1

Chemistry II (Organic)

Heteroaromatic Chemistry

LECTURE 8

Diazoles & diazines: properties, syntheses &

reactivity

Alan C. Spivey a.c.spivey@imperial.ac.uk

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