Chapter 24: Amines Amines: Nitrogen containing organic compounds

Organic derivatives of ammonia, NH3, Nitrogen atom have a lone pair of electrons, which potentially make amines both basic and nucleophilic There are many naturally occurring organic compounds that contain nitrogen (alkaloids)

H3C CH3 H N O O H CO NH CO2CH3 3 2 O Ph NH H C N N H 3 H3CO N O HO CH CH cocaine 3 3 OCH3 physostigmine mescaline H3CO HO2C CH3 HO N H N O quinine N N H H CH NH CH3 3 N HO N H nicotine coniine 286 lysergic acid morphine

24.1: Naming Amines Alkyl-substituted (alkylamines) or aryl-substituted (arylamines) H H N C N H H sp3 alkylamines arylamines + Classified: 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°) secondary (2°) tertiary (4°) quarternary (4°) amines amines amines ammonium ion Although the terminology is the same, this designation of amines is different from that of alcohols. R R H R C O C O C O C O R R H H H H H R H H H H 1° carbon 2° carbon 3° carbon methanol primary secondary tertiary 287

145 Amine nomenclature: The nomenclature for primary amines is similar to that of alcohols, the suffix -amine can be used in place of the final -ol

Consider the -NH2 group as an amino substituent on the parent chain

CH3CH2CH2CH3 CH3CH2CH2CH2OH NH2 OH NH2 butane 1-butanol 2-butanol CO2H cyclohexanamine 2-amino-3-phenyl- CH3CH2CH2CH2NH2

NH2 (cyclohexylamine) propanoic acid 1-butanamine 2-butanamine (butylamine) (2-aminobutane)

NH 2 H N NH H2N 2 2 1,4-diaminobutane 1,5-diaminopentane (putrescine) (cadaverine) 288

Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group Unsymmetrical secondary and tertiary amines are named as N-substituted primary amines. The largest alkyl group is the parent name, and other alkyl groups are considered N-substituents.

H CH3 H C CH N H3CH2C CH2CH3 3 3 N N N N CH2CH3 CH CH CH2CH2CH3 H 2 3 diphenylamine diisopropylamine triethylamine N,N-dimethyl- N-ethyl-N-methyl- propylamine cyclohexylamine

Many arylamines go by non-systematic nomenclature

NH2 NH2 NH2

H2N CH3

aniline o-toluidine p-phenylenediamine 289

146 The nomenclature of heterocyclic amines is highly specialized and often non-systematic N N N N N N N H H pyridine pyrrole quinoline imidazole pyrimidine

O N

N N N N H N H H H indole quinoxoline pyrrolidine piperidine morpholine

24.2 Structure and Bonding in Amines The nitrogen of alkylamines is sp3 hybridized and tetrahedral

290

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).

291

147 24.3 Properties and Aources of Amines Primary and secondary amines, likes water and alcohols, can be hydrogen bond donors (N-H) and hydrogen bond acceptors (the lone pair)

24.5 Basicity of Amines The chemistry of amines is dominated by the basicity of the nitrogen lone pair

O O N H N H + + O R O R

292

Alkyl amines are stronger bases than water, alcohols or ethers + - R3N: + H2O R3NH + HO + - [R3NH ] [HO ] Kb = pKb = - log Kb [R3N] pKb values are rarely used. Amines basicity is measured by the pKa of the conjugate acid. (pKb + pKa = 14) 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

Lower pKa = stronger acid = weaker conjugate base + + R3NH + H2O H3O + R3N: lower pKa + higher pKa R3NH more acidic + R3NH less acidic R3N less basic 293 R3N more basic

148 Table 24.1 (p. 899): 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 ~ 9.25) The ammonium ions of aryl amines and heterocyclic aromatic amines are considerably less basic than alkyl amines

(pKa ~ 5 or less). The nitrogen lone pair is less basic if it is in an sp2 hybridized orbital (versus an sp3)

+ NH3 + NH4 pKa= 9.26 pKa= 4.6 + (H3CH2C)NH3 10.8 + + N H 5.2 (H3CH2C)2NH2 10.7 (H CH C) NH+ 11.0 3 2 3 + H N H 0.4 + NH2 7.0

O + - 1.0 NH3 294

24.5 Basicity of Substituted Arylamines 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.

Substituents can greatly influence the basicity of the aniline. The effect is dependent upon the nature and position of the subtituent (recall the acidity of substituted phenols)

295

149 Electron-donating substituents (-CH3, -OH, -OCH3) make the substituted aniline more basic than aniline itself (the pKa of the 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 anilinium ion is lower than 4.6) See Table 24.2 (p. 903)

+ + Y NH2 + H3O Y NH3 + H2O

Y= -NH2 pKa= 6.15 less acidic -OCH3 pKa= 5.34 (more basic) -CH3 pKa= 5.08 -H pKa= 4.63 -Cl pKa= 3.98 more acidic -CN pKa= 1.74 (less basic) -NO2 pKa= 1.00

296

Problem 24.4: Which compound is more basic? a) O b) c) (CH3)2NH -or- N -or- NaOH -or- H3C NH2 H3CH2C NH2 C H3CH2C NH2

Problem 24.6: Rank the following in order of increasing basicity?

O a) O2N NH2 NH2 Br NH2 , , H

O b) NH Cl NH2 2 H3C NH2 , ,

c) NH F3C NH2 H3C 2 H2FC NH2 , ,

297

150 24.6 Synthesis of Amines Reduction of Nitriles, Amides and Nitro Compounds

2 N LiAlH N + NH NaCN LiAlH4 4 H3O 2 R-Br R C N C C C ether R H R H R H H H

+ H3O 1° amine -or- NaOH, H2O

Mg(0), CO2 O O SOCl2 O H3C-NH2 LiAlH4 H H R-Br C C CH C CH + C 3 -or- 3 then H3O R OH R Cl R N R N H BH3 H 1°, 2° or 3° amine

HNO , H SO NO2 NH2 3 2 4 H2, Pd/C -or- H2O SnCl2 1° arylamines

298

2 SN reaction of alkyl halides and tosylates Ammonia and other alkylamines are good nucleophiles and react with 1° and 2° alkyl halides or tosylates via 2 and SN reaction to give 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

299

151 Synthesis of primary amines from the reaction of alkyl halides or tosylates with “ammonia equivalents” Azide ion is a very strong nucleophile and react with 1° or 2° 2 alkyl halides or tosylates via an SN reaction. The resulting azide can be reduced to a 1° amine.

H 2 H H N N N C X SN H2, Pd/C H N N N C N3 C R2 R2 R2 H2N C R1 -or- R1 R1 R2 LiAlH4 R azide 1° or 2° alkyl halide Alkyl azide 1 or tosylate 1° amine Gabriel amine synthesis: reaction of potassium phthalimide with 2 alkyl halides or tosylates via an SN reaction. The resulting N-substituted phthalimide can be hydrolyzed to a 1° amine.

O K+ O O H KOH H H N C X NaOH/H2O N H H N C H2N C EtOH H R R1 2 O R1 R1 O O Potassium 1° amine Phthalimide phthalimide N-substituted phthalimide 300

Reductive amination: synthesis of an amine by the reduction of an imine from the condenstion of an aldehyde or ketone with ammonia, 1° or 2° amine.

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

301

152 – 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 imine. Does not reduce ketones and reduced aldehydes slowly

Reductive amination with NaB(CN)H3: 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 practice problem 24.1 (p. 908)

Hoffmann and Curtius rearrangements (please read) 302

24.7: Reactions of Amines Acylation: ammonia, 1° and 2° amines react with acid chlorides and anhydrides to give amides (Chapt. 21.4, 21.5 & 21.8)

NH3 O unsubstitiuted C R NH2 (1°) amide

O O SOCl O R'NH 2 2 mono-substitiuted C C C R' R OH R Cl R N (2°) amide H carboxylic acid acid chloride

O R'2NH C R' di-substitiuted R N (3°) amide R'

303

153 Hofmann elimination: E2 elimination of a trimethyl ammonium group to give an alkene

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

H3C-I

I- N(CH3)3 - + + + (H3C)3CO K (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

304

24.8 Reactions of Arylamines Electrophilic aromatic substitution: an amino group is a very strong activating group and an ortho/para director. The amino group is incompatible with the Friedel-Crafts reactions (Ch. 16.3).

Electrophilic aromatic substitution of phenyl acetamides (amides of aniline).

O O NH NH2 2 HN CH3 HN CH3 (H3CCO)2O, Br pyridine Br Br 2 NaOH, H2O

CH CH3 3 CH3 CH3 The acetamide group is still a strong activator and an ortho/para director. (see Fig. 16.10, page 541) 305

154 Advantages of the acetamide over the amino group for electrophilic aromatic substitution: Anilines are so activated that multiple substitution reactions can be a problem. The reactivity of the acetamide is attenuated so that mono substitution NH is achieved. NH2 2 Br Br Br2, H2O

Br The acetamide group is compatiable with the Friedel- Crafts reactions. NH2

(H3CCO)2O, pyridine O O O NH2 NH2 NaOH, NaOH, HN CH3 HN CH3 H2O H2O (H3C)3C-Cl HN CH3 H3CCOCl

AlCl3 AlCl3

O CH3 O CH3 306

Diazonium salts: The Sandmeyer reaction primary arylamines (anilines) react with nitrous acid (HNO2, generated from the reaction of NaNO2 and H2SO4) to form a stable aryl diazonium salt.

H OH OH + 2 - H O N O H 2 N H2N - H N N N O O O

N N N OH + N OH2 N H N HSO3 Aryl diazonium salts react with nucleophiles in a substitution reaction. N2 is one of the best leaving groups.

N N Nu + Nu: + N N

What is the mechanism? rate= k [Ar-N≡N+]

N N N N N N + 307

155 Some reactions of aryl diazonium salts NaI I

- N2

N F N HBF4

- N2

H H3PO2

- N2

Synthesize 3,5-dibromotoluene from bromobenzene or toluene

CH3 CH3

Br Br Br

308

Some more reactions of aryl diazonium substitution reactions promoted by Cu(I) salts (Sandmeyer reaction).

HCl, CuCl Cl

- N2

Br HBr, CuBr

- N2 N N

CN Cu(CN)

- N2

OH Cu2O, H2O

- N2

The mechanism of the Sandmeyer reaction (Cu+ promoted) involves an aryl radical intermediate.

309

156 Synthesize 2-iodoethylbenzene from benzene:

I CH2CH3

Diazonium coupling reaction (please read)

24.9 Tetraalkylammonium Salts as Phase-Transfer Catalysts (please read)

310

24.10 Spectroscopy of Amines IR: N-H stretches in the range of 3300 - 3500 cm-1 same range as O-H stretch, but N-H stretches are sharper and less intense.

H O

311

157 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

NMR: Hydrogens on the carbon attached to a nitrogen of an amine have a chemical shift of δ 2.2 - 3.0

CH2 N CH2CH3 H 3H, t 5H, m -CH2-CH3 C6H5- 2H, s 2H, q

Ph-CH2-N- -N-CH2-CH3

1H, m -N- H

312

13C NMR: Carbons attached to a nitrogen of an amine are deshielded about 20 ppm downfield from where they would absorb in an alkane

CH2 N CH2CH3 H 128.3 128.0 54.0 43.7 15.3

126.8

140.6 CDCl3

38.2 CH2 CH2 CH3 24.2 13.7 313

158 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:

314

159