Amines: Preparation and Physical Properties PDF

Chapter Amines I. Preparation and 22 Physical Properties 22.1 Structure Nearly all the organic compounds that we have studied so far are bases, although very weak ones. Much of the chemistry of alcohols...

Chapter Amines I. Preparation and 22 Physical Properties 22.1 Structure Nearly all the organic compounds that we have studied so far are bases, although very weak ones. Much of the chemistry of alcohols, ethers, esters, and even of alkenes and aromatic hydrocarbons is understandable in terms of the basicity of these compounds. Of the organic compounds that show appreciable basicity (for example, those strong enough to turn litmus blue), by far the most important are the amines. An amine has the general formula 2, RNH R 2 NH, or R 3N, where R is any alkyl or aryl group. For example: CH NH 2 3 (CH 3 ) 2NH (CH 3) 3N H 2NCH2CH 2NH2 Methylamine Dimethylamine Trimethylamine Ethylenediamine (1) (2) (3) (1) N-Mcthylaniline N,N-Dimethylanilinc (2) (3) 22.2 Classification Amines are classified as primary, secondary, or tertiary, according to the number of groups attached to the nitrogen atom. H H R R-N-K R N-R R-N-R Primary Secondary Tertiary 1 2 727 728 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 In their fundamental properties bastfity and the accompanying nucleo- philicity amines of different classes are very much the same. In many of their reactions, however, the final products depend upon the number of hydrogen atoms attached to the nitrogen atom, and hence are different for amines of different classes. 22.3 Nomenclature named by naming the alkyl group or groups attached to Aliphatic amines are nitrogen, and following these by the word -amine. More complicated ones are often named by prefixing amino- (or N-methylamina-, N,N-diethylamino-> etc.) to the name of the parent chain. For example: H CH 3 CH _ -C-CH 3 3 CH CH 2-N-CH 3 3 CH N CHCH 2CH 3 3 NH2 CH 3 te/7-Butylamine Methylethylamine Dimethyl-jec-butylamine (1) (2) (3) H H 2NCH2CH 2 CH COOH 2 H 2NCH 2 CH2 OH CH N CH(CH )4CH 3 2 3 y-Aminobutyric acid 2-Aminoethanol CH 3 (1) (Ethanolamine) 2-(N-Methylamino)heptane (1) (2) Aromatic amines those in which nitrogen is attached directly to an aromatic ring are generally named as derivatives of the simplest aromatic amine, aniline. An aminotoluene is given the special name of toluidine. For example: 2,4,6-Tribromoaniline N-Methyl-N-cthylaniline (1) (3) />-Nitroso-N,N-dimethylaniline (3) Diphcnylamine 4,4'-Dinitrodiphcnylaminc (2) (2) SEC. 22.4 PHYSICAL PROPERTIES OF AMINES 729 Salts of amines are generally named by replacing -amine by -ammonium (or -aniline by -anilinium), and adding the name of the anion (chloride, nitrate, sulfate, etc.). For example: - (C 2 H 5 NH 3 +) 2 S(V (CH 3) 3 NH + N0 3 C 6 H 5 NH 3 cr Ethylairmonium Trimethylammonium Anilinium sulfate nitrate chloride 22.4 Physical properties of amines Like ammonia, amines are polar compounds and, except for tertiary amines, can form intermolecular hydrogen bonds. Amines have higher boiling points H CH H 3 I H -N H N-CH, than non-polar compounds of the same molecular weight, but lower boiling points than alcohols or carboxylic acids. Amines of all three classes are capable of forming hydrogen bonds with water. As a result, smaller amines are quite soluble in water, with borderline solubility Table 22.1 A MINTS Name Methylamine Dimethylamine Trimethylamine Ethylamine Diethylamine Triethylamine /t-Propylamine Di-w-propylamine Tri-w-propylamine Isopropylamine w-Butylamine Isobutylamine s^c-butylamine terf-Butylamine Cyclohexylamine Benzylamine a-Phenylethylamine j8-Phenylethylamine Ethylenediamine Tetramethylenediamine [H 2N(CH2)4NH 2 ] Hexamethylenediamine 39 196 v.sol. Tetramethylammonium hydroxide 63 \35d 220 strong base 730 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 Table 22.1 AMINES (continued) being reached at about six carbon atoms. Amines are soluble in less polar solvents like ether, alcohol, benzene, etc. The methylamines and ethylamines smell very much like ammonia; the higher alkylamines have decidedly "fishy" odors. Aromatic amines are generally very toxic; they are readily absorbed through the skin, often with fatal results. Aromatic amines are very easily oxidized by air, and although most are color- less when pure, they are often encountered discolored by oxidation products. SEC. 22.6 STEREOCHEMISTRY OF NITROGEN 731 22.5 Salts of amines Aliphatic amines are about as basic as ammonia; aromatic amines are con- siderably less basic. Although amines are much weaker bases than hydroxide ion or ethoxide ion, they are much stronger bases than alcohols, ethers, esters, etc. ; they are much stronger bases than water. Aqueous mineral acids or carboxylic acids readily convert amines into their salts; aqueous hydroxide ion readily converts the salts baclc into the free amines. As with the carboxylic acids, we can do little with amines without encountering this conversion into and from their salts; therefore worthwhile to look at the properties of these salts. it is In Sec. 18.4 we contrasted physical properties of carboxylic acids with those of their salts; amines and their salts show the same contrast. Amine salts are typical ionic compounds. They are non-volatile solids, and when heated generally decompose before the high temperature required for melting is reached. The halides, nitrates, and sulfates are soluble in water but are insoluble in non-polar solvents. The difference in solubility behavior between amines and their salts can be used both to detect amines and to separate them from non-basic compounds. A water-insoluble organic compound that dissolves in cold, dilute aqueous hydro- chloric acid must be appreciably basic, which means almost certainly that it is an amine. An amine can be separated from non-basic compounds by its solubility in acid; once separated, the amine can be regenerated by making the aqueous solu- tion alkaline. (See Sec. 18.4 for a comparable situation for carboxylic acids.) Problem 22.1 Describe exactly how you would go about separating a mixture of the three water-insoluble liquids, aniline (b.p. 184), n-butylbenzene (b.p. 183), and /r-valeric acid (b.p. 187), recovering each compound pure and in essentially quanti- tative yield. Do the same for a mixture of the three water-insoluble solids, p-toluidine, 0-bromobenzoic acid, and p-nitroanisole. 22.6 Stereochemistry of nitrogen So far in our study of organic chemistry, we have devoted considerable time to the spatial arrangement of atoms and groups attached to carbon atoms, that is, to the stereochemistry of carbon. Now let us look briefly at the stereochemistry of nitrogen. Amines are simply ammonia in which one or more hydrogen atoms have been replaced by organic groups. Nitrogen uses s/> 3 orbitals, which are directed 732 AMINES I, PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 to the corners of a tetrahedron. Three of these orbitals overlap s orbitals of hydro- gen or carbon; the fourth contains an unshared pair of electrons (see Fig. 1.11, p. 18). Amines, then, are like ammonia, pyramidal, and with very nearly the same bond angles (108 in trimethylamine, for example). From an examination of models, we can see that a molecule in which nitro- gen carries three different groups is not superimposable on its mirror image; it is chiral and should exist in two enantiomeric forms (I and 11) each of which separated from the other might be expected to show optical activity. But such enantiomers have not yet been isolated for simple amines and spectroscopic studies have shown why: the energy barrier between the two pyra- midal arrangements about nitrogen is ordinarily so low that they are rapidly interconverted. Just as rapid rotation about carbon-carbon single bonds pre- vents isolation of conformational enantiomers (Sec. 4.20), so rapid inversion about nitrogen prevents isolation of enantiomers like I and II. Evidently, an un- shared pair of electrons of nitrogen cannot ordinarily serve as a fourth group to maintain configuration. Next, let us consider the quaternary ammonium salts, compounds in which four alkyl groups are attached to nitrogen. Here all four sp* orbitals are used to form bonds, and quaternary nitrogen is tetrahedral. Quaternary ammonium salts in which nitrogen holds four different groups have been found to exist as con- figurat tonal enantiomers, capable of showing optical activity: methylallylphenyl- benzylammonium iodide, for example. Problem 22*2 At room temperature, the nmr spectrum of 1-ethylaziridine (III) shows the triplet-quartet of an ethyl group, and two other signals of equal peak area. When the temperature is raised to 120, the latter two signals merge into a single signal. How do you interpret these observations? \ N-C 2 H 5 N-CI H 2C HC CH 3 in iv Problem 22.3 Account for the following, drawing all pertinent stereochemical formulas, (a) l-Chloro-2-methylaziridine (IV, above) was prepared in two isomeric forms separable at 25 by ordinary gas chromatography. (b) The reaction of (C 6 H 5 ) 2 C^NCH 3 with R-(+)-2-phenylpcroxypropionic acid gave a product, C| 4 H|jbN, with [a] + 12.5, which showed no loss of optical activity up to (at least) SEC. 22J PREPARATION 733 Problem 22.4 Racemization in certain free-radical and carbonium ion reac- tions has been attributed (Sees. 7.10 and 14.13) to loss of configuration in a jtat inter* mediate. Account for the fact that the formation of alkyl carbanions, R: which are believed to be pyramidal can also lead to racemization. 22.7 Industrial source Some of the simplest and most important amines are prepared on an industrial scale by processes that are not practicable as laboratory methods. The most important of all amines, aniline, is prepared in several ways: (a) reduction of nitrobenzene by the cheap reagents, iron and dilute hydrochloric acid (or by catalytic hydrogenation, Sec. 22.9); (b) treatment of chlorobenzen&with o Nitrobenzene Anilinium chloride Aniline NH,, Cu 20. 200. 900 lb/in.* ammonia at high temperatures and high pressures in the presence of a catalyst. Process (b), we shall see (Chap. 25), involves nucleophilic aromatic substitution. Methylamine, dimethylamine, and trimethylamine are synthesized on an industrial scale from methanol and ammonia: NH 3 -38?* CH 3 NH 2 -SjgU ' (CH 3 ) 2NH -SigU CH ( 3)3 N 450 450 450 Ammonia Methylamine Dimethylamine Trimethylamine AlKyl halides are used to make some higher alkylamines, just as in the laboratory (Sec. 22.10). The acids obtained from fats (Sec. 33.4) can be converted into long-chain 1-aminoalkanes of even carbon number via reduction of nitriles (Sec. 22.8). N " 3theat RCOOH > RCONH 2 hcat > RGs=N H2>ca S RCH NH 2 2 Acid Amide Nitrile Amine 22.8 Preparation Some of the many methods that are used to prepare amines in the laboratory are outlined on the following pages. 734 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 PREPARATION OF AMINES 1. Reduction of nitro compounds. Discussed in Sec. 22.9. ArN 2 Ar* H2 Chiefly for or *" or aromatic amines RN0 2 RNH 2 Nitro compound 1 amine Examples: COOC2Hs (8) NO 2 NH 2 Ethyl /7-nitrobcnzoate Ethyl />-aminobenzoate NH 2 NH 2 Sn,HCI NO2 NH 2 p-Nitroaniline p-Phenylenediamine Fc>HC1 CH 3CH 2CH 2N0 2 CH CH 2CH 2NH 2 3 1-Nitropropane n-Propylamine 2. Reaction of halides with ammonia or amines. Discussed in Sees. 22.10 and 22.13. ** N H3 RNH2 > R 2NH > R 3N 1 amine 2 amine 3 amine Quaternary ^,. , w,,-*i.^ electron-withdrawing M w,.- ammonium salt substituents Examples: CH3COOH ^> CH2COOH CH2COOH (or CH2COO~) Cl NH2 NH2 + NH 3 Acetic Chlorqacetic Aminoacetic acid acid (Glycine; an amino acid) (1) H I C2H 5C1 - C2H 5NH2 Ethyl chloride Ethylamine Methylethylamine (1) (2) Benzyl chloride Benzylamine Benzyldimethylamine (H (3) SEC. 22.8 PREPARATION 735 CIW )N(CH 3) 2 N(CH 3 )3 +I- N,N-Dimethylaniline Phcnyltrimethylammonium iodide (3') (4) Cl NHCH 3 N0 2 NO2 2,4-Dinitrochlorobenzcnc N-Methyl-2,4-dinitroaniline (2) 3. Reductive amination. Discussed in Sec. 22.11. 1 amine X or NaBHjCN CH-NHR 2 amine H 2.Ni ^ \ CH-NR 2 or NaBHjCN / Examples: : 3 + NH 3 + H2 CH3 CH~CH 3 4 NH2 Acetone Isopropylamine (1) H NaBHjCN. (CH 3 ) 2CHC=0 + )NH 2 )NCH 2CH(CH 3) 2 Isobutyraldehyde Aniline N-Isobutylaniline (1) (2) H CH3 CH 3O=0 + (CH 3)2NH4-H 2 CH 3CH2-N-CH3 Acetaldehyde Dimethylamine Dimethylethylamine (2) (3) 4. Reduction of nitrites. Discussed in Sec. 22.8. RC=N RCH 2NH 2 Nitrite 1 amine Examples: )CH 2Ci :H 2CN - >CH 2CH 2 NH 2 Benzyl chloride Phenylacetonitrite /5-Phcnylcthylamine (Benzyl cyanide) 736 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 NaCN "2>Ni C1CH 2 CH 2 CH 2 CH 2C1 > NC(CH 2)4CN > H 2NCH 2(CH 2)4CH 2NH 2 1,4-DichIorobutane Adiponitrile Hexamethylenediamine (1 ,6-Diaminohexanc) (1) 5. Hofmaim degradation of amides. Discussed in Sees. 22.13 and 28.2-28.5. RCONH 2 or ArCONH 2 -^-+ RNH 2 or Amide 1 amine Examples: KOBf CH 3 (CH2) 4CONH 2 > CH (CH 2) 4 NH 2 3 Caproamide n-Pentylamine (Hexanamide) EJr Br m-Bromobenzamide m-Bromoanilinc Reduction of aromatic nitro compounds is by far the most useful method of preparing amines, since uses readily available starting materials, and yields the it most important kind of amines, primary aromatic amines. These amines can be converted into aromatic diazonium salts, which are among the most versatile class of organic compounds known (see Sees. 23.11-23.17). The sequence nitro compound > amine > diazonium salt provides the best possible route to dozens of kinds of aromatic compounds. Reduction of aliphatic nitro compounds is limited by the availability of the starting materials. Ammonolysis of halides is usually limited to the aliphatic series, because of the generally low reactivity of aryl halides toward nucleophilic substitution. (How- ever, see Chap. Ammonolysis has the disadvantage of yielding a mixture of 25.) different classes of amines. It is important to us as one of the most general methods of introducing the amino ( NH 2) group into molecules of all kinds; it can be used, for example, to convert bromoacids into amino acids. The exactly analogous reaction of halides with amines permits the preparation of every class of amine (as well as quaternary ammonium salts, R 4 N + X~). Reductive animation, the catalytic or chemical reduction of aldehydes (RCHO) and ketones (RaCO) in the presence of ammonia or an amine, accomplishes much the same purpose as the reaction of halides. tt too can be used to prepare any classof amine, and has certain advantages over the halide reaction. The formation of mixtures is more readily controlled in reductive amination than in ammonolysis of halides. Reductive amination of ketones yields amines containing a sec-alky! group; these amines are difficult to prepare by ammonolysis because of the tendency of jii-alkyl halides to undergo elimination rather than substitution.  SEC. 22.9 REDUCTION OF NITRO COMPOUNDS 737 Synthesis via reduction of nitrites has the special feature of increasing the length of a carbon chain, producing a primary amine that has one more carbon atom than the alkyl halide from which the nitrile was made. The Hofmann degradation of amides has the feature of decreasing the length of a carbon chain by one carbon atom; it is also of interest as an example of an important class of reactions involving rearrangement. KMnO, SOCU OBr Lower > RNH 2 carbon, OH number RCH 2OH RCH 2 Br NH 3 , H,, Ni Same carbon number Problem 22.5 Show how ft-penty)amine can be synthesized from available mate- rials by the four routes just outlined. 22.9 Reduction of nitro compounds Like many organic compounds, nitro compounds can be reduced in two general ways: (a) by catalytic hydrogenation using molecular hydrogen, or (b) by chemical reduction, usually by a metal and acid. Hydrogenation of a nitro compound to an amine takes place smoothly when a solution of the nitro compound in alcohol is shaken with finely divided nickel or platinum under hydrogen gas. For example: NHCOCH 3 NHCOCH 3 N 2 (g) o-Nitroacctanilidc o-Aminoacetanilide This method cannot be used when the molecule also contains some other easily hydrogenated group, such as a carbon-carbon double bond* Chemical reduction in the laboratory is most often carried out by adding hydrochloric acid to a mixture of the nitro compound and a metal, usually granulated tin. In the acidic solution, the amine is obtained as its salt; the free amine is liberated by the addition of base, and is steam-distilled from the reaction 738 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 SnCV mixture. The crude amine is generally contaminated with some unreduced nitro compound, from which it can be separated by taking advantage of the basic properties of the amine; the amine is soluble in aqueous mineral acid, and the nitro compound is not. Reduction of nitro compounds to amines is an essential step in what is probably the most important synthetic route in aromatic chemistry. Nitro compounds are readily prepared by direct nitration when a mixture of o- and p-isomers is obtained, ; it can generally be separated to yield the pure isomers. The primary aromatic amines obtained by the reduction of these nitro compounds are readily converted into diazonium salts; the diazonium group, in turn, can be replaced by a large number of other groups (Sec. 23. 11). In most cases this sequence is the best method of introducing these other groups into the aromatic ring. In addition, diazonium salts can be used to prepare the extremely important class of compounds, the azo dyes. ->ArX > AcOH ArH > ArNO 2 > ArNH 2 -> ArN 2 + > ArCN I > azo dyes 22.10 Ammonolysis of halides Many organic halogen compounds are converted into amines by treatment with aqueous or alcoholic solutions of ammonia. The reaction is generally carried out either by allowing the reactants to stand together at room temperature or by heating them under pressure. Displacement of halogen by 3 yields the amineNH salt,from which the free amine can be liberated by treatment with hydroxide ion. RX + NH 3 > RNH + X- 3 RNH 3 +X- + OH' --> RNH 2 + H 2 O + X~ Ammonolysis of halides belongs to the class of reactions that we have called nucleophilic substitution. The organic halide is attacked by the nucieophilic ammonia molecule in the same way that it is attacked by hydroxide ion, alkoxide ion, cyanide ion, acetylide ion, and water: 8-1 - HjN-R-X > H 3N-R + X- [3+ Like these other nucleophilic substitution reactions, ammonolysis is limited chiefly to alkyl halides or substituted alkyl halides. As with other reactions of this kind, elimination tends to compete (Sec. 14.23) with substitution: ammonia can attack SEC. 22.10 AMMONOLYSIS OF HAL1DES , 739 hydrogen to form alkene as well as attack carbon to form amine. Ammonolysis thus gives the highest yields with primary halides (where substitution predominates) and is virtually worthless with tertiary halides (where elimination predominates). CH 3 CH CH CH 2 2 2 Br > CH R 2 NH 2 + X 7 NH,- > R 2 NH 1 amine 2 amine The secondary amine. which is in equilibrium with its salt, can in turn attack the alkyl halide to form the salt of a tertiary amine: 740 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 NH, R 2 NH RX t R 3N 2 amine 3 amine Finally, the tertiary amine can attack the alkyi halide to form a compound of the formula R 4 N 4 X~, called a quaternary ammonium salt (discussed in Sec. 23.5): R 3 N + RX > R 4 N + X- 3 amine Quaternary ammonium salt (4) The presence of a large excess of ammonia lessens the importance of these*last reactions and increases the yield of primary amine; under these conditions, a molecule of alkyl halide is more likely to encounter, and be attacked by, one of the numerous ammonia molecules rather than one of the relatively few amine mole- cules. At best, the yield of primary amine is always cut down by the formation of the higher classes of amines. Except in the special case of methylamine, the primary amine can be separated from these by-products by distillation. 22.11 Reductive amination Many aldehydes (RCHO) and ketones (R 2 CO) are converted into amines by reductive amination: reduction in the presence of ammonia. Reduction can be accomplished catalytically or by use of sodium cyanohydridoborate, 3 CN. NaBH Reaction involves reduction of an intermediate compound (an imine, RCH NH or R 2 C-^NH) that contains a carbon -nitrogen double bond. H H H 1 R--C O + NH 3 R C NH R-C An aldehyde An immc H A 1 amine R' R-0 O + NH 3 > A ketone Reductive amination has been used successfully with a wide variety of aldehydes and ketones, both aliphatic and aromatic. For example: CH (CH CHO -2-^^-, 3 2)5 Heptaldehyde w-Heptylamine (Heptanal) (1-Aminoheptane) :H 2 NH 2 Benzaldchydc Bcnzylamine SEC. 22.12 HOFMANN DEGRADATION OF AMIDES 741 CH 3 (CH 2 2CCH 3 ) CH 3(CH 2 2 CHCH 3 ) NH 2 2-Pcntanonc 2-Aminopentane (Methyl n-propyl ketone) -CH, NH 2 Acetophenone a-Phenylcthylamine (Methyl phenyl ketone) Reductive amination of ketones yields amines containing a sec-alkyl group; such amines are difficult to obtain by ammonolysis because of the tendency for sec-alkyl halides to undergo elimination. For example, cyclohexanone is converted into cyclohexylamine in good yield, whereas ammonolysis of bromocyclohexane yields only cyclohexene. K 2 Cr2 7 / \ NH 3 ,H 2.Ni ^ Cyclohexanone O-l Cyclohexylamine Cyclohcxanol ^O Bromocyclohexane NH> Cyclohexene During reductive amination the aldehyde or ketone can react not only with ammonia but also with the primary amine that has already been formed, and thus yield a certain amount of secondary amine. The tendency for the reaction to go H H H R C=-O H 2 N-CH 2 R -C=N~- CH 2 R RCH 2 N-CH 2 R Aldehyde 1 amine Imine 2 amine beyond the desired stage can be fairly well limited by the proportions of reactants employed and is seldom a serious handicap. 22.12 Hofmann degradation of amides As a method of synthesis of amines, the Hofmann degradation of amides has the special feature of yielding a product containing one less carbon than the start- ing material. As we can see, reaction involves migration of a group from carbonyl OBr- X A NH 2 1 amine An amide 742 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 carbon to the adjacent nitrogen atom, and thus is an example of a molecular rearrangement. We shall return to the Hofmann degradation (Sees. 28.2-28.5) and discuss its mechanism in detail. Problem 22.6 Using a different method in each case, show how the following amines could be prepared from toluene and any aliphatic reagents: H 2 NH 2 (c) (OXH CH NH2 2 2 NH 2 22.13 Synthesis of secondary and tertiary amines So far we have been chiefly concerned with the synthesis of primary amines. Secondary and tertiary amines are prepared by adaptations of one of the processes already described: ammonolysis of halides or reductive animation. For example: H CH CH 2CH2CH2NH2 + CH CH2 Br 3 3 CH CH 2CH2CH 2 N-CH2CH3 3 /7-Butylamine Ethyl bromide Ethyl-/i-butylamine (1) (2) CH CH2CCH 3 3 CH 3 NH 2 Methyiamine ^ CH 3 CH 2CHCH 3 & Butanone Methyl-sec-butylamine (Methyl ethyl ketone) (2) >NHCH 3 Aniline N-Methylaniline N.N-Dimethylaniline (1) (2) (3) H CH 3 CH CH 2 CH2CH 2-N-CH2 CH3 + CH 3 3 Br CH3 CH 2CH 2CH2-N~CH2CH3 Ethyl-if-butylamine Methyl Methylethyl-/i-butylamine /2\ bromide Where ammonia has been used to produce a primary amine, a primary amine can be used to produce a secondary amine, or a secondary amine can be used to pro- duce a tertiary amine. In each of these syntheses there is a tendency for reaction to proceed beyond the first stage and to yield an amine of a higher class than the one that is wanted.  PROBLEMS 743 PROBLEMS 1. Draw structures, give names, and classify as primary, secondary, or tertiary: (a) the eight isomeric amines of formula C 4 H n N (b) the five isomeric amines of formula C 7 H 9 N that contain a benzene ring 2. Give the structural formulas of the following compounds: (a) rcc-butylamine (i) N,N-dimethylaniline (b) 0-toluidine (j) ethanolamine (2-aminoethanol) (c) anilinium chloride (k) -phenylethylamine (d) diethylamine (1) N,N-dimethyIaminocyciohexane (e) p-aminobenzoic acid (m) diphenylamine (f) benzylamine (n) 2,4-dimethylaniline (g) isopropylammonium benzoate (o) tetra-/?-butylammonium iodide (h) o-phenylenediamine (p) p-anisidine 3. Show how w-propylamine could be prepared from each of the following: (a) w-propyl bromide (e) propionitrile (b) /i-propyl alcohol (f) //-butyram'de (c) propionaldehyde (g) w-butyl alcohol (d) 1-nitropropane (h) ethyl alcohol Which of these methods can be applied to the preparation of aniline? Of benzylamine? 4. Outline all steps in a possible laboratory synthesis of each of the following com- pounds from benzene, toluene, and alcohols of four carbons or less, using any needed inorganic reagents. (a) isopropylamine (h) /7-aminobenzoic acid (b) /i-pentylamine (i) 3-aminoheptane (c) /Moluidine (j) N-ethylaniline (d) ethylisopropylamine (k) 2,4-dinitroaniline (e) a-phenylethylamine (I) the drug 6ewz/rwe(2-arnino-l-phenylpropane) (f) j9-phenylethylamine (m) p-nitrobenzylamine (g) m-chloroaniline (n) 2-aminol-phenylethanol 5. Outline all steps in a possible laboratory synthesis from palmitic acid, /i-C 15 H 31 COOH, of: (a) /z-C l6 H 33 NH 2 (c) /i-C 15 H ,NH 2 3 (b) /i-C 17 H 35 NH2 (d) w-C 15 H 3I CH(NH 2 ).w-C 16 H 33 6. On the basis of the following synthesis give the structures of putrescine and cadaverine, found in rotting flesh: (a) ethylene bromide -^> C H N 4 4 2 **> c #>+ pu trescine (C 4 H I2 N 2 ) (b) Br(CH 2 ) 5 Br *-+ cadaverine (C 5 H I4 N 2) One of the raw materials for the manufacture of Nylon 66 is hexamethylenediamine, 7. NH 2(CH 2) 6NH 2 Much of this amine is made by a process that begins with the 1,4-. addition of chlorine to 1,3 -butadiene. What do you think might be the subsequent steps in this process? 8. Outline all steps in a possible synthesis of /?-alanine (/9-aminopropionic acid) from succinic anhydride. 9. Using models and then drawing formulas, show the stereoisomeric forms in which each of the following compounds can exist. Tell which stereoisomers when separated from all others would be optically active and which would be optically inactive. (a) a-nhenylethylaminc hyl-N-ethylaniline yl-rt-propylphenylammoniurn bromide 744 AMINES I. PREPARATION AND PHYSICAL PROPERTIES CHAP. 22 (d) CH,, -, CH2-CH, CH, Br N N Br- 2H3 CH2 CH2 (e) H CH2-CH2 H X x CHz-CH^ X COOC 2 H 5 (f) methylethylphenylamine oxide, (CH 3)(C 2 H5XC 6 H 5 )N O 10. Two H geometric isomers of benzaldoxime, C 6 5 CH=NOH, are known, (a) Draw their structures, showing the geometry of the molecules, (b) Show how this geometry results from their electronic configurations, (c) Would you predict geometric isomerism for benzophenoneoxime, NOH? (C 6 Hs) 2 C For acetophenoneoxime, C 6 H 5 C(CH3>= NOH? For azobenzene, C 6 H 5 N=-NC 6H 5 ? 11. (a) Give structural formulas of compounds A through D. phthalimide (Sec. 20.14) -f KOH (ale.) >A(C 8 H 4O 2 NK) A + CH CH 2 CH 2 Br, heat 3 > B(C u H n O 2 N) B -f H 2 O, OH-, heat > C (C 3 H 9 N) -h D (b) This sequence illustrates the Gabriel synthesis. What class of compounds does it produce? What particular advantage does it have over alternative methods for the produc- tion of these compounds? On what special property of phthalimide does the synthesis depend?  Chapter Amines II. Reactions 23 23.1 Reactions Like ammonia, the throe classes of amines contain nitrogen that bears an unshared pair of electrons; as a result, amines closely resemble ammonia in chemical properties. The tendency of nitrogen to share this pair of electrons under- lies the entire chemical behavior of amines: their basicity, their action as nucleo- philes, and the unusually high reactivity of aromatic rings bearing amino or sub- stituted amino groups. REACTIONS OF AMINES I. Basicity. Salt formation. Discussed in Sees. 22.5 and 23.2 23.4. RNH + H + 2 ^ RNJV R : NH I- Fr ^Z: R.NIV RjN + H + II R,NH + Examples; HCI >NH 3 Cl Aniline Anilinium chloride (Aniline hydrochloride) (CH 3 ) 2 NH + HNO 3 JI Dimethylamine Dimethylammonium nitrate >N(CH 3 ) 2 : CH COOH *= 3 U^hHtCHjh' OOCCH 3 N,N-Dimethylaniline N,N-Dimethylanilinium acetate 745 746 AMINES II. REACTIONS CHAP. 23 2, Alkylation. Discussed in Sees. 22.13 and 23.5. RNH , _"*> R ,NH > R 3N > ArNH , _**> ArNHR -> ArNR 2 Examples: (-C 4 H 9 2 NH a ) (Q/ CH 2 Di-n-butylamine Benzyl chloride Benzyldi(/?-butyl)amine (2) H CH 3 CH 3 -C 3 H 7 NH 2 ^^-> ;;-C 3 H 7 NCH 3 ^^> w-C 3 H NCH 7 3 - //-Propylamine c //-Propylmethylamine w-Propyldimethylamine CH 3 (l ) (2") (3) /i-Propyltrimethylammonium iodide (4) 3. Conversion into amides. Discussed in Sec. 23.6. R'COCI R'CONHR An N-substituted amide Primary: RNH 2 ArSO^CI ArSOjNHR An N-substituted sulfonamide R'CONR 2 An N,N-disubstituled amide Secondary: R 2 NH ArSO 2 NR 2 An N,N-disubstituted sulfonamide No reaction Tertiary: R 3N No reaction under conditions of Hinsbcrg test(6/// see Sec. 23.18). Examples: H -N-C-CH 3 Acetanilide >NH 2 (N-Phenylacetamide) Aniline H O (1) QH S0 CI 5 2 1 I NaOH -N S- aq. Bcnzcnesulfonanilide (N-Phcnylbenzenesulfonamide) SEC. 23.1 REACTIONS 747 CH 3 C,H 5 COCl _ : N pyridme 11 H N-Methyl-N-ethylbenzamide Methylethylamine (2) />-CH,CH 4S0 2 Cl NaOH S-N aq. N-Methyl-N-ethyl-p-toluenesulfonamide 4. Ring substitution in aromatic amines. Discussed in Sees. 23.7, 23.10, and 23.17. Activate powerfully, and direct ortho,para - NHR I aromatic substitution in electrophilic | -NHCOR: Less powerful activator than --NH 2 Examples: NH 2 r Br (0) NH 2 Br 2A6-Tribroir.oaml'ne Aniline NHCOCH 3 NHCOCH 3 NH 2 - ^> (Oj Br Br Acetanilide /7-BromoacetaniIide />-Bromoaniline N(CH 3 )2 N(CH 3 ) 2 NaNO 2 HC1 , NO - N,N-Dimethyl ^-Nitroso-N.N-dimcthylaniline aniline acid (CH 3 2 N< ) >N 2 +C1 HC1 N,N-Dimethyl- Benzenediazonium An azo compound aniline chloride 5. Hofmann elimination from quaternary ammonium salts. Discussed in Sec. 23.5. H OH ~, heat R 3N + H 2O , 3 amine Alkene Quaternary ammonium ion 748 AMINES II. REACTIONS CHAP. 23 *6. Reactions with nitrous acid. Discussed in Sees. 23.10-23.11. MONO Primary aromatic: ArNH 2 Ar N~N + Diazonium salt HO Primary aliphatic: RNH 2 -> [R-N-N + ? N2 + mixture of alcohols and alkenes Secondary aromatic ArNHR QNO ArN N=O or aliphatic: or > or N-Nitrosoamine R 2 NH R 2 N- />-Nitroso Tertiary aromatic: compound 23.2 Basicity of amines. Basicity constant salts by aqueous mineral acids Like ammonia, amines are converted into their and are liberated from by aqueous hydroxides. Like ammonia, therefore, their salts amines are more basic than water and less basic than hydroxide ion: RNH 2 RNH, + H 2O Stronger Weaker base base RNH 2 + HO 2 Stronger Weaker base base We found it convenient to compare acidities of carboxylic acids by measuring the extent to which they give up hydrogen ion to water; the equilibrium constant for this reaction was called the acidity constant, a K In the same way, it is con-. venient to compare basicities of amines by measuring the extent to which they accept hydrogen ion from water; the equilibrium constant for this reaction is called a basicity constant, Kb. RNH 2 + H O 2 R C-Z nucleophilic substitution W Trigonal C Tetrahedral C Attack relatively Stable octet unhindered O Sulfonyl Ar S W + :Z nucleophilic substitution O Tetrahedral S Pentavalent S Attack hindered Unstable decet 758 AMINES II. REACTIONS CHAP. 23 carbon of the acyl intermediate makes use of the permitted octet of electrons; al- though sulfur may be able to use more than eight electrons in covalent bonding, this is a less stable system than the octet. Thus both steric and electronic factors tend to make sulfonyl compounds less reactive than acyl compounds. There is a further contrast between the amides of the two kinds of acids. The substituted amide from a primary amine has a hydrogen attached to nitrogen, still and as a result is acidic: in the case of a sulfonamide, this acidity is appreciable, and much greater than for the amide of a carboxylic acid. monosubstituted A sulfonamide is less acidic than a carboxylic acid, but ibout the same as a phenol (Sec. 24.7); it reacts with aqueous hydroxides to form salts. O j Ar-S NHR + OH- > O This difference in acidity, too, is understandable. A sulfonic acid is more acidic than a carboxylic acid because the negative charge of the anion is dispersed over three oxygens instead of just two. In the same way, a sulfonamide is more acidic than the amide of a carboxylic acid because the negative charge is dispersed over two oxygens plus nitrogen instead of over just one oxygen plus nitrogen. Problem 23.7 Although amides of carboxylic acids are very weakly acidic (a) (Ka - 10" 14 to 10~ they are still enormously more acidic than ammonia (Ka = 15 ), 10" 33 ) or amines, RNH 2 Account in detail for this.. (b) Diacetamide, (CH 3 CO) 2 NH, is much more acidic (Ka = 10~ ) than acetamide ll (Ka = 8.3 x 10" 16 ), and roughly comparable to benzenesulfonamidc (Ka =* 10" 10). How can you account for this? Problem 23.8 In contrast to carboxylic esters, we know, alkyl sulfonates undergo nucleophilic attack at alkyl carbon. What two factors are responsible for this difference R_ Ar-S-O- R* z in behavior? (Hint: See Sec. 14.6.) The conversion of an amine into a sulfonamide is used in determining the class of the amine; this is discussed in the section on analysis (Sec. 23.18). 23.7 Ring substitution in aromatic amines We have already seen that the 2 NHR, and NH 2 groups act as , NR powerful activators and ortho.para directors in electrophilic aromatic substitution. These effects were accounted for by assuming that the intermediate carbonium ion is stabilized by structures like I and II in which nitrogen bears a positive charge SEC. 23.7 RING SUBSTITUTION IN AROMATIC AMINES 759 +NH 2 H Y l n and is joined to the ring by a double bond. Such structures are especially stable since in them every atom (except hydrogen) has a complete octet of electrons; indeed, structure I or 11 by itself must pretty well represent the intermediate. In such structures nitrogen shares more than one pair of electrons with the ring, and hence carries the charge of the "carbonium ion." Thus the basicity of nitrogen accounts for one more characteristic of aromatic amines. The acetamido group, NHCOCH 3 is also activating and ortho,para~ , directing, but less powerfully so than a free amino group. Electron withdrawal by oxygen of the carbonyl group makes the nitrogen of an amide a much poorer source of electrons than the nitrogen of an amine. Electrons are less available for sharing with a hydrogen ion, and therefore amides are much weaker bases than amines: amides of carboxylic acids do not dissolve in dilute aqueous acids. Elec- trons are less available for sharing with an aromatic ring, and therefore an acetamido group activates an aromatic ring less strongly than an amino group. More precisely, electron withdrawal by carbonyl oxygen destabilizes a positive charge on nitrogen, whether this charge is acquired by profanation or by electrophilic. attack on the ring.^- (We have seen (Sec. 1 1.5) that the NR 3 + group a powerful deactivator and is meta director. In a quaternary ammonium salt, nitrogen no longer has electrons to share with the ring; on the contrary, the full-fledged positive charge on nitrogen makes the group strongly electron-attracting.) In electrophilic substitution, the chief problem encountered with aromatic amines is that they are too reactive. In halogenation, substitution tends to occur at every available ortho or para position. For example: NH 2 CH 3 CH 3 ^-Toluidine 3,5-Dibromo-4-aminotolucne Nitric acid not only nitrates, but oxidizes the highly reactive ring as well, with loss of much material as tar. Furthermore, in the strongly acidic nitration medium, the amine is converted into the anilinium ion; substitution is thus controlled not by the NH 2 group but by the NH 3 + group which, because of its positive charge, directs much of the substitution to the meta position. There is, fortunately, a simple way out of these difficulties. We protect the amino group: we acetylate the amine, then carry out the substitution, and finally hydrolyze the amide to the desired substituted amine. For example:  CHAP. 23 J5L H2 (OP CH 3 /?-Toluidine Aceto-/?-toluidide 3-Bromo-4-aminotoluene NHCOCH 3 NHCOCH 3 N^H 2 HNO H 2 SO 4 15 H 3 Q. H * }.. > ff^l heat LJ^J Acetanilide "&- NO 2 /7-Nitroacetanilide ^-Nitroaniline Problem 23.9 Nitration of un-acetylated aniline yields a mixture of about t\\o- thirds meta and one-third para product. Since almost all the aniline is in the form of the anilinium ion, how do you account for the fact that even more meta product is not obtained? 23.8 Sulfonation of aromatic amines. Dipolar ions Aniline is usually sulfonated by "baking" the salt, anilinium hydrogen sulfate, at 180-200; the chief product is the /Msomer. In this case we cannot discuss orientation on our usual basis of which isomer is formed faster. Sulfonation is Aniline Anilinium hydrogen sulfate Sulfanihc acid known to be reversible, and the p-isomer is known to be the most stable isomer ; itmay well be that the product obtained, the ^-isomer, determined by the is position of an equilibrium and not by relative rates of formation (see Sec. 8.22 and Sec. 12.11). It also seems likely that, in some cases at least, Sulfonation of amines proceeds by a mechanism that is entirely different from ordinary aromatic substitution. Whatever the mechanism by which it is formed, the chief product of this reaction is/?-aminobenzenesulfonic acid, known as sulfanilic acid; it is an important and interesting compound. 'First ofits properties are not those we would expect of a compound all, containing an amino group and a sulfonic acid group. Both aromatic amines and aromatic sulfonic acids have low melting points; benzenesuifonic acid, for example, melts at 66, and aniline at -6. Yet sulfanilic acid has such a high melting point that on being heated it decomposes (at 280-300) before its melting point can be reached. Sulfonic acids are generally very soluble in water; indeed, we have seen that the sulfonic acid group is often introduced into a molecule to make it water- soluble. Yet sulfanilic acid is not only insoluble in organic solvents, but also nearly insoluble in water. Amines dissolve in aqueous mineral acids because of their conversion into water-soluble salts. Sulfanilic acid is soluble in aqueous bases but insoluble in aqueous acids. SEC. 23.9 SULFANJLAMIDE. THE SULFA DRUGS 761 These properties of sulfanilic acid are understandable when we realize that sulfanilic acid actually has the structure I which contains the NH 3 + and 803" groups. Sulfanilic acid is a salt, but of a rather special kind, called a dipolar ion T II Insoluble in water Soluble in water (sometimes called a zwitterion* from the German, Znitter, hermaphrodite). It is the product of reaction between an acidic group and a basic group that are part of the same molecule. The hydrogen ion is attached to nitrogen rather than oxygen ~ simply because the NH 2 group is a stronger base than the ~-SO 3 group. A high melting point and insolubility in organic solvents are properties we would expect of a salt. Insolubility in water is not surprising, since many salts are in- soluble in water. In alkaline solution, the strongly basic hydroxide ion pulls hydrogen ion away from the weakly basic -NH 2 group to yield the p-amino- benzenesulfonate ion (II), which, like most sodium salts, is soluble in water. In aqueous acid, however, the sulfanilic acid structure not changed, and therefore is the compound remains insoluble; sulfonic acids are strong acids and their anions (very weakbases) show little tendency to accept hydrogen ion from H^O*. Wecan expect to encounter dipolar ions whenever we have a molecule con- taining both an amino group and an acid group, providing the amine is more basic than the anion of the acid. Problem 23.10 p-Aminobenzoic acid is not a dipolar ion, whereas glycine (amino- acetic acid) is How can you account for this? a dipolar ion. 23.9 Sulfanilamide. The sulfa drugs The amide of sulfanilic acid (sulfanilamlde) and certain related substituted amides are of considerable medical importance as the sulfa drugs. Although they have been supplanted to a wide extent by the antibiotics (such as penicillin, terra- mycin, chloromycetin, and aureomycin), the sulfa drugs still have their medical uses, and make up a considerable portion of the output of the pharmaceutical industry. Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an amine. The presence in a sulfonic acid molecule of an amino group, however, poses a special problem if sulfanilic acid were converted to the acid chloride, the : sulfonyl group of one molecule could attack the amino group of another to form an amide linkage. This problem is solved by protecting the amino group through acetylation prior to the preparation of the sulfonyl chloride. Sulfanilamide and related compounds are generally prepared in the following way: 762 AMINES II. REACTIONS CHAP. 23 jmcocH 3 HCOCH CISO,H Aniline Acctanilide 2Cl /7-Acetamidobenzencsulfonyl chloride NHR S0 2NHR Substituted sulfanilamide The selective removal of the acetyl group in tjie final step is consistent with the general observation that amides of carboxylic acids are more easily hydrolyzed than amides of sulfonic acids. CH 3-C NH ir o O Sulfanilamide Hydrolysis occurs here The antibacterial activity and toxicity of a sulfanilamide stems from a rather simple enzymes in the bacteria (and in the patients) confuse it for /?-amino- fact: benzoic acid, which is an essential metabolite. In what is known as metabolite antagonism, the sulfanilamide competes with p-aminobenzoic acid for reactive NH 2 (0) COOH SO 2NHR /^-Aminobenzoic acid Substituted sulfanilamide sites on the enzymes; deprived of the essential metabolite, the organism fails to reproduce, and dies. Just how good a drug the sulfanilamide is depends upon the nature of the group R attached to amido nitrogen. This group must confer just the right degree of acidity to the amido hydrogen (Sec. 23.6), but acidity is clearly only one of the factors involved. Of the hundreds of such compounds that have been synthesized, only a half dozen or so have had thejproper combination of high antibacterial activity and low toxicity to human beings that is necessary for an effective drug; in nearly all these effective compounds the group R contains a heterocyclic ring (Chap. 31). SEC. 23.10 REACTIONS OF AMINES WITH NITROUS ACID 763 Sulfamerazine Succinoylsulfathiazolc 23.10 Reactions of amines with nitrous acid Each class of amine yields a different kind of product in its reaction with nitrous acid, HONO. This unstable reagent is generated in the presence of the amine by the action of mineral acid on sodium nitrite. Primary aromatic amines react with nitrous acid to yield diazonium salts; this is one of the most important reactions in organic chemistry. Following sec- tions are devoted to the preparation and properties of aromatic diazonium salts. ArNH 2 + NaNO 2 + 2HX -^-> ArN 2 + X- + NaX + 2H 2O 1 aromatic A diazonium salt amine Primary aliphatic amines also react with nitrous acid to yield diazonium salts; but since aliphatic diazonium salts are quite unstable and break down to yield a complicated mixture of organic products (see Problem 23. 1 1 below), this reaction is , of little synthetic value. The fact that nitrogen is evolved quantitatively is of some RNH 2 + NaNO 2 + HX > [RN 2 +X-J S5> N2 + mixture of alcohols and alkenes 1 aliphatic Unstable amine , importance in analysis, however, particularly of amino acids and proteins. Problem 23.11 The reaction of n-butytamine with sodium nitrite and hydrochloric acid yields nitrogen and the following mixture: it-butyl alcohol, 25%; sec-butyl alco- hol, 13%; 1-butene and 2-butene, 37%; *-butyl chloride, 5%; iwvbutyl chloride, 3%. (a)What is the most likely intermediate common to all of these products? (b) Outline reactions that account for the various products. Problem 23.12 Predict the organic products of the reaction of: (a) isobutylamine with nitrous acid; (b) neopentylamine with nitrous acid. Secondary amines, both aliphatic and aromatic, react with nitrous acid to yield N-nitrosoamines. CH 3 >N H + NaNO2 + HC1 - * W^N CH 3 N=O + NaCl + H 2O N-Methylaniline N-Nitroso-N-methylaniline Tertiary aromatic amines undergo ring substitution, to yield compounds in which a nitroso group, ~N O, is joined to carbon; thus N,N-dimethylaniline yields chiefly ;>-mtroso-N,N-dimethylaniline. 764 AMINES II. REACTIONS CHAP. 23 NaNOi, HC1. 0-10^ (CH 3 ) 2 N N,N-Dimethylaniline />-Nitroso-N,N-dimethylaniline Ring nitrosation is an electrophiiic aromatic substitution reaction, in which the attacking reagent is either the nitrosoniwn ion, +NO, or some species (like + H 2O NO or NOC1) that can easily transfer +NO to the ring. The nitrosonium ion very weakly electrophiiic compared with the reagents involved in nitration, is sulfonation, halogenation, and the Friedel-Crafts reaction nitrosation ordinarily ; occurs only in rings bearing the powerfully activating dialkylamino ( NR 2) or hydroxy (OH) group. +NO N,N-Dimcthylaniline H CH 3 CH 3 O N=0 jp-Nitroso-N.N- dimethylaniline Despite the differences in final product, the reaction of nitrous acid with all these amines involves the same initial step: electrophiiic attack by *NO with dis- + placement 0/H. This attack occurs at the position of highest electron availability in primary and secondary amines: at nitrogen. Tertiary aromatic amines are attacked at the highly reactive ring. Tertiary aliphatic amines (and, to an extent, tertiary aromatic amines, too, particu- blocked) react with nitrous acid to yield an N-nitroso derivative larly if the para position is of a secondary amine; the group that is lost from nitrogen appears as an aldehyde or ketone. Although this reaction is not really understood, it too seems to involve the initial attack by + NO on nitrogen. Problem 23.13 (a) Write equations to show how the molecule H 2 O NO is formed in the nitrosating mixture, (b) Why can this transfer +NO to the ring more easily than MONO can? (c) Write equations to show ho\v NOC1 can be formed from NaNO 2 and aqueous hydrochloric acid, (d) Why is NOC1 a better nitrosating agent than MONO? SEC. 23.11 DIAZONIUM SALTS. PREPARATION AND REACTIONS 75 Problem 23.14 (a) Which, if cither, of the following seems likely? (i) The ring of N-methylaniline is much less reactive toward electrophilic attack than the ring of N,N-dimethylaniline. (ii) Nitrogen of N-methylaniline is much more reactive toward electrophilic attack than nitrogen of N,N-dimethylaniline. (b) How do you account for the fact that the two amines give different products with nitrous acid? 23.11 Diazonium salts. Preparation and reactions Whena primary aromatic amine, dissolved or suspended in cold aqueous mineral acid, is treated with sodium nitrite, there is formed a diazonium salt. cold ArNH 2 + NaNO 2 2HX NaX + 2H 2O 1 aromatic A diazonium salt amine Since diazonium salts slowly decompose even at ice-bath temperatures, the solu- tion is used immediately after preparation. The large number of reactions undergone by diazonium salts may be divided into two classes: replacement, in which nitrogen is lost as N2 and some other , atom or group becomes attached to the ring in its place; and coupling, in which the nitrogen is retained in the product. REACTIONS OF DIAZONIUM SALTS 1. Replacement of nitrogen ArN 2 + + :Z > ArZ + N2 (a) Replacement by --C1, Br, and CN. Sandmeyer reaction. Discussed in Sees. 23.12-23.13. ~S* Ard + N2 CuBr ArBr + N2 ArCN + N2 Examples: 0-Chlorotoluene o-Toluidinc o-Bromotolucne 7(6 AMINES IL REACTIONS CHAP. 23 N.NOHC. j o-Toluidine o-Tolunitrile (b) Replacement by I. Discussed in Sec. 23.12. -4-1- Arl + N2 H2 N 2 +HSO4 - Aniline lodobenzene v (c) Replacement by F. Discussed in Sec. 23.12. ArN 2 + BF4 - heat ArF + N2 + BF3 NH 2 2+cr HBF4 but [Ql BF3 Aniline Benzenediazonium Bcnzcnediazonium Fluorobenzene chloride fluoboimte (d) Replacement by -OH. Discussed in Sec. 23.14. H2O JL^ ArOH + N2 A phenol NH2 aj o-Toluidinc o-Cretol (e) Replacement by H. Discussed in Sec. 23.15. + H 3PO2 52^ ArH + H 3PO3 4- N2 O^Sci J 2,4-Dkhk>roniline m-Dichlorobenzcnc SEC. 23.12 DIAZONIUM SALTS. REPLACEMENT BY HALOGEN 767 2. Coupling. Discussed in Sec. 23.17. G must be a strongly ArN 2 +X~ + (O)G > Ar-N=N G electron-releasing group: An azo compound OH, NR 2 NHR, NH a , Example: N=N- Eenzenediazonium /7-Hydroxyazobenzene chloride p-( Phenylazo)phcnol Replacement of the diazonium group is the best general way of introducing F, Cl, Br, I, CN, OH, and H into an aromatic ring. Diazonium salts are valuable in synthesis not only because they react to form so many classes" of compounds, but also because they can be prepared from nearly all primary aromatic amines. There are few groups whose presence in the molecule interferes with diazotization; in this respect, diazonium salts are quite different from Grignard reagents (Sec. 15.15). The amines from which diazonium compounds are prepared are readily obtained from the corresponding nitro compounds, which are prepared by direct nitration. Diazonium salts are thus the most important link in the sequence: Ar~F Ar-Cl ArBr ArH ArN0 2 * ArNH 2 Ar-I Ar-CN Ar-COOH Ar OH Ar H In addition to the atoms and groups just listed, there are dozens of other groups that can be attached to an aromatic ring by replacement of the diazonium nitrogen, as, for example, -Ar, -NO 2 , OR, -SH, -SR, NCS, -NCO, -PO 3 H 2 , AsO 3 H 2 , SbO 3 H 2 ; the best way to introduce most of these groups is via diazotization. The coupling of diazonium salts with aromatic phenols and amines yields azo compounds, which are of tremendous importance to the dye industry. 23.12 Diazonium salts. Replacement by halogen* Sandmeyer reaction Replacement of the diazonium group by Cl or Br is carried out by mixing the solution of freshly prepared diazonium salt with cuprous chloride or cuprous 768 AMINES n. REACTIONS CHAP. 23 bromide. At room temperature, or occasionally at elevated temperatures, nitrogen is steadily evolved, and after several hours the aryl chloride or aryl bromide can be isolated from the reaction mixture. This procedure, using cuprous halides, is generally referred to as the Sandmeyer reaction. ArN2 +X~ ^U ArX + N2 Sometimes the synthesis is carried out by a modification known as the Gatter- mann reaction, in which copper powder and hydrogen halide are used in place of the cuprous halide. Replacement of the diazonium group by I does not require the use of a cuprous halide or copper; the diazonium salt and potassium iodide are simply mixed together and allowed to react. ArN 2 + X- + I- > Arl + N 2 + X~ Replaccment of the diazonium group by F is carried out in a somewhat different way. Addition of fluoborie acid, HBF 4 to the solution of diazonium , salt causes the precipitation of the diazonium fluoborate, ArN 2 +BF4 ~, which can be collected on a filter, washed, and dried. The diazonium fluoborates are unusual among diazonium salts in being fairly stable compounds. On being heated, the dry diazonium iluoborate decomposes to yield the aryl fluoride, boron tri fluoride, ArN 2 + X~ HBF 4> ArN 2 +BF4 ***' > ArF + BF 3 + N2 and nitrogen. An analogous procedure involves the diazonium hexafluorophos- phate, ArNz+PFa-. The advantages of the synthesis of aryl halides from diazonium salts will be discussed in detail in Sec. 25.3. Aryl fluorides and iodides cannot generally be prepared by direct halogenation. Aryl chlorides and bromides can be prepared by direct halogenation, but, when a mixture of 0- and p-isomers is obtained, it is difficult to isolate the pure compounds because of their similarity in boiling point. Diazonium salts ultimately go back to nitro compounds, which are usually obtain- able in pure form. 23.13 Diazonium salts. Replacement by CN. Synthesis of carboxylic adds Replacement of the diazonium group by CN is carried out by allowing the diazonium salt to react with cuprous cyanide. To prevent loss of cyanide as HCN, the diazonium solution is neutralized with sodium carbonate before being mixed with the cuprous cyanide. ArCN + N2 SEC. 23.15 DtAZONIlJM SALTS. KEPLACUJVliUN l iii n ,^ Hydrolysis of nitriles yields carboxylic acids. The synthesis of nitrites from diazonium salts thus provides us with an excellent route from nitro compounds to carboxylic acids. For example: CH 3 CH 3 p-Toluic p-Tolunitrilc p-Toluenediazonium /?-Toluidine p-Nitrotoluene Toluene acid chloride This way of making aromatic carboxylic acids is more generally useful than either carbonation of a Grignard reagent or oxidation of side chains. We have just seen that pure bromo compounds, which are needed to prepare the Grignard reagent, are themselves most often prepared via diazonium salts; furthermore, there are many groups that interfere with the preparation and use of the Grignard reagent (Sec. 15.15). The nitro group can generally be introduced into a molecule more readily than an alkyl side chain ; furthermore, conversion of a side chain into a carboxyl group cannot be carried out on molecules that contain other groups sensitive to oxidation. 23.14 Diazonium salts. Replacement by OH. Synthesis of phenols Diazonium salts react with water to yield phenols. This reaction takes place ArN 2 +X- + H2 > ArOH + N 2 + H+ slowly in the ice-cold solutions of diazonium salts, and is the reason diazonium salts are used immediately upon preparation; at elevated temperatures it can be made the chief reaction of diazonium salts. As we shall see, phenols can couple w&h diazonium salts toform azo com- pounds (Sec. 23.17); the more acidic the solution, however, the more slowly this coupling occurs. To minimize coupling during the synthesis of a phenol, therefore coupling, that is, between phenol that has been formed and diazonium ion that has not yet reacted the diazoaiuin solution is added slowly to a large volume of boiling dilute sulfuric acid. This is the best general way to make the important class of compounds, the phenols. 23.15 Diazonium saks. Replacement fcy H Replacement of the diazonium group by H can be brought about by a number of red