1 Chemistry II (Organic)
Heteroaromatic Chemistry LECTURE 7 Deprotonation & Benzo-heterocyces: Indoles & (Iso)quinolines
Alan C. Spivey [email protected]
Mar 2012 2 Format & scope of lecture 7
• Deprotonation of heteroaromatics: – Thermodynamic vs. kinetic deprotonation – azines – 5-membered heteroaromatics
• Benzo-heterocycles – Indoles & (iso)quinolines: – structure & properties – syntheses – reactivity 3 Deprotonation - thermodynamic vs kinetic
• Overall process:
• thermodynamic deprotonation using hindered lithium amide bases: – amine anions are poorly nucleophilic and undergo slow competitive addition reactions
– reversible equilibration, success depends on the pKa of the heteroaryl proton being lower than that of the amine:
LiTMP > LDA ArH + R2NLi ArLi + R2NH pK 37.3 N N a pKa 35.7 reversible Li Li
• kinetic deprotonation using alkyl lithium bases (RLi): – branched alkyl lithiums undergo slow competitive nucleophilic addition reactions – irreversible loss of RH, maximum basicity of alkyl lithiums is in non-co-ordinating solvents e.g. hexane (with TMEDA co-solvent to break up aggregates – i.e. form monomeric species)
Me2 Me2N Me2 ArH + RLi ArLi + RH (g) N Li N Li ~ ~ Li pKa ~45 irreversible N Me2N Me2 Me2N 4 Deprotonation - regioselectivity • kinetically and thermodynamically most acidic protons may differ: Deprotonation – azines 5 • Deprotonation of pyridines (and other azines): – Thermodynamically more favourable and kinetically faster than for benzene particularly for protons: • ortho to ring N • ortho to a “directing group (DG)” (see later)
– Thermodynamics: (pKa ArC=NH ~35 cf. benzene ~40) due to:
DG DG BUT: inductive and chelative pair-pair stabilisation stabilisation electron N Li N Li N Li repulsion
– Kinetics: due to:
DG DG Complex Induced inductive acidification and Li Proximity Effects H of ortho-protons R # N N H stabilising TS
– Low temperatures & bulky bases required to supress addition reactions to C=N function:
RLi as RLi as nucleophile base + RH (g) N R addition N lithiation N Li Li
– Reviews: Snieckus & Beak Angew. Chem. Int. Ed. 2004, 43, 2206 (DOI), Schlosser Angew. Chem. Int. Ed. 2005, 44, 376 (DOI). Deprotonation - 5-ring heteroarenes 6 • furans and thiophenes: – facile kinetic and thermodynamic deprotonation of hydrogens ortho to ring heteroatom
• pyrroles: N-protection is required to avoid NH deprotonation (see lecture 2) – electron withdrawing protecting groups enhance kinetic and thermodynamic acidity of ortho-hydrogens
• The concept of lateral protection can also be applied to deprotonation (cf. SEAr):
• NOT generally susceptible to addition reactions
Directing Groups - directed ortho-metalation (DoM) 7 • Many substituents kinetically and thermodynamically acidify hydrogens ortho to themselves: – e.g. 8 Pharmaceutical preparation by DoM
• losartan potassium: antihypertensive – Process route for Merck (Rouhi Chem. Eng. News 2002, July 22, 46) (DOI)
• efavirenz: anti-viral, anti-AIDS – Process route for Bristol-Myers Squibb (Rouhi Chem. Eng. News 2002, July 22, 46) (DOI) Indoles – Importance
Natural products: HO2C NMe N H H
H N N N NH2 N HO N H H H H H H H H H N NH O O O H H H MeO C 2 MeO2C OH 5-hydroxytryptamine lysergic acid strychnine ajmalicine yohimbine (seratonin) (ergot alkaloid psychadelic) (strychnos alkaloid poison) (vinca alkaloid) Pharmaceuticals:
Agrochemicals: O OH O OH O OH N N N H H H heteroauxin indole-3-propanoic acid seradix (plant growth regulator) (plant growth regulator) (plant growth regulator) Indole – Structure and Properties
A colourless, crystalline solid, mp 52 °C Bond lengths and 1H NMR chemical shifts as expected for an aromatic system:
bond lengths: 1 1.44 Å H NMR: 1.36 Å cf. ave C-C 1.48 Å 6.3 ppm ave C=C 1.34 Å 6.5 ppm 1.38 Å N N ave C-N 1.45 Å H H ~7 ppm 1.37 Å
Resonance energy: 196 kJmol-1 [most of which is acounted for by the benzenoid ring (cf. benzene, 152 kJmol-1, naphthalene, 252 kJmol-1 & pyrrole, 90 kJmol-1)]: → resonance energy associated with pyrrolic ring is significantly less than for pyrrole itself – hence enamine character of N1-C2-C3 unit is pronounced
Electron density: pyrrolic ring is electron rich, just a little less electron rich than pyrrole; benzenoid ring has similar electron density to benzene: electron neutral electron rich → very reactive towards electrophilic substitution (SEAr) at C3 (cf. benzene) N (cf. pyrrole) → unreactive towards nucleophilic substitution (S Ar) N H
NH-acidic (pKa 16.2; cf. pyrrole 17.5). Non-basic; as for pyrrole, the N lone pair is involved in aromatic system; protonation occurs at C3 (as for an enamine):
H H H
N N H H Quinolines & Isoquinolines – Importance
Natural products: OH HO HO HO H HO 9 N ISOQUINOLINE HO 9 N HO O N H H MeO OMe O H Me O N O N QUINOLINE QUINOLINE N N OMe HO tetrahydroISOQUINOLINES
quinine quinidine papaverine morphine lycorine (antimalarial) (opium alkaloid (analgesic) (anti-tumour) Pharmaceuticals: vasodilator)
Chiral catalysts: Sharpless Angew. Chem. Int. Ed. 2002, 41, 2024 (DOI): N N (DHQD) PHAL O O 2 N N H H (in AD-mix for Sharpless AD) MeO OMe
QUINOLINES N N Quinolines & Isoquinolines – Structure and Properties
Quinoline: colourless liquid, bp 237 °C; isoquinoline: colourless plates, mp 26 °C Bond lengths and 1H NMR chemical shifts as expected for aromatic systems:
bond lengths: 1H NMR: 8.00 ppm 7.50 ppm 1.39 Å 1.45 Å 1.38 Å 1.35 Å 8.45 ppm cf. ave C-C 1.48 Å 7.26 ppm 1.44 Å 1.39 Å N N ave C=C 1.34 Å N N 8.81 ppm 1.33 Å 1.34 Å ave C-N 1.45 Å 9.15 ppm
quinoline isoquinoline quinoline isoquinoline
Resonance energies: quinoline = 222 kJmol-1 (cf. 252 kJmol-1 naphthalene)
Electron density: for both systems the pyridinyl ring is electron deficient (cf. ~pyridine); the benzenoid ring is slightly electron deficient relative to benzene itself:
electron neutral electron deficient electron neutral electron deficient (cf. benzene) N N (cf. pyridine) (cf. benzene) (cf. pyridine)
quinoline isoquinoline
→ both quinoline and isoquinoline are:
. reactive towards electrophiic substitution (SEAr) in the benzenoid ring
. reactive towards nucleophilic subnstitution (SNAr) in the pyridinyl ring
Basic: both systems have pKas similar to pyridine (5.2): N N quinoline: pKa = 4.9 H H
isoquinoline: pKa = 5.1 isoquinoline (pKa 5.1) Indoles – Syntheses
Fischer: aryl hydrazine with enolisable ketone
R imine tautomer enamine tautomer R + R' R R H pt R' NH N 2 O N N N R' N N R' NH R'' [3,3]-sigmatropic N 2 H H2O R'' H R'' H2 rearangement R'' aryl hydrazine protonated aryl hydrazone
R H R R' R' N N NH3 R'' R'' H NH3
NOTES: aryl hydrazone cyclisation under acidic or Lewis acidic conditions high temperature (≥150 °C) but varies with catalyst & solvent etc. ketones that are able to form regioisomeric enamines can give mixtures of products but cyclisation is preferred via more substituted enamine (i.e. the more thermodynamically stable one) driving forces:
. 1) loss of H2O & NH3 [i.e. DS° +ive, entropically favourable] . 2) N-N (weak bond) broken & C-C (strong bond) formed [i.e. DH° -ive, enthalpically favourable] . 3) aromaticity of product indole [i.e. DH° -ive, enthalpically favourable] Quinolines & Isoquinolines – Syntheses
Quinolines:
Doebner-von Miller: enone with aniline then in situ oxidation:
. via apparent 1,4-addition of aniline NH2 group to enone then cyclodehydration then dehydrogenation (oxidation) by the imine formed between the enone and aniline in a side reaction
(Tetrahydro)isoquinolines:
Pictet-Spengler: -phenethylamine with aldehyde (intramolecular Mannich)
(Dihydro)isoquinolines:
Bischler-Napieralski: -phenethylamine with acid chloride
Cl N NH pt 2 HN R N R N H NH Cl O O H Cl N O O Cl Cl H HCl P P R R Cl HCl R R CCl l Cl Cl PO2Cl Cl O Indoles – Reactivity
Electrophilic substitution: via addition-elimination (SEAr) in the pyrrolic ring reactivity: reactive towards many electrophiles (E+); ~pyrrole regioselectivity: the kinetic 3-substituted product predominates (cf. 2-position for pyrrole); predict by estimating the energy of the respective Wheland intermediates → 3-substitution is favoured:
stable because positive E E charge is on nitrogen H 3 H N N major product 3 H H (3-subst.) E 2 N H E 2 E minor product N H N H (2 subst.) H H
benzylic cation but can't derive stabilisation from nitrogen without disrupting benzenoid aromaticity
+ + e.g. nitration: (E = NO2 ) NO 3 2 BzONO2 N N H H Indoles – Reactivity cont.
th Metallation: (NH pKa = 16.2) NB. For an overview & mechanistic discussion see Joule & Smith (5 Ed) chapter 4.
Reaction as an enamine:
e.g. as hetero-Diels-Alder dienophile Quinolines & Isoquinolines – Reactivity
Electrophilic substitution: via addition-elimination (SEAr) in the benzenoid ring (i.e. more electron rich ring) reactivity: reactive towards many electrophiles (E+);
regioselectivity: substitution at C5 (& C8 for quinolines) predominate – via most stable Wheland intermediates:
+ + e.g. nitration: (E = NO2 ) NO2 5 quinoline + N N 8 N [43%] NO [47%] c.HNO3 2 c.H2SO4 NO2 25°C 5 isoquinoline + N N N 8 [80%] [10%] NO2 Quinolines & Isoquinolines – Reactivity cont.
Nucleophilic substitution: via addition-elimination (SNAr) reactivity: reactive towards nucleophilies (Nu-) provided leaving group is situated at appropriate carbon regioselectivity: reactive at positions for which the Meisenheimer type intermediates have negative charge
stabilised on the electronegative nitrogen [‘leaving group’ (LG) can be H but Cl, Br, NO2 etc. more facile]: . quinoline: C4 > C2 – i.e. as for pyridine . isoquinoline: C1 > C3
qu inolines isoquinolines LG Nu 4 3 LG > > 2 N N Nu N N LG 1 LG Nu Nu
- - e.g. the Chichibabin reaction: (Nu = NH2 , LG = H) Quinolines & Isoquinolines – Reactivity cont.
Metallation: deprotonation by strong bases ortho to the N is difficult due to competing addition reactions but can be achieved using e.g. highly basic and non-nucleophilic zincates:
Li N t Zn t Bu Bu Et2O, rt I2 [93%] N N N 1 1 Li I
Metallation at benzylic positions: deprotonation at benzylic positions that give enaminate anions (i.e. C4 > C2 for quinoline; C1 > C3 for isoquinoline) are facile (i.e. as for pyridine):
1) NaOEt, EtOH 2) (CO2Et)2 O 2 OEt N Me N O 1) NaOEt, EtOH 2) PhCHO N N 1 Me Ph