H - Loy Research Group

Example of biologically ac0ve amines H2NCH2CH2CH2CH2NH2
putrescine
H2NCH2CH2CH2CH2NCH2CH2CH2CH2NH2
spermidine
H
H2NCH2CH2CH2CH2CH2NH2
H2N(CH2)N(CH2)4N(CH2)3NH2
spermine
H
H
H OH
HO
H OH
NHCH3
HO
NH2
HO
HO
epinephrine
(adrenaline)
cadaverine
HO
NH2
HO
dopamine
norepinephrine
(noradrenaline)
Heterocyclic amines •  Some amines have a nitrogen as part of a ring. These generally have common (non-­‐systema0c) names, which should be memorized: NH2
N
N
aniline N
N
pyridine pyrimidine N
N
N
quinoline indole H
N
H
imidazole H
pyrrole N
N
H
benzimidazole NH2
N
N
N
H
N
O
N
N
H
adenine
NH
N
guanine
NH2
O
N
N
H
cytosine
NH2
NH
O
N
H
thymine
O
More biologically ac0ve amines… H CH3
H CH3
NH2
NHCH3
CH3O
NH2
CH3O
amphetamine
(benzadrine)
CO2H
N
nicotinic acid
(niacin)
OCH3
methamphetamine
(speed)
mescaline
CH2CH2NH2
CH2CH2NH2
HO
N
serotonin H
N
N
histamine
H
More biologically ac0ve amines… H
O
(CH3CH2)2N
C
H
N
CH3
H
N
HO
N
H
H
N
N
quinine
N
O
H
strychnine
lysergic acid diethylamide (LSD)
H
N
CH2CH2CH3
H
coniin (the poison from
hemlock used to kill Socrates)
O
More biologically ac0ve amines… H
N
Cl
O
O
CH3CH2O
H
CH3
N
N
N
N
N
CH2CH2CH3
O
O S N
O
diazepam (Valium)
O
H2N
C OCH2CH3
benzocaine
(a topical anesthetic)
N
CH3
Sildenafil (Viagra)
More biologically ac0ve amines… RO
O
H3C
O
CH3
N
C OCH
3
H
N
O
H
CH3
R'O
O
N
N
N
O
NCH3
H3C
C
cocaine
caffeine
O
codeine (R = CH3, R' = H)
morphine (R and R' = H)
heroin (R and R' = COCH3)
CH3
H
N
N
CH3
nicotine
CH3CH2O
C
NCH3
CH3CH2
C
O
O
mepiridine
(Demerol)
C6H5 NCH3
CH3
Methadone
Electrophilic Aromatic Substitution preferred at the 2-position
NO2
AcONO2, AcOH/ -10 C
N
N
H
H
NO2
+
N
H
13%
Normal acidic nitration causes polymerization 51%
Vilsmeier Reaction
O
+
N
1. POCl3
2. Na2CO3, H2O
H
H
NMe2
N
H
H
O
59%
O
O
Me
Ac2O, AlCl3
rt
N
SO2Ph
Me
NaOH (aq)
N
N
SO2Ph
H
82%
Electron-withdrawing group allows substitution at the 3-position
Organic Synthesis with Pyrrole should avoid strong acids
H
H+
H
N
H
N+
N
H
H
H
H
reaction continues to give polymer
N
N+
H
H
i
i; 1 X SO2Cl2, Et2O
Cl
N
N
H
H 80%
Cl
Cl
ii; 4 X SO2Cl2, Et2O
ii
N
H
Cl
N
Cl
H 80%
Other Five Membered Heterocycles
N
H
S
O
Thiophene
Furan
Least reactive
The least aromatic:
The O atom is too electronegative
Pyrrole
More aromatic than Furan
Less reactive than pyrrole,
but substitution always at 2position
Electrophilic Substitution, not addition
Can give addition, as well as substitution products when
reacted with E+
Thiophene has similar reactivity to benzene
Electrophilic Aromatic Substitution of Thiophene
Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3
HNO3, AcOH, Ac2O / -10 C
NO2
S
S
85%
O
+
S
1. POCl3
2. Na2CO3, H2O
H
H
NMe2
S
68%
O
Cl
SO2Cl2, heat
S
S
43%
Cl
S
10%
Cl
Some Reactions of Furan
+
S
S
O
O
83%
ZnCl2, 0 C
O
+
O
ZnCl2, 100 C
O
O
O
Furan is more reactive than thiophene
O
O
O
95%
Br
Br
Br2, MeOH
Br2, CCl4
Br
Br
O
not a clean reaction
H+, H2O
MeO
O
H
Wittig reaction
OHC
CHO
Hydrolysis of acetal
Ph3P
+
O
_
OMe
O
H
Addition product
OHC
CHO
Furan is easily cleaved to dicarbonyls
OHC
CHO
MeO
H
H+, H2O
OMe
O
acetal
O
H
H
H
cis-butenediol
(too unstable to isolate)
acetal
O
R
O
+
H
aldehyde
O R1
1
H O R
H
- H2 O
1
R O
R
+ 2 x alcohol
1
O R
H
acetal
acid-catalysed
H+, H2O
R
O
R
O
O
R
R
Furan is a source of 1,4-dicarbonyls in Organic Synthesis
Five-membered Rings with Two or More Nitrogens
N
Diazoles
N
pKa = 14.5
(imidazole)
pKa = 16.5
(pyrrole)
N
N
H
H
Pyrazole
Imidazole
Imidazole is more basic than pyridine, but more acidic than pyrrole
H
H
N+
N
Imidazole + H+
Imidazole - H+
N
N
H
H
N
NaOH
- H 2O
N
_
N
_
N
Properties: Very stable cation and anion of imidazole is formed
Some Natural Imidazole Compounds
Histidine
Important ligand to many metalloproteins
Is one of the essential amino acids.
A relatively small change in cellular pH can result in a change in its charge
Body neurotransmitter & local immune response
histamine
histidine carboxylase
Dipeptide in high concentrations in the brain & muscles
- Improves social interactions & treatment of autism
Carnosine
E+
E
N
N
N
H
N
H
Pyrazole
4-substituted
N-like pyridine deactivate its vicinal positions
4
N3
2
5
most strongly activated position
N1
H
H2SO4 / SO3
N
N
H
HO3S
100 C°
N
N
H
HNO3 / H2SO4
160 C °
N
H
N
N
O2N
N
H
Br
Br2 / CHCl3
N
H
N
N
H
N
N
Ph N=N +Cl-
N
N
N
H
Lithiation
N
N
BuLi
N
N
ph
ph
CH3
N
R
N
BuLi
N
Ac2O
N
H
N
N
N
COCH3
Alkylation
CO2CH3
H3C
N
H
N
CH2N2
CO2CH3
H3C
N
N
ph
CH3
Li
N
R
Acylation
Li
RX
N
N
CH3
R
N=NPh
N
pyridine
N
H
piperidine
Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)
Hybridization = sp2 with similar resonance stabilization energy
Lone pair of electrons not involved in aromaticity
1H
NMR: δ
Pyridinium ion: pKa = 5.5
Piperidine: pKa = 11.29
diethylamine : pKa = 10.28
H 7.5
H 7.1
H
H
N
pyridine
H 8.5
Pyridine is a weak base
Pyridine is π-electron deficient
Electrophilic aromatic substitution is
difficult
Nucleophilic aromatic substitution is easy
NH2
N
aniline pKa = 4.6 N
H
pyridine pyrrole 5.2 0.4 pK a of
conj. acid:
NH2
NO2
NH2
NH2
4.6
OCH3
5.3
NH2
O
N
O
NH2
NO2
1.0
(much weaker base)
NH2
O
N
O
O
NH2
NH3
N
NO2
O
Resonance stabilizes free base, destabilizes its protonated form (see next slide) Pyridine as a nucleophile
Me I
N
N+ I
Me
_
Use Pyridine as a solvent to make esters
O
R
X
+
O
Pyr
R1-OH
1
R
O
R
X = OAc, Cl, Br
N+
E.g.
O
O
O
OH
+
Pyr
O
O
O
R
Acyl pyridinium ion
Reactive intermediate
Attempted Electrophilic Aromatic Substitution
i
i
N+
H
NO2
N
N
i, HNO3, H2SO4
Unreactive, Stable
ii
N+
_
AlCl3
N
ii, AlCl3, RCOCl
O
ii
R
N
NO2
H2O2, AcOH
HNO3, H2SO4
N+
_
O
Pyridine N-oxide
N
N+
_
O
85%
We now have an activating and protecting group
_
O
+
O N H
O N O
+
Mechanism
N+
_
O
NO2
N+
O
NO2
PPh3
N+
_
O
+
N
75%
O PPh3
Nucleophilic Substitution at 2- and 4-positions of
pyridine is most favoured
Nu
N
_
Cl
Nu
N
_
E.g.
Cl
N
PhSH, NEt3
N
Cl
N
SPh
93%
Br
Br
N
NH2
Br
NH3 (aq)
N
65%
Nu
Indole
Aromatic due to 10 π-electrons
Benzene part is non-reactive
N
H
Electrophilic aromatic substitution
occurs at the 3-position
CHO
Indole
Vilsmeier
N
Indole Alkaloids
N
H
H
O
OCONH2
H 2N
OMe
N
Me
Lysergic acid (LSD)
Strychnine
55%
NH
O
Mitomycin C
Bioac&ve Indoles CO2H
NH2
HO
NH2
N
H
Serotonin
Neurotransmitter
N
OR
S
O2
N
N
H
Sumatriptan, Imigran ®
Drug against Migraine
serotonin reseptor antagonist
MeO
HN
N
H
Melatonin
Hormone
Halucinogens from Psilocybe sopper
R=H: Psilocin
R=PO3H: Psilocybin
N
H
H
N
N
H
Tryptophan
Essential amino acid
in vivo
Serotoninagonists,
not broken down in the body
strong, continuos nerve impulse
Psilocybe semilanceata
(Spiss fleinsopp)
Psilocybe Mexicana
CO2H
N
H
Auxine
Plant growth hormone
O
Bioac&ve Indoles Rauwolfia serpentina
India, Thailand etc
H
N
O
N H
H
H
MeO2C
MeO
OMe
OMe
O
OMe
O
Vinca alkaloids
from Vinca rosea
Anticancer comp.
HO
Vinca rosea
(Catharantus roseus)
From Madagaskar
Perivinkle
N
H
MeO2C
MeO
N
H
OCOMe
CO2Me
N
OH
R
R=-Me: Vinblastin, Oncovin®
R=-CHO: Vinkristin, Velbe®
N
R'
H
X=H, R'=Me, R=OH: Lysergic acid
X=H, R'=Me, R=NEt 2: LSD
OMe
Reserpine
from Rauwolfia sp.
Reduce blood pressure
N
Secale alkaloids and derivatives
from Claviceps purpurea (meldrøye)
R
N
H
X
X=H, R'=Me, R=-NHCH(Et)CH2OH: Metylergometrin,
Uterus contractions, drug used after birth
HO
O
N
X=Br, R'=Me, R=
N
N
O
H
Bromokriptin, Parlodel®
O
Prolactine inhibitor
O
NH
X=H, R'=Allyl, R=
N
Kabergolin, Dostinexl®
N
Prolactine inhibitor
N
X=H, R'=Me, R=
H
Ergotamin, Anervanel®
Drug against migraine
HO
O
N
O
N
O
N
H
E
X H
Cation II
>
O
>
S
>
N
H
E
α attack
β attack
X
H
X
Cation I
More preferred
the 6-membered ring is aroamtic
H
+
H
N
H
H
N
H
NO2
PhCOONO2
N
H
N
H
O
CH3
N
O
Ac2O
AcOH / Δ
CH3
Ac2O
N
H
Na Ac /Δ
N
Ac
I
Br
Br2
I2
N
H
EtOH
N
H
SO3-
N
SO3N Pyridine / heat
H
N
H
Dioxan / 0°C
SO3H
H+
N
H
N
H
CH2N2
SO3Me
N
H