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286

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 nucleophilicThere are many naturally occurring organic compounds that

contain nitrogen (alkaloids)

N

N

CH3

nicotine

N

H3C

CO2CH3

O Ph

O

cocaine

O

HO

N

CH3HH

HO

morphine

NH

N

HO

H3CO

H

quinine

NH2

OCH3

H3CO

H3CO

mescaline

NH

coniine

N

NH

HO2C

H

CH3

lysergic acid

N

CH3

N

CH3 CH3

OO

NHH3C

physostigmine

287

24.1: Naming AminesAlkyl-substituted (alkylamines) or aryl-substituted (arylamines)

Classified: 1° (RNH2), 2° (R2NH), 3° (R3N) and 4° (R4N+)

NC

H

sp3

NH

HH

alkylamines arylamines

primary (1°) amines

secondary (2°) amines

tertiary (4°) amines

quarternary (4°) ammonium ion

NH2

NH

N

H3CH2CNCH2CH3

CH2CH3H

H

N

H

H3C N

methanol primary secondary tertiary

Although the terminology is the same, this designation of amines is different from that of alcohols.

OC

H

HH H

OC

R

HH H

OC

R

HR H

OC

R

RR H

1° carbon 2° carbon 3° carbon

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288

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

chainCH

3CH

2CH

2CH

3 CH

3CH

2CH

2CH

2OH

OH

CH3CH

2CH

2CH

2NH

2

NH2

butane 1-butanol 2-butanol

1-butanamine 2-butanamine(butylamine) (2-aminobutane)

CO2H

NH2NH2

cyclohexanamine 2-amino-3-phenyl-(cyclohexylamine) propanoic acid

H2NNH2

H2N NH2

1,4-diaminobutane 1,5-diaminopentane(putrescine) (cadaverine)

289

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.

diphenylamine diisopropylamine triethylamine N,N-dimethyl- N-ethyl-N-methyl- propylamine cyclohexylamine

N

H

H3CH2CNCH2CH3

CH2CH3

N

H

NCH2CH3

CH3H3C

NCH3

CH2CH2CH3

Many arylamines go by non-systematic nomenclatureNH2 NH2

CH3

NH2

H2N

aniline o-toluidine p-phenylenediamine

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290

The nomenclature of heterocyclic amines is highly specializedand often non-systematic

24.2 Structure and Bonding in AminesThe nitrogen of alkylamines is sp3 hybridized and

tetrahedral

pyridine pyrrole quinoline imidazole pyrimidine

indole quinoxoline pyrrolidine piperidine morpholine

N

N

NH

NH N

N

N

H

N

H

N

O

H

N

N

HN

N

291

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 pyramidalinversion of nitrogen is a racemization mechanism

The barrier to nitrogen inversion is about 25 KJ/mol (very rapidat room temperature).

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292

24.3 Properties and Aources of AminesPrimary 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 AminesThe chemistry of amines is dominated by the basicity of

the nitrogen lone pair

NO R

O

H N HO R

O

++

293

Alkyl amines are stronger bases than water, alcohols or ethers

R3N: + H2O R3NH + HO+ -

Kb = [R3NH+] [HO-][R3N]

pKb = - log Kb

pKb values are rarely used. Amines basicity is measured bythe 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 baseLower pKa = stronger acid = weaker conjugate base

R3NH+ + H2O H3O + R3N:+

lower pKaR3NH+ more acidicR3N less basic

higher pKaR3NH+ less acidicR3N more basic

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294

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 ifit is in an sp2 hybridized orbital (versus an sp3)

NH4+ pKa= 9.26

(H3CH2C)NH3+ 10.8

(H3CH2C)2NH2+ 10.7

(H3CH2C)3NH+ 11.0

pKa= 4.6

5.2

0.4

7.0

- 1.0

NH3

+

N H

+

NH

H+

NH2

+

NH3

O

+

295

24.5 Basicity of Substituted ArylaminesThe lone pair of electrons on the nitrogen of aniline are

conjugated to the π-electrons of the aromatic ringand 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)

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296

Electron-donating substituents (-CH3, -OH, -OCH3) make thesubstituted aniline more basic than aniline itself (the pKaof the anilinium ion is higher than 4.6)

Electron-withdrawing substituents (-Cl, -NO2) make thesubstituted aniline less basic than aniline itself (the pKaof the anilinium ion is lower than 4.6)

See Table 24.2 (p. 903)

NH2Y NH3 + H2O+ H3O

+Y

+

Y= -NH2 pKa= 6.15 -OCH3 pKa= 5.34 -CH3 pKa= 5.08 -H pKa= 4.63 -Cl pKa= 3.98 -CN pKa= 1.74 -NO2 pKa= 1.00

less acidic(more basic)

more acidic(less basic)

297

Problem 24.4: Which compound is more basic?a) b) c)

NaOH -or- H3C NH2N-or-(CH3)2NH

H3CH2C NH2H3CH2C NH2

C

O

-or-

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

a)

b)

c)

NH2O2N,

NH2,

NH2Br

NH2Cl, ,

NH2H3CNH2

O

NH2F3C, ,

NH2H2FCNH2H3C

O

H

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298

24.6 Synthesis of AminesReduction of Nitriles, Amides and Nitro Compounds

R-BrMg(0), CO2

then H3O+

R NC

LiAlH4

ether R

N

CH R

N

C

H

H

2

H3O+

R

NH2

C

H

H

LiAlH4

R-BrNaCN

1° amine

1°, 2° or 3° amine

H3O+

-or-

NaOH, H2O

R OHC

O SOCl2

R ClC

O H3C-NH2

R NH

C

O

CH3

LiAlH4

R NH

C CH3

HH

-or-

BH3

HNO3, H2SO4NO2

H2O

H2, Pd/C

-or-

SnCl2

NH2

1° arylamines

299

SN2 reaction of alkyl halides and tosylates

Ammonia and other alkylamines are good nucleophiles andreact with 1° and 2° alkyl halides or tosylates viaand SN

2 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

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300

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° alkyl halides or tosylates via an SN

2 reaction. The resultingazide can be reduced to a 1° amine.

Gabriel amine synthesis: reaction of potassium phthalimide with alkyl halides or tosylates via an SN

2 reaction. The resultingN-substituted phthalimide can be hydrolyzed to a 1° amine.

XC

H

R1

R2

N N N

1° or 2° alkyl halideor tosylate

SN2

N C

H

R1

R2

NN N3 C

H

R1

R2

Alkyl azide

H2, Pd/C

-or-LiAlH4

H2N C

H

R1

R2

1° amine

azide

N

O

O

H

KOH

EtOH

N

O

O

K+

PhthalimidePotassiumphthalimide

XC

H

R1

H

H

R1

HN

O

O

C

N-substitutedphthalimide

NaOH/H2O

H2N C

H

R1

R2

1° amine

301

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.

NH+ H3N

-H2O H2/ Pd/C NH2O

H

O

+ H3CNH2

-H2O NCH3

H2/ Pd/C HN

H

CH3

3-phenyl-2-propanone (P2P) amphetamine

methamphetamine

O

+ (H3C)2NH-H2O

NCH3H3C

H2/ Pd/CN H

CH3H3C

+

1° amine

2° amine

ammonia

1° amine

2° amine

3° amine

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302

Sodium cyanoborohydride, Na+ N≡C-BH3– : the cyano ligand

makes cyanoborohydride a weak hydride source and itwill react with only the most easily reduced functional groups. such as an imine. Does not reduce ketones andreduced aldehydes slowly

Reductive amination with NaB(CN)H3: one-pot reaction

practice problem 24.1 (p. 908)

Hoffmann and Curtius rearrangements (please read)

CHO

+ H3C-NH2

NaB(CN)H3

CN

H

CH3

H

CNCH3

H

H H

NH2

+ H2C=ONaB(CN)H3

NCH2

H

CNCH3

H

H H

303

24.7: Reactions of AminesAcylation: ammonia, 1° and 2° amines react with acid chlorides

and anhydrides to give amides (Chapt. 21.4, 21.5 & 21.8)

R ClC

O

R NC

O

acid chloride

R'NH2

R OHC

O

carboxylic acid

SOCl2

R'2NH

NH3

di-substitiuted (3°) amide

R'

R'

R NH

C

O

R'

R NH2

C

O

mono-substitiuted (2°) amide

unsubstitiuted (1°) amide

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304

Hofmann elimination: E2 elimination of a trimethyl ammoniumgroup to give an alkene

NH2

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

H3C-I

N(CH3)3I-

+ (H3C)3CO - K+ +

Hofmann elimination gives the less substituted alkene, whereE2 elimination of an alkyl halide or tosylate will followZaitsev rule to give the more substituted alkene

(major) (minor)

305

24.8 Reactions of ArylaminesElectrophilic aromatic substitution: an amino group is a

very strong activating group and an ortho/paradirector.

The amino group is incompatible with the Friedel-Craftsreactions (Ch. 16.3).

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

NH2

CH3

HN

CH3

CH3

O

(H3CCO)2O,pyridine Br2

HN

CH3

CH3

O

BrNaOH, H2O

NH2

CH3

Br

The acetamide group is still a strong activator and an ortho/paradirector. (see Fig. 16.10, page 541)

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306

Advantages of the acetamide over the amino group forelectrophilic aromatic substitution:Anilines are so activated that multiple substitution

reactions can be a problem. The reactivity of theacetamide is attenuated so that mono substitution is achieved.

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

NH2

Br2, H2O

NH2

Br Br

Br

NH2

HN CH3

O

(H3CCO)2O,pyridine

H3CCOCl

AlCl3

HN CH3

O

O CH3

(H3C)3C-Cl

AlCl3

HN CH3

O

NaOH, H2O

NH2

O CH3

NH2 NaOH, H2O

307

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

N

OH

O

H+

N

OH2

O

- H2O N

O

HNNO

- H

NNOH

H+ NNOH2

NN

HSO3

H2N

Aryl diazonium salts react with nucleophiles in a substitutionreaction. N2 is one of the best leaving groups.

NN

+ Nu:

Nu

N N+

NN

NN

+

NN

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

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308

Synthesize 3,5-dibromotoluene from bromobenzene or toluene

BrBr

CH3

CH3

Br

Some reactions of aryl diazonium salts I

- N2

NN

- N2

F

- N2

HH3PO2

HBF4

NaI

309

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

Cl

- N2

NN

- N2

Br

- N2

CNCu(CN)

HBr, CuBr

HCl, CuCl

- N2

Cu2O, H2OOH

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

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310

Diazonium coupling reaction (please read)

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

Synthesize 2-iodoethylbenzene from benzene:

I CH2CH3

311

24.10 Spectroscopy of AminesIR: N-H stretches in the range of 3300 - 3500 cm-1

same range as O-H stretch, but N-H stretches are sharperand less intense.

OH

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312

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

H

CH2CH3

1H, m-N-H

2H, q-N-CH2-CH3

5H, mC6H5- 2H, s

Ph-CH2-N-

3H, t-CH2-CH3

313

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

140.6

128.3 128.0

126.8

54.0 43.7 15.3

CDCl3

CH2 N

H

CH2CH3

38.224.213.7

CH2 CH2 CH3

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314

C9H13NO[α]D +23°

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

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

3.60 (1H, dd, J= 10.7, 4.1)

3.38 (1H, dd, J= 10.7, 7.0)

3.05-3.12 (1H, m)

2.77 (1H, dd, J= 13.3, 5.0)

2.49 (1H, dd, J= 13.3, 8.8)

2.35-2.45 (3H, br s)

IR: