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 C6H5NHCCH 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 NH2 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 p-nitroaniline; he wever, it is 10a s just noted, aniline is 3800 times as strong a base 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 queous 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 mi lion times less basic than piperidine is more basic than Pyridine (Kb=1.6×10-3;pKb=2.8) (Kb=1.4×10-;pKb=8.8) Imidazole and its derivatives form an interesting and important class of hetero- aoole were cyclic aromatic amines. Imidazole is approximately 100 times more basic than pyridine wo of the heter Protonation of imidazole yields an ion that is stabilized by the electron delocalization represented in the resonance structures shown in Section 11.2 H Imidazole Imidazolium ion (K,=1×10-;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 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
868 CHAPTER TWENTY-TWO Amines PROBLEM 22.8 Each of the following is a much weaker base than aniline. Present a resonance argument to explain the effect of the substituent in each case. (a) o-Cyanoaniline (c) p-Aminoacetophenone (b) 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. 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 109 times more basic than 2,4-dinitroaniline. A practical consequence of this is that arylamines that bear two or more strongly electron-withdrawing groups are often not capable of being extracted from ether solution into dilute aqueous acid. Nonaromatic heterocyclic compounds, piperidine, for example, are similar in basicity to alkylamines. When nitrogen is part of an aromatic ring, however, its basicity decreases markedly. Pyridine, for example, resembles arylamines in being almost 1 million times less basic than piperidine. Imidazole and its derivatives form an interesting and important class of heterocyclic 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: 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. H N N Imidazole (Kb 1 107 ; pKb 7) N H H N H N H N Imidazolium ion H H N Piperidine (Kb 1.6 103 ; pKb 2.8) Pyridine (Kb 1.4 109 ; pKb 8.8) N is more basic than NH2 N C C NH2 N C6H5NHCCH3 O Pyridine and imidazole were two of the heterocyclic aromatic compounds described in Section 11.21. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
22.5 Basicity of Amines AMINES AS NATURAL PRODUCTS The ease with which amines are extracted into aque. erties led amines obtained from plants to be called ous acid, combined with their regeneration on treat- alkaloids. The number of known alkaloids exceeds ment with base, makes it a simple matter to separate 5000. They are of special interest because most are amines from other plant materials, and nitrogen- characterized by a high level of biological activity containing natural products were among the earliest Some examples include cocaine, coniine, and mor organic compounds to be studied. their basic prop- phine. N CH H Coniine orpine (A central nervous system (Present along with other (An m alkaloid. Although it is an excellent stimulant obtained from the leaves of the coca plant extract used to poison potential for addiction. heroin is diacetate ester of morphine.) Many alkaloids, such as nicotine and quinine, of a substituted quinoline and pyridine ring, respec- highlighted in yellow in quinine and nicotine are part tively contain two(or more)nitrogen atoms. The nitrogens tively CH3O H (Alkaloid of cinchona bark (An alkaloid present in tobacco used to treat malaria a very toxic compound sometimes ed as an insecticide Several naturally occurring amines mediate the and serotonin. (Strictly speaking, these compounds transmission of nerve impulses and are referred to as are not classified as alkaloids, because they are not neurotransmitters. Two examples are epinephrine isolated from plants. The isolation of alkaloids from plants is reviewed in the august 1991 issue of the Journal of Chemical Education, pp. 700-703 Cont Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
22.5 Basicity of Amines 869 AMINES AS NATURAL PRODUCTS The ease with which amines are extracted into aqueous acid, combined with their regeneration on treatment with base, makes it a simple matter to separate amines from other plant materials, and nitrogencontaining natural products were among the earliest organic compounds to be studied.* Their basic properties 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 morphine. Many alkaloids, such as nicotine and quinine, contain two (or more) nitrogen atoms. The nitrogens highlighted in yellow in quinine and nicotine are part of a substituted quinoline and pyridine ring, respectively. CH3 N C O OCH3 OCC6H5 O Cocaine (A central nervous system stimulant obtained from the leaves of the coca plant.) N CH2CH2CH3 H Coniine (Present along with other alkaloids in the hemlock extract used to poison Socrates.) HO HO NCH3 O H 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.) Several naturally occurring amines mediate the transmission of nerve impulses and are referred to as neurotransmitters. Two examples are epinephrine and serotonin. (Strictly speaking, these compounds are not classified as alkaloids, because they are not isolated from plants.) CH3O H N N H HO Quinine (Alkaloid of cinchona bark used to treat malaria) N N CH3 Nicotine (An alkaloid present in tobacco; a very toxic compound sometimes used as an insecticide) —Cont. * The isolation of alkaloids from plants is reviewed in the August 1991 issue of the Journal of Chemical Education, pp. 700–703. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-TWo Amines CH2 CH2NH2 Epinephrine (Also called adrenaline: a (a hormone synthesized in ormone se adrenal gland that prepare mental dis he organism for "flight or lieved to b Bioactive amines are also widespread in ani- painkiller isolated from the skin of an Ecuadoran frog mals. a variety of structures and properties have been Another family of frogs produces a toxic mixture of found in substances isolated from frogs for example. several stereoisomeric amines, called dendrobine, on One, called epibatidine, is a naturally occurring their skin that protects them from attack (Once used as an arro (lsolated from frogs of the it is hundreds of ti Dendrobatidae family Related powerful than mor compounds have also been relieving pain. It is to isolated from certain ants Among the more important amine derivatives as polyamines, which contain two to four nitrogen bund in the body are a group of compounds known atoms separated by several methylene units HN H2N H2N These compounds are present in almost all mam- spectively, in body fluids. Structural studies suggest malian cells, where they are believed to be involved that these polyammonium ions affect the conforma- in cell differentiation and proliferation. Because each tion of biological macromolecules by electrostatic nitrogen of a polyamine is protonated at physiologi- binding to specific anionic sites-the negatively cal pH (7. 4), putrescine, spermidine, and spermine ex- charged phosphate groups of dNa, for example ist as cations with a charge of 2, +3, and+ 4, re- Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
870 CHAPTER TWENTY-TWO Amines Bioactive amines are also widespread in animals. A variety of structures and properties have been found in substances isolated from frogs, for example. One, called epibatidine, is a naturally occurring painkiller isolated from the skin of an Ecuadoran frog. Another family of frogs produces a toxic mixture of several stereoisomeric amines, called dendrobines, on their skin that protects them from attack. Among the more important amine derivatives found in the body are a group of compounds known as polyamines, which contain two to four nitrogen atoms separated by several methylene units: These compounds are present in almost all mammalian cells, where they are believed to be involved in cell differentiation and proliferation. Because each nitrogen of a polyamine is protonated at physiological pH (7.4), putrescine, spermidine, and spermine exist as cations with a charge of 2, 3, and 4, respectively, in body fluids. Structural studies suggest that these polyammonium ions affect the conformation of biological macromolecules by electrostatic binding to specific anionic sites—the negatively charged phosphate groups of DNA, for example. Dendrobine (Isolated from frogs of the Dendrobatidae family. Related compounds have also been isolated from certain ants.) N H H H N Cl HN Epibatidine (Once used as an arrow poison, it is hundreds of times more powerful than morphine in relieving pain. It is too toxic to be used as a drug, however.) H2N NH2 Putrescine H N H2N NH2 Spermidine H N NH2 H2N N H Spermine H C HO HO CH2NHCH3 OH Epinephrine (Also called adrenaline; a hormone secreted by the adrenal gland that prepares the organism for “flight or fight.”) HO CH2CH2NH2 N H Serotonin (A hormone synthesized in the pineal gland. Certain mental disorders are believed to be related to serotonin levels in the brain.) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
22.6 Tetraalkylammonium Salts as Phase- Transfer Catalysts 22.6 TETRAALKYLAMMONIUM SALTS AS PHASE-TRANSFER CATALYSTS In spite of being ionic, many quaternary ammonium salts dissolve in nonpolar media The four alkyl groups attached to nitrogen shield its positive charge and impart lipophile character to the tetraalkylammonium ion. The following two quaternary ammonium salts, for example, are soluble in solvents of low polarity such as benzene, decane, and halo- genated hydrocarbons CH3N(CH, CH, CH,CH,CH,CH,CH, CH3)3 CI CH,N(CH, CH3)3 Cl Methyltrioctylammonium chloride Benzyltriethy lammonium chloride This property of quaternary ammonium salts is used to advantage in an experi mental technique known as phase-transfer catalysis. Imagine that you wish to carry out the reaction CH3 CH,CH,CH,Br CH3 CH, CH,CH,CN NaBr Butyl bromide Pentanenitrile Sodium Sodium cyanide does not dissolve in butyl bromide. The two reactants contact each other only at the surface of the solid sodium cyanide, and the rate of reaction under these con- ditions is too slow to be of synthetic value. Dissolving the sodium cyanide in water is of little help, since butyl bromide is not soluble in water and reaction can occur only at the interface between the two phases. Adding a small amount of benzyltrimethylammo nium chloride, however, causes pentanenitrile to form rapidly even at room temperature The quaternary ammonium salt is acting as a catalyst; it increases the reaction rate. How? Quaternary ammonium salts catalyze the reaction between an anion and an organic ubstrate by transferring the anion from the aqueous phase, where it cannot contact the substrate, to the organic phase. In the example just cited, the first step occurs in the aque ous phase and is an exchange of the anionic partner of the quaternary ammonium salt for cyanide ion CHS CHN(CH3)3 CI+ Cn F C6H5CH2N(CH3)3 CN+ CI Benzyltrimethylammot Cyanide Benzyltrimethylammonium Chloride chloride yanide The benzyltrimethylammonium ion migrates to the butyl bromide phase, carrying a cyanide ion along with it. C6HS CH,N(CH3)3 CN F CHs CH,N(CH3)3 CN Benzyltrimethy lar cyanide (aqueous (in butyl bromide) Once in the organic phase, cyanide ion is only weakly solvated and is far more reactive than it is in water or ethanol, where it is strongly solvated by hydrogen bonding. Nucle- ophilic substitution takes place rapidly Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
22.6 TETRAALKYLAMMONIUM SALTS AS PHASE-TRANSFER CATALYSTS In spite of being ionic, many quaternary ammonium salts dissolve in nonpolar media. The four alkyl groups attached to nitrogen shield its positive charge and impart lipophilic character to the tetraalkylammonium ion. The following two quaternary ammonium salts, for example, are soluble in solvents of low polarity such as benzene, decane, and halogenated hydrocarbons: This property of quaternary ammonium salts is used to advantage in an experimental technique known as phase-transfer catalysis. Imagine that you wish to carry out the reaction Sodium cyanide does not dissolve in butyl bromide. The two reactants contact each other only at the surface of the solid sodium cyanide, and the rate of reaction under these conditions is too slow to be of synthetic value. Dissolving the sodium cyanide in water is of little help, since butyl bromide is not soluble in water and reaction can occur only at the interface between the two phases. Adding a small amount of benzyltrimethylammonium chloride, however, causes pentanenitrile to form rapidly even at room temperature. The quaternary ammonium salt is acting as a catalyst; it increases the reaction rate. How? Quaternary ammonium salts catalyze the reaction between an anion and an organic substrate by transferring the anion from the aqueous phase, where it cannot contact the substrate, to the organic phase. In the example just cited, the first step occurs in the aqueous phase and is an exchange of the anionic partner of the quaternary ammonium salt for cyanide ion: The benzyltrimethylammonium ion migrates to the butyl bromide phase, carrying a cyanide ion along with it. Once in the organic phase, cyanide ion is only weakly solvated and is far more reactive than it is in water or ethanol, where it is strongly solvated by hydrogen bonding. Nucleophilic substitution takes place rapidly. Benzyltrimethylammonium cyanide (aqueous) CN C6H5CH2N(CH3)3 Benzyltrimethylammonium cyanide (in butyl bromide) CN C6H5CH2N(CH3)3 fast CN Cyanide ion (aqueous) Cl Chloride ion (aqueous) Benzyltrimethylammonium chloride (aqueous) Cl C6H5CH2N(CH3)3 Benzyltrimethylammonium cyanide (aqueous) CN C6H5CH2N(CH3)3 fast CH3CH2CH2CH2Br Butyl bromide CH3CH2CH2CH2CN Pentanenitrile NaCN Sodium cyanide NaBr Sodium bromide CH3N(CH2CH2CH2CH2CH2CH2CH2CH3)3 Cl Methyltrioctylammonium chloride CH2N(CH2CH3)3 Cl Benzyltriethylammonium chloride 22.6 Tetraalkylammonium Salts as Phase-Transfer Catalysts 871 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-TWo Amines CH3,CH,CH2 Br+ C6HsCH,N(CH3)3CN-> Butyl bromide Benzyltrimethylammonium cyanide (in butyl bromide) CH3CH, CH,CH,CN C6HS CH,N(CH3)3 Br (in butyl bromide) (in butyl bromide) The benzyltrimethylammonium bromide formed in this step returns to the aqueous phase, where it can repeat the cycle Phase-transfer catalysis is the Phase-transfer catalysis succeeds for two reasons. First, it provides a mechanism ubject 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' already seen phase-transfer catalysis in another form in Section 16. 4, where the metal- ludes examples of a varie complexing properties of crown ethers were described. Crown ethers permit metal f reactions carried out un- to dissolve in nonpolar solvents by surrounding the cation with a lipophilic cloak, der phase-transfer condi ing the anion free to react without the encumbrance of strong solvation force 22.7 REACTIONS THAT LEAD TO AMINES: A REVIEW AND A PREVIEW Methods for preparing amines address either or both of the following questions l. 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 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 princi at you've already learned. You will 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+2NH3一>RNH2+NH4X Alkyl Primary Ammonium 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 expected primary amine product is itself a nucleophile and competes with ammonia the alkyl halide Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The benzyltrimethylammonium bromide formed in this step returns to the aqueous phase, where it can repeat the cycle. Phase-transfer catalysis succeeds for two reasons. First, it provides a mechanism for introducing an anion into the medium that contains the reactive substrate. More important, the anion is introduced in a weakly solvated, highly reactive state. You’ve already seen phase-transfer catalysis in another form in Section 16.4, where the metalcomplexing properties of crown ethers were described. Crown ethers permit metal salts to dissolve in nonpolar solvents by surrounding the cation with a lipophilic cloak, leaving 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 -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 procedures are described in the following sections, you will see that they are largely applications 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. Although this reaction is useful for preparing -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. RX Alkyl halide RNH2 Primary amine 2NH3 Ammonia NH4 X Ammonium halide salt Benzyltrimethylammonium bromide (in butyl bromide) Br C6H5CH2N(CH3)3 Benzyltrimethylammonium cyanide (in butyl bromide) CN C6H5CH2N(CH3)3 CH3CH2CH2CH2Br Butyl bromide CH3CH2CH2CH2CN Pentanenitrile (in butyl bromide) 872 CHAPTER TWENTY-TWO Amines Phase-transfer catalysis is the subject of an article in the April 1978 issue of the Journal of Chemical Education (pp. 235–238). This article includes examples of a variety of reactions carried out under phase-transfer conditions. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website