Chapter 21: Amines. Organic derivatives of ammonia, NH3. Nitrogen atoms have a lone pair of electrons, making the amine both basic and nucleophilic 21.1: Amines Nomenclature. (please read) H H N C N H H sp3 alkylamines arylamines Amines are classified according to the degree of nitrogen + substitution: 1° (RNH2), 2° (R2NH), 3° (R3N) and 4° (R4N ) NH2 H H3CH2C CH2CH3 N H3C N N N N H H CH2CH3 H primary (1°) amines secondary (2°) amines tertiary (3°) amines quarternary (4°) ammonium ion Note: Although the terminology is the same, the classification of amines is different from that of alcohols. 223 21.2: Structure and bonding. The nitrogen of alkylamines is sp3 hybridized and tetrahedral. The nitrogen of arylamines (aniline) is slightly flatten, reflecting resonance interactions with the aromatic ring. 224 112 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). 21.3: Physical Properties. (please read) 21.4: Basicity of Amines. The basicity is reflective of and is expressed as the pKa of the conjugate acid. The conjugate base of a weak acid is a strong base: Higher pKa = weaker acid = stronger conjugate base The conjugate base of a strong acid is a weak base 225 Lower pKa = stronger acid = weaker conjugate base Table 21.1 (p. 964): pKa values of ammonium ions + - Alkyl ammonium ions, R3NH X , have pKa values in the range of + - 10-11 (ammonium ion, H4N X , has a pKa ~ 9.3) The ammonium ions of aryl amines and heterocyclic aromatic amines are considerably more acidic than alkyl amines (pKa < 5). The nitrogen lone pair is less basic if it is in an sp2 hybridized orbital (versus an sp3) NH3 pKa = 4.6 + NH4 pKa= 9.3 + N H 5.2 (H3CH2C)NH3 10.8 (H CH C) NH + 11.1 H 3 2 2 2 N H 0.4 + (H3CH2C)3NH 10.8 H N N H 6.9 NH 2 7.0 O - 1.0 NH3 226 113 Arylamines are 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. NH NH2 NH NH2 2 2 NH2 R R R R R 227 Electron-donating substituents (-CH3, -OH, -OCH3) make the substituted aniline more basic than aniline itself (the pKa of the substituted anilinium ion is higher than 4.6) Electron-withdrawing substituents (-Cl, -NO2) make the substituted aniline less basic than aniline itself (the pKa of the substituted anilinium ion is lower than 4.6) + + Y NH2 + H3O Y NH3 + H2O Y= -NH2 pKa= 6.2 less acidic -OCH3 pKa= 5.3 (more basic) -CH pK = 5.1 3 a -H pKa= 4.6 -Cl pKa= 4.0 more acidic -CF3 pKa= 3.5 (less basic) -CN pKa= 1.7 -NO2 pKa= 1.0 228 114 21.5: Tetraalkylammonium Salts as Phase-Transfer Catalysts (please reads) 21.6: Reactions That Lead to Amines: A Review and Preview Formation of C–N bonds (Table 21.3, p. 871): a. Nucleophilic substitution with azide ion (Ch. 8.1, 8.10) 2 [H] SN + RH2C N N N RH2C NH2 RH2C X N N N 1° amine b. Nitration of arenes (Ch. 12.3) NH NO2 2 HNO3 [H] H2SO4 R R R 1° arylamine c. Nucleophilic ring opening of epoxides with NH3 (Ch. 16.11) 2 R OH O SN + R2NH N R 229 d. Reaction of amines with ketones and aldehydes (Ch. 17.10 - 17.11) R [H] R O N HN + RNH2 H ketone or aldehyde d. Nucleophilic substitution of α-halo acids with NH3 (Ch. 20.1) Br 2 R N SN 2 + R NH R' C CO2H 2 R' C CO2H H H f. Nucleophilic acyl substitution (Ch. 19.4, 19.5, 19.10) O R2NH O [H] R'H C NR2 R'CO2H C C 2 R' Cl R NR2 230 115 21.7: Preparation of Amines by Alkylation of Ammonia Ammonia and other alkylamines are good nucleophiles and react 2 with 1° and 2° alkyl halides or tosylates via an SN reaction yielding alkyl amines. (2 equiv) 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. 231 21.8: The Gabriel Synthesis of Primary Alkylamines. Reaction of potassium phthalimide with alkyl halides or tosylates 2 via an SN reaction. The resulting N-susbtituted phthalimide can be hydrolyzed with acid or base to a 1° amine. The Gabriel amine synthesis is a general method for the preparation of 1° alkylamines (but not anilines) 232 116 21.9: Preparation of Amines by Reduction. Alkyl azides, nitriles, amides, and nitroarene can be reduced to the corresponding amines. LiAlH4 reduces alkyl azides to 1° amines LiAlHLiAl4H, 4THF;, 2 ether SN then H2O RH C N N N RH C NH RH C X + N N N 2 - or - 2 2 2 then H2O H2, Pt 1° amine LiAlH4 reduces nitriles to 1° amines LiAlH4, 2 ether SN RH C X + C N RH2C C N RH2C-H2C NH2 2 then H2O 1° amine Nitroarenes are reduced to anilines NH NO2 2 HNO3 H2, Pd/C -or- H SO R R 2 4 R Fe, HCl 1° arylamine 233 LiAlH4 reduces amides to 1°, 2° or 3° amines (mechanism 21.1, p. 877) R R 2 3 O LiAlH4, O N R2 H C R ether R N 2 R H C N R1CO2H C 1 1 2 R1 Cl then H2O R R3 3 21.10: Reductive Amination. Imines and iminium ions are easily reduced to amines. O -H O H / Pd/C 2 NH 2 NH2 + H3N 1° amine H 3-phenyl-2-propanone (P2P) ammonia amphetamine CH CH3 3 O -H O N H2/ Pd/C HN 2 2° amine + H3CNH2 H 1° amine methamphetamine H3C + CH3 CH3 O N H3C N H -H2O H2/ Pd/C + (H3C)2NH 3° amine 2° amine 234 117 + – Sodium cyanoborohydride, Na N≡C-BH3 : 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. NaB(CN)H3 reduces ketones and aldehydes slowly. Reductive amination with NaB(CN)H3 is a one-pot reaction H H CHO NaB(CN)H3 + H C-NH N N 3 2 C CH C CH3 3 H H H H H N N NH2 NaB(CN)H C CH 3 CH2 3 + H2C=O H H 235 21.11: Reactions of Amines: A Review and a Preview. Table 21.4, p. 880 Reaction of ammonia and 1° amines with aldehyde and ketones to afford imines (w/ loss of H2O) (Ch. 17.10) O R' + R'NH2 N C + H2O R R C R R Reaction of 2° amines with aldehyde and ketones (w/ an α-proton) to afford an enamine (w/ loss of H2O) (Ch. 17.11) R' R' O N R C R' R' R + N R C + H O H R 2 H H H Reaction of ammonia, 1°, and 2° amines with acid chloride, Anhydrides, and esters to afford amides. (Ch. 19.4) O R' R' O C + N C R' R X H R N + H-X R' 236 118 21.12: Reaction of Amines with Alkyl Halides. Amines react 2 with alkyl halides and tosylates by nucleophilic substitution (SN ). Products from multiple alkylation often results. 21.13: The Hoffmann Elimination. 1° amine react with excess methyl iodide yielding quarternary (4°) ammonium salts. E2 elimination of the resulting trimethyl ammonium group gives an alkene. NH2 - + - + (H3C)3CO K No reaction (H2N is a very poor leaving group) Ag2O" H3C-I I- Δ N(CH3)3 - + + + (H3C)3CO K 237 (major) (minor) Hofmann 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 21.5, p. 883 238 119 21.14: Electrophilic Aromatic Substitution in Arylamines. The amino group is a strongly activating, ortho/para director; however, it is largely incompatible with Friedel-Crafts reactions. Electrophilic aromatic substitution of phenyl acetamides (amides of aniline): The acetamide group is still activating and an ortho/para director. O O NH NH2 2 HN CH3 HN CH3 (H3CCO)2O, Br pyridine Br Br 2 NaOH, H2O CH CH3 3 CH3 CH3 The acetamides 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 compatable with Friedel-Crafts reactions. 239 21.15: Nitrosation of Alkylamines. (please read) 22.16: Nitrosation of Arylamines. Reaction of aniline with + nitrous acid (NaNO2 + H → HONO) leads to an aryl diazonium cation, which are value precursors to other functional groups. Aryl diazonium salts react with nucleophiles in a substitution reaction. N2 is one of the best leaving groups. N N Nu + Nu: + N N 240 120 21.17: Synthetic Transformations of Aryl Diazonium Salts. (Fig. 21.6, p. 888) N X N H O, Δ CuCl CuBr 2 KI HBF Cu(CN) H3PO2 (CuO) 4 (HCl) (HBr) OH I F Cl Br CN H Sandmeyer reaction: promoted by Cu(I) salts 241 Advantages of the aryl diazonium salt intermediate: 1) Introduces aryl substituents that are not otherwise accessible, such as -OH, -F, -I, and -CN.