1559T_ch21_373-38810/18/0518:42Pa9e373 EQA 21 Amines and Their Derivatives:Functional Groups Containing Nitrogen s that you will encounter in nic chemistry.The are not entirely new to you.of course.They p ane Mo ou have bee roduced to amin ine the erties of amines as a class of com pounds.It then fo cuses in more detail on the limitations and variatior on t mines are not involved in of disti nctly dif- ferent types of reactions.Thus.you should find this aspect of amine chemistry relatively manageable. Outline of the Chapter 21-1 Nomenclature 21z,213,2148cls2oeonndAcad8ae oup. 215,216,.2178ewdwg9mhicne 21-8 through 21-10 Reactions Mostly extensions of earlier material;a couple of special reactions.too. Keys to the Chapter 21-1.Nomenclature line-based name.The s nize that it works in much the same way that the IUPAC alcohol (alkanol)naming system works. 22hogh214epeaofAne 21-2 throu the same ess electronega- 373
21 Amines and Their Derivatives: Functional Groups Containing Nitrogen Amines represent the last of the simple functional groups that you will encounter in organic chemistry. They are not entirely new to you, of course. They popped up as early as Chapter 6, as the results of nucleophilic substitution reactions between ammonia and haloalkanes. More recently, you have been introduced to amine syntheses starting from carboxamides and nitriles (Sections 20-6 through 20-8). As usual, the chapter begins by presenting the usual body of descriptive information concerning the properties of amines as a class of compounds. It then focuses in more detail on the limitations and variations associated with several amine syntheses, finishing with sections on their reactions. Amines are of substantial importance biologically. But unlike other biologically important compound classes, amines are not involved in a very wide range of distinctly different types of reactions. Thus, you should find this aspect of amine chemistry relatively manageable. Outline of the Chapter 21-1 Nomenclature 21-2, 21-3, 21-4 Physical, Spectroscopic, and Acid-Base Properties of Amines Qualitative and quantitative characteristics of the functional group. 21-5, 21-6, 21-7 Synthesis Guidelines for choosing synthetic strategies. 21-8 through 21-10 Reactions Mostly extensions of earlier material; a couple of special reactions, too. Keys to the Chapter 21-1. Nomenclature To an even greater extent than with most other compounds, common names for amines are still almost universally used. It is therefore necessary to be able to recognize structures from either their alkylamine- or aniline-based name. The systematic alkanamine method looks tricky at first but becomes simple once you recognize that it works in much the same way that the IUPAC alcohol (alkanol) naming system works. 21-2 through 21-4. Properties of Amines Amines are related to alcohols in the same way that ammonia is related to water. This parallel makes the properties of amines easy to predict, because the main qualitative difference is simply that N is less electronega- 373 1559T_ch21_373-388 10/18/05 18:42 Page 373
1559Tch21373-38810/18/0518:42Page374 EQA 374.chapter 21 AMINES AND THEIR DERIVATIVES:FUNCTIONAL GROUPS CONTAINING NITROGEN gen b ling in ass spe tra are rather predictable.Tertiary amines (RaN)may be view ed as nitrogen analogs of ethers (R2O). alythe way the nice,tidy analog es do not ex he st s pos ost amines WI include na es like cadaverin putrescine,and skatole.D d be an improvem ia acids and st ger bases than are water of alcohols.Iw time 21-5,21-6,and 21-7.Synthesis muh bete of the peNongothve clea monoakyation prod which ed into ines.For simple systems sens ctional groups.all example.1.Ns 2.LiAH,would be a p poor choice for the conversion of Br(CH)COCH into the com sponding amine.because the ketone will reduced b oluliehydnid etone is a better way to make an amine at You've already seen how to make an amine with one more carbon by using S2 reaction with CN-.fol- owed W t would ou do.howe vel,n you laced you could add a carbo the wil be e thin one for awhile.You will find help in Section 19-6.The solution answer to roblen 21-8hr 21-10. Reaction important in s than anything els It is frequently combined with the Mannich reactio tumor agents he nitr Chapter 22.As you plowth nation and deprotonation.combined with elimination or addition. Solutions to Problems 24.(a)3-Hexanamine,3-aminohexane:(b)N-methyl-2-propanamine,2-(methylamino)propane isopropylmethylamine:(c)2-chlorobenzenamine.o-chloroaniline:
374 • Chapter 21 AMINES AND THEIR DERIVATIVES: FUNCTIONAL GROUPS CONTAINING NITROGEN tive than O. So, hydrogen bonding in amines is present, but it is weaker than in alcohols; deshielding of nearby 1 H and 13C NMR signals is observed but to a lesser extent than in alcohols; IR spectra are similar; mass spectra are rather predictable. Tertiary amines (R3N) may be viewed as nitrogen analogs of ethers (R2O). By the way, all these nice, tidy analogies do not extend to the smells possessed by most amines. Whereas alcohols tend to have, at worst, somewhat heavy, sweetish odors, amines, at best, smell like ammonia, and, at worst, richly deserve the common names that have been bestowed upon some of their representatives. These include names like cadaverine, putrescine, and skatole. Dead fish would be an improvement. The acid-base properties of amines are an extension of what you know about ammonia: They are weaker acids and stronger bases than are water or alcohols. It will repay you many times over, however, to go over the information involving pKa’s and pKb’s of these molecules. The qualitative ability to handle acid-base concepts is one of the more useful capabilities you can take out of a course in organic chemistry. 21-5, 21-6, and 21-7. Synthesis By the time you finish reading these sections of the text, you will be aware of the fact that the first amine synthesis you learned, alkylation of NH3 via SN2 reaction, is also generally the worst amine synthesis as well. It is much better to use any one of the special N-containing nucleophiles that give clean monoalkylation products, which can then be turned into amines. For simple systems lacking sensitive functional groups, all the methods will work comparably well. The choice becomes more critical if the molecule is more sensitive. For example, 1. N3 , 2. LiAlH4 would be a poor choice for the conversion of Br(CH2)3COCH3 into the corresponding amine, because the ketone will be reduced by the hydride reagent along with the azide group. The ketone could be protected before starting, but a better solution would be the Gabriel sequence, which involves hydrolysis instead of reduction in the second step. An important additional amine synthesis in this section is reductive amination of aldehydes and ketones. In particular, reductive amination of a ketone is a better way to make an amine attached to a 2° alkyl group than is SN2 reaction with a 2° haloalkane. You’ve already seen how to make an amine with one more carbon by using SN2 reaction with CN, followed by reduction. What would you do, however, if you faced the particularly nasty problem of needing to make an amine attached to a 3° alkyl group (R3CNH2)? That’s tricky, because SN2 reactions won’t work. If you could add a carbon somehow to get to R3CCONH2, then you would be all set to use one of the above rearrangements, right? O.K., think about that one for awhile. You will find help in Section 19-6. The solution will be given in the answer to Problem 35(b). 21-8 through 21-10. Reactions Beyond simple displacement reactions in which an amine behaves as a nucleophile, there is a small group of specialized reactions of amines, each of which has a very specific use. The Hofmann elimination has been more important in structure determination than anything else. It is frequently combined with the Mannich reaction, however, to make an important synthetic entry to cyclic carbonyl compounds with methylene groups next to the carbonyl (see Problem 46). Such structures are present in many naturally occurring (plant-derived) antitumor agents. The nitrosation reactions and the chemistry of diazoalkanes are also used in synthesizing just certain specific types of compounds, like cyclopropanes. The mechanisms here are more involved, however, and an understanding of their steps at this point is helpful because similar types of chemistry will be seen again later, in Chapter 22. As you plow through this, try to focus on the relationship of each mechanistic step to processes you’ve seen before. Almost all of this chemistry is based on relatively fundamental sorts of events, like protonation and deprotonation, combined with elimination or addition. Solutions to Problems 24. (a) 3-Hexanamine, 3-aminohexane; (b) N-methyl-2-propanamine, 2-(methylamino)propane, isopropylmethylamine; (c) 2-chlorobenzenamine, o-chloroaniline; 1559T_ch21_373-388 10/18/05 18:42 Page 374
1559T_ch21_373-38810/18/0521:02Pa9e375 EQA Solutions to Problems.375 (h)NN-diethy-propen-1-amine,3-(N.N-diethylamino)-1-propene N(CH3)2 25.(a) -CH,CH,NHCH,CH: NHz (c)HOCH,CH2NH2 26.(a)5-7 kcal mol-1 rctrons,respectively,are more stable when tgonal planar.They gain bond strengn by in the o b with eithe a singly occup in an unhybridized p orbital is quite unfavorable in the absence of oter Such electrons are far from and attracted only poorly by the atom's nucleus. N+1919Hs+ can be d ula fo each of these unknowns.Degrees of unsaturation (see Section 11-8):H16+2+1(for the N)=19: compounds are saturated A NMR: CH-C-ad一c,-cH-N 090 27023 Notice that the signal at=2.7 is not split by the-NH hydrogens (as is the case for alcohols as well). 2-NH.J B NMR (CH3)C- 2CH:-
Solutions to Problems • 375 (d) N-methyl-N-propylbenzenamine; N-methyl-N-propylaniline; (e) N,N-dimethylmethanamine (common: trimethylamine); N,N-dimethylaminomethane; (f) 4-(N,N-dimethylamino)-2-butanone (only satisfactory name); (g) 6-chloro-N-cyclopentyl-N,5-dimethyl-1-hexanamine (numbers refer to substituents on parent hexane chain); 1-chloro-6-(N-cyclopentyl-N-methylamino)-2-methylhexane; (h) N,N-diethyl-2-propen-1-amine, 3-(N,N-diethylamino)-1-propene 25. (a) (b) (c) HOCH2CH2NH2 (d) 26. (a) 5–7 kcal mol1 , approximately equal to Ea for inversion. (b) Methyl anion is isoelectronic with ammonia and, likewise, is tetrahedral (sp3 hybridized). Methyl radical and cation, with one and two fewer electrons, respectively, are more stable when trigonal planar. They gain bond strength by rehybridizing to use sp2 orbitals in the bonds, with either a singly occupied or vacant p orbital “left over.’’ The sp2 scheme is not as good for the anion or for the ammonia because two electrons in an unhybridized p orbital is quite unfavorable in the absence of other stabilizing influences: Such electrons are far from and attracted only poorly by the atom’s nucleus. 27. The odd atomic weights suggest that each contains a single nitrogen. The total number of hydrogens is available from the NMR, so the number of carbons can be determined by difference: m/z 129 14 (one N) 19 (19 H’s) weight of carbons. Weight of carbons 96 n 8 carbons; C8H19N is the formula for each of these unknowns. Degrees of unsaturation (see Section 11-8): Hsat 16 2 1 (for the N) 19; compounds are saturated. Notice that the signal at 2.7 is not split by the ONH2 hydrogens (as is the case for alcohols as well). The splittings nicely reveal the number of neighboring H’s. MS: m/z 30 for [CGH2ON .. H2 mn CH2PN G H2] fragment. All that remains is to insert C4H8, and the simplest way to do that is as CH3(CH2)7NH2 (1-octanamine). Other isomers would show additional methyl signals in the NMR near 0.9–1.0. Perhaps a CH2 and an NH2? (Signals at 1.3 and 1.4). MS: m/z 114 is [M CH3] , 72 is [M (CH3)3C], and 58 is most likely an iminium ion. Before guessing, notice that there are no NMR B NMR: (CH3)3C 1.0(s) Likely, 1.2 Also two equivalent methyl groups 2 CH3 , CH3 A NMR: 0.9(t) 2.7(t) 2.3 CH2 and CH2 CH2 NH2 NH2 Cl CH2CH2NHCH2CH3 N(CH3)2 1559T_ch21_373-388 10/18/05 21:02 Page 375
15597.ch21_373-38810/18/0518:42Pag0376 376.chapter 21 AMINES AND THEIR DERIVATIVES:FUNCTIONAL GROUPS CONTAINING NITROGEN ⊕ signals in the=2.7 region,where you might expect to find-C-N signals.So.most likely the N is attached to a tertiary carbon.Possible pieces: (CHa)aC- 2 CHa--CHz--C-NHz All atoms in the formula are present,so put it together CHa (CH):C-CH2-C-NHa The m/58 fragment therefore is [(CHa)C-NH2] 8.As you do each of these.keep the CHN formula in mind. (a)NMR:The 8=23.7 peak may correspond to one or more than one equivalenr CH-groups,and the peak at=45.3 is one or more equivalentCH-units(attached to N due to chemical -NH-.No other signals are present,so attach as many of each answe n. CH、 (d)NMR:One CHs-and five-CHz-'s.IR:Primary amine (-NH2).This is CH3(CH2)sNH2. one 38 7)attached to N. C attached molecule: 一waH,> 53.2 This is the answer
signals in the 2.7 region, where you might expect to find signals. So, most likely the N is attached to a tertiary carbon. Possible pieces: A (CH3)3CO 2 CH3O OCH2O OCONH2 A All atoms in the formula are present, so put it together CH3 A (CH3)3COCH2OCONH2 A CH3 The m/z 58 fragment therefore is [(CH3)2CPNH2] . 28. As you do each of these, keep the C6H15N formula in mind. (a) NMR: The 23.7 peak may correspond to one or more than one equivalent CH3O groups, and the peak at 45.3 is one or more equivalent units (attached to N due to chemical shift). IR: A secondary amine, ONHO. No other signals are present, so attach as many of each as are necessary. The answer is (b) NMR: Now you have only CH3O and OCH2O groups (the latter attached to N); IR: A tertiary amine. So, the answer is (CH3CH2)3N. (c) NMR: CH3O groups, OCH2O groups not attached to N, and OCH2O groups that are attached to N. IR: Amine is secondary. So the answer is CH3CH2CH2NHCH2CH2CH3. (d) NMR: One CH3O and five OCH2O’s. IR: Primary amine (ONH2). This is CH3(CH2)5NH2. (e) NMR: Two different CH3O types, one ( 38.7) attached to N; also a quaternary C attached to N ( 53.2). IR: A tertiary amine. Remembering the C6H15N formula, you can construct the molecule: 29. Figure 21-5 is (CH3CH2)3N for comparison purposes. Look in each case for important fragments from CO† CON cleavage to make iminium ions. (a) m/z 72 is important, which is [M 29] or loss of CH3CH2O. The only amine that should easily lose an ethyl group from those in Problem 28 is CH3CH2O† CH2ONHOCH2CH2CH3 [see (c)]. This is the answer. 25.6 (CH3)3C 53.2 N 38.7 CH3 CH3 CH3 CH N H CH CH3 CH3 CH3 CH H C N 376 • Chapter 21 AMINES AND THEIR DERIVATIVES: FUNCTIONAL GROUPS CONTAINING NITROGEN 1559T_ch21_373-388 10/18/05 18:42 Page 376
1559T_ch21_373-38810/18/0521:06Pa9e377 ⊕ EQA Solutions to Problems.377 the loss s in Problet because its MS (Figure 21-5)docsn't match.Them58 peak is loss of 43.or C.That's casy to visualize from(a):(CH3)2CH--NF CH(CH3)2 (the correct answer),but not from amine (e). 30.The base in question(call it"B")is stronger.If its conjugate acid (BH)has a high pKthen that acid is weak;consequently,its corresponding conjugate base is strong.Here's the equation B +B*一BH*+B songer base (stronger acid 31.(a)To the left.NHs andOH are weaker acids and bases.respectively,than are H2O and NH2- (b)To the left.CHaNH2 is a weaker base thanOH,and H2O is a weaker acid than CHaNH3' (e)To the right.CHaNH2 is a stronger base (see textbook Section 21-4)than (CHa)N. 32.(a)Weaker bases because lone pair onN is"tied up"by resonance 0°1 0 0-1 (b)Same as carboxamides,only to a greater extent for both acidity and basicity due to the two carbonyl groups. (c)Somewhat weaker bases because of resonance 一- Not acidic,because of lack of H'sn nitrogen. (d)Weaker bases and stronger acids,for the same reasons given in (a)for carboxamides 33.Protonatea doubly bonded nitrogen stabilized cation a-ah-a DBN-derived(ti rm
Solutions to Problems • 377 (b) m/z 86 is rather large, corresponding to the loss of CH3O. Three amines in Problem 28 should lose CH3O easily: (a), (b), and (e). N,N-Diethylethanamine [(triethylamine, b)] is ruled out because its MS (Figure 21-5) doesn’t match. The m/z 58 peak is loss of 43, or C3H7. That’s easy to visualize from (a): (CH3)2CHO† NHOCH(CH3)2 (the correct answer), but not from amine (e). 30. The base in question (call it “B1 :”) is stronger. If its conjugate acid (B1 H) has a high pKa, then that acid is weak; consequently, its corresponding conjugate base is strong. Here’s the equation: 31. (a) To the left. NH3 and OH are weaker acids and bases, respectively, than are H2O and NH2 . (b) To the left. CH3NH2 is a weaker base than OH, and H2O is a weaker acid than CH3NH3 . (c) To the right. CH3NH2 is a stronger base (see textbook Section 21-4) than (CH3)3N. 32. (a) Weaker bases because lone pair on N is “tied up” by resonance: Stronger acids because the conjugate base is stabilized by both the inductive effect of the carbonyl group and by resonance: (b) Same as carboxamides, only to a greater extent for both acidity and basicity due to the two carbonyl groups. (c) Somewhat weaker bases because of resonance: Not acidic, because of lack of H’s on nitrogen. (d) Weaker bases and stronger acids, for the same reasons given in (a) for carboxamides. 33. Protonate a doubly bonded nitrogen in each case to get a resonance stabilized cation. N NH N N H N DBN-derived cation (cation from DBU is similar) N H CCN CCN RC O RCNH2 O H RC NH O NH RC O NH2 RC O NH2 B1 B2 H stronger base B2 (stronger acid) (weaker base) B1 H weaker acid (higher pKa) 1559T_ch21_373-388 10/18/05 21:06 Page 377