User:Benjah-bmm27/degree/3/KIBM

=Heterocycles, KIBM=
 * Hantzsch–Widman nomenclature

Azoles

 * 1,3-azoles
 * Imidazole
 * Oxazole
 * Thiazole
 * 1,2-azoles
 * Pyrazole
 * Isoxazole
 * Isothiazole
 * Other azoles
 * Triazoles
 * 1,2,3-triazole
 * 1,2,4-triazole
 * Tetrazole
 * Pentazole
 * Metallacycles

Reactivity

 * 1,3-azoles tend to undergo clean electrophilic substitution at C5, but are less reactive than pyrrole
 * 1,2-azoles generally undergo electrophilic substitution at C4

Synthesis

 * Imidazoles from α-aminoketones and nitriles
 * Thiazoles from α-haloketones and thioamides
 * Pyrazoles from 1,3-dicarbonyls and hydrazines
 * Isoxazoles from 1,3-dicarbonyls and hydroxylamine
 * 1,3-Dipolar cycloadditions: 1,3-dipoles (ozone, azides, nitrile oxides) + alkenes or alkynes
 * Azide alkyne Huisgen cycloaddition - click chemistry, forms tetrazoles
 * Nitrile oxides from chlorination of oximes, followed by elimination of hydrogen chloride
 * Nitrile oxides + alkynes → isoxazoles (as seen in VKA's course)

Anion chemistry

 * Lithiation by deprotonation of 1,3-azoles at C2 with butyllithium, followed by an electrophile (e.g. alkyl halide, carbonyl compound)
 * 1,2-azoles are deprotonated at C3, but these can ring-open to give α-cyanoenolates, which react with electrophiles to form α-cyanoketones

Indoles

 * Indole
 * Can think of as pyrrole and benzene fused together
 * 10 π electrons, so aromatic according to Hückel's rule
 * Many important drugs are indoles, probably due to their similarity to the essential amino acid tryptophan...
 * ...and its important natural derivatives, such as the neurotransmitter serotonin, which is important in regulating mood
 * Serotonin analogues are important antidepressants: selective serotonin reuptake inhibitors
 * Polyhydroxylation of tryptophan as a mistake in the biosynthesis of serotonin may produce powerful hallucinogenic molecules (similar to mescaline), a process which may be implicated in schizophrenia
 * Skatole (and 2-methylindole) stinks of dog poo - best avoided

Reactions of indoles

 * Electrophilic substitution at C3 is preferred, but may also get 2,3-disubstitution
 * Mannich reaction with formaldehyde and dimethylamine, forming the important building block gramine
 * Electrophilic bromination with Br2
 * Friedel-Crafts acylation with Ac2O and AcOH
 * Vilsmeier reaction with DMF and POCl3

Indole syntheses

 * Reissert indole synthesis, starting from ortho-nitrotoluenes
 * Leimgruber modification
 * ortho-nitrotoluenes + acetal of an amide → enamine
 * enamine undergoes reductive cyclisation with acid (converts enamine to ketone) and Pd/H2 (reduces ArNO2 to ArNH2)
 * Bischler-Möhlau indole synthesis
 * Fischer indole synthesis
 * Starts with a phenylhydrazine, which reacts with a ketone to form a hydrazone
 * The hydrazone is protonated, tautomerises, then undergoes a [3,3]-sigmatropic rearrangement
 * The weak N-N bond is broken, and a stronger C-C bond formed, although the aromaticity of the benzene ring is sacrificed
 * Acid-catalysed elimination of ammonia leads to the indole

Carbazoles

 * Fischer synthesis not useful because the requisite ketones exist as their phenol tautomers
 * Use nitrene pathway or the Graebe-Ullmann reaction

Benzofurans

 * Benzofuran

Reactions of benzofurans

 * Benzofurans differ from indoles in that they tend to undergo electrophilic substitution in the 2 position, rather than the 3 position
 * This is probably because furan is far less aromatic than pyrrole, so the benzene ring of a benzofuran has more influence on the substitution pattern
 * Vilsmeier reaction, nitration and lithiation at occur at the 2 position
 * With bromine, benzofurans undergo electrophilic addition across the furan double bond - suggesting less aromaticity than indole

Benzofuran syntheses

 * O-Aryl hydroxylamines react with ketones to give O-aryl ketoximes, which cyclize and dehydrate in acid to benzofurans, by a mechanism analogous to that of the Fischer indole synthesis
 * Sodium phenoxides react with α-bromoketones to give α-phenoxyketones, which cyclize and dehydrate in acid to benzofurans. This is the oxygen equivalent of the Bischler indole synthesis.

Quinolines and isoquinolines

 * Quinoline
 * Isoquinoline
 * Both π deficient heterocycles
 * Their physical properties and chemical reactivity are very similar, but their syntheses are very different

Electrophilic aromatic substitution

 * Quinoline undergoes nitration and bromination in the 5 and 8 positions (1:1 mixture of isomers)
 * Isoquinoline is more selective and only the 5 position is substituted

Nucleophilic substitution

 * Both are attacked by nucleophiles at the 2 position, much like imines
 * A nitrogen-stabilised anion is the intermediate
 * Acid and oxidation generates the substituted quinoline or isoquinoline
 * Both undergo the Chichibabin reaction, with potassium amide and high temperatures, forming the 2-amino product
 * 2-chloroquinolines and isoquinolines (much like 2-chloropyridines) are excellent electrophiles and undergo nucleophilic aromatic substitution at much lower temperatures. As chloride is a good leaving group, aromatisation is spontaneous.

Anion chemistry

 * 2-alkylquinolines have an acidic proton that can be removed by BuLi, forming an aza enolate that reacts with electrophiles

Reduction

 * There are a number of important dihydroquinoline and tetrahydroquinoline drugs, so reduction of quinolines is industrially important
 * Lithium aluminium hydride reduces quinolines to dihydroquinolines, formally adding H2 across the N=C2 double bond
 * H2/Pt reduces the pyridine ring, leaving the benzene ring intact, thereby forming the tetrahydroquinoline
 * H2/Pd in concentrated hydrochloric acid reduces only the benzene ring, leaving the pyridine ring untouched
 * HCl must protonate the nitrogen sp2 lone pair, somehow deactivating the pyridine ring to hydrogenation.

Quinoline syntheses

 * Skraup synthesis
 * Vicious conditions: aniline, glycerol, sulfuric acid, air, 180° C in nitrobenzene (high boiling solvent)
 * Glycerol dehydrates to 1,3-propenediol, which tautomerises to 3-hydroxypropanal, then dehydrates to acrolein
 * Aniline's nitrogen lone pair does Michael attack (1,4 or conjugate addition) on acrolein, forming 3-(phenylamino)propanal
 * 3-(phenylamino)propanal cyclizes to 1,2,3,4-tetrahydroquinolin-4-ol, which dehydrates to 1,2-dihydroquinoline in the presence of acid and air
 * Air oxidises 1,2-dihydroquinoline to 1,2,3,4-tetrahydroquinoline

Isoquinoline syntheses

 * Bischler–Napieralski reaction
 * Pictet–Spengler reaction

Others

 * Coumarins and chromones
 * Bergapten (5-methoxypsoralen) - 1970s sunscreen, now known to be carcinogenic
 * Chromone synthesis: Kostanecki-Robinson reaction

Quiz

 * Heterocycle nomenclature quiz