Professional Documents
Culture Documents
IN POSITIONS 1, 2
1. General
2. Syntheses
2.1. Isoxazoles and pyrazoles
2.2. Isothiazoles
3. Functionalisation
3.1. Functionalisation by electrophilic substitution at C-4
a) Nitration
b) Sulfonation
c) Halogenation
HETARENE PENTAATOMICE CU
DOI HETEROATOMI IN POZITIILE 1,2
1. Generalitati:
a) reprezentanti tipici: 1,2 - azolii
4
N2
N2
N
H
1,2-tiazOL
izotiazol
N2
O
1
1,2-diazOL
pirazol
1,2-oxazOL
izoxazol
b) caracterul aromatic: caracter aromatic in general mai scazut decat analogii 1,3 - azoli: S >
NH > O.
_
_
N
1 2N
X
+
X
+
N-2:
_
N
(O > S > N)
N
X
+
X
+
c) caracterul acido bazic: bazicitate sensibil mai scazuta decat analogii 1,3-azoli
Echilibrul
+H+
-H+
NH
NH
N
N
H
N
+H+
-H+
+H+
+ NH pKb
pKa
X
11.5
2.5
14.5
- 0.5
17.0
- 3.0
pKa
pKb
14.2
- 0.2
pKb
pKa
7.0
7.0
11.5
2.5
13.2
0.8
14.4
- 0.4
N
N
NH
NH
N
N_
X
+
NH
+H+
-H+
N
H
-H+
Marimea de
definitie
N
N_
NH
+
X
_
N
pKa
pKb
+ 0.025
N - 0.269
+ 0.051
N1
H
charges
N
N
H
values (ppm)
7.35
_N N
1
1H - NMR
8.57
NH
pyrazolium
cation
- 0.097
3
2
N
O1
+ 0.075
N - 0.279
O + 0.200
+ 0.101
izoxazole
as neutral form
4
5
O1
values (ppm)
charges
- 0.095
+ 0.052
+ 0.047
N - 0.283
S + 0.280
8.54
7.26
1H - NMR
8.72
NH
izothiazolium
cation
13C - NMR
9.60
157.0
9.10
1H - NMR
123.4
147.8
values (ppm)
charges
7.90
2
NH
values (ppm)
S1
9.01
izothiazole
as neutral form
9.18
7.26
1H - NMR
S1
8.14
8.39
HH
NH
6.28
izoxazolium
cation
4
8.57
1H - NMR
3
2
N
N
H
values (ppm)
N
H
values (ppm)
N1
H
134.6
_N N
6.87
2
134.6
values (ppm)
pyrazole
as anionic form
4
105.8
7.35
6.05
1H - NMR
2
5
13C - NMR
7.61
N + 0.300
H
pyrazole
as neutral form
7.61
7.31
1H - NMR
NH
values (ppm)
values (ppm)
Nota 1: influenta - vecinatatii heteroatomilor se face resimtita mai mult asupra valorilor pKa ale
speciilor protonate (1,3 - azolii protonati sunt specii mai slab acide decat 1,2 - azolii protonati)
Consecinta 1: functionalizarea prin SE la CH= heterociclic se realizeaza in conditii mai putin dure
Nota 2: influenta - vecinatatii atomilor de azot este nesemnificativa asupra valorilor pKa ale
speciilor neutre (pirazol vs. imidazol).
Nota 3: in ambele cazuri se manifesta direct efectul I al heteroatomului X asupra azotului piridinc
(paralelism accentuat intre intensitatea efectului I si valorile pKb ale speciilor neutre)
c) tautomeria pirazolilor:
-fenomen dinamic rapid (tautomerie prototropica) in scala de timp spectrala
- consecinta: echivalenta pozitiilor C-3 si C-5 in cazul derivatilor mono-, di- sau tri- Csubstituiti
3
N baza tare
N1
H
baza tare
acid slab
tautomer 2H
tautomer 1H
R3
R2
R3
R2
R1
N H acid slab
N1 2
5
1
N2
R1
N1
H
NH
N
2
2. Sinteze:
2.1. Izoxazoli si pirazoli:
a) deconectare hidrolitica: (1-5)-(2-3)
R2
R3
R3
R2
R1
R2
R3
N2
X
OH HX
R2
R1
R3
R1
XH
R1
R3
R2
R1
R2
O
O HX
NH2
-2H2O
R1
R2
R2
O
N2
X
1
ciclizarii daca R R R3 si X NH
R3
R3
HX
X = O, hidroxilamina
X = NH, NR hidrazina
(optional) substituita
1,3-dicetona
-aspect particular: r e g i o s e l e c t i v i t a t e a
NH2
R1
O H2N
XH
R3
5
-2H2O
R1
X1
N
2
O2N
O2N
NO2
5-(4-Methoxyphenyl)-3-(3-nitrophenyl)-izoxazole
4
-H2O
NH2
O HO
CH3O
CH3O
OH
N2
O
1
C6H4-OCH 3-p
CH3O
p+ = - 0.78
m-O2N-C6H4
N2
O
1
Cl p = + 0.24
3-(4-Chlorophenyl)-4-methyl-5-phenylizoxazole
Cl
H3C
H3C
H3C
-2H2O
NH2
O HO
Ph
4 3
p-Cl-C 6H4
N2
N2
O
OEt
COOEt
3
4
N2
-2H2O
NH2
N1
EtOOC
5-Cyclopropyl-3-ethoxycarbonyl-1-phenylpyrazole
Ph
N2
N1
Ph
O HN
Ph
A=B
A=B
CH3
O
efect
X NH2
O
O
H
O
H
89.2% ca enol
D
A=B: electronoatragatori
D: electronodonori
4e
_
_
Dipol
#
_
2e
ST
Stare de Tranzitie
+
Dipolarofil
E ( < 0 !)
- 0.577
Dipola rofil
+ 0.577
OMA*
LUMO: - 1.414
+ 0.707
+ 0.577
- 0.707
LUMO: - 1.000
+ 0.707
E min. = -1.000
E max. = -2.414
OMN
HOMO: 0.000
- 0.707
+ 0.707 + 0.707
HOMO: + 1.000
+ 0.577
+ 0.577
OML
NHOMO: + 1.414
+ 0.577
orbitali s t e r e o d i r e c t o r i: - 1.000
LUMO
DIPOLAROFIL
ACCEP TOR
HOMO
DIPOL
DONOR
4e
2e
ST
Stare de Tranzitie
anion ciclopentadienil
Dipol
Dipolarofil
OMF implicati
LUMO
Anion alil
Acetilena
HOMO
0.000
+ 1.500
- 1.414
- 1.300
4e
_
#
_
N
2e
N _
N
_
ST
Stare de Tranzitie
anion pirolat
Dipol
Dipolarofil
OMF implicati
Anion azaalil
Acetilena
S
T
E
R
E
O
D
I
R
E
C
T
O
R
I
LUMO
HOMO
- 1.117
- 1.300
0.000
+ 1.500
+ 0.707
Acceptor
Donor
+ 0.707
Limitele teoriei: in pofida faptului ca diferentele de energie minime calculate (LUMO HOMO)
sunt aceleasi in ambele cazuri, numai aditia anionilor azaalil (substituiti) se cunoaste la
acetilena
Dipol
nitriloxid
Exemplul 1:
CH3
H3C
EX CLUS I V
CH3O
CH3O
O
1
CH3O
CH3O
H3C
CH3
3
N2
N 2 5-Methoxy-3-methylizoxazole
LIPSA
E ( < 0 !)
CH3
CH3O
Dipolarofil
LUMO
ELUMO = - 1.361
LUMO
Dipol
ELUMO = - 0.245
E = - 1.418
E = - 2.764
EHOMO = + 1.173
HOMO
orbitali
st e r e o d i r e c t o r i
HOMO
EHOMO = + 1.403
LUMO Dipol
ACCEP TOR
CH3O
+ 0.631
H3C
+ 0.772
+ 0.483
CH3O
N
O
ST
starea de tranzitie
CH3
+ 0.238
-
CH3O
N
O
R3
R3
R2(1)
R2(1)
C
R1(2)
LG
Dipola rofil
N+
R1(2)
LG
4
5
- LGH
R3
R2(1)
4
5
R1(2)
N2
O
N2
O
2-izoxazolina
Dipol
C
H3CO
CH3O
N+
O
EHOMO (+ 0.809 )
ELUMO (- 1.068 )
HOMO Dipolarofil
DONOR
CH3
CH3
CH3
- MeOH
N2
N 2 majoritar
O
3-Methyl-5-methoxy-2-izoxazoline
LUMO Dipol
ACCEP TOR
ELUMO (- 0.245 )
EHOMO (+ 1.403 )
+ 0.709
H3C
+ 0.772
CH3O
+ 0.574
N
O
CH3O
ST
starea de tranzitie
+ 0.238
-
CH3
CH3O
N
O
R-CH=N-OH
H
CH N O H
Cl
O H
-H2O
R C N O
Cl
_ H+
R-C N +-O_
N O
Cl
Cl
oxidanti: Cl2/NaOH
Pb(OAc)2
NBS
R1(2)
R2(1)
R3
CH
N2
N+
R3
R2(1)
N1
H
R1(2)
R3
_
CH
N
+N
Dipola rofil
Dipol
Exemplul 1:
- sinteza pirazolului ca atare:
+ 0.707
CH2
+ 0.672
_
N
N+
N
H
N
- 0.707
- 0.483
HOMO - donor
LUMO - acceptor
Orbitali stereodirectori
Acetilena
Diazometan
()
EHOMO
ELUMO
+ 1.500
+ 0.536
E = -1.836
- 1.300
- 0.924
Exemplul 2:
- regioselectivitate practic totala la prepararea 4-cianopirazolului
N
C
+ 0.575
NC
CH2
N+
CN
+ 0.672
_
N
N
N
H
N
Orbitali stereodirectori
- 0.378
LUMO - acceptor
()
EHOMO
+ 1.132
+ 0.536
NC
- 0.483
HOMO - donor
ELUMO
- 0.920
- 0.924
E = -1.456
N
N
H
urme
Br
4
N
H
1
5
HO
N2
O
1
Br
Br
N
Br
K2CO3
-HBr
+
N
[4 + 2]
total
regioselectiva
Br
Br
O
O
N+
Br2
-HBr
regioizomer unic
generata in situ
Br
Br
N
O
H2N
Br
NaBH4
Br
Br
+ NaH
N
N
O
HO
- H2, -NaBr
H:
Br
N
H
N
HO
deschidere total
regioselectiva
prin control steric
al t-Bu
2.2. Izotiazoli:
a) ciclizarea redox a - iminotioamidelor:
Grupare +E
H3C
OEt
exces NH3
O
H3C
H
H3C
HN
NH
N
H3C
oxidare
NH
-HCl Me
N
H +
blanda
Cl
NH2
H3C
NH H
- NH3
tionare
oxidare blanda
O
NH S
Cl
NH2
Me
NH
NH2
5
Cl
5-Amino-3-methyl
izothiazole
R
+
2+
O
R
O
+
2 Na
SO3H
acid S-sulfonic
(tiosulfatul alchenei)
O
S
N
R
NH3
S O
- H+
HO
SO3H
SO3H - + H
3. Functionalizarea:
-
orientarea data de
catre N-piridinic
E+ ( pozitie "orto" )
+
N
X
+ N
X
( pozitie "para" ) E
N
X
i) in C - SE
ii) in metalare
orientarea data de
catre heteroatom
R-Li
N
X
1
OH
HO3S
O3S
NH
+
NH
N
H
N
H
+
N
H
N
N
H
N
H
pKa = + 6.9
pKa = + 2.5
HO3S
N
O3S
NH
+
NH
S
+
S
N
S
pKa = - 0.5
O2N
la f i e r b e r e a
amestecului n i t r a n t
N
N
H
N
H
Br
Br
Br
Br
-HBr
N
X
X
+
X
-
H Br
X = O; Br2 (l)
X = NH; Br 2 / AcONa
Br
Br
Br
H2N
N
S
+
H2N
H Br
Br
i) -HBr
N
S
ii) HO -
H2N
NH
250oC
pKa = + 2.5
O2N
N
H
NH
160oC
N
S
Li
- EtOLi
N
S
N
S
EtO
5-Ethoxyoxalylizothiazole
O
i) n-BuLi (-78 oC)
H3C
N
N
N
N
Ph
Ph
Ph
Ph
N
Ph
Ph
Li
N
O
Ph
OLi
instabil
CN
CH3
H3C
Li
H2C
CH3
PhCH2Br
-LiBr
Ph
analogie cu deprotonarea
compusilor crotonici
CH3
H2C
Li
OLi
Li
CH3
Br
O C O
CH3
Li
OH
O
CH3
CH3
4
H3C
N
O
Br2
H3C
N
O
H3C
N
O
H3C
N2
O
1
4-Carboxy-3,5-dimethyl
izoxazole
- unii pirazoli N - metilati pot stabiliza carbanioni prin deprotonarea selectiva a acestei
grupe ( - stabilizare) in prezenta altora:
-pozitie fata de
carbonil mascat
CH3
CH3
Me
+ MeI
H3C
-pozitie fata de
carbonil mascat
H3C
N
CH3
N
N
Me
-LiI
Li
N
N
Et
Nu au valoare preparativa
sunt reactii electrociclice permise fotochimic
sunt cunsocute doua mecanisme principale prin care unii 1,2-azoli se transforma in 1,3-azoli:
a) izoxazoli oxazoli (via 2H - azirine):
*
N
H
N
H
N
2
1H - azirina
2H - azirina
Ph
h
N
S
Ph
Ph
S
aziridina