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Chemistry II (Organic)

Heteroaromatic Chemistry
LECTURE 8
Diazoles & diazines: properties, syntheses &
reactivity
Alan C. Spivey
[email protected]

Mar 2012
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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:
NH2 NH3
O
N N CO2 MeN N Me PYRAZOLE
IMIDAZOLE NH
N IMIDAZOLE N IMIDAZOLE O N N N
H H Me HO 2C
histamine histidine caffeine 4-methylpyrazol-3(5)-carboxylic acid
(inflammatory) (protein constituent) (tea/coffee stimulant) ('fire sponge' marine natural product)

 Pharmaceuticals:

 Agrochemicals:

O H2N Cl PYRAZOLE IMIDAZOLE

S O
F3C N CF3 N Cl
N N
N
N Cl Cl
fipronil prochloraz
(insecticide) Cl (fungicide)
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:
3
N
pyrazole N
N1 2 imidazole
N1
H H
 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:

H H
N H N H
N
N N H N H
N N N N N
N N N
H H H H H H
H H

imidazole (pKa 7.0) pyrazole (pKa 2.5) 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:
bond lengths: 1
H NMR:
1.38 Å 1.42 Å
cf. ave C-C 1.48 Å 7.1 ppm 6.3 ppm 7.6 ppm
1.36 Å N 1.33 Å 1.37 Å 1.31 Å N
N ave C=C 1.34 Å 7.1 ppm 7.7 ppm N
N N 7.6 ppm
N ave C-N 1.45 Å N
1.37 Å H 1.35 Å 1.36 Å 1.35 Å
H H H
imidazole pyrazole imidazole pyrazole

 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

p-electron densities: 1.056 4 1.105 4 3 0.972

N 1.502 1.090
0.957 5 N 1.278 1.087
1.056 5 2 0.884
N 1.502 N 1.649 1.647 N
H H
H
imidazole pyrazole pyrrole

 → 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)
Imidazoles and pyrazoles – Syntheses

 Imidazoles:
 a-haloketone with amidine:
R R OH H R
O R R
N pt pt pt pt N
R' NH NH N H N
R R' R' R''
N Cl R' R' N
H2N R''
Cl
HN R''
Cl
HN R'' N R''
H2O H HCl H

 1,2-dicarbonyl & an aldehyde with NH3:

R
N R O NH3 pt R NH pt R N R'' pt N
O O
+ + +
N R' O NH3 R'' R' NH R'' R' N H R' N R
2x H 2O H2O H

 Pyrazoles:
 hydrazine with 1,3-dicarbonyl:
R R R H R OH2 R
O pt O pt O pt
N + H NH
N NH2 N NH2 NH2 H N N H
O H2N R' N
OH N
R' R' H2O R' R' H2O H
H

 1,3-dipolar cycloaddition of diazoalkane with alkyne:

R R'' # R R''
R'' H R''
R R pt

N N N N
R' N
N R' N R' N
R' H
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

imidazole E pyrazole E
4 N 4
5 N
N N
E H H

 e.g. nitration: (E+ = NO2+)

 imidazole: O2N 4
1) HNO3
HNO3 N 2) NaOH O2N 4
N N
5
N N O2N N
H H H

 e.g. chlorination: (E+ = Cl+)

 pyrazole: Cl 4
Cl2, AcOH
N N
N N
H H

 NB. electron donating substituents enhance reactivity towards electrophiles

Imidazoles and pyrazoles – Reactivity cont.
 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

imidazole N 3 LG
2 pyrazole
N LG (difficult) 5
N
LG N Nu
H
H
Nu
Nu

 e.g. displacement of Br by amine: (Nu- = R2N-, LG = Br)

 imidazole:

HN
N N
2
N Br N N
200 °C
Me Me

 NB. electron withrawing substituents enhance reactivity towards nucleophiles

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:
O NH2
Me Cl
N PYRIMIDINONE PYRIMIDINE N Me PYRAZINONE
N N
HO2C N O Et Me
S N Me N O
H
OH Me H
orotic acid thiamine - vitamin B1 aspergillic acid
(biosynthetic intermediate (essential vitamin) (fungal antibiotic)
for natural pyrimidines)

 Pharmaceuticals:

 Agrochemicals:
PYRIMIDINE
OMe But PYRIDIZINONE
Cl OH N PYRAZINE
MeO C S
N O O 2O O
S
N P OEt
O N N O OEt
MeO N N N N H PYRIDIZINONE
H H N tBu

bensulfuronmethyl pyridaben maleic hydrazide thionazin

(herbicide) (herbicide) (plant growth inhibitor) (soil insecticide)
Diazines – Bonding, Structure & Properties

 Diazines can be considered as related to pyridine but containing an additional N in place of one CH group:
4
N
pyrimidine N3 pyrazine pyridazine
N N N2 N2
1 1 N N
1 1

 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:

N N N N
N
N

pyrimidine pyrazine pyridazine

 All three diazines are significantly less basic than pyridine:

H
H H N H N
N N
N N
N N N N N N H
H

pyrimidine (pKa 1.3) pyrazine (pKa 0.4) pyridazine (pKa 2.3)

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:

bond lengths: 1
H NMR:
7.5 ppm
N 1.37 Å 1.39 Å N
N 7.4 ppm N 9.2 ppm
cf. ave C-C 1.48 Å
1.40 Å 1.39 Å 1.34 Å N
N ave C=C 1.34 Å 8.8 ppm N 9.3 ppm N 8.6 ppm N
1.35 Å N 1.34 Å N 1.34 Å N
1.33 Å ave C-N 1.45 Å
pyrimidine pyrazine pyridazine pyrimidine pyrazine pyridazine

 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)
Diazines – Syntheses

 Pyrimidines:
 Pinner: 1,3-dicarbonyl with amidine
O O O OH
N OEt NH pt N pt N pt N
N R O OEt H2N H O OEt NH2 O N O N
EtOH EtOH H H

 Pyrazines:
 dimerisation of a-aminoketone/aldehyde then aerial oxidation:

R N N2 NH2 O Bn pt H2N O Bnpt H N Bn

O CH2N2 H2, Pd/C air N Bn

N R Bn Cl Bn O Bn O H2N Bn N Bn N H Bn N
H2O H2O 2H

 Pyridazines:
 ‘Paal-Knorr’: 1,4-dicarbonyl with hydrazine

HO Me pt HO Me pt HO Me pt HO Me pt Me
O HN NH2 N
N Me O 2 N NH N
N Me O NH2 Me N Me N Me N
H2O H2O H2O

NB. hydroxyl 'leaving group' in 1,4-dicarbonyl obviates oxidation

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:

3x electron releasing OH OH O
c.HNO3/HOAc
i.e. 'activating' groups O2N 5 O2N
N 20°C N NH [85%]
Me N OH NB. no reaction on Me N OH Me N O
pyrimidine itself H

 regioselectivity: via most stable Wheland intermediate

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):

N N N I2 N
Li
pyrazine [44%]
N N 2 Li N I

Bu N N Bu N Bu N
Li I2
pyrazine-N-oxide [73%]
N Bu Li N Bu I N Bu
O O O