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: NH NH 2 3 O N N CO2 N Me PYRAZOLE MeN 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 N 1.649 N 1.502 1.647 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'' H2N R'' HN R'' H O HN R'' H 2 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 <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: 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 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 NH Me Cl 2 PYRIMIDINE N Me PYRAZINONE N PYRIMIDINONE N N Et Me HO2C N O S N N O H 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.