1
Chemistry II (Organic)
Heteroaromatic Chemistry
LECTURE 8
Diazoles & diazines: properties, syntheses &
reactivity
Alan C. Spivey [email protected]
Mar 2012
2
Format & scope of lecture 8
• Diazoles:
– Imidazole & pyrazole
– Structure & properties
– Synthesis
– Reactivity
• Diazines:
– pyrimidines, pyrazines & pyridazines:
– structure & properties
– syntheses
– reactivity
Diazoles: Imidazoles & Pyrazoles – Importance
Natural products:
Pharmaceuticals:
Agrochemicals:
histamine(inflammatory)
N
NH
NH2
histidine(protein constituent)
N
NH
NH3
CO2 MeN
NMe
N
N
O
O
caffeine(tea/coffee stimulant)
IMIDAZOLE IMIDAZOLEIMIDAZOLE
NNH
Me
HO2C
PYRAZOLE
4-methylpyrazol-3(5)-carboxylic acid('fire sponge' marine natural product)
PYRAZOLE
NN CF3
Cl
ClN
SF3C
H2NO
fipronil(insecticide)
IMIDAZOLE
NN
prochloraz(fungicide)
O
NCl
Cl
Cl
Diazoles – Bonding & acid/base properties of pyrazole and imidazole
Diazoles can be considered as related to pyrrole but containing an additional N in place of one CH group:
in both cases the ‘new’ N is pyridine-like, i.e. this N contributes just 1 electron to the aromatic p-system and has
a basic lone pair in the sp2 orbital in the plane of the ring:
For a recent theoretical discussion of pyridine- vs. pyrrole-like Ns in imidazole see: Richaud Org. Lett. 2011, 972
[DOI]
Imidazole and pyrazole are both NH-acidic (pKas 14.5 & 14.2 respectively; cf. pyrrole 17.5). The basicity of the
pyridine-like N varies significantly:
imidazole is a stronger base than pyridine whereas pyrazole is a weaker base than pyridine:
NN
H
N
N
H
pyrazole imidazole1
2
1
3
H
imidazole (pKa 7.0)
NN
H
N
N
H
pyrazole (pKa 2.5)
N
N
H
H
N
N
H
HH
NN
H
HN
N
H
HN
HN
H
pyridine (pKa 5.2)
Imidazole and pyrazole – Structure and Properties
Imidazole: colourless prisms, mp 88 °C; pyrazole: colourless needles, mp 70 °C
Bond lengths and 1H NMR chemical shifts as expected for aromatic systems:
Resonance energies: both systems have lower resonance energies than pyrrole (i.e. <90 kJmol-1)
Electron density: relative to pyrrole, the additional (electronegative) N atom decreases the overall electron density
on the remaining carbons. The precise distribution is rather uneven:
for imidazole: C4 & C5 are electron rich, C2 is electron deficient
for pyrazole: C4 is electron rich, C3 & C5 are electron deficient
→ both pyrazole and imidazole are:
significantly less reactive towards electrophilic aromatic substitution (SEAr) than pyrrole (but >benzene)
reactive towards nucleophilic aromatic substitution (SNAr) at certain Cs (cf. pyrrole which does not react
with nucleophilies)
1H NMR:
1.33 Å1.36 Å
1.35 Å
cf. ave C-C 1.48 Å
ave C=C 1.34 Å
ave C-N 1.45 Å
bond lengths:
7.1 ppm1.38 Å
7.7 ppmN
N
H
N
N
H1.37 Å
N
N
H
7.1 ppm
1.35 Å1.36 Å
1.37 Å
1.42 Å
1.31 Å
NN
H
7.6 ppm
6.3 ppm 7.6 ppm
imidazole pyrazole imidazole pyrazole
NN
H
N
N
H
NH
p-electron densities:
1.087
1.647
1.0900.957
1.649
0.972
1.502
0.884
1.5021.056
1.056 1.278
1.105
imidazole pyrazole pyrrole
2
4
5
34
5
Imidazoles and pyrazoles – Syntheses
Imidazoles:
a-haloketone with amidine:
1,2-dicarbonyl & an aldehyde with NH3:
Pyrazoles:
hydrazine with 1,3-dicarbonyl:
1,3-dipolar cycloaddition of diazoalkane with alkyne:
Hpt N
N
H
N
N R R''
R
R'O
ClNH
H2N R''
NH
HN R''
R OH
R'Cl
pt
H2O
N
HN R''
R
R'Cl
pt
HClH
N
N
R
R' R''H
R
R'
pt
NN
H
R
R'
N
N
R''
NN
R
R'
R'' #
N
N
H R''R
R'
pt
R''R
R'
pt
2x H2O
N
N
H
N
RN
OR
OR'
+NH3
NH3
NHR
NHR'
+O
R''
pt
H2ON
NR
R'
R''
H
ptR
R'+
O
R''
H
pt
H2NNH2
+H
NN
H
NN
R'
RO
O
R'
RO pt
H2O R'
RO
NNH2
HN
OH
NH2
H
pt NH
N
R'
R OH2
H
H2O
R
R'
Imidazoles and pyrazoles – Reactivity
Electrophilic substitution: via addition-elimination (SEAr):
reactivity: reactive towards many electrophiles (E+); >benzene but <pyrrole, furan & thiophene
regioselectivity: substitution at electron rich carbons predominate (cf. electronic distribution):
imidazole: C4 > C5 (for NR systems; if NH then C4 and C5 are identical)
pyrazole: C4 – less reactive than imidazole
e.g. nitration: (E+ = NO2+)
imidazole:
e.g. chlorination: (E+ = Cl+)
pyrazole:
NB. electron donating substituents enhance reactivity towards electrophiles
NH
N
N
NH
4imidazole
4
5
pyrazole
E
E E
HNO3N
NH
4N
NH
4O2N
N
NH
1) HNO3
2) NaOH O2N
O2N5
Cl2, AcOH
NH
NNH
N
4Cl
Nucleophilic substitution: via addition-elimination (SNAr)
reactivity: reactive towards good nucleophilies (Nu-) provided leaving group is situated at appropriate carbon
regioselectivity: substitution of leaving groups (e.g. Cl, Br, NO2) at electron deficient centres possible (cf.
electronic distribution):
imidazole: C2 – relatively reactive centre
pyrazole: C5 ~ C3 – neither centre very reactive
e.g. displacement of Br by amine: (Nu- = R2N-, LG = Br)
imidazole:
NB. electron withrawing substituents enhance reactivity towards nucleophiles
Imidazoles and pyrazoles – Reactivity cont.
NH
N
N
NH
3
5
imidazole2 pyrazole
(difficult)
Nu
LGLG
LG
Nu
Nu
N
N
2N
N
Me
Br
HN
200 °CN
Me
Imidazoles and pyrazoles – Reactivity cont.
Metallation: (imidazole NH pKa = 14.5; pyrazole NH pKa = 14.2)
deprotonation by strong bases more facile than for pyrrole (pKa = 17.5) or indole (pKa = 16.2):
Diazines: Pyrimidines, Pyridazines & Pyrazines – Importance
Natural products:
Pharmaceuticals:
Agrochemicals:
orotic acid(biosynthetic intermediate
for natural pyrimidines)
thiamine - vitamin B1(essential vitamin)
NH
N
N
N
NH2O
HO2C O Me
N
S
Me
OH
Cl
NH
N Me
MeO
Me
Et
aspergillic acid(fungal antibiotic)
PYRIMIDINONE PYRIMIDINE PYRAZINONE
N
N
NH N
N tBu
O
ClBu
tOMe
MeO NH
O
S
MeO2CO O
NH
NO
OH
bensulfuronmethyl(herbicide)
pyridaben(herbicide)
maleic hydrazide(plant growth inhibitor)
N
N
OP
S
OEtOEt
thionazin(soil insecticide)
PYRIMIDINEPYRIDIZINONE
PYRIDIZINONE
PYRAZINE
Diazines – Bonding, Structure & Properties
Diazines can be considered as related to pyridine but containing an additional N in place of one CH group:
in all cases the ‘new’ N is pyridine-like, i.e. this N contributes just 1 electron to the aromatic p-system and has a
basic lone pair in the sp2 orbital in the plane of the ring:
All three diazines are significantly less basic than pyridine:
pyrimidine
N
N
1
3
NN
1
2pyridazine
NN
1
2pyrazine
N
N
1
4
H
pyrimidine (pKa 1.3)
N
N
NN
pyridazine (pKa 2.3)pyrazine (pKa 0.4)
N
N
N
NH H
N
N
H
H NN
H
N
N
pyrimidine pyridazinepyrazine
NN N
N
Diazines – Structure and Properties
Pyrimidine: colourless prisms, mp 22 °C
Pyridazine: colourless liquid, bp 208 °C
Pyrazine: colourless prisms, mp 57 °C
Bond lengths and 1H NMR chemical shifts as expected for aromatic systems:
Resonance energies: all three systems have lower resonance energies than pyridine (117 kJmol-1)
→ susceptible to nucleophilic addition reactions
Electron density: all three systems are highly electron deficient (cf. ~pyridine)
→ unreactive towards electrophiic substitution (SEAr)
→ reactive towards nucleophilic substitution (SNAr)
1H NMR:
1.33 Å1.35 Å
cf. ave C-C 1.48 Å
ave C=C 1.34 Å
ave C-N 1.45 Å
bond lengths:
9.3 ppm
1.39 Å1.37 Å
8.6 ppm
1.34 Å
1.34 Å
1.40 Å
7.5 ppm
8.8 ppm
9.2 ppm
pyrimidine
N
N
pyridazine
NN
pyrazine
N
N
1.34 Å
1.39 Å
pyrazine
N
N
pyrimidine
N
N
pyridazine
NN
7.4 ppm
Diazines – Syntheses
Pyrimidines:
Pinner: 1,3-dicarbonyl with amidine
Pyrazines:
dimerisation of a-aminoketone/aldehyde then aerial oxidation:
Pyridazines:
‘Paal-Knorr’: 1,4-dicarbonyl with hydrazine
ptNH
H2N NH
NOEt
O
OEtO H
OH
O
N
N R
N
O OEt NH2
O
EtOH
pt
EtOHNH
N
O
O
pt
pt
N
pt
H2ON
NH2H2N NN
Me
MeMe O
Me
O
HO
NOMe
HO
NH2
Me
NN
Me
Me
HO
H2O
pt
H2O
pt
NNH
Me
Me
HO
NB. hydroxyl 'leaving group' in 1,4-dicarbonyl obviates oxidation
pt
N RH2O
NR NH2
OBn N
N Bn
Bn
H2, Pd/C
Bn Cl
O CH2N2 pt
H2O
N2
OBn H2N
O Bn
2H
NBn
H2N O Bn
N
N
Bn
Bn air
H
H
Diazines – Reactivity
Electrophilic addition at N:
formation of N-oxides as for pyridine; these derivatives are more susceptible to SNAr (and SEAr) than the parent
diazines:
Electrophilic substitution: via addition-elimination (SEAr)
all diazines are highly electron deficient → very unreactive towards SEAr
electron donating substituents and/or N-oxides (see above) required to allow reaction even at C5 of
pyrimidine:
regioselectivity: via most stable Wheland intermediate
N
N
OH
OHMe N
N
OH
OHMe
O2N
NH
NH
O
OMe
O2Nc.HNO3/HOAc
20°C [85%]5
3x electron releasingi.e. 'activating' groups
NB. no reaction onpyrimidine itself
Diazines – Reactivity
Nucleophilic substitution: via addition-elimination (SNAr)
all diazines are highly electron deficient → very reactive towards SNAr (>pyridines)
all halodiazines except 5-halopyrimidines react readily with nucleophilies:
Metallation:
all diazines can be metalated ortho to N by LiTMP (pyrimidine at C4 not C2):
2
pyrazine
N
N
[44%]
NLi
N
N
Li
I2
N
N
I
[73%]N
NBu
Bu
O
N
NBu
Bu
O
I
pyrazine-N-oxide
NLi
N
NBu
Bu
O
Li
I2