senyawa amina dalam kimia organik

1. Amina
Senyawa Organik Basa

2. 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+

3. 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

4. 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

5. 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

6. 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
H
N
aniline pyridine pyrimidine pyrrole
quinoline indole imidazole benzimidazole

7. 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
Y
Z
X
N
Y
Z
X
fast

8. 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.

9. Contoh amina biologically active
H2NCH2CH2CH2CH2NH2 putrescine H2NCH2CH2CH2CH2CH2NH2 cadaverine
H2NCH2CH2CH2CH2NCH2CH2CH2CH2NH2
spermidineH
H2N(CH2)N(CH2)4N(CH2)3NH2
spermineH H
NHCH3
OHH
HO
HO
epinephrine
(adrenaline)
NH2
OHH
HO
HO
norepinephrine
(noradrenaline)
NH2HO
HO
dopamine

10. 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

11. Lanjut-----
H2N C OCH2CH3
O
benzocaine
(a topical anesthetic)
Cl
N
N
H
O
O
diazepam (Valium)
N
N
O
N
N
CH3
CH2CH2CH3
H
SO
O
N
N
CH3
CH3CH2O
Sildenafil (Viagra)

12. 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
H3C
CH3
caffeine
N
N
CH3
H
nicotine
N
H3C
C
O
H
O
C
O
H
OCH3
cocaine
NCH3C
O
CH3CH2O
Methadone
C6H5 NCH3C
O
CH3CH2
CH3
CH3

13. Lanjut -----
N
HO
H
N
H
H
quinine
N
O
N
O
H
H
strychnine
N
N
H
C
O
(CH3CH2)2N
CH3
lysergic acid diethylamide (LSD)
N
H
CH2CH2CH3
H
coniin (the poison from
hemlock used to kill Socrates)

14. 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 + OH
Kb =
[RNH3 ] [OH ]
[RNH2]

15. Kebasaan amina -------
 Biasa digunakan nilai Ka asam konjugat amina
 Asam konjugat lebih lemah, lebih basa (amina)
 Amina sejenis mempunyai Ka values (conjugate
acids) dari 10-10
sampai 10-11
(nilai pKa 10 sampai
11.)
RNH3 RNH2 + H Ka =
[RNH3 ]
[RNH2] [H ]

16. 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)

17. 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

18. 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 π electrons to make 6 π e-.
Therefore, the lp is unavailable to act as a base.
aniline pyridine pyrrole
pKa = 4.6 5.2 0.4
NH2
N
N
H

19. 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
N
OO
NH2
N
OO
NH2
N
OO
NH3
NO2

20. Pengaruh Substituent pada kebassan
Anilin
NH3
NH3CH3O
NH3O2N
Reaction progress (protonation)
Energy

21. 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
C
H2N NH2
NH2
C
H2N NH2
NH2
C
H2N NH2
NH2
C
H2N NH2
NH2
C
H2N NH2

22. 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 10
3
=
;
;
[RNH2]
[RNH3
+
]
5 x 10
- 4
=

23. 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 :

24. 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.
=>

25. Chapter 19 25
Aniline Substitution
=>

26. 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, 230
o
C
N
SO3H
=>

27. Chapter 19 27
Nucleophilic Substitution
of 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
_
=>

28. 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.
=>

29. Chapter 19 29
Useful Alkylations
 Exhaustive alkylation to form the
tetraalkylammonium salt.
CH3CH2CHCH2CH2CH3
N(CH3)3
CH3CH2CHCH2CH2CH3
NH2
3 CH3I
NaHCO3
+ _
I
• Reaction with large excess of NH3 to
form the primary amine.
CH3CH2CH2Br
NH3 (xs)
CH3CH2CH2NH2 + NH4Br
=>

30. Chapter 19 30
Acylation of Amines
by 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
N
H
C
O
CH3
N
to remove HCl
=>

31. 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
=>

32. 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-
)
=>

33. 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 O
H
+
H O N O
H
+
H2O + N O
+
N O
+
=>

34. 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.
=>

35. Chapter 19 35
Arenediazonium Salts
 Stable in solution at 0°–10°C.
 The -+
N≡N 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)
phenols
aryl halides
benzonitriles
aryl halides
benzene
azo dyes =>

36. 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. =>

37. Chapter 19 37
Examples
primary amine
CH3CH2CH2 CH
NH2
CH3
Ni
H2
CH3CH2CH2 C
N
CH3
OH
H
+
NH2 OH
CH3CH2CH2 C
O
CH3
secondary amine
CH3 CH
NHCH3
CH3
2)
1)
H2O
LiAlH4
CH3 C
NCH3
CH3
H
+
CH3NH2
CH3 C
O
CH3
tertiary amine
=>
C
N
H
CH3H3C
H
Na(CH3COO)3BHC
N
H
CH3H3C
+
H
+
HN(CH3)2C
O
H
CH3COOH

38. 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.
=>

39. Chapter 19 39
Examples
CH3 C
O
Cl
NH3
CH3 C
O
NH2
LiAlH4
H2O
1)
2)
CH3 CH2 NH2
primary amine
LiAlH4
H2O
1)
2)
C
O
Cl
HN(CH3)2
C
O
N(CH3)2
CH2 N(CH3)2
tertiary amine
=>

40. 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 Br
NH3
+CH3CH2CH2 NH2 NH4Br
=>

41. 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
N3
LiAlH4
H2O
1)
2)
NH2
=>

42. Chapter 19 42
Nitrile Reduction (1°)
 Nitrile, -C≡N, is a good SN2 nucleophile.
 Reduction with H2 or LiAlH4 adds -CH2NH2.
Br
NaCN
CN
LiAlH4
H2O
1)
2)
CH2NH2
=>

43. 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
=>

44. 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
NH2
H2O
Br2, OH
_
NH2
=>

45. 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 X
N
O
O
R H2N NH2
heat
NH
NH
O
O
R NH2
=>