Chapter 21: . Organic derivatives of , NH3. have a of , making the 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 CH CH H H H 2 3 primary (1°) amines secondary (2°) amines tertiary (3°) amines quarternary (4°)

Note: Although the terminology is the same, the classification of amines is different from that of . 223

21.2: Structure and bonding. The nitrogen of alkylamines is sp3 hybridized and tetrahedral.

The nitrogen of arylamines () is slightly flatten, reflecting interactions with the aromatic ring.


112 In principle an amine with three different on the nitrogen is chiral with the lone pair of electrons being the fourth ; however, for most amines the pyramidal inversion of nitrogen is a racemization mechanism. The barrier to 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 .

The conjugate of a weak acid is a strong base:

Higher pKa = weaker acid = stronger conjugate base The conjugate base of a strong acid is a 225 Lower pKa = stronger acid = weaker conjugate base

Table 21.1 (p. 964): pKa values of ammonium

+ - 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 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 . 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



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) -CH3 pKa= 5.1 -H pK = 4.6 a -Cl pKa= 4.0 more acidic -CF3 pKa= 3.5 (less basic) -CN pKa= 1.7 -NO2 pKa= 1.0


114 21.5: Tetraalkylammonium as -Transfer Catalysts (please reads) 21.6: Reactions That to Amines: A Review and Preview Formation of C–N bonds (Table 21.3, p. 871): a. Nucleophilic substitution with ion (Ch. 8.1, 8.10)

2 [H] SN + RH2C N N N RH2C NH2 RH2C X N N N 1° amine

b. of arenes (Ch. 12.3) NH NO2 2 HNO3 [H]

H2SO4 R R R 1° arylamine

c. Nucleophilic ring opening of with NH3 (Ch. 16.11) 2 R OH O SN + R2NH N R 229

d. Reaction of amines with and (Ch. 17.10 - 17.11) R [H] R O N HN + RNH2 H


d. Nucleophilic substitution of α-halo 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


115 21.7: Preparation of Amines by of Ammonia Ammonia and other alkylamines are good and react 2 with 1° and 2° alkyl 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.


21.8: The Gabriel Synthesis of Primary Alkylamines. Reaction of 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 ) 232

116 21.9: Preparation of Amines by Reduction. Alkyl , , , and nitroarene can be reduced to the corresponding amines.

LiAlH4 reduces alkyl azides to 1° amines

LiAlHLiAl4H, 4THF;, 2 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 . 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

CH CH3 3 O -H O N H2/ Pd/C HN 2 2° amine + H3CNH2 H

1° amine

H3C + CH3 CH3 O N H3C N H -H2O H2/ Pd/C + (H3C)2NH 3° amine

2° amine 234

117 + – cyanoborohydride, Na N≡C-BH3 : the cyano makes cyanoborohydride a weak 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


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-) to afford an (w/ loss of H2O) (Ch. 17.11) R' R' O N R C R' R' + N R C + H O R H R 2 H H H Reaction of ammonia, 1°, and 2° amines with acid chloride, Anhydrides, and 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 yielding quarternary (4°) ammonium salts. E2 elimination of the resulting trimethyl ammonium gives an .

NH2 - + - + (H3C)3CO K No reaction (H2N is a very poor )



I- Δ N(CH3)3 - + + + (H3C)3CO K 237 (major) (minor)

Hofmann elimination gives the less substituted alkene, where E2 elimination of an alkyl or tosylate will follow Zaitsev rule to give the more substituted alkene

Fig 21.5, p. 883


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 (amides of aniline): The group is still activating and an ortho/para director. O O NH NH2 2 HN CH3 HN CH3 (H3CCO)2O, Br Br Br 2 NaOH, H2O

CH CH3 3 CH3 CH3 The acetamides acts as a 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: of Alkylamines. (please read) 22.16: Nitrosation of Arylamines. Reaction of aniline with + (NaNO2 + H → HONO) to an aryl diazonium cation, which are value precursors to other functional groups.

Aryl diazonium salts react with nucleophiles in a . 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)


H O, Δ CuCl CuBr 2 KI HBF Cu(CN) H3PO2 (CuO) 4 (HCl) (HBr)


Sandmeyer reaction: promoted by Cu(I) salts


Advantages of the aryl diazonium intermediate: 1) Introduces aryl substituents that are not otherwise accessible, such as -OH, -F, -I, and -CN. 2) Allows preparation of substituted arenes with substitution patterns that can not be prepared by other means.

Synthesis 3,5-dibromotoluene


Br Br Br


121 Synthesize 2-iodoethylbenzene from :


21.18: Azo Coupling. (please read) 243

21.19: Spectroscopic Analysis of Amines. IR: N-H stretches in the range of 3300 - 3500 cm-1; this is the same range as an O-H stretch, but N-H stretches are less intense.



R N -O-H H3C(H2C)3H2C-OH N-H C=O H


122 1H NMR: Nitrogen is less deshielding than . on the attached to the amino nitrogen have a typical chemical shift of δ 2.2 - 3.0


-CH2CH2CH3 2H, s 3H, t 5H, m -CH -CH HO-CH2- Ph-CH2-N- 2 3 C6H5-

2H, q -N-CH2-CH3 -CH2CH2CH3 1H, s -N- HO- H


13C NMR: The of carbon attached to a nitrogen of an amine are deshielded about 20 ppm downfield from those of an .

CH2 N CH2CH3 HO-CH2CH2CH3 10.3 H 128.3 25.9 128.0 64.3 43.7 54.0 15.3 126.8 140.6

Mass Spectrum: Nitrogen 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 even mass 246

123 3.60 (1H, dd, 3.38 (1H, dd, 3.05-3.12 2.77 (1H, dd, 2.49 (1H, dd, C9H13NO J= 10.7, 4.1) J= 10.7, 7.0) (1H, m) J= 13.3, 5.0) J= 13.3, 8.8) 2.35-2.45 [α]D +23° (3H, br s)

7.21-7.32 (m, 2H) 7.15-7.21 (m, 3H)

13C NMR: 138.6, 129.1, 128.5, 126.3, 65.9, 54.2, 40.6 IR:


Alkaloids: Naturally occurring compounds that contain a basic nitrogen HO NH2 H3CO NH2 CO2H HO NH2

CO H NH2 N H3CO 2 HO H OCH 3 NH2 HO N mescaline H CH3 tyrosine O O H3C N N NH CO2CH3 H3C N N CH N 3 O Ph N CH3 CH3 physostigmine O H N H H H O O N H N H H OH coniine H N HO HO Histrionicotoxin N H3CO HO HO2C CH3 N N H N O NH H O quinine MeO2C OH N O H H MeO N CH3 CO2CH3 NH HO R

R= -CH3 vinblastine 248 lysergic acid R= -CHO vincristine