Amina

Senyawa Organik Basa

Kelompok Amin

Berdasarkan jumlah alkil/aril yang terikat dengan atom N :

1º ( amina primer ) RNH2

2º (amina sekunder ) R2NH

3º (amina tersier ) R3N

4º (Garam amina kuartener ) R4N+

Penamaan amina sederhana

Amina primer sederhanan “alkilamina” Contoh :

metillamina CH3NH2

etilamin CH3CH2NH2

butilamin CH3CH2CH2CH2NH2

Amina 2º atau 3º simetris “dialkilamina” atau “trialkiamina” Contoh:

dietilamina (CH3CH2)2NH; trimetilamina (CH3)3N

Penamaan amina lebih lanjut Amina dengan lebih dari satu jenis gugus alkil

dinamai N-subtituen amina primer . Rantai alkil terpanjang menentukan nama dasar .

Contoh N-methylpropylamine CH3NHCH2CH2CH3

N,N-dimethylethylamine (CH3)2NCH2CH3

Penamaan lebih lanjut

Amina yang mempunyai lebih dari satu gugus fungsi menggunakan namanya “amino” sebagai substituen pada molekul induknya

Prioritas N paling rendah dibandingkan dengan gugus fungsi lainnya : amina < etanol, maka N-amino----

Examples: 2-aminoethanol H2NCH2CH2OH

4-aminobutanoic acid H2NCH2CH2CH2CO2H

Amina Heterosiklik

Amina yang unsur N merupakan bagian dari penyusun cincin . Penamaannya tidak sistemantik (non-systematic),

NH2

N N

N

N

H

N

N

H

N

H

N

N

HN

aniline pyridine pyrimidine pyrrole

quinoline indole imidazole benzimidazole

Struktur amines

Amina mempunyai sp3 hybridized nitrogen In principle, tertiary amines with three different R

groups should be chiral (i.e., have a stereocenter). However, rapid pyramidal inversion of the amine

nitrogen prevents isolation of the enantiomers except where the nitrogen is part of a ring or has other geometrical constraint.

N

YZ

X

N

YZ

Xfast

Properties of amines

Amines are moderately polar and are capable of hydrogen bonding.

Low MW amines (up to about C5) are soluble in water; higher MW amines will dissolve in acidic solution (as their conjugate acid).

Many amines have foul odors. Amines are weak bases.

Contoh amina biologically active

H2NCH2CH2CH2CH2NH2 putrescine H2NCH2CH2CH2CH2CH2NH2 cadaverine

H2NCH2CH2CH2CH2NCH2CH2CH2CH2NH2 s permidineH

H2N(CH2)N(CH2)4N(CH2)3NH2 s permineH H

NHCH3

OHH

HO

HO

epinephrine(adrenaline)

NH2

OHH

HO

HO

norepinephrine(noradrenaline)

NH2HO

HO

dopamine

Lanjut …

NH2

CH3H

amphetamine(benzadrine)

N

CH2CH2NH2

HO

H

NHCH3

CH3H

methamphetamine (speed)

serotonin

mescaline

NH2CH3O

CH3O

OCH3

N

CO2H

nicotinic acid(niacin)

NN

CH2CH2NH2

H

histamine

Lanjut-----

H2N C OCH2CH3

O

benzocaine(a topical anesthetic)

Cl

N

N

H

O

O

diazepam (Valium)

N

N

O

NN

CH3

CH2CH2CH3

H

SOO

N

NCH3

CH3CH2O

Sildenafil (Viagra)

Lanjut-----

R'O

O

RO

NCH3

codeine (R = CH3, R' = H)morphine (R and R' = H)heroin (R and R' = COCH3)

mepiridine(Demerol)

N

N

N

N

O

O

CH3

H3CCH3

caffeine

N

N

CH3

H

nicotine

NH3C

C

O

HO

C

O

H

OCH3

cocaine

NCH3C

O

CH3CH2O

Methadone

C6H5 NCH3C

O

CH3CH2

CH3

CH3

Lanjut -----

N

HO

H N

H

H

quinineN

O

N

O

H

H

strychnine

N

NH

C

O

(CH3CH2)2NCH3

lysergic acid diethylamide (LSD)

N

H

CH2CH2CH3

H

coniin (the poison from hemlock used to kill Socrates)

Kebassan amina

Amin sedikit basa, karena mempunyai pasangan elektron bebas dapat mendonorkan ke proton, bersifat nucleophiles.

Amina mempunyai nilai Kb = 10-3 to 10-4

RNH2 + H OH RNH3 + O H

Kb = [RNH3 ] [OH ]

[RNH2]

Kebasaan amina -------

Biasa digunakan nilai Ka asam konjugat amina Asam konjugat lebih lemah, lebih basa (amina) Amina sejenis mempunyai Ka values (conjugate

acids) dari 10-10sampai 10-11 (nilai pKa 10 sampai 11.)

RNH3 RNH2 + H Ka = [RNH3 ]

[RNH2] [H ]

Nilai pKa asam konjugat amina

CH3NH2 10.7

CH3CH2NH2 10.8

(CH3)2NH 10.7

(CH3CH2)2NH 10.5

(CH3)3N 9.8

(CH3CH2)3N 11.0

pKa = 14 – pKb atau pKb = 14 - pKa

Semua nya mempunyai nilai yang sama .

Efek substituen sama menstabilkan karbokation, maka .

Gugus pelepas elektron (alkil) , pada nitrogen menaikkan kebasaan

N nya lebih banyak mengikat substituen gugs alkil nilai pKa lebih rendah (kurang asam atau lebih basa)

Kebasaan amina

1. Jika amina bebas terstabilkan terhadap kationnya, maka amina merupakan basa yang lebih lemah

2. Jika kation itu relatf terstabilkan terhadap amina bebasnya , maka aminanya basa lebih kuat

Amina basanya lemah

(conj. acid)

Anilin basa lemah karena adanya delokalisasi elektron melalui resonansi

Pyridine is weaker because it is an imine (C=N). Pyrrole is much weaker because the lp of electrons is

delocalized with the other electrons to make 6 e-. Therefore, the lp is unavailable to act as a base.

aniline pyridine pyrrole pKa = 4.6 5.2 0.4

NH2

NN

H

Efek Substituent pada kebasaan anilin

Resonance stabilizes free base, destabilizes its protonated form (see next slide)

2 Penjelasan mengenai kebasaan :

NH2 NH2

OCH3

NH2

NO2pKa of conj. acid: 5.3 1.04.6

(much weaker base)

NH2

NO2

NH2

NOO

NH2

NOO

NH2

NOO

NH3

NO2

Pengaruh Substituent pada kebassan Anilin

NH3

NH3CH3O

NH3O2N

Reaction progress (protonation)

Energy

Amina yang tingkat kebasan lebih kuat Hanya satu jenis amine : basanya lebih kuat

Basa guanidin Guanidine basa kuat karena asam konjugatnya terstabilkan melalui resonansi

guanidine pKa = 13.6(conj. acid)

A guanidine group is part of the structure of the amino acid arginine.

NH

CH2N NH2

NH2

CH2N NH2

NH2

CH2N NH2

NH2

CH2N NH2

NH2

CH2N NH2

Amina terprotonasi pada pH Physiological

Persamaan Henderson-Hasselbalch :

Consider the neurotransmitter dopamine, a typical amine (having a pKa of its conjugate acid = 10.6) in a living cell (buffered at pH = 7.3):

That is, the concentration of the protonated amine is 2000x that of the neutral amine! Typical amines are >99.9% protonated at physiological pH.

pH = pKa + log [RNH2]

[RNH3+]

7.3 = 10.6 + log [RNH2]

[RNH3+]

log [RNH2]

[RNH3+]

-3.3 =

[RNH2]

[RNH3+]

2 x 103 =

;

;[RNH2]

[RNH3+]

5 x 10- 4 =

Sintesis Amina

Sintesis amina, melalui :

reaksi Substitusi, reaksi reduksi dan penataan ulang

a. Substitusi Nu :

SN2 OH-

a. RX + NH3 RNH3+ X- RNH2

b. Reduksi

c. Penataan ulang amida :

Chapter 19 24

Electrophilic Substitution of Aniline

-NH2 is strong activator, o-,p-directing. May trisubstitute with excess reagent. H+ changes -NH2 to -NH3

+, a meta-directing deactivator.

Attempt to nitrate aniline may explode.

=>

Chapter 19 25

Aniline Substitution

=>

Chapter 19 26

Electrophilic Substitution of Pyridine

Strongly deactivated by electronegative N. Substitutes in the 3-position. Electrons on N react with electrophile.

N

fuming H2SO4

HgSO4, 230oC

N

SO3H

=>

Chapter 19 27

Nucleophilic Substitutionof Pyridine

Deactivated toward electrophilic attack. Activated toward nucleophilic attack. Nucleophile will replace a good leaving

group in the 2- or 4-position.

N Cl

OCH3

_

N OCH3

+ Cl_

=>

Chapter 19 28

Alkylation of Amines Amines react with 1 alkyl halides via the SN2

mechanism. Mixtures of the mono-, di-, and tri-alkylated

products are obtained.

=>

Chapter 19 29

Useful Alkylations Exhaustive alkylation to form the

tetraalkylammonium salt.

CH3CH2CHCH2CH2CH3

N(CH3)3

CH3CH2CHCH2CH2CH3

NH23 CH3I

NaHCO3

+ _I

• Reaction with large excess of NH3 to form the primary amine.

CH3CH2CH2BrNH3 (xs)

CH3CH2CH2NH2 + NH4Br

=>

Chapter 19 30

Acylation of Aminesby Acid Chlorides

Amine attacks C=O, chloride ion leaves. Product is amide, neutral, not basic. Useful for decreasing activity of aniline toward

electrophilic aromatic substitution.

NH2

CH3 C

O

Cl

NH

C

O

CH3

N

to remove HCl

=>

Chapter 19 31

Formation of Sulfonamides Primary or secondary amines react with

sulfonyl chloride.

R NH2 S

O

O

R' Cl S

O

O

R' NH R

H

+Cl

_base S

O

O

R' NH R

• Sulfa drugs are sulfonamides that are antibacterial agents.

NH2

S OO

NH2

=>

Chapter 19 32

Oxidation of Amines Amines are easily oxidized, even in air. Common oxidizing agents: H2O2 , MCPBA. 2 Amines oxidize to hydroxylamine (-NOH) 3 Amines oxidize to amine oxide (-N+-O-)

=>

Chapter 19 33

Nitrous Acid Reagent

Nitrous acid is produced in situ by mixing sodium nitrite with HCl.

The nitrous acid is protonated, loses water to form the nitrosonium ion.

H O N OH

+

H O N O

H

+H2O + N O

+N O

+

=>

Chapter 19 34

Reaction with Nitrous Acid

1 Amines form diazonium salts, R-N+N. Alkyldiazonium salts are unstable, but

arenediazonium salts are widely used for synthesis.

2 Amines form N-nitrosoamines, R2N-N=O, found to cause cancer in laboratory animals.

=>

Chapter 19 35

Arenediazonium Salts Stable in solution at 0°–10°C. The -+NN group is easily replaced by

many different groups. Nitrogen gas, N2, is a by-product.

HBF4 (KI)

H3O+

CuCl (Br)

CuCN

H3PO2

H Ar'

Ar N N+

Ar OH

Ar Cl

Ar C N

Ar F

Ar H

Ar N N Ar'

(Br)

(I)

phenolsaryl halides

benzonitriles

aryl halides

benzene

azo dyes =>

Chapter 19 36

Synthesis by Reductive Amination To produce a 1 amine, react an aldehyde

or ketone with hydroxylamine, then reduce the oxime.

To produce a 2 amine, react an aldehyde or ketone with a 1 amine, then reduce the imine.

To produce a 3 amine, react an aldehyde or ketone with a 2 amine, then reduce the imine salt. =>

Chapter 19 37

Examples

primary amine

CH3CH2CH2 CH

NH2

CH3NiH2CH3CH2CH2 C

N

CH3

OH

H+

NH2 OHCH3CH2CH2 C

O

CH3

secondary amine

CH3 CH

NHCH3

CH32)

1)

H2O

LiAlH4CH3 C

NCH3

CH3H+

CH3NH2CH3 C

O

CH3

tertiary amine=>

C

N

H

CH3H3C

HNa(CH3COO)3BHC

N

H

CH3H3C+

H+

HN(CH3)2C

O

HCH3COOH

Chapter 19 38

Acylation-Reduction

An acid chloride reacts with ammonia or a 1 amine or a 2 amine to form an amide.

The C=O of the amide is reduced to CH2 with lithium aluminum hydride.

Ammonia yields a 1 amine. A 1 amine yields a 2 amine. A 2 amine yields a 3 amine.

=>

Chapter 19 39

Examples

CH3 C

O

ClNH3

CH3 C

O

NH2

LiAlH4

H2O

1)

2)CH3 CH2 NH2

primary amine

LiAlH4

H2O

1)

2)C

O

ClHN(CH3)2

C

O

N(CH3)2CH2 N(CH3)2

tertiary amine =>

Chapter 19 40

Direct Alkylation (1)

Use a large excess (10:1) of ammonia with a primary alkyl halide or tosylate.

Reaction mechanism is SN2.

CH3CH2CH2 BrNH3

+CH3CH2CH2 NH2 NH4Br

=>

Chapter 19 41

Azide Reduction (1)

Azide ion, N3-, is a good nucleophile.

React azide with unhindered 1 or 2 halide or tosylate (SN2).

Alkyl azides are explosive! Do not isolate.

Br

NaN3

N3LiAlH4

H2O

1)

2)

NH2

=>

Chapter 19 42

Nitrile Reduction (1)

Nitrile, -CN, is a good SN2 nucleophile.

Reduction with H2 or LiAlH4 adds -CH2NH2.

Br

NaCN

CNLiAlH4

H2O

1)

2)

CH2NH2

=>

Chapter 19 43

Reduction of Nitro Compounds (1) -NO2 is reduced to -NH2 by catalytic

hydrogenation, or active metal with acid. Commonly used to synthesize anilines.

CH3

NO2

Zn, HCl

CH3CH2OH

CH3

NH2

=>

Chapter 19 44

Hofmann Rearrangement of Amides (1)

In the presence of a strong base, primary amides react with chlorine or bromine to form amines with one less C.

C

O

NH2H2O

Br2, OH_

NH2

=>

Chapter 19 45

Gabriel Synthesis (1) Use the phthalimide anion as a form of

ammonia that can only alkylate once. React the anion with a good SN2

substrate, then heat with hydrazine.

+N

O

O_

R XN

O

O

R H2N NH2heat

NH

NH

O

O

R NH2

=>