1 1B Oxidation of Tertiary Amines. Amine OxidesFor the oxidation of a tertiary amine by reagents such as hydrogen peroxide,

H202,or peroxycarboxylic acids, RC\ , which can supply an

oxygen atom with six electrons, the expected product is an azane oxide (amineoxide). Thus N,N-diethylethanamine (triethylamine) can be oxidized to tri-ethylazane oxide (triethylamine oxide):

Amine oxides are interesting for two reasons. First, amine oxides de-compose when strongly heated, and this reaction provides a useful preparationof alkenes. With triethylazane oxide (triethylamine oxide), ethene is formed:

N,N-diethylazanol(N,N-d ethyl hydroxylam ine)The second interesting point about amine oxides is that, unlike amines, theydo not undergo rapid inversion at the nitrogen atom, and the oxides fromamines with three different R groups are resolvable into optically active forms.This has been achieved for several amine oxides, including the one from N-ethyl-N-methyl-2-propenamine.

Exercise 23-39 Show how one could synthesize and resolve the oxide from N-ethyl-N-methyl-2-propenamine with the knowledge that amine oxides are somewhatbasic substances having K , values of about 10-l1 (K, -

23-1 1C Oxida t ion of Pr imary and Secondary AlkanaminesAddition of an oxygen atom from hydrogen peroxide or a peroxyacid to a pri-mary or secondary amine might be expected to yield an amine oxide-type


50/72

1144 23 Organonitrogen Compounds I. Aminesintermediate, which then could rearrange to an azano l (hydroxylamine):

However, these oxidations usually take a more complicated course, becausethe azanols themselves are oxidized easily, and in the case of primary amines,oxidation occurs all the way to nitro compounds, in fair-to-good yields:

23-110 Oxida t ion of Aromatic Am inesWe shall use benzenamine to illustrate some typical oxidation reactions ofarenamines. The course of oxidation depends on the nature of the oxidizingagent and on the arenamine. With hydrogen peroxide or peroxycarboxylicacids, each of which functions to donate oxygen to nitrogen, oxidation to theazanol, the nitroso, o r the nitro com pound may occur, depending o n the tem-perature, the pH , and the am ount of oxidizing agent:


51/72

23-12 Synthesis of Amines 1145Oxidizing agents that abstract a hydrogen atom or hydride ion lead to morecomplex reactions, which often result in highly colored products. One of thebest black dyes for fabric (Aniline Black) is produced by impregnating clothwith phenylammonium chloride solution and then oxidizing, first with sodiumchlorate (NaClO,) and finally with sodium dichromate (Na,Cr20,). AnilineBlack probably is not a single substance, and its exact structure(s) is not known;but its formation certainly involves addition reactions in which carbon-nitrogenbonds are made. A possible structure is shown in which there are seven anilineunits:

Oxidation of benzenamine with sodium dichromate in aqueous sulfuric acidsolution produces 1,4-cyclohexadienedione (para-benzoquinone), which is thesimplest member of an interesting class of conjugated cyclic diketones that willbe discussed in more detail in Chapter 26:

1,4-cyclohexadienedioneW2S04,10' (para-benzoquinone,1,4-benzenedione)0

23-12 SYNTHESIS OF AMINES23-1 2A M ain Types of SynthesisThere are seemingly many different ways in which amines can be prepared.Ho we ver, a careful look a t these me thods reveals that they fall into three maingroups of reactions. The first group starts with a simple amine, or with am-monia, an d builds up the carbon fram ew ork by alkylation or arylation reac tionson nitrogen, as discussed in Section 23-9D:

T h e second group sta rts with compounds of the sam e carbon-nitrogen frame-work as in the desired am ine but with nitrogen in a higher oxidation state. Th eamine then is obtained from these compounds by catalytic hydrogenation ormetal-hydride reduction, as will be described in the next section:P tR N O , + 3H 2 ---+ R N H , -I- 2 H 2 0


52/72

1946 23 Organonitrogen Compounds I. AminesT he third group of reactions relies on the fact that am ides usually can beconverted to amines, either by reduction, hydrolysis, or rearrangement, sothat any viable synthesis of amides usually is also a synthesis of amines:

I I1R1-C-NHR > R1-C-OH + RNH, (Sections 23-12D0 and 24-4)IR'-C-NHR Pt R1CH2NHRor LiAlH, (Section 23-12B)

(Section 23-12E)These and related reactions are discussed in further detail in thefollowing sections. For your convenience, a tabular summary of methods forthe synthesis of am ines appea rs in Tables 23-6 and 23-7.

23-126 Formation of Amines by Reduct ionExcellent procedu res are available for the preparation of primary, secondary,and tertiary amines by the reduction of a variety of nitrogen compounds.Primary amines can be obtained by hydrogenation or by lithium aluminumhydride reduction of nitro compounds, azides, oximes, imines, nitriles, orunsubstituted amides [all possible with H , over a metal catalyst (Pt or Ni)or with LiAlH,] :nitro R-NO2 ---+ RNH, imine R,C=NH ---+2CHNH2

0 0 nitrile RC-N --+ RCH2NH2azide R-N=N=N --+ RNH,oxime R,C=N-OH ---+ R,CHNH, amide RCNH, ---+ RCH,NH,I

Some care must be exercised in the reduction of nitro compounds becausesuch reductions can be highly ex othermic. F o r example, the reaction of 1 mole(61 g) of nitromethane with hydrogen to give methanamine liberates sufficienthea t to increase the tem pera ture of a 25-lb iron bomb 100":

Secondary and tertiary amines, particularly those with different Rgroups, are prepared easily by lithium aluminum hydride reduction of substi-tuted amides (Section 18-7C).


53/72

Table 23-6 i-0?J__IPract ical Examples of the Synthesis of Amines NV)Y27Reaction Comment E.

1 . Reduction of nitrogen compoundsa. nitro compoundsL iA IH > CH3CH,CHCH3H3CH,CHCH3

Iether

I

2,4-dinitromethyl benzene 4-methyl-l,3-benzenediamineb. nitriles

butanenitrilec. amides

butanamine57%

LiAIH,, H,Oether fp)--;--CH2CH3N-ethyl-N-methyl benzenamine91%

Lithium aluminum hyd ride is aconvenient reagent for reduction ofnitro compounds, nitriles, amides,azides, and oximes to primary amines.Catalytic hydrogenation works also.Aromatic nitro compounds are reducedbest by reaction of a metal andaqueous acid or with ammonium orsodium polysulfides (see Section23-12B). Reduction of N-substitutedamides leads to secondary amines.

See Section 23-128.

See Section 23-129.

(Table continued on next page.)


54/72

23 Organonitrogen Compounds I. Amines

(I)a,2m


55/72

23-12 Synthesis of Amines

LP C3- 0.-E m - .-o a r 0.= c g, s $.E m .? ,G2! 2 FZ Dg p g :

a , & gNo q U 7 . z: sg a $: a,.- c & g 22 r m .2( d o k ~ ~ r i.c ;E 2 E ?2 m Z E 2 2


56/72

7. Hofmann degradat ion of amidesCH3 CH3ICH2=CHCCONH2 Il o % NaoH > CH2=CHC-NH2I NaOCI I

8. Curt ius degradaf ion of acyl azidesa. acyl azide from hydrazideNH2NH2 NCCH2CONHNH2 NaNO,, HCINCCH2C02C,H5ethyl cyanoethanoate cyanoethanoyl hydrazine 0"

0NCCH2CON, I 1 . OH @C2H50H > NCCH2NHCOC2H5- 02CCH2NH2cyanoethanoyl azide 2 H@ aminoethanoic acid(g lycine)54%

b. acyl azide from acyl chloride

ethanoyl chloride ethanoyl azide 65%

See Section 23-12E. Either NaOCI orNaOBr may be used.

Hofmann, Curtius, and Schmidtreactions yield primary amines freeof secondary or tertiary amines. Thethree reactions are closely relatedbut differ in reaction conditions.They apply to alkyl, al lyl , and a rylderivatives. See Section 23-1 2E.

9. Schmidt degradat ion of acyl azides (obta ined from carboxyl ic acids) See Section 23-12E.

phenylethanoic acid hydrazoic aci d phenylmethanamine92 %


57/72

Table 23-7Pract ical Exam ples of the Synthesis of Aromat ic Amines

Reaction Comment1 . Reduction of nitro compounds

)='CH O3-nitrobenzenecarbaldehydeSnCI,, HCI

)"CH O3-aminobenzenecarbaldehyde

HC(OCH,),(3-nitropheny1)dimethoxy-methane

HC(OCH,)~(3-aminopheny1)dimethoxy-methane67-78%

C. Fe, HCIc ~ 3 ~ N 0 2C2 ti5 0H ,re flu x> CH3NH2 -

NO,2,4-dinitrornethyl benz ene

Reducing agents commonly employedare iron, tin, or SnCI, in hydroc hloricacid; an d ammonium or alkal i-metalsulfides; catalytic hydrogenation andelectrolytic reduction also are em-ployed (see Section 23-12 8 ) .

Notice, in the example given, that theacetal function is a protecting groupfor CHO.

Notice that, with the right conditionsand red ucing agent, one nitro groupcan be selectively reduced in thepresence of another.

(Table continued on next page.)


58/72

23 Organonitrogen Com pounds I. Amines

KC 0a, 'GO 0 -0 a , E o N, a @ z.E a. - a )0 u G - uC 0 3 ga , c n m ,E 3 2 . -: . 2 ( d &(du Q U J-a,( / , -0K (do? m m 1 1 : ,0 a,- e z $ -F z r F %g z . t ;Z:a, x r n a -2:yzoz o - 5 2


59/72

23-1 2 Synthesis of Amines


60/72

1154 23 Organonitrogen Com pounds I. Amines23-12C Amines by R educt ive Alkylat ion of Aldehydesand, KetonesA useful synthesis of primary and secondary amines that is related to thereductions just described utilizes the reaction of an aldehyde or a ketone withammonia or a primary amine in the presence of hydrogen and a metal catalyst:

PtRCHO + NH3+ Hz RCH2NH2+ H 2 0PdR2C=0 + CH3NH2+ H2+ 2CHNHCH3+ H 2 0

It is reasonable to suppose that the carbonyl compound first forms theimine derivative by way of the aminoalcohol (see Section 16-4C), and thisderivative is hydrogenated under the reaction conditions:

NH2I -H20R-CH=O + NH3 R-CH-OH

Other reducing agents may be used, and the borohydride salt NaB@BH3(CN)is convenient to use in place of H2 and a metal catalyst.

In a formal sense, the carbonyl compound is reduced in this reactionwhile the amine is alkylated, hence the term reductive alkylation or reductiveamination.r . t **L- - = a - s -a* *.aG -x"*ah-& v;i-~-w~-rx-waa=~-r&~~a-w=w+awe"J&v~v~~mddw?- ,TExercise 23-40 Show how the fol lowing transformations may be achieved. Listreagents and approximate react ion condit ions.a. 3-bromopropene to 3-butenamineb, cyclohexanone to cyclohexana minec. benzenecarboxylic acid to phenylmethanamine (not N-phenylmethanamine)d. benzenecarbaldehyde to N-methylphenylmethanamine (C,H,CH,NHCH,)

23-12D Amines f rom Am ides by H ydrolysis or Reduct ionThere are a number of ways in which an amide can be transformed into anamine. Two of these ways have been mentioned already and involve hydrolysisor reduction:


61/72

23-12E Amines from Amides by the Hofmann Degradation 1155A s a m eans of am ine synthesis, both methods depend o n the availabili ty or theease of synthesis of the corresponding amide.

23-12E Amines from Amides by the Hofmann DegradationAn interesting and general reaction for the preparation of primary amines isthe Hofmann degradation, in which an unsubstituted amide is converted to anamine by bromine (or chlorine) in sodium hydroxide solution:/PR- C + Br, + 4 N a O H -+ R N H , + 2Na Br + Na,CO, + 2 H 2 0\

T h e mechan ism of this unusual reaction first involves base-catalyze d bromina-tion of the amjde on nitrogen to give an N-bromoam ide intermediate:

There follows a base-induced elimination of HBr from nitrogen to form a"nitrene" intermed iate, which is analogous to the form ation of a carbene(Section 14-7B):

P 0R - C + O H *\N-Br1 acyl nitreneHA s you might exp ect from the structure of an acyl nitrene (only six electronsin the v alence shell of nitrogen), it is highly unstable b ut can b ecom e stabilizedby having the substituent group move as R :@ ro m ca rb on to n i t r ~ g e n : ~

R--c' d =C=N- R an isocyanate\ f 2The rearrangement is stereospecific and the configuration at the migratingcarbon is retained (see Section 2 1-10F). T h e rearrangemen t product is calledan isocyanate and is a nitrogen analog of a ketene (R ,C =C = O ) ; ike ketenes ,5There are several analogies for this kind of rearrangement that involve electron-deficient carbon (Sections 8-9B and 15-5E) and oxygen (Sections 16-9E).


62/72

23 Organonitrogen Com pounds I. Aminesisocyanates readily add water. The products are carbamic acids, which arenot very stable, especially in basic solution, and readily lose carbon dioxideto give the a mine:

a carbamic ac id(unstable)A practical exa mp le of this reaction is given in Tab le 23-6 together with exam -ples of related reactions known as the Curtius and Schmidt rearrangements.The latter two probably also involve rearrangement of an acyl nitrene, thistime formed by decom position of an acy l azide:

Exercise 23-41 The p oint of this e xerc ise i s to show that rea ctions of known stereo-specif ici ty can be used to establish configurat ion at chiral centers.A carboxyl ic ac id of (+) op tical rotat ion was converted to an am ide b y way of

the acyl chloride. The amide in turn was converted to a primary amine of one lesscarbon atom than the start ing carboxyl ic acid. The primary amine was identif ied as2-S-am inobutane. What was the structure and configu ration of the (+)-carboxylic ac id?Indicate the reagents you would need to carry out each step in the overall sequ enceRC0,H - COCl- CONH, --+ RNH,.Exercise 23-42 Draw the structures of the products expected to be formed in thefol lowing react ions:

a. (CH,),CHCH,CONH, Br,, NaOH /CoNH2 NaOClc. (CH2 )4\ NaOH '

b. O C H , C O N H , CI,, NaOH d.c{HN3 conc. H2S04OH


63/72

23-13 Protection of Amino Groups in Synthesis23-13 PROTECTION OF AMINO GROUPS IN SYNTHESISWe have mentioned previously that it may be difficult to ensure selectivechemical reaction at one functional group when other functional groups arepresent in th e same molecule. Amino g roups are particularly susceptible toreactions with a wide variety of reagents, especially oxidizing reagents, al-kylating reagents, and many carbonyl compounds. Therefore, if we wish toprevent the amino group from undergoing undesired reactions while chemicalchange occurs elsewhere in the molecule, it must be suitably protected. Thereis more documented chemistry on methods of protecting amino groups thanof any oth er functional group. This is because pep tide synthesis has becomevery important and , as we shall see in Chap ter 25, it is not possible to build apeptide of specific s truc ture from its com ponen t amino acids unless the aminogroups can be suitably protected. Therefore we now will consider the moreuseful protecting groups that a re available- how the y ar e introduc ed and howthey are removed.

23-13A ProtonationIt should be c lear that th e reactivity of amines normally involves some processin which a bond is made to the unsha red electron pair on nitrogen. There foreany reaction of an am ine that red uces t he reac tivity of this electron pair shouldreduc e the reactivity of the nitrogen atom . Th e simplest way to do this wouldbe to convert the amine to an ammonium salt with an acid. Protonationamoun ts to protection of the amine function:

0 0R N H 2+ WX R N H , XExam ples are known in which am ines indeed can be protected in this mann er,but unless the acid concentration is very high, there will be a significant pro-portion of unprotected free base present. A lso, many desirable reactions arenot feasible in acid solution.

23-13B AlkylationA related protection proced ure is alkylation (Equation s 23-8 and 23-9), whichis suitable for primary and secondary amines:


64/72

23 Organonitrdgen Compounds I.AminesAt first glance, you may not consider that such reactions achieve pro-

tection because there is an electron pair on nitrogen in the products. However,if a suitably bulky alkylating agent, RX , is used the reactivity of the resultingalkylated amine can be reduced considerably by a steric effect. The mostuseful group of this type is the triphenylmethyl group (C,W5)3C-7 which canbe introduced on the amine nitrogen by the reaction of triphenylmethyl chloride("trityl" chloride) with the amine in the presence of a suitable base to removethe HCl that is formed:

The triphenylmethyl group can be removed from the amine nitrogen under verymild conditions, either by catalytic hydrogenation or by hydrolysis in thepresence of a weak acid:

Exercise 23-43 Cleavag e of C-N bon ds by catalyt ic hydrogenation is achievedmuch more readily with diphenylmethanamine or tr iphenylmethanamine than withalkanamines. Explain why this should be so on the basis that the cleavage is ahom olyt ic react ion.Exercise 23-44 Write the steps involve d in (a) the formation of tripheny lme thana minefrom tr iphenylmethyl ch loride in aqueous ammonia containing sodium hydroxide and(b) the

bpo c chapter 23

Documents