(Organic) Heteroaromatic Chemistry LECTURE 8 Diazoles & Diazines: Properties, Syntheses & Reactivity

1 Chemistry II (Organic)

Heteroaromatic Chemistry LECTURE 8 Diazoles & diazines: properties, syntheses & reactivity

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:

NH2 NH3 O N N CO N PYRAZOLE 2 MeN Me IMIDAZOLE NH N IMIDAZOLE N IMIDAZOLE O N N N H H Me HO2C 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 Cl N CF3 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:

N 3 N pyrazole N 2 imidazole 1 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 H N H N N N N N N N H H N N N N N N H H H H H H H H

pyridine (pKa 5.2) imidazole (pKa 7.0) pyrazole (pKa 2.5) 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:

b ond lengths: 1H NMR: 1.38 Å 1.42 Å cf. ave C-C 1.48 Å 7.1 ppm 6.3 ppm N 1.31 Å N 7.6 ppm 1.36 Å 1.33 Å 1.37 Å ave C=C 1.34 Å N 7.1 ppm 7.7 ppm 7.6 ppm N N N N N 1.36 Å 1.35 Å ave C-N 1.45 Å 1.37 Å H 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: 1.105 4 3 1.056 4 N 1.502 0.972 1.090 0.957 1.056 5 2 0.884 5 N 1.278 1.087 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 R O pt pt R pt N N pt N R' NH R' NH R' N H R'' R Cl R' N N Cl Cl R' N R'' H N R'' HN R'' HN R'' H 2 H2O H HCl

 1,2-dicarbonyl & an aldehyde with NH3: R R O R NH pt R pt N NH3 O pt O N R'' N + + + N H R R' O NH3 R'' R' NH R'' R' N R' N 2x H O H O H 2 2  Pyrazoles:  hydrazine with 1,3-dicarbonyl: R R R R H R OH2 O pt O pt O N + H pt NH NH NH2 H N H N O H N 2 N NH2 N R' N 2 OH N R' R' R' R' H O H H2O 2 H

 1,3-dipolar cycloaddition of diazoalkane with alkyne: R'' R R'' R'' # R R H R''  R pt N N N N R' N N N N R' R' R' H Imidazoles and pyrazoles – Reactivity

 Electrophilic substitution: via addition-elimination (SEAr):  reactivity: reactive towards many electrophiles (E+); >benzene but C5 (for NR systems; if NH then C4 and C5 are identical) . pyrazole: C4 – less reactive than imidazole

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

+ +  e.g. nitration: (E = NO2 )

. imidazole: 1) HNO3 O2N 4 HNO O2N 4 N 3 N 2) NaOH 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 LG (difficult) 5 N N Nu H LG N H Nu Nu

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

HN N N 2 Br N 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 NH Me Cl 2 PYRIMIDINE N Me PYRAZINONE N PYRIMIDINONE N N Et Me HO2C N O S N O H N Me 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 2 O O O N P OEt S O N N O OEt MeO N N N N t H PYRIDIZINONE H H N Bu

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 N 3 pyrazine pyridazine N 2 N 2 N N N N 1 1 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 H N 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 1.39 Å N 1.37 Å 7.4 ppm N N cf. ave C-C 1.48 Å N 9.2 ppm 1.40 Å 1.39 Å 1.34 Å N ave C=C 1.34 Å N N N N 8.8 ppm N 9.3 ppm N 8.6 ppm N 1. 35 Å 1.34 Å 1.34 Å 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 N NH O Bn H N O Bn H N Bn O CH2N2 2 H2, Pd/C 2 pt 2 pt 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 NH2 N Me O H2N N 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 elec tron releasing OH OH O c.HNO3/HOAc i.e. 'acti vating' groups O N 5 O N N 20°C 2 N 2 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 Li N I2 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