hapter 22: Amines. rganic derivatives of ammonia, 3. itrogen atom have a lone pair of electrons, making the amine both basic and nucleophilic 22.1: Amines omenclature. (please read) sp 3 Amines are classified according to the degree of nitrogen substitution: 1 ( 2 ), 2 ( 2 ), 3 ( 3 ) and 4 ( 4 ) 2 3 alkylamines arylamines 3 2 2 3 2 3 primary (1 ) amines secondary (2 ) amines tertiary (3 ) amines quarternary (4 ) ammonium ion ote: Although the terminology is the same, this classification of amines is different from that of alcohols. 203 22.2: Structure and bonding. The nitrogen of alkylamines is sp 3 hybridized and tetrahedral. The nitrogen of arylamines (aniline) is slightly flatten, reflecting resonance interactions with the aromatic ring. 204 104
In principle an amine with three different substituents on the nitrogen is chiral with the lone pair of electrons being the fourth substituent; however, for most amines the pyramidal inversion of nitrogen is a racemization mechanism. The barrier to nitrogen inversion is about 25 KJ/mol (very rapid at room temperature). 22.3: Physical Properties. (please read) 22.4: Basicity of Amines. The basicity is reflective of and is expressed as the pk a s of the conjugate acid. The conjugate base of a weak acid is a strong base: igher pk a = weaker acid = stronger conjugate base The conjugate base of a strong acid is a weak base Lower pk a = stronger acid = weaker conjugate base 205 Table 22.1 (p. 915): pk a values of ammonium ions Alkyl ammonium ions, 3 X -, have pka values in the range of 10-11 (ammonium ion, 4 X -, has a pk a ~ 9.3) The ammonium ions of aryl amines and heterocyclic aromatic amines are considerably more acidic than alkyl amines (pk a < 5). The nitrogen lone pair is less basic if it is in an sp 2 hybridized orbital (versus an sp 3 ) 4 pk a = 9.3 ( 3 2 ) 3 10.8 ( 3 2 ) 2 2 11.1 ( 3 2 ) 3 10.8 3 2 pk a = 4.6 5.2 0.4 7.0 3-1.0 206 105
Arylamines are much less basic than alkylamines. The lone pair of electrons on the nitrogen of aniline are conjugated to the π-electrons of the aromatic ring and are therefore less available for acid-base chemistry. Protonation disrupts the conjugation. Substitutents can greatly influence the basicity of the aniline. The effect is dependent upon the nature and position of the substitutent. 2 2 2 2 3 207 Electron-donating substituents (- 3, -, - 3 ) make the substituted aniline more basic than aniline itself (the pk a of the anilinium ion is higher than 4.6) Electron-withdrawing substituents (-l, - 2 ) make the substituted aniline less basic than aniline itself (the pka of the anilinium ion is lower than 4.6) Y 3 2 Y 2 3 Y= - 2 pk a = 6.2-3 pk a = 5.3-3 pk a = 5.1 - pk a = 4.6 -l pk a = 4.0 -F 3 pk a = 3.5 - pk a = 1.7-2 pk a = 1.0 less acidic (more basic) more acidic (less basic) 208 106
22.5: 4 Salts as Phase-Transfer atalysts (please reads) 22.6: eactions That Lead to Amines: A eview and Preview Formation of - bonds: a. ucleophilic substitution with azide ion (h. 8.1, 8.11) S 2 [] 2 X 2 2 2 1 amine b. itration of arenes (h. 12.3) 3 2 [] 2 2 S 4 1 arylamine c. ucleophilic ring opening of epoxides with 3 (h. 16.12) 2 S 2 209 d. eaction of amines with ketones and aldehydes (h. 17.10) 2 [] ketone or aldehyde e. ucleophilic substitution of α-halo acids with 3 (h. 19.16) ' Br S 2 2 2 2 ' 2 f. ucleophilic acyl substitution (h. 20.4, 20.5, 20.11) ' 2 ' l 2 2 [] ' 2 2 210 107
22.7: Preparation of Amines by Alkylation of Ammonia Ammonia and other alkylamines are good nucleophiles and react with 1 and 2 alkyl halides or tosylates via an S 2 reaction yielding alkyl amines. 1, 2, and 3 amines all have similar reactivity; the initially formed monoalkylation product can undergo further reaction to yield a mixture of alkylated products 211 22.8: The Gabriel Synthesis of Primary Alkylamines. reaction of potassium phthalimide with alkyl halides or tosylates via an S 2 reaction. The resulting -susbtituted phthalimide can be hydrolyzed with acid or base to a 1 amine. The Gabriel amine synthesis is a general method for the prepartion of 1 alkylamines (but not arylamines) 212 108
22.9: Preparation of Amines by eduction. Alkyl azides, nitriles, amides, and nitroarene can be reduced to the corresponding amines. LiAl 4 reduces alkyl azides to 1 amines LiAl 4, 2 X S 2 ether 2 2 2 then 2 1 amine LiAl 4 reduces nitriles to 1 amines LiAl 4, 2 X S 2 ether 2 2-2 2 then 2 1 amine LiAl 4 reduces amides to 1, 2 or 3 amines 1 2 1 l 2 3 LiAl 4, 1 2 ether 2 1 2 then 2 3 3 213 itroarenes are reduced to anilines 3 2 2, Pd/ 2 2 S 4 -or- Fe, l 1 arylamine 22.10: eduction Amination. Imines and iminium ions are easily reduced to amines. 3-2 2 / Pd/ 2 1 amine 3-phenyl-2-propanone (P2P) ammonia amphetamine 3 2-2 3 2 / Pd/ 3 2 amine 1 amine methamphetamine ( 3 ) 2-2 3 3 2 / Pd/ 3 3 3 amine 2 amine 214 109
Sodium cyanoborohydride, a -B 3 : the cyano ligand makes cyanoborohydride a weak hydride source and it will react with only the most easily reduced functional groups, such as an iminium ion. ab() 3 reduces ketones and aldehydes slowly. eductive amination with ab() 3 is a one-pot reaction 3-2 ab() 3 3 3 2 2 = ab() 3 2 3 215 22.11: eactions of Amines: A eview and a Preview. eaction of ammonia and 1 amines with aldehyde and ketones to afford imines (w/ loss of 2 ) (h. 17.10-17.11) ' 2 ' 2 eaction of 2 amines with aldehyde and ketones (w/ an α-proton) to afford an enamine (w/ loss of 2 ) (h. 19.16) ' ' ' ' 2 eaction of ammonia, 1, and 2 amines with acid chloride, anhydrides and esters to afford amides. (h. 20.4, 20.5, 20.11) X ' ' ' ' -X 216 110
22.12: eaction of Amines with Alkyl alides. Amines react with alkyl halides and tosylates by nucleophilic substitution (S 2 ). Products from multiple alkylation often results. 22.13: The offmann Elimination. 1 amine react with excess methyl iodide yield quarternary (4 ) ammonium salts. E2 elimination of the resulting trimethyl ammonium group to give an alkene. 2 ( 3 ) 3 - K o reaction ( 2 - is a very poor leaving group) 3 -I ( 3 ) 3 I - ( 3 ) 3 - K (major) (minor) 217 ofmann elimination gives the less substituted alkene, where E2 elimination of an alkyl halide or tosylate will follow Zaitsev rule to give the more substituted alkene Fig 22.4, p.933 218 111
22.14: Electrophilic Aromatic Substitution in Arylamines. The amino group is strongly activating, ortho/para director; however, it is largely incompatible with Friedel-rafts reactions. Electrophilic aromatic substitution of phenyl acetamides (amides of aniline). The acetamide group is still activating and an ortho/para director. 2 ( 3 3 ) 2, pyridine Br Br 2 3 a, 2 Br 2 3 3 The acetamides is acts as a protecting group for the arylamine Anilines are so activated that multiple substitution reactions can be a problem. The reactivity of the acetamide is attenuated so that mono substitution is achieved. The acetamide group is compatiable with the Friedel-rafts reactions 3 3 219 22.15: itrosation of Alkylamines. (please read) 22.16: itrosation of Arylamines. eaction of aniline with nitrous acid (a 2 ) leads to an aryl diazonium cation, which are value precursors to other functional groups. Aryl diazonium salts react with nucleophiles in a substitution reaction. 2 is one of the best leaving groups. u: u 220 112
22.17: Synthetic Transformations of Aryl Diazonium Salts. (Fig. 22.5, p. 938) X u 2, 2 ai BF 4 l, ul Br, ubr u() 3 P 2 I F l Br Sandmeyer reaction: promoted by u(i) salts Advantages of the aryl diazonium salt intermediate: 1) Introduces aryl substituents that are not otherwise accessible, such as -, -F, -I, and -. 221 Advantages of the aryl diazonium salt intermediate: 2) Allows preparation of substituted arenes with substitution patterns that can not be prepared by other means. Synthesis 3,5-dibromotoluene 3 3 Br Br Br 222 113
Synthesize 2-iodoethylbenzene from benzene: I 2 3 22.18: Azo oupling. (please read) 223 22.19: Spectroscopic Analysis of Amines. I: - stretches in the range of 3300-3500 cm -1 ; this is the same range as an - stretch, but - stretches are less intense. 3 ( 2 ) 4 2-2 3 2 2 2 2 3 -- 3 ( 2 ) 3 2-224 114
1 M: itrogen is less deshielding than oxygen. ydrogens on the carbon attached to the amino nitrogen have a typical chemical shift of δ 2.2-3.0-2 2 3 5, m 6 5-2 2 3 2, s Ph- 2 -- 3, t - 2-3 - 2 - - 2 2 3 2, q -- 2-3 1, s -- - 2 2 3-225 13 M: The resonances of carbon attached to a nitrogen of an amine are deshielded about 20 ppm downfield from those of an alkane. 128.3 128.0 140.6 126.8 2 2 3-2 2 3 64.3 43.7 54.0 15.3 25.9 10.3 Mass Spectrum: itrogen rule: small organic compounds with an odd number of nitrogen atoms have an odd mass; compounds with an even number of nitrogen atoms have an 226 even mass 115
9 13 [α] D 23 3.60 (1, dd, J= 10.7, 4.1) 3.38 (1, dd, J= 10.7, 7.0) 3.05-3.12 (1, m) 2.77 (1, dd, J= 13.3, 5.0) 2.49 (1, dd, J= 13.3, 8.8) 2.35-2.45 (3, br s) 7.21-7.32 (m, 2) 7.15-7.21 (m, 3) 13 M: 138.6, 129.1, 128.5, 126.3, 65.9, 54.2, 40.6 I: 227 116