Baixe Carey - Organic Chemistry - chapt22 e outras Manuais, Projetos, Pesquisas em PDF para Química, somente na Docsity! CHAPTER 22 AMINES itrogen-containing compounds are essential to life. Their ultimate source is atmo- spheric nitrogen which, by a process known as nitrogen fixation, is reduced to ammonia, then converted to organic nitrogen compounds. This chapter describes the chemistry of amines, organic derivatives of ammonia. Alkylamines have their nitro- gen attached to sp*-hybridized carbon; arylamines have their nitrogen attached to an sp?-hybridized carbon of a benzene or benzene-like ring. RNÉ ArRÉ x x R=alkyigroup: — Ar= arylgroup: alkylamine arylamine Amines, like ammonia, are weak bases. They are, however, the strongest uncharged bases found in significant quantities under physiological conditions. Amines are usually the bases involved in biological acid-base reactions; they are often the nucleophiles in biological nucleophilic substitutions. Our word “vitamin” was coined in 1912 in the belief that the substances present in the diet that prevented scurvy, pellagra, beriberi, rickets, and other diseases were “vital amines.” In many cases, that belief was confirmed; certain vitamins did prove to be amines. In many other cases, however, vitamins were not amines. Nevertheless, the name vitamin entered our language and stands as a reminder that early chemists recognized the crucial place occupied by amines in biological processes. 858 22.1 Amine Nomendlature 859 22.1 AMINE NOMENCLATURE Unlike alcohols and alky1 halides, which are classified as primary, secondary, or tertiary according to the degree of substitution at the carbon that bears the functional group, amines are classified according to their degree of substitution at nitrogen. An amine with one carbon attached to nitrogen is a primary amine, an amine with two is a secondary amine, and an amine with three is a tertiary amine. H R' R' / , , R—NÍ R—Ní R—Ní Ss, SN, N, H H R” Primaryamine Secondary amine Tertiary amine The groups attached to nitrogen may be any combination of alkyl or aryl groups. Amines are named in two main ways, in the TUPAC system: either as alkylamines or as alkanamines. When primary amines are named as alkylamines, the ending -amine is added to the name of the alkyl group that bears the nitrogen. When named as alkan- amines, the alkyl group is named as an alkane and the -e ending replaced by -amine. NH, CH.CH;NH, CHSCHCHACH CH; NH, Ethylamine Cyclohexylamine 1-Methylbutylamine (ethanamine) (cyclohexanamine) (2-pentanamine) PROBLEM 22.1 Give an acceptable alkylamine or alkanamine name for each of the following amines: (a) CoHsCH>CHaNH> (b) GoHs(HNHo CHs (0) CH;=CHCH,NH, SAMPLE SOLUTION (a) The amino substituent is bonded to an ethyl group that bears a phenyl substituent at C-2. The compound CsHsCH>CH>NH> may be named as either 2-phenylethylamine or 2-phenylethanamine. Aniline is the parent IUPAC name for amino-substituted derivatives of benzene. ie was firstisolatedin Substituted derivatives of aniline are numbered beginning at the carbon that bears the 1826 as a degradation prod- amino group. Substituents are listed in alphabetical order, and the direction of number- uctofindigo, a dark blue o ” E : ' dye obtained from the West ing is governed by the usual “first point of difference” rule. Indian plant indigofera anil, from which the name aniline NH, is derived. CH>CH; p-Fluoroaniline 5-Bromo-2-ethylaniline Arylamines may also be named as arenamines. Thus, benzenamine is an alterna- tive, but rarely used, name for aniline. E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 862 CHAPTER TWENTY-TWO — Amines unshared electron pair on nitrogen occupies an sp>-hybridized orbital. This Ione pair is o o involved in reactions in which amines act as bases or nucleophiles. The graphic that You can examine the opened this chapter is an electrostatic potential map that clearly shows the concentration structure of methylamine, in- of electron density at nitrogen in methylamine. cluding its electrostatic poten- Doda onleaming Arylamines: —Aniline, like alkylamines, has a pyramidal arrangement of bonds around nitrogen, but its pyramid is somewhat shallower. One measure of the extent of this flat- tening is given by the angle between the carbon-nitrogen bond and the bisector of the H—N—H angle. =125º - 142.5º 180 Methylamine Aniline Formamide (CH5NHo) (CoH5 NH) (0=CHNH,) For sp”-hybridized nitrogen, this angle (not the same as the C—N—H bond angle) is 125º, and the measured angles in simple alkylamines are close to that. The correspond- DD ing angle for sp? hybridization at nitrogen with a planar arrangement of bonds, as in The geometry at nitrogen in amics tsciarscdinamana amides, for example, is 180º. The measured value for this angle in aniline is 142.5º, sug- cle entitled "What Isthe gesting a hybridization somewhat closer to sp? than to sp?. rea et TrigonaN The structure of aniline reflects a compromise between two modes of binding the gen?" in the January 1998 is- . rs E Ele the Joumal of) nitrogen lone pair (Figure 22.3). The electrons are more strongly attracted to nitrogen Chemical Education, pp. when they are in an orbital with some s character —an sp"-hybridized orbital, for exam- 108-109. ple—than when they are in a p orbital. On the other hand, delocalization of these elec- trons into the aromatic system is better achieved if they occupy a p orbital. A p orbital of nitrogen is better aligned for overlap with the p orbitals of the benzene ring to form (a) 0) FIGURE 22.3 Electrostatic potential maps of the aniline in which the geometry at nitrogen O is (a) nonplanar and (b) planar. In the nonplanar geometry, the unshared pair occupies an sp” hy- brid orbital of nitrogen. The region of highest electron density in (a) is associated with nitrogen. in the planar geometry, nitrogen is sp2-hybridized and the electron pair is delocalized between a p orbital of nitrogen and the x system of the ring. The region of highest electron density in (b) encompasses both the ring and nitrogen. The actual structure combines features of both; nitro- gen adopts a hybridization state between sp” and sp?. E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 22.3 Physical Properties an extended 7 system than is an sp?-hybridized orbital. As a result of these two oppos- ing forces, nitrogen adopts an orbital hybridization that is between sp? and sp?. The corresponding resonance description shows the delocalization of the nitrogen lone-pair electrons in terms of contributions from dipolar structures. CNH, “NH, “NH, “NH, H H H >H H H Ho H IMÃ H H H H H <“"H H H H H H H Most stable Dipolar resonance forms of aniline Lewis structure for aniline The orbital and resonance models for bonding in arylamines are simply alternative ways of describing the same phenomenon. Delocalization of the nitrogen lone pair decreases the electron density at nitrogen while increasing it in the 7 system of the aro- matic ring. We've already seen one chemical consequence of this in the high level of reactivity of aniline in electrophilic aromatic substitution reactions (Section 12.12). Other ways in which electron delocalization affects the properties of arylamines are described in later sections of this chapter. PROBLEM 22.4 As the extent of electron delocalization into the ring increases, the geometry at nitrogen flattens. p-Nitroaniline, for example, is planar. Write a resonance form for p-nitroaniline that shows how the nitro group increases elec- tron delocalization. Examine the electrostatic potential of the p-nitroaniline model on Learning By Modeling. Where is the greatest concentration of negative charge? 22.3 PHYSICAL PROPERTIES We have often seen that the polar nature of a substance can affect physical properties such as boiling point. This is true for amines, which are more polar than alkanes but less polar than alcohols. For similarly constituted compounds, alkylamines have boiling points higher than those of alkanes but lower than those of alcohols. CHsCH,CH; CH:;CH,NH, CH;CH,0H Propane Ethylamine Ethanol E =0D pS12D E=17D bp 42º bp ITC bp 78ºC Dipole-dipole interactions, especially hydrogen bonding, are present in amines but absent in alkanes. The less polar nature of amines as compared with alcohols, however, makes these intermolecular forces weaker in amines than in alcohols. Among isomeric amines, primary amines have the highest boiling points, and ter- tiary amines the lowest. CH;CH,CH;NH, — CH;CH;NHCH; (CH5)N Propylamine N-Methylethylamine — Trimethylamine (a primary amine) (a secondary amine) (a tertiary amine) bp 50ºC bp 34º€ bp3ºC 863 A collection of physical prop- erties of some representative amines is given in Appendix 1. Most commonly encoun- tered alkylamines are liquids with unpleasant, “fishy” odors. Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 864 CHAPTER TWENTY-TWO — Amines Primary and secondary amines can participate in intermolecular hydrogen bonding, but tertiary amines cannot. Amines that have fewer than six or seven carbon atoms are soluble in water. All amines, even tertiary amines, can act as proton acceptors in hydrogen bonding to water molecules. The simplest arylamine, aniline, is a liquid at room temperature and has a boiling point of 184ºC. Almost all other arylamines have higher boiling points. Aniline is only slightly soluble in water (3 g/100 mL). Substituted derivatives of aniline tend to be even less water-soluble. 22.4 MEASURES OF AMINE BASICITY Two conventions are used to measure the basicity of amines. One of them defines a basicity constant Ky for the amine acting as a proton acceptor from water: a + -. RN: H-LOH = RN>H + 0H — IR;NH“J[HO”] Ko [RAN] and pk, = —log K, For ammonia, K, = 1.8 X 107º (pk, = 4.7). A typical amine such as methylamine (CH5NH>) is a stronger base than ammonia and has K, = 4.4 X 107“ (pk, = 3.3). The other convention relates the basicity of an amine (R3N) to the acid dissocia- tion constant K, of its conjugate acid (R;NH”): E RNZH => H' + RN: where K, and pK, have their usual meaning: + a = EMRNT and pk = log ks [R5NH"] The conjugate acid of ammonia is ammonium ion (NH, *), which has K, = 5.6 X 107!º (pK, = 9.3). The conjugate acid of methylamine is methylammonium ion (CH;NH;*), which has K, = 2 X 107 (pk, = 10.7). The more basic the amine, the weaker is its conjugate acid. Methylamine is a stronger base than ammonia; methylammonium ion is a weaker acid than ammonium ion. The relationship between the equilibrium constant K, for an amine (R5N) and K, for its conjugate acid (R5NH*) ist Kk, = 107" and pk +pk=I4 PROBLEM 22.5 A chemistry handbook lists K, for quinine as 1 x 108. What is pk» for quinine? What are the values of K, and pkK, for the conjugate acid of qui- nine? Citing amine basicity according to the acidity of the conjugate acid permits acid-base reactions involving amines to be analyzed according to the usual Brónsted relationships. By comparing the acidity of an acid with the conjugate acid of an amine, for example, we see that amines are converted to ammonium ions by acids even as weak as acetic acid: E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 22.5 Basicity of Amines 867 PROBLEM 22.7 The two amines shown differ by a factor of 40,000 in their Kb values. Which is the stronger base? Why? View their structures on Learning By o Modeling. What are the calculated charges on the two nitrogens? 9 GA. Tetrahydroquinoline | Tetrahydroisoquinoline Conjugation of the amino group of an arylamine with a second aromatic ring, then a third, reduces its basicity even further. Diphenylamine is 6300 times less basic than aniline, whereas triphenylamine is scarcely a base at all, being estimated as 10º times less basic than aniline and 10! times less basic than ammonia. CoH5NH, (CoHs))NH (CgHs)3N Aniline Diphenylamine Triphenylamine (Kb 3.8 x 10710, (K, 6X 10714; (Ko = 10 "9; pk, 9.4) pKp 13.2) pk = 19) Im general, electron-donating substituents on the aromatic ring increase the basic- ity of arylamines slightly. Thus, as shown in Table 22.2, an electron-donating methyl group in the para position increases the basicity of aniline by a factor of only 5-6 (less than 1 pK unit). Electron-withdrawing groups are base-weakening and exert larger effects. A p-trifluoromethyl group decreases the basicity of aniline by a factor of 200 and a p-nitro group by a factor of 3800. In the case of p-nitroaniline a resonance inter- action of the type shown provides for extensive delocalization of the unshared electron pair of the amine group. Electron delocalization in p-nitroaniline Just as aniline is much less basic than alkylamines because the unshared electron pair of nitrogen is delocalized into the 7 system of the ring, p-nitroaniline is even less basic because the extent of this delocalization is greater and involves the oxygens of the nitro group. J[1:020»24) Effect of Substituents on the Basicity of Aniline x Kb PKb H 4x 10719 9.4 NH CH 2x 10º 8.7 = CFs 2x 1012 11.5 ON 1x 103 13.0 E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 868 Pyridine and imidazole were two of the heterocyclic aro- matic compounds described in Section 11.21. E Forward CHAPTER TWENTY-TWO — Amines PROBLEM 22.8 Each of the following is a much weaker base than aniline. Pre- sent a resonance argument to explain the effect of the substituent in each case. (a) o-Cyanoaniline (c) p-Aminoacetophenone (b) 9? CoHsNHCCH; SAMPLE SOLUTION (a) A cyano substituent is strongly electron-withdrawing. When present at a position ortho to an amino group on an aromatic ring, a cyano substituent increases the delocalization of the amine lone-pair electrons by a direct resonance interaction. :NH> . “NH SE em: <—s This resonance stabilization is lost when the amine group becomes protonated, and o-cyanoaniline is therefore a weaker base than aniline. Multiple substitution by strongly electron-withdrawing groups diminishes the basicity of arylamines still more. As just noted, aniline is 3800 times as strong a base as p-nitroaniline; however, it is 10º times more basic than 2,4-dinitroaniline. A practical consequence of this is that arylamines that bear two or more strongly electron-with- drawing groups are often not capable of being extracted from ether solution into dilute aqueous acid. Nonaromatic heterocyclic compounds, piperidine, for example, are similar in basic- ity to alkylamines. When nitrogen is part of an aromatic ring, however, its basicity decreases markedly. Pyridine, for example, resembles arylamines in being almost 1 mil- lion times less basic than piperidine. is more basic than Piperidine Pyridine (K, = 1.6 X 10? pk, = 2.8) (K, = 14X 10º; pk, = 88) Imidazole and its derivatives form an interesting and important class of hetero- cyclic aromatic amines. Imidazole is approximately 100 times more basic than pyridine. Protonation of imidazole yields an ion that is stabilized by the electron delocalization represented in the resonance structures shown: PA + Po N+ : : +H' == : «— : NyN=H H-NQYEN-H H-NiN=H Imidazole Imidazolium ion (K, = 1X 1077; pk, = 7) An imidazole ring is a structural unit in the amino acid histidine (Section 27.1) and is involved in a large number of biological processes as a base and as a nucleophile. MainMenu| TOC] Study Guide TOC) StudentOLC| — MHHE Website Back| 22.5 Basicity of Amines 869 AMINES AS NATURAL PRODUCTS The ease with which amines are extracted into aque- ous acid, combined with their regeneration on treat- ment with base, makes it a simple matter to separate amines from other plant materials, and nitrogen- containing natural products were among the earliest organic compounds to be studied.” Their basic prop- (A O OCH; c N í a CH OCCsHs Cocaine Coniine (A central nervous system stimulant obtained from the leaves of the coca plant.) Many alkaloids, such as nicotine and quinine, contain two (or more) nitrogen atoms. The nitrogens highlighted in yellow in quinine and nicotine are part = cH;o. Quinine (Alkaloid of cinchona bark used to treat malaria) Several naturally occurring amines mediate the transmission of nerve impulses and are referred to as neurotransmitters. Two examples are epinephrine NT “eCHaCHaCHs (Present along with other alkaloids in the hemlock extract used to poison Socrates.) * The isolation of alkaloids from plants is reviewed in the August 1991 issue of the Joumal of Chemical Education, pp. 700-703. erties led amines obtained from plants to be called alkaloids. The number of known alkaloids exceeds 5000. They are of special interest because most are characterized by a high level of biological activity. Some examples include cocaine, coniine, and mor- phine. HO. Morphine (An opium alkaloid. Although it is an excellent analgesic, its use is restricted because of the potential for addiction. Heroin is the diacetate ester of morphine.) of a substituted quinoline and pyridine ring, respec- tively. x N d N CHs Nicotine (An alkaloid present in tobacco; a very toxic compound sometimes used as an insecticide) and serotonin. (Strictly speaking, these compounds are not classified as alkaloids, because they are not isolated from plants.) —Cont. Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 872 CHAPTER TWENTY-TWO — Amines z CH;CH,CH,CH;Br + CoHsCH,N(CH;); CNT —> Butyl bromide Benzyltrimethylammonium cyanide (in butyl bromide) = CH;CH,CH,CH;CN + CoHsCH5N(CHs)s Br” Pentanenitrile Benzyltrimethylammonium (in butyl bromide) bromide (in butyl bromide) The benzyltrimethy lammonium bromide formed in this step returns to the aqueous phase, where it can repeat the cycle. Reese . Phase-transfer Catalysis succeeds for two reasons. First, it provides a mechanism subject of an article in the for introducing an anion into the medium that contains the reactive substrate. More April 1978 issue of the Jour- important, the anion is introduced in a weakly solvated, highly reactive state. You've nal of Chemical Education (pp. 235-238). This article in- already seen Phase-transfer catalysis in another form in Section 16.4, where the metal- cludes examples of a variety complexing properties of crown ethers were described. Crown ethers permit metal salts of reactions carried out un- to dissolve in nonpolar solvents by surrounding the cation with a lipophilic cloak, leav- der phase-transfer condi- Pra ing the anion free to react without the encumbrance of strong solvation forces. 22.7 REACTIONS THAT LEAD TO AMINES: A REVIEW AND A PREVIEW Methods for preparing amines address either or both of the following questions: 1. How is the required carbon-nitrogen bond to be formed? 2. Given a nitrogen-containing organic compound such as an amide, a nitrile, or a nitro compound, how is the correct oxidation state of the desired amine to be achieved? A number of reactions that lead to carbon-nitrogen bond formation were presented in earlier chapters and are summarized in Table 22.3. Among the reactions in the table, the nucleophilic ring opening of epoxides, reaction of a-halo acids with ammonia, and the Hofmann rearrangement give amines directly. The other reactions in Table 22.3 yield products that are converted to amines by some subsequent procedure. As these proce- dures are described in the following sections, you will see that they are largely applica- tions of principles that you”ve already learned. You will encounter some new reagents and some new uses for familiar reagents, but very little in the way of new reaction types is involved. 22.8 PREPARATION OF AMINES BY ALKYLATION OF AMMONIA Alkylamines are, in principle, capable of being prepared by nucleophilic substitution reactions of alkyl halides with ammonia. = RX + 2NH; —> RNH, + NH, X” Alkyl Ammonia Primary Ammonium halide amine halide salt Although this reaction is useful for preparing a-amino acids (Table 22.3, fifth entry), it is not a general method for the synthesis of amines. Its major limitation is that the expected primary amine product is itself a nucleophile and competes with ammonia for the alkyl halide. E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 28 Preparation of Amines by Alkylation of Ammonia 873 [NBP 2M) Methods for Carbon-Nitrogen Bond Formation Discussed in Earlier Chapters Reaction (section) and comments General equation and specific example Nucleophilic substitution by azide ion on an alkyl halide (Sections 8.1, 8.13) Azide ion is a very good nucleophile and reacts with primary and secondary alkyl halides to give alkyl azides. Phase-transfer cata- lysts accelerate the rate of reaction. Nitration of arenes (Section 12.3) The standard method for introducing a nitro- gen atom as a substituent on an aromatic ring is nitration with a mixture of nitric acid and sulfuric acid. The reaction pro- ceeds by electrophilic aromatic substitu- tion. Nucleophilic ring opening of epoxides by ammonia (Section 16.12) The strained ring of an epoxide is opened on nucleo- philic attack by ammonia and amines to give B-amino alcohols. Azide ion also reacts with epoxides; the products are B-azido alcohols. Nucleophilic addition of amines to alde- hydes and ketones (Sections 17.10, 17.11) Primary amines undergo nucleo- philic addition to the carbonyl group of aldehydes and ketones to form carbinol- amines. These carbinolamines dehydrate under the conditions of their formation to give N-substituted imines. Secondary amines yield enamines. e E a “+ IN=N=N: + RX 0 —S :N=N+ E ia x Azide ion Alkyl halide Alkyl azide Halide ion NaNs phase-transfer catalyst CHsCH>CH>CH>CH>Br Pentyl bromide (1-bromopentane) CHsCH>CH>CH>CH>N3 Pentyl azide (89%) (1-azidopentane) Hsso, ArH + HNO; —2> ArNO, + HO Arene Nitric acid Nitroarene Water ON 7 as HNOs €H usos? ca Benzaldehyde m-Nitrobenzaldehyde (75-84%) E HaN: + R2C—CR,; —> H;N—C—C—OH NY [1 RR Ammonia — Epoxide B-Amino alcohol CHs Ha€ H OH H NH Han. H 1 o HO] HC CHs (2R,3R)-2,3-Epoxybutane (2R,38)-3-Amino-2-butanol (70%) í JE RNH, + R'CR” —> R'CR” + H,0 Primary — Aldehyde Imine Water amine — orketone o CHaNH, + Cotsbh —S CGHCH=NCH; Methylamine — Benzaldehyde N-Benzylidenemethylamine (70%) Back Forward Main Menul Toe] (Continued) Study Guide TOC Student OLC MHHE Website 87 CHAPTER TWENTY-TWO — Amines (Continued) [104 Reaction (section) and comments Methods for Carbon-Nitrogen Bond Formation Discussed in Earlier Chapters General equation and specific example ic substitution by ammonia on s (Section 19.16) The a-halo acids obtained by halogenation of car- boxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reac- tive substrates in nucleophilic substitu- tion processes. A standard method for the preparation of a-amino acids is dis- placement of halide from a-halo acids by nucleophilic substitution using excess aqueous ammonia. Nucleophilic acyl substitution (Sections 20.3, 20.5, and 20.11) Acylation of ammo- nia and amines by an acyl chloride, acid anhydride, or ester is an exceptionally effective method for the formation of carbon-nitrogen bonds. The Hofmann rearrangement (Section 20.17) Amides are converted to amines by reaction with bromine in basic media. An N-bromo amide is an intermediate; it rearranges to an isocyanate. Hydrolysis of the isocyanate yields an amine. HoNi + REHCOH — ROHCO;" + x Ammonia a-Halo (excess) carboxylic acid NH: (CHa)2CHCHCO,H | —> ] HO Br 2-Bromo-3-methylbutanoic acid o 4 RNH + RC N x Primaryor — Agyl chloride, acid secondary anhydride, or ester amine, or ammonia í 20 ) + cada — N H Pyrrolidine Acetyl chloride 7 Br, HO RCNH, > RNH, 7 Amide Amine | Bra HO. (CH5)3CCNH, os H,0' 2,2-Dimethylpropanamide NHX “NHs a-Amino Ammonium acid halide (CHs)2CHCHCO, | “NH 2-Amino-3-methylbutanoic acid (47-48%) o | — RANCR' + HX Amide Water 7 NCCH + L,)a N /N HH N-Acetylpyrrolidine (19%) Pyrrolidine hydrochloride (CH3)3CNH> tert-Butylamine (64%) + RX + RNH, + NH; —> RNHR + NH X” Alkyl halide Primary Ammonia amine Secondary amine Ammonium halide salt When 1-bromooctane, for example, is allowed to react with ammonia, both the primary amine and the secondary amine are isolated in comparable amounts. NH, (2 mol) CH(CH,)CH,Br 220, CH(CH,)CH;NH, + [CHs(CH;)CHo NH 1-Bromooctane (1 mol) (45%) Octylamine N,N-Dioctylamine (43%) mM a similar manner, competitive alkylation may continue, resulting in formation of a trialkylamine. Back Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website Back| 22.10 Preparation of Amines by Reduction 87 22.10 PREPARATION OF AMINES BY REDUCTION Almost any nitrogen-containing organic compound can be reduced to an amine. The syn- thesis of amines then becomes a question of the availability of suitable precursors and the choice of an appropriate reducing agent. Alkyl azides, prepared by nucleophilic substitution of alkyl halides by sodium azide, as shown in the first entry of Table 22.3, are reduced to alkylamines by a variety of reagents, including lithium aluminum hydride. reduce a EB RE = R—N=N=N: > RNH, Alkyl azide Primary amine 1 LAH, diethyl ethe CoHsCH,CH,N; =” CoHsCH,CH,NH, 2-Phenylethyl azide 2-Phenylethylamine (89%) Catalytic hydrogenation is also effective: OH OH O NaN; Ho, Pt dioxane-water ha ha, “Na “NH, 1,2-Epoxyeyclo- trans-2-Azidoeyclo- trans-2- Aminocyelo- hexane hexanol (619%) hexanol (81%) Mm its overall design, this procedure is similar to the Gabriel synthesis; a nitrogen nucle- ophile is used in a carbon-nitrogen bond-forming operation and then converted to an amino group in a subsequent transformation. The same reduction methods may be applied to the conversion of nitriles to pri- mary amines. as LiAIH, or RCSN O» RCHNH, Nitile Primary amine 1 LiAIH,, re Scnen Do, pe A cnc, pA(Trifluoromethy)benzyl 2(p-Trifluoromethy)phenylethyI- cyanide amine (53%) CHsCH>CHaCH;CN EEE, CH;CHoCH>CH>CHoNH> Pentanenitile 1-Pentanamine (56%) TT The preparation of pen- - as . a imti ' tanenitrile under phase- Since nitriles can be prepared from alkyl halides by nucleophilic substitution with dansfer conditions was cyanide ion, the overall process RX > RC=N —» RCH,NH, leads to primary amines described in Section 22.6. that have one more carbon atom than the starting alkyl halide. Cyano groups in cyanohydrins (Section 17.7) are reduced under the same reaction conditions. Nitro groups are readily reduced to primary amines by a variety of methods. Cat- alytic hydrogenation over platinum, palladium, or nickel is often used, as is reduction by iron or tin in hydrochloric acid. The ease with which nitro groups are reduced is Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 878 CHAPTER TWENTY-TWO — Amines especially useful in the preparation of arylamines, where the sequence ArH — ArNO, — ArNH, is the standard route to these compounds. CH(CHy)» o” o-Isopropyinitrobenzene For reductions carried out in acidic media, a pH adjust- CH(CH5)> Ho Ni Em +, methanol o-Isopropylaniline (92%) A rene, 2 NaOH 0 p-Chloronitrobenzene ment with sodium hydroxide is required in the last step in order to convert ArNH;' to ArNHo. p-Chloroaniline (95%) sem dm HN m-Nitroacetophenone m-Aminoacetophenone (82%) benzene: (a) o-Isopropylaniline (b) p-Isopropylaniline (c) 4-Isopropyl-1,3-benzenediamine (d) p-Chloroaniline (e) m-Aminoacetophenone tion of isopropylbenzene. CH(CH3) CH(CH5a CH(CH3) NO, HNO; > + NO, Isopropylbenzene o-Isopropyinitrobenzene p-Isopropyinitrobenzene (bp 110º) (bp 131º0) ucts has been obtained with an ortho-para ratio of about 1:3. using isopropyl chloride and aluminum chloride (Section 12.6). PROBLEM 22.11 Outline syntheses of each of the following arylamines from SAMPLE SOLUTION (a) The last step in the synthesis of o-isopropylaniline, the reduction of the corresponding nitro compound by catalytic hydrogenation, is given as one of the three preceding examples. The necessary nitroarene is obtained by fractional distillation of the ortho-para mixture formed during nitra- As actually performed, a 62% yield of a mixture of ortho and para nitration prod- Isopropylbenzene is prepared by the Friedel-Crafts alkylation of benzene Reduction of an azide, a nitrile, or a nitro compound fumishes a primary amine. A method that provides access to primary, secondary, or tertiary amines is reduction of the carbonyl group of an amide by lithium aluminum hydride. E Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 22.11 | Reductive Amination 879 f RCNR$ > RCH;NR$ Amide Amine In this general equation, R and R' may be either alkyl or aryl groups. When R' = H, the product is a primary amine: 1. LiAIH,, Cor HCELONH; — — Cor querem NH, cH; cH; 3-Phenylbutanamide 3-Phenyl-1 -butanamine (59%) N-Substituted amides yield secondary amines: 7 1. LiAIHs, Acetanilide N-Ethylaniline (92%) Acetanilide is an acceptable IUPAC synonym for N- phenylethanamide. N,N-Disubstituted amides yield tertiary amines: 7 1. LiAIH,, (ameno, ET (enem, N,N-Dimethyleyclohexane- N,N-Dimethyl(eyclohexylmethyl)- carboxamide amine (88%) Because amides are so easy to prepare, this is a versatile method for the prepara- tion of amines. The preparation of amines by the methods described in this section involves the prior synthesis and isolation of some reducible material that has a carbon-nitrogen bond: an azide, a nitrile, a nitro-substituted arene, or an amide. The following section describes a method that combines the two steps of carbon-nitrogen bond formation and reduction into a single operation. Like the reduction of amides, it offers the possibility of prepar- ing primary, secondary, or tertiary amines by proper choice of starting materials. 22.11 REDUCTIVE AMINATION A class of nitrogen-containing compounds that was omitted from the section just dis- cussed includes imines and their derivatives. Imines are formed by the reaction of alde- hydes and ketones with ammonia. Imines can be reduced to primary amines by catalytic hydrogenation. Í Te RCR' + NH, —>>RCR' —D> RCHR' catalyst Aldehyde — Ammonia Imine Primary amine or ketone E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website Back| 882 CHAPTER TWENTY-TWO — Amines JH=P4MS Reactions Reaction (section) and comments of Amines Discussed in Previous Chapters* General equation and specific example Reaction of primary amines with aldehydes and ketones (Section 17.10) Imines are formed by nucleophilic addition of a primary amine to the carbonyl group of an aldehyde or a ketone. The key step is formation of a carbinolamine intermedi- ate, which then dehy- drates to the imine. Reaction of secondary amines with aldehydes and ketones (Section 17.11) Enamines are formed in the correspond- ing reaction of secondary amines with aldehydes and ketones. Reaction of amines with acyl chlorides (Section 20.3) Amines are convert- ed to amides on reaction with acyl chlorides. Other acylating agents, such as carboxylic acid anhydrides and esters, may also be used but are less reactive. R' R' R' . N ' I “HO 4 RNHo + 0-0 — RNH—C0H —S RN—CÍ R o R Primary — Aldehyde Carbinolamine Imine amine — orketone 7 CHaNH, + GHSCH — — GHsCH=NCH; + HO Methylamine — Benzaldehyde NBenzylidenemethylamine Water (70%) R'CH> CHAR! CHR' ae x “ —H,0, “ / RANH + emo — Rai 0H —5 Raio R R R Secondary Aldehyde Carbinolamine Enamine amine or ketone o benzene, (3+ O dee, CH + Ho N H Pyrrolidine Cyclohexanone N-(1-Cyclohexenyl) pyrrolidine (85-90%) o N ] gd na el RNH + RICCI — RohiGcl —S RANCR k Primary or Ag Tetrahedral Amide secondary amine chloride intermediate í í CHsCH>CH>CHNH> + CHaCH>CH>CH>CCI —> CHaCH>CH>CH>CNHCH>CH>CH>CH3 Butylamine Pentanoyl chloride N-Butylpentanamide (81%) *Both alkylamines and arylamines undergo these reactions. Forward Main Menul TOC| Study Guide TOC] StudentOLC| — MHHE Website 22.14 — The Hofmann Elimination 88 22.13 REACTION OF AMINES WITH ALKYL HALIDES Nucleophilic substitution results when primary alkyl halides are treated with amines. H mo S|+ ma RNH, + R'CHX — Ec XxX —s Ec + HX H H Primary Primary Ammonium Secondary Hydrogen amine alkyl halide halide salt amine halide NaHCO, CoHsNH, + CoHsCH>5CI > CoH5NHCH,CoHs Aniline (4mol) Benzyl chloride N-Benzylaniline (1 mol) (85-87%) A second alkylation may follow, converting the secondary amine to a tertiary amine. Alkylation need not stop there; the tertiary amine may itself be alkylated, giving a qua- temary ammonium salt. R'CH,X R'CH,X R'CH,X RNH; EU, RNHCHGR' ELES, RN(CHAR a ELES RN(CHAR': X Primary Secondary Tertiary Quaternary amine amine amine ammonium salt Because of its high reactivity toward nucleophilic substitution, methyl iodide is the alkyl halide most often used to prepare quaternary ammonium salts. m (erra, + 3H E, CHN(CH;)a 1 (Cyclohexylmethyl- — Methyl (Cyclohexylmethyl)trimethyl- amine iodide ammonium iodide (99%) Quaternary ammonium salts, as we have seen, are useful in synthetic organic chem- istry as phase-transfer catalysts. In another, more direct application, quatemary ammo- nium hydroxides are used as substrates in an elimination reaction to form alkenes. 22.14 THE HOFMANN ELIMINATION The halide anion of quaternary ammonium iodides may be replaced by hydroxide by treatment with an aqueous slurry of silver oxide. Silver iodide precipitates, and a solu- tion of the quaternary ammonium hydroxide is formed. + + — URANT) + AgO + HO — MR4N 0H) + 2Agl Quaternary Silver Water Quaternary Silver ammonium iodide oxide ammonium hydroxide iodide + - Ago + = CHAN(CH5)s [7 oco CH;N(CH;); HO (CyclohexyImethyDtrimethyl- (Cyclohexylmethyl)trimethylammonium ammonium iodide hydroxide E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website Back| Forward CHAPTER TWENTY-TWO — Amines When quaternary ammonium hydroxides are heated, they undergo B-elimination to form an alkene and an amine. | CH, N(CH5). n DEP es Ot cm a HS H (Cyclohexylmethyltrimethyl- Methylenecyclohexane Trimethylamine Water ammonium hydroxide (69%) This reaction is known as the Hofmann elimination; it was developed by August W. Hofmann in the middle of the nineteenth century and is both a synthetic method to pre- pare alkenes and an analytical tool for structure determination. A novel aspect of the Hofmamn elimination is its regioselectivity. Elimination in alkyltrimethy lammonium hydroxides proceeds in the direction that gives the less substi- tuted alkene. hear CH;CHCH,CH; HO” — > CH,=CHCH.CH, + CH;CH=CHCH, NH (CH N sec-Butyltrimethylammonium 1-Butene (95%) 2-Butene (5%) hydroxide (cis and trans) The least sterically hindered B hydrogen is removed by the base in Hofmann elim- ination reactions. Methyl groups are deprotonated in preference to methylene groups, and methylene groups are deprotonated in preference to methines. The regioselectivity of Hofmann elimination is opposite to that predicted by the Zaitsev rule (Section 5.10). Elimination reactions of alkyltrimethylammonium hydroxides are said to obey the Hofmann rule; they yield the less substituted alkene. PROBLEM 22.13 Give the structure of the major alkene formed when the hydroxide of each of the following quaternary ammonium ions is heated. (a) xo (o) Ps , N(CHa)s CHaCHaNICHaCHaCHoCHa + CHs (b) (CH=)3CCH>C(CH3)> “N(CHa)s SAMPLE SOLUTION (a) Two alkenes are capable of being formed by B-elimina- tion, methylenecyclopentane and 1-methylcyclopentene. CHs ' CX HO —E Dm + [Sc N(CHs)a (Ca (1-Methylcyclopentyltrimethyl- Methylenecyclopentane | 1-Methylcyclopentene ammonium hydroxide Methylenecyclopentane has the less substituted double bond and is the major product. The reported isomer distribution is 91% methylenecyclopentane and 9% 1-methylcyclopentene. MainMenu| TOC] Study Guide TOC) StudentOLC| — MHHE Website 22.15 Electrophilic Aromatic Substitution in Arylamines 887 o ArNHCCH, Ds ArNH, 1. HO! 2. HO N-Acetylarylamine Arylamine o | NHCCH; NH, NO, NO, KOH, ethanol heat (deprotection” step) CH(CH;), CH(CH;), 4-Isopropyl-2-nitroacetanilide 4-Isopropyl-2-nitroaniline (100%) The net effect of the sequence protect-nitrate-deprotect is the same as if the substrate had been nitrated directly. Because direct nitration is impossible, however, the indirect route is the only practical method. PROBLEM 22.14 Outline syntheses of each of the following from aniline and any necessary organic or inorganic reagents: (a) p-Nitroaniline (c) p-Aminoacetanilide (b) 2,4-Dinitroaniline SAMPLE SOLUTION (a) It has already been stated that direct nitration of ani- line is not a practical reaction. The amino group must first be protected as its N-acetyl derivative. 2 9? NHóct, NHdcH; NHécH, HNO: jolie, ordodem, Ó SO, O Q Aniline Acetanilide o-Nitroacetanilide pNitroacetanitide Nitration of acetanilide yields a mixture of ortho and para substitution products. The para isomer is separated, then subjected to hydrolysis to give p-nitroaniline. nude, torto, Ho 1 Rot 2. HO pnirocetaniide picoantne E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 888 CHAPTER TWENTY-TWO — Amines Unprotected arylamines are so reactive toward halogenation that it is difficult to limit the reaction to monosubstitution. Generally, halogenation proceeds rapidly to replace all the available hydrogens that are ortho or para to the amino group. NH, acetic “etc add” “o Co,H Cco,H p-Aminobenzoic acid 4-Amino-3,5-dibromobenzoic acid (82%) Decreasing the electron-donating ability of an amino group by acylation makes it possi- ble to limit halogenation to monosubstitution. Ho 0 Lim, NHCCH; > mic 2-Methylacetanilide 4-Chloro-2-methylacetanilide (74%) Friedel-Crafts reactions are normally not successful when attempted on an aryl- amine, but can be carried out readily once the amino group is protected. o o I Eosa ACI NHCCH,; + CH;CCl — mEdcs, CH>CH; CH>CHs 2-Ethylacetanilide 4-Acetamido-3-ethylacetophenone (57%) 22.16 NITROSATION OF ALKYLAMINES When solutions of sodium nitrite (NaNO») are acidified, a number of species are formed Nitrosyl cation is also called that act as nitrosating agents. That is, they react as sources of nitrosyl cation, :IN=O:. nitrosonium ion. It can be In order to simplify discussion, organic chemists group all these species together and represented by the two reso- speak of the chemistry of one of them, nitrous acid, as a generalized precursor to nitro- nance structures - syl cation. A INTO: e: Nitrite ion Nitrous acid Nitrosyl (from sodium nitrite) cation Nitrosation of amines is best illustrated by examining what happens when a sec- ondary amine “reacts with nitrous acid.” The amine acts as a nucleophile, attacking the nitrogen of nitrosyl cation. E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 22.16 Nitrosation of Alkylamines + + mu a Rap N=O: —s» RN 1: RN— H H Secondary Nitrosyl N-Nitroso alkylamine cation amine The intermediate that is formed in the first step loses a proton to give an N-nitroso amine as the isolated product. NaNO,, HCI > (CHyAH Dimethylamine (CH)N—N=0: N-Nitrosodimethylamine (88-90%) PROBLEM 22.15 N-Nitroso amines are stabilized by electron delocalization. Write the two most stable resonance forms of N-nitrosodimethylamine, (CHs)pNNO. N-Nitroso amines are more often called nitrosamines, and because many of them are potent carcinogens, they have been the object of much recent investigation. We encounter nitrosamines in the environment on a daily basis. A few of these, all of which are known carcinogens, are: Hsc, O PN / na N N N N HC 1 Nº | N N So o N-Nitrosodimethylamine (formed during tanning of leather; also found in beer and herbicides) N-Nitrosopyrrolidine (formed when bacon that has been cured with sodium nitrite is fried) N-Nitrosonornicotine (present in tobacco smoke) Nitrosamines are formed whenever nitrosating agents come in contact with secondary amines. Indeed, more nitrosamines are probably synthesized within our body than enter it by environmental contamination. Enzyme-catalyzed reduction of nitrate (NO; ) produces nitrite (NO, ), which combines with amines present in the body to form N-nitroso amines. When primary amines are nitrosated, their N-nitroso compounds can't be isolated because they react further. H H RNHo > RN o RNO =. N y NH 9H Primary (Not isolable) (Not isolable) alkylamine |- + mos E ' RN=N: <!2 pN=n£OM, <> RN=N—0H Alkyl diazonium (Not isolable) (Not isolable) ion E Forward Main Menul Toe] Study Guide TOC Student OLC 889 O to the molecular model of nitrosyl cation on Learning By Modeling to verify that the region of positive elec- trostatic potential is concen- trated at nitrogen. The July 1977 issue of the Journal of Chemical Educa- tion contains an article enti- tled “Formation of Nitrosa- mines in Food and in the Di- gestive System.” MHHE Website 892 FIGURE 22.6 Flowchart showing the synthetic origin of aryl diazonium ions and their most useful transfor- mations. E Forward Main Menul CHAPTER TWENTY-TWO Amines no ArOH o Am - HBE, ArF Schiemann 2. heat reaction CuCl ArH ArNO, ArNH; - ArCI Aryl CuBr Sandmeyer diazonium ArBr reactions ion CuCN ArCN HPO, or CH,CH,OH ArH 22.18 SYNTHETIC TRANSFORMATIONS OF ARYL DIAZONIUM SALTS An important reaction of aryl diazonium ions is their conversion to phenols by hydrolysis: + ArN=N: Aryl diazonium ion + HO —> ArOH + Hº +:N=N: Water A phenol Nitrogen This is the most general method for preparing phenols. It is easily performed; the aqueous acidic solution in which the diazonium salt is prepared is heated and gives the phenol directly. An aryl cation is probably generated, which is then captured by water acting as a nucleophile. 1. NaNO», H,SO,, HO cena (O St EO a > cena ( Son p-Isopropylaniline p-Isopropylphenol (73%) Sulfuric acid is normally used instead of hydrochloric acid in the diazotization step so as to minimize the competition with water for capture of the cationic intermediate. Hydrogen sulfate anion (HSO, ) is less nucleophilic than chloride. [PRoBLEM 22.17 Design a synthesis of m-bromophenol from benzene. ] The reaction of an aryl diazonium salt with potassium iodide is the standard method for the preparation of aryl iodides. The diazonium salt is prepared from a primary aro- matic amine in the usual way, a solution of potassium iodide is then added, and the reac- tion mixture is brought to room temperature or heated to accelerate the reaction. + Ar>NESN: + Do > Ad +:N= Aryl diazonium — Todide Aryl — Nitrogen ion ion iodide NaNO,, HCI, H,0,0-5ºC NH, KI, room temperature I Br Br o-Bromoaniline o-Bromoiodobenzene (72-83%) TOC| Study Guide TOC] — Student OLC MHHE Website 22.18 — Synthetic Transformations of Aryl Diazonium Salts | rouem 22.18 Show by a series of equations how you could prepare ] m-bromoiodobenzene from benzene. Diazonium salt chemistry provides the principal synthetic method for the prepara- tion of aryl fluorides through a process known as the Schiemann reaction. In this pro- cedure the aryl diazonium ion is isolated as its fluoroborate salt, which then yields the desired aryl fluoride on being heated. E s heat Ar—N=N: BE, > AP + BE, +:N=N: Aryl diazonium Ary Boron — Nitrogen fluoroborate fluoride trifluoride A standard way to form the aryl diazonium fluoroborate salt is to add fluoroboric acid (HBF,) or a fluoroborate salt to the diazotization medium. NH, F 1. NaNO,, H,0, HCI 2. HBFs 3. heat qCHnCHs qCHCHs O O m-Aminophenyl ethyl ketone Ethyl m-fluorophenyl ketone (68%) [ ron 22.19 Show the proper sequence of synthetic transformations in ve] conversion of benzene to ethyl m-fluorophenyl ketone. Although it is possible to prepare aryl chlorides and aryl bromides by electrophilic aromatic substitution, it is often necessary to prepare these compounds from an aromatic amine. The amine is converted to the corresponding diazonium salt and then treated with copper(I) chloride or copper(I) bromide as appropriate. + CuX Ar—N=SN: > AXO +ENSN: Ary diazonium Arylchloride Nitrogen ion or bromide NH, fo] 1. NaNO», HCI, HO, 2. CuCl, hear NO, NO, m-Nitroaniline m-Chloronitrobenzene (68-71 %) cl cl NH, Br 1. NaNO;, HE, H,0,0-10:C 2. CuBr, heat o-Chloroaniline o-Bromochlorobenzene (89-95%) E Forward Main Menul Toe] Study Guide TOC Student OLC 893 MHHE Website 894 Back| Forward CHAPTER TWENTY-TWO — Amines Reactions that employ copper(I) salts as reagents for replacement of nitrogen in diazo- nium salts are called Sandmeyer reactions. The Sandmeyer reaction using copper(I) cyanide is a good method for the preparation of aromatic nitriles: e CuCN Ar—N=N: SÉ> ArCN + :N=N: Aryl diazonium Aryl Nitrogen ion nitrile cH; cH; NH, CN 1. NaNO», HCI, H,0,0ºC 2. CuCN, hear o"Toluidine o-Methylbenzonitrile (64-70%) Since cyano groups may be hydrolyzed to carboxylic acids (Section 20.19), the Sand- meyer preparation of aryl nitriles is a key step in the conversion of arylamines to sub- stituted benzoic acids. In the example just cited, the o-methyIbenzonitrile that was formed was subsequently subjected to acid-catalyzed hydrolysis and gave o-methylbenzoic acid in 80-89 percent yield. The preparation of aryl chlorides, bromides, and cyanides by the Sandmeyer reac- tion is mechanistically complicated and may involve arylcopper intermediates. It is possible to replace amino substituents on an aromatic nucleus by hydrogen by reducing a diazonium salt with hypophosphorous acid (H;PO>) or with ethanol. These reductions are free-radical reactions in which ethanol or hypophosphorous acid acts as a hydrogen atom donor: Tor. HPOs or E Ar>NEN: caem At + :N=N: Aryl diazonium Arene Nitrogen ion Reactions of this type are called reductive deaminations. CHs CHs o-Toluidine Toluene (70-75%) CH(CH5)> CH(CH5)> NaNO», HCI, H; CH;CH;0H NO, NO, NH, 4-Isopropyl-2-nitroaniline m-Isopropylnitrobenzene (59%) Sodium borohydride has also been used to reduce aryl diazonium salts in reductive deam- ination reactions. MainMenu| TOC] Study Guide TOC) StudentOLC| — MHHE Website 22.20 Spectroscopic Analysis of Amines 897 Bacteria require p-aminobenzoic acid in order to biosynthesize folic acid, a growth factor. Structurally, sulfanilamide resembles p-aminobenzoic acid and is mistaken for it by the bacteria. Folic acid biosynthesis is inhibited and bacterial growth is slowed sufficiently to allow the body's natural defenses to effect a cure. Since animals do not biosynthesize folic acid but ob- tain it in their food, sulfanilamide halts the growth of bacteria without harm to the host. Identification of the mechanism by which Pron- tosil combats bacterial infections was an early tri- umph of pharmacology, a branch of science at the in- s Han )soam— J N Sulfathiazole We tend to take the efficacy of modern drugs for granted. One comparison with the not-too- distant past might put this view into better perspec- tive. Once sulfa drugs were introduced in the United States, the number of pneumonia deaths alone de- creased by an estimated 25,000 per year. The sulfa terface of physiology and biochemistry that studies the mechanism of drug action. By recognizing that sulfanilamide was the active agent, the task of preparing structurally modified analogs with poten- tially superior properties was considerably simplified. Instead of preparing Prontosil analogs, chemists syn- thesized sulfanilamide analogs. They did this with a vengeance; over 5000 compounds related to sulfanil- amide were prepared during the period 1935-1946. Two of the most widely used sulfa drugs are sulfathi- azole and sulfadiazine. na4 son dO) Sulfadiazine drugs are used less now than they were in the mid- twentieth century. Not only are more-effective, less- toxic antibiotics available, such as the penicillins and tetracyclines, but many bacteria that were once sus- ceptible to sulfa drugs have become resistant. oH oH N=NCsHs + O 1 SMsNEENtEI > CI 1-Naphthol Benzenediazonium chloride 2-(Phenylazo)-1-naphthol The colors of azo compounds vary with the nature of the aryl group, with its substituents, and with pH. Substituents also affect the water-solubility of azo dyes and how well they bind to a particular fabric. Countless combinations of diazonium salts and aromatic sub- strates have been examined with a view toward obtaining azo dyes suitable for a par- ticular application. A number of pH indicators — methyl red, for example — are azo compounds. 22.20 SPECTROSCOPIC ANALYSIS OF AMINES Infrared: The absorptions of interest in the infrared spectra of amines are those asso- ciated with N—H vibrations. Primary alkyl- and arylamines exhibit two peaks in the range 3000-3500 em”!, which are due to symmetric and antisymmetric N—H stretch- ing modes. H , Td DE Piá R>N, Das Symmetric N—H stretching of a primary amine Antisymmetric N—H stretching of a primary amine O symmetric and anti- symmetric stretching vibrations of methylamine can be viewed on Learning By Modeling. Back| Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 898 CHAPTER TWENTY-TWO — Amines Wave number, em”! FIGURE 22.7 Portions É . of the infrared spectrum of (a) butylamine and (b) di- ethylamine. Primary amines exhibit two peaks due to N—H stretching, whereas secondary amines show only one. Transmittance (%) «o 2509 ado 2509 “om E E CH.CH.CH,CH,NH, (CH;CHo)NH E (a) b) These two vibrations are clearly visible at 3270 and 3380 cm”! in the infrared spec- trum of butylamine, shown in Figure 22.7a. Secondary amines such as diethylamine, shown in Figure 22.7b, exhibit only one peak, which is due to N—H stretching, at 3280 em”! Tertiary amines, of course, are transparent in this region, since they have no N—H bonds. cH; GENE, | CH; CHAN ArH NH, FIGURE 22.8 The 200-MHz 'H NMR spectra of (a) 4- ) methylbenzylamine and of (b) 4-methylbenzyl alcohol. The singlet corresponding to 90 80 70 60 5.0 40 3.0 2.0 LO o CH,N in (a) is more shielded Chemical shift (ô, ppm) than that of CH,0 in (b). (a) Back| Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website Back| 2220 —Spectroscopic Analysis of Amines !H NMR: Characteristics of the nuclear magnetic resonance spectra of amines may be illustrated by comparing 4-methylbenzy lamine (Figure 22.84) with 4-methylbenzyl alco- hol (Figure 22.8h). Nitrogen is less electronegative than oxygen and so shields neigh- boring nuclei to a greater extent. The benzylic methylene group attached to nitrogen in 4-methylbenzylamine appears at higher field (8 3.8 ppm) than the benzylic methylene of 4-methylbenzyl alcohol (8 4.6 ppm). The N—H protons are somewhat more shielded than the O—H protons of an alcohol. In 4-methyIbenzylamine the protons of the amino group correspond to the signal at à 1.5 ppm, whereas the hydroxyl proton signal of 4- methyIbenzyl alcohol is found at 3 2.1 ppm. The chemical shifts of amino group pro- tons, like those of hydroxyl protons, are variable and are sensitive to solvent, concen- tration, and temperature. VC NMR: Similarly, carbons that are bonded to nitrogen are more shielded than those bonded to oxygen, as revealed by comparing the "C chemical shifts of methylamine and methanol. 269 ppm CH;NH, 48.0 ppm CH;0H Methylamine Methanol UV-VIS: Im the absence of any other chromophore, the UV-Vis spectrum of an alkyl- amine is not very informative. The longest wavelength absorption involves promoting one of the unshared electrons of nitrogen to an antibonding o orbital (n > o%) with a Amax in the relatively inaccessible region near 200 nm. Arylamines are a different story. CH; EGOR CH; ArH cH,O oH DM Ja 9.0 80 7.0 60 50 40 30 20 Lo 0 Chemical shift (8, ppm) (Figure 22.8) Forward Main Menul Toe] Study Guide TOC Student OLC 899 MHHE Website 902 CHAPTER TWENTY-TWO — Amines ABLE 22. Preparation of Amines (Continued) Reaction (section) and comments General equation and specific example Alkylation of phthalimide. The Gabriel synthesis (Section 22.9) The potassium salt of phthalimide reacts with alkyl hal- ides to give N-alkylphthalimide deriva- tives. Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine. Reduction methods Reduction of alkyl azides (Section 22.10) Alkyl azides, prepared by nucleophilic substitution by azide ion in primary or secondary alkyl halides, are reduced to primary alkylamines by lithium aluminum hydride or by catalytic hydrogenation. Reduction of nitriles (Section 22.10) Nitriles are reduced to primary amines by lithium aluminum hydride or by catalytic hydrogenation. Reduction of aryl nitro compounds (Sec- tion 22.10) The standard method for the preparation of an arylamine is by nitra- tion of an aromatic ring, followed by reduction of the nitro group. Typical reducing agents include iron or tin in hydrochloric acid or catalytic hydrogena- tion. o o RX + NK! —» NR o o Alkyl— NPotassiophthalimide NeAlkylphthalimide halide o o NH NR + HANNH, —> RNH, + | NH o N-Alkylphthalimide — Hydrazine Primary Phthalhydrazide amine 1. Nopotassiophthalimide, DMF CHsCH=CHCH>CI 2. HoNNH,, ethanol 1-Chloro-2-butene CH;CH=CHCH;NH, 2-Buten-1-amine (95%) reduce a E RN=N=N: ———» Alkyl azide RNH> Primary amine » Pd, CFsCHaCHCO:CHaCHs to, CFaCHaCHCOsCHaCHs N NH> Ethyl 2-azido-4,4,4- Ethyl 2-amino-4,4,4- trifiuorobutanoate trifluorobutanoate (96%) di RC=N LS, RcHaNH, Nitrile Primary amine 1. LiAlHa Den 2. HO [chata Cyclopropyl cyanide Cyclopropylmethanamine (75%) di ArNO, LS, arNH, Nitroarene Arylamine 1. Fe Hel CHsNO, 5" Nitrobenzene CoHsNH> Aniline (97%) Back Forward Main Menul (Continued) TOC| Study Guide TOC] StudentOLC| — MHHE Website 22.21 Summary 903 02740: Preparation of Amines (Continued) Reaction (section) and comments General equation and specific example Reduction of amides (Section 22.10) Lithi- um aluminum hydride reduces the car- ] reduce, bonyl group of an amide to a methylene RCNR5 ——> RCH>NR$ group. Primary, secondary, or tertiary Amide Amine amines may be prepared by proper choice of the starting amide. R and R' may be 9? either alkyl or aryl. CHSCNHC(CHo)3 + ea CHaCHNHC(CH3) N-tert-Butylacetamide N-Ethyl-tert-butylamine (60%) Reductive amination (Section 22.11) Reac- o reducing NR tion of ammonia or an amine with an 1 m agent , aldehyde or a ketone in the presence of a RCRC + R$NH RCR reducing agent is an effective method for d the preparation of primary, secondary, or tertiary amines. The reducing agent may Aldehyde Ammonia or Amine be either hydrogen in the presence of a or ketone an amine metal catalyst or sodium cyanoborohy- NH> HNCH(CH3)> dride. R, R', and R” may be either alkyl or o El ] tia Pt CH;CCH; + 0, Acetone | Cyclohexylamine N-Isopropylcyclohexylamine (79%) Sections The reactions of amines are summarized in Tables 22.6 and 22.7. 22.12-22.19 Section 22.20 The N—H stretching frequency of primary and secondary amines appears in the infrared in the 3000-3500 cm”! region. In the NMR spectra of amines, protons and carbons of the type H—C—N are more shielded than H—C—O. ! —NH, ne ton N IN H 847 ppm 3 65 ppm [ HC ç H 538 ppm” B46 ppm” Amines have odd-numbered molecular weights, which helps identify them by mass spectrometry. Fragmentation tends to be controlled by the formation of a nitrogen-stabilized cation. e ll N 7 N —N—C—C— > 4N=C + c— Pl / No Back| Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 904 CHAPTER TWENTY-TWO — Amines 02hH5) Reactions of Amines Discussed in This Chapter Reaction (section) and comments General equation and specific example Alkylation (Section 22.13) Amines act as nucleophiles toward alkyl halides. Primary amines yield sec- ondary amines, secondary amines yield tertiary amines, and tertiary amines yield quaternary ammoni- um salts. R'CHX RNH, SD RNHCH;R' Primary amine Secondary amine | CHX R'CHX RN(CHOR);X- <SL RA(CHARY> Quaternary ammonium salt Tertiary amine = CHI + HN Es WVy 2-Chloromethylpyridine | Pyrrolidine 2-(Pyrrolidinylmethylpyridine (93%) Hofmann elimination (Section , heat , 22.14) Quaternary ammonium RCH>CHR' HO — RCH=CHR' + :N(CHs) + HO hydroxides undergo elimination *N(CH: on being heated. It is an anti elim- (Chada ination of the E2 type. The regio- Alkyltrimethylammonium Alkene Trimethylamine Water selectivity of the Hofmann elimi- hydroxide nation is opposite to that of the Zaitsev rule and leads to the less ' [Rea highly substituted alkene. N(CHa); HO => Cycloheptyltrimethylammonium Cycloheptene (87%) hydroxide Electrophilic aromatic substitution Arm + E —» ArE + Hº en a para lee A Arylamine — Electrophile Product of electrophilic Proton aromatic substitution. It is custom- aromatiosuusttution ary to protect arylamines as their NH> NH, N-acyl derivatives before carrying Br Br out ring nitration, chlorination, 2Br, bromination, sulfonation, or Frie- Ea del-Crafts reactions. NO> NO p-Nitroaniline 2,6-Dibromo-4-nitroaniline (95%) Nitrosation (Section 22.16) Nitro- NaNO;, + sation of amines occurs when RNHz H”, HO RN sodium nitrite is added to a solu- Primary amine Diazonium ion tion containing an amine and an acid. Primary amines yield alkyl NH, N=N diazonium salts. Alkyl diazonium NENO, HS04, SO. o salts are very unstable and yield “HO, 0-5 > Hso, carbocation-derived products. Aryl . diazonium salts are exceedingly useful synthetic intermediates. NO, Their reactions are described in m-Nitroaniline m-Nitrobenzenediazonium Table 22.7. hydrogen sulfate (Continued) Back) Forward] MainMenu) TOC] Study Guide TOC] StudentOLC| | MHHE Website Back| Problems 907 [NJH=PrMVA Synthetically Useful Transformations Involving Aryl Diazonium lons (Continued) Reaction and comments General equation and specific example Preparation of aryl nitriles Cop- per(l) cyanide converts aryl diazo- nium salts to aryl nitriles. Reductive deamination of primary arylamines The amino substituent of an arylamine can be replaced by hydrogen by treatment ofits derived diazonium salt with etha- nol or with hypophosphorous acid. 1. NaNO,, H,0. ArNH, — ArCN Primary Aryl nitrile arylamine NH> 1. NaNO,, HCI, 50. 1 NaNO» HC, HO, 2. CUCN NO, o-Nitroaniline O NO> o-Nitrobenzonitrile (87%) 1. NaNO;, Hº, HO ArNH> 5 cHscH,OH or HsPO; Primary arylamine CH CHs ArH Arene 1. NaNO,, HCI, 50. 2. HiPO, NO, NO, NH> 4-Methyl-2-nitroaniline m-Nitrotoluene (80%) PROBLEMS 22.21 Write structural formulas or build molecular models for all the amines of molecular formula C4HniN. Give an acceptable name for each one, and classify it as a primary, secondary, or tertiary 2 amine. 22.22 Provide a structural formula for each of the following compounds: (a) 2-Ethyl-I-butanamine (b) N-Ethyl-I-butanamine (c) Dibenzylamine (d) Tribenzylamine (e) Tetraethylammonium hydroxide () N-Allyleyclohexylamine (g) N-Allylpiperidine (h) Benzyl 2-aminopropanoate (i) 4-(N,N-Dimethylamino)cyclohexanone ()) 2,2-Dimethyl-1,3-propanediamine 22.23 Many naturally occurring nitrogen compounds and many nitrogen-containing drugs are bet- ter known by common names than by their systematic names. A few of these follow. Write a struc- tural formula for each one. (a) trans-2-Phenyleyclopropylamine, better known as tranyleypromine: an antidepressant drug Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 908 CHAPTER TWENTY-TWO — Amines (b) N-Benzyl-N-methyl-2-propynylamine, better known as pargyline: a drug used to treat high blood pressure (c) 1-Phenyl-2-propanamine, better known as amphetamine: a stimulant (d) 1-(m-Hydroxyphenyl)-2-(methylamino)ethanol: better known as phenylephrine: a nasal decongestant 22.24 (a) Give the structures or build molecular models and provide an acceptable name for all 2) the isomers of molecular formula C,HoN that contain a benzene ring. (b) Which one of these isomers is the strongest base? (c) Which, if any, of these isomers yield an N-nitroso amine on treatment with sodium nitrite and hydrochloric acid? (d) Which, if any, of these isomers undergo nitrosation of their benzene ring on treatment with sodium nitrite and hydrochloric acid? 22.25 Arrange the following compounds or anions in each group in order of decreasing basicity: (a) HC”, Nº, HO, F (b) HO, NHs, HO, HoN (0) HO”, HoN ,:C=NE NO; o o (a) NA. No. OD» o 22.26 Arrange the members of each group in order of decreasing basicity: (a) Ammonia, aniline, methylamine (b) Acetanilide, aniline, N-methylaniline (c) 2,4-Dichloroaniline, 2,4-dimethylaniline, 2,4- (d) 3,4-Dichloroaniline, 4-chloro-2-nitroaniline, 4-chloro-3-nitroaniline linitroaniline (e) Dimethylamine, diphenylamine, N-methylaniline 22.27 Physostigmine, an alkaloid obtained from a West African plant, is used in the treatment of glaucoma. Treatment of physostigmine with methyl iodide gives a quaternary ammonium salt. What is the structure of this salt? q ço NON OCNHCH, | Physostigmine 22.28 Describe procedures for preparing each of the following compounds, using ethanol as the source of all their carbon atoms. Once you prepare a compound, you need not repeat its synthe- sis in a subsequent part of this problem. (a) Ethylamine (b) N-Ethylacetamide E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website Problems 909 (c) Diethylamine (e) Triethylamine (d) N,N-Diethylacetamide (f) Tetraethylammonium bromide 22.29 Show by writing the appropriate sequence of equations how you could carry out each of the following transformations: (a) 1-Butanol to 1-pentanamine (b) tert-Butyl chloride to 2,2-dimethyl-1-propanamine (c) Cyclohexanol to N-methyleyclohexylamine (d) Isopropyl alcohol to 1-amino-2-methyl-2-propanol (e) Isopropyl alcohol to 1-amino-2-propanol (f) Isopropyl alcohol to 1-(N,N-dimethylamino)-2-propanol O. O (g) X to CoHs CH5 y CoHsCHCHs 22.30 Each of the following dihaloalkanes gives an N-(haloalkyl)phthalimide on reaction with one equivalent of the potassium salt of phthalimide, Write the structure of the phthalimide derivative formed in each case and explain the basis for your answer. (a) FCH;CH,Br (b) BrCH,CH:CH>CHCH; dr CH; (0) BrCH>CCH>CHoBr CH; 22.31 Give the structure of the expected product formed when benzylamine reacts with cach of the following reagents: (a) Hydrogen bromide (b) Sulfuric acid (c) Acetic acid (d) Acetyl chloride (e) Acetic anhydride (f) Acetone (g) Acetone and hydrogen (nickel catalyst) (h) Ethylene oxide () 1,2-Epoxypropane () Excess methyl iodide (k) Sodium nitrite in dilute hydrochloric acid 22.32 Write the structure of the product formed on reaction of aniline with each of the following: (a) Hydrogen bromide (b) Excess methyl iodide E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 912 CHAPTER TWENTY-TWO — Amines 2 22.36 Provide a reasonable explanation for cach of the following observations: (a) 4-Methylpiperidine has a higher boiling point than Nemethylpiperidine. nl aa, CHN > 4-Methylpiperidine | N-Methylpiperidine (bp 129º0) (bp 106º0) (b) Two isomeric quatenary ammonium salts are formed in comparable amounts when 4- tert-butyl-N-methyIpiperidine is treated with benzyl chloride. (Hint: Building a molec- ular model will help.) cH (een 4-tert-Butyl-N-methylpiperidine (c) When tetramethylammonium hydroxide is heated at 130ºC, trimethylamine and methanol are formed. (d) The major product formed on treatment of 1-propanamine with sodium nitrite in dilute hydrochloric acid is 2-propanol. 22.37 Give the structures, including stereochemistry, of compounds A through C. (8)-2-Octanol + cn Ssoa Pride, compound A NaN, methanol-water 1. LiAlHo Compound C <= Compound B 22.38 Devise efficient syntheses of each of the following compounds from the designated starting materials. You may also use any necessary organic or inorganic reagents. (a) 3,3-Dimethyl-1-butanamine from 1-bromo-2,2-dimethylpropane (b) CH» cucnnea—] from 10-undecenoic acid and pyrrolidine (e) Sm from CoHsO CHsO oH (d) Cos CHaNNCHaCH CH>CH;NH, from CoHsCH;NHCH; and BrCH,CH,CH CH; (8) no! Sense ftom no Sea, 22.39 Each of the following compounds has been prepared from p-nitroaniline. Outline a reason- able series of steps leading to cach one. (a) p-Nitrobenzonitrile (d) 3,5-Dibromoaniline (b) 3,4,5-Trichloroaniline (e) p-Acetamidophenol (aceraminophen) (c) 1,3-Dibromo-S-nitrobenzene E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website Problems 22.40 Each of the following compounds has been prepared from o-anisidine (o-methoxyaniline). Outline a series of steps leading to each one. (a) o-Bromoanisole (d) 3-Fluoro-4-methoxybenzonitrile (b) o-Fluoroanisole (e) 3-Fluoro-4-methoxyphenol (c) 3-Fluoro-4-methoxyacetophenone 22.41 Design syntheses of each of the following compounds from the indicated starting material and any necessary organic or inorganic reagents: (a) p-Aminobenzoic acid from p-methylaniline o I (b) p-FC;HuCCH>CH from benzene (c) 1-Bromo-2-fluoro-3,5-dimethylbenzene from m-xylene Br NH, CH; CH; o eo tom o F NO, (8) oBICHC(CH;); from p-O;NCH;C(CHa) () mCICHCCHo: from p-OsNCH,C(CHa)s (g) 1-Bromo-3,5-diethylbenzene from -m-diethylbenzene cr; CF; 1 nHtca, h) from Br 9 NH citdocn, | ve co 154) cH;O ON cH;O 22.42 Ammonia and amines undergo conjugate addition to c-unsaturated carbonyl compounds (Section 18.12). On the basis of this information, predict the principal organic product of each of the following reactions: | (a) (CH)C=CHCCH; + NH; —> b) (o + HN I TN (0) CHsCCH=CHCGH; + HN O— No E Forward Main Menul Toe] Study Guide TOC Student OLC 913 MHHE Website 914 CHAPTER TWENTY-TWO — Amines (d) O, CHNO (CH,) QUUCH)sCHs NH, 22.43 A number of compounds of the type represented by compound A were prepared for evalu- ation as potential analgesic drugs. Their preparation is described in a retrosynthetic format as DO | | | R R R Compound A RNH, + CH;=CHCO,CH,CH, €| RN(CH,CH;CO,CH,CH;)» On the basis of this retrosynthetic analysis, design a synthesis of N-methyl-4-phenylpiperidine (compound A, where R = CHs, R' = CsHs). Present your answer as a series of equations, show- ing all necessary reagents and isolated intermediates. 22.44 Mescaline, a hallucinogenic amine obtained from the peyote cactus, has been synthesized in two steps from 3,4,5-trimethoxybenzyl bromide. The first step is nucleophilic substitution by sodium cyanide. The second step is a lithium aluminum hydride reduction. What is the structure of mescaline? 22.45 Methamphetamine is a notorious street drug. One synthesis involves reductive amination of benzyl methyl ketone with methylamine. What is the structure of methamphetamine? 22.46 The basicity constants of N,N-dimethylaniline and pyridine are almost the same, whereas o 4(N,N-dimethylamino)pyridine is considerably more basic than either. N(CH;) N(CH3)» Í “= A N N.N-Dimethylaniline Pyridine 4(N.N-Dimethylamino )pyridine K, 13X 107º K,2X 10º K=5X 10 pk, 89 pk, 87 pk, 43 Identify the more basic of the two nitrogens of 4-(N, N-dimethylamino)pyridine, and suggest an explanation for its enhanced basicity as compared with pyridine and N,N-dimethylaniline. Refer to Leaming By Modeling and compare your prediction to one based on the calculated charge and electrostatic potential of cach nitrogen. 22.47 Compounds A and B are isomeric amines of molecular formula CsH,N. Identify cach iso- mer on the basis of the !H NMR spectra given in Figure 22.9. E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website