Química Orgânica Avançada · Advanced synthesis
Sínteses de heterociclos e multicomponentes
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O que você vai aprender
- Assign every ring atom of a heterocycle to the dicarbonyl and heteroatom components that supply it.
- Draw condensation, ring-closure and dehydration steps with the acid and base actually present in the flask.
- Predict the order of bond formation in multicomponent and benzo-fused heterocycle syntheses.
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Count the atoms between the carbonyls
Most classical heterocycle syntheses join a dicarbonyl compound to a heteroatom partner, so the ring size is fixed by counting atoms. In hexane-2,5-dione (left) the two carbonyl carbons are separated by two CH2 groups: the chain from one carbonyl carbon to the other supplies four ring atoms, and a single nitrogen from an amine, or the oxygen of one carbonyl, closes a five-membered ring, a pyrrole or a furan. In pentane-2,4-dione (right) only one CH2 lies between the carbonyls, so three carbons are supplied and a two-atom partner such as hydrazine (N–N) or hydroxylamine (N–O) is needed to reach five: a pyrazole or an isoxazole. Before drawing any arrow, number the target ring and assign each atom to a starting material.
Condense, cyclise, dehydrate
These syntheses repeat one short sequence. First a nitrogen nucleophile adds to a carbonyl carbon and proton transfers give a hemiaminal, the species drawn here from methylamine and hexane-2,5-dione. Second, a nucleophile already in the molecule attacks the other carbonyl, closing the ring quickly because the partners are held close together. Third, each C–OH is protonated and leaves as water, pushed out by a neighbouring nitrogen or oxygen lone pair, and loss of a C–H or N–H proton creates the new π bond. Aromatic products such as pyrroles make the dehydrations effectively irreversible. Use the real acid and base of the medium for every proton transfer: acetic acid and acetate in a buffered condensation, hydronium and water in dilute mineral acid.
Multicomponent order of events
In a multicomponent reaction several partners are mixed at once, but bonds still form one at a time, in an order set by reactivity. In the Hantzsch dihydropyridine synthesis, benzaldehyde condenses with one ethyl acetoacetate (a Knoevenagel reaction) to give the benzylidene ketoester on the right, an electron-poor alkene. A second ethyl acetoacetate condenses with ammonia to give the enamine on the left, nucleophilic at the carbon next to the ester. The enamine carbon adds to the benzylic carbon of the alkene (a Michael addition), its NH2 then closes the six-membered ring on the remaining ketone, and loss of water gives the 1,4-dihydropyridine. Each component therefore contributes a predictable set of ring atoms.
Benzo-fused rings
A benzene ring carrying two ortho nucleophiles is a ready-made half of a fused heterocycle. Benzene-1,2-diamine (right) supplies N–C–C–N and benzil (left) supplies C–C from its two adjacent carbonyls, so two imine condensations build a six-membered pyrazine ring fused to the benzene: 2,3-diphenylquinoxaline. With a one-carbon partner such as formic acid the same diamine gives the five-membered imidazole ring of benzimidazole, and 2-aminophenol with an acetyl group gives benzoxazole. The benzene ring is never attacked; it only holds the two nucleophiles side by side, which is why the second, intramolecular ring closure is fast.
What to carry forward
Count the ring atoms and assign them to the components, identify the nucleophile and electrophile for each new bond, then repeat condense–cyclise–dehydrate with the real acid and base of the medium.
Problemas de prática (24)
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Desenhe o mecanismo 18
Design the disconnection
- Aza-Michael addition and lactamisation: methylamine and dimethyl 2-ethylidenebutanedioateDraw how methylamine converts dimethyl 2-ethylidenebutanedioate into a γ-lactam: conjugate addition to the alkene, proton transfers, then intramolecular attack on the correct ester and loss of methoxide.
- Piperidin-4-one by double aza-Michael addition of ammonia to penta-1,4-dien-3-oneDraw how ammonia builds piperidin-4-one from penta-1,4-dien-3-one by two conjugate additions, the second one intramolecular, with the proton transfers between them.
- 3-Methyl-5-phenyl-2-pyrazoline from benzalacetone and hydrazineDraw how hydrazine turns (E)-4-phenylbut-3-en-2-one into 3-methyl-5-phenyl-4,5-dihydro-1H-pyrazole: hydrazone formation at the ketone, then intramolecular conjugate addition of the free NH2 to the alkene.
Fused and benzo heterocycles
- Benzimidazole from benzene-1,2-diamine and formic acidDraw the formic acid route to benzimidazole: formylate one amino group by addition–elimination at formic acid, then let the second amino group attack the protonated formamide and remove water to close the aromatic five-membered ring.
- 2-Methylbenzoxazole from 2-aminophenol and acetyl chlorideDraw the two-stage synthesis of 2-methylbenzoxazole: N-acetylation of 2-aminophenol with acetyl chloride, then acid-promoted ring closure of the phenol oxygen onto the amide carbonyl and loss of water.
- Hantzsch synthesis of 2,4-dimethylthiazole from chloroacetone and thioacetamideDraw the Hantzsch thiazole synthesis: S-alkylation of thioacetamide by chloroacetone, ring closure of the thioimidate nitrogen onto the ketone, and dehydration to 2,4-dimethylthiazole.
Six-membered rings and multicomponent reactions
- Biginelli synthesis of a dihydropyrimidinone from benzaldehyde, ethyl acetoacetate and ureaDraw the Biginelli reaction by the N-acyliminium route: condense urea with benzaldehyde to the iminium ion, add the enol of ethyl acetoacetate, close the ring with the second urea nitrogen and dehydrate to the dihydropyrimidinone.
- Friedländer synthesis of 2-methylquinoline from 2-aminobenzaldehyde and acetoneDraw the base-catalysed Friedländer synthesis: an aldol reaction of the acetone enolate with 2-aminobenzaldehyde, dehydration to the enone, then imine formation by the aryl NH2 to close the pyridine ring of 2-methylquinoline.
- Hantzsch 1,4-dihydropyridine synthesis from benzaldehyde, ethyl acetoacetate and ammoniaDraw the Hantzsch synthesis in order: Knoevenagel condensation of benzaldehyde with one ethyl acetoacetate, enamine formation from the second with ammonia, Michael addition, ring closure on the ketone and loss of water to give the 1,4-dihydropyridine.
- Pechmann synthesis of 7-hydroxy-4-methylcoumarin from resorcinol and ethyl acetoacetateDraw the Pechmann condensation: transesterify ethyl acetoacetate onto one phenol oxygen of resorcinol, close the ring by attack of the ring carbon para to the other OH on the protonated ketone, then dehydrate to 7-hydroxy-4-methylcoumarin.
- Pictet–Spengler cyclisation of tryptamine with formaldehydeDraw the Pictet–Spengler reaction of tryptamine and formaldehyde: form the iminium ion from the amine, let the indole ring attack it to close a six-membered ring, and restore the aromatic indole to give tetrahydro-β-carboline.
- 2,3-Diphenylquinoxaline from benzil and benzene-1,2-diamineDraw the double condensation of benzene-1,2-diamine with benzil: form one imine, close the six-membered ring with the second NH2 on the other carbonyl, and lose a second water to give 2,3-diphenylquinoxaline.
Five-membered rings from dicarbonyls
- Fischer indole synthesis of 1,2,3,4-tetrahydrocarbazole from cyclohexanone phenylhydrazoneDraw the Fischer indole synthesis from cyclohexanone phenylhydrazone: tautomerise to the ene-hydrazine, carry out the [3,3] shift that breaks the N–N bond, rearomatise, close the five-membered ring and lose ammonia to reach 1,2,3,4-tetrahydrocarbazole.
- 3,5-Dimethylisoxazole from pentane-2,4-dione and hydroxylamineDraw how hydroxylamine turns pentane-2,4-dione into 3,5-dimethylisoxazole: oxime formation at one ketone, ring closure by the oxime oxygen onto the other ketone, and dehydration to the aromatic ring.
- Knorr synthesis of 3-methyl-5-phenyl-1H-pyrazole from 1-phenylbutane-1,3-dione and hydrazineDraw the Knorr pyrazole synthesis: hydrazine condenses with the methyl ketone to a hydrazone, its free NH2 closes the ring on the benzoyl carbonyl, and dehydration gives the aromatic pyrazole.
- Knorr pyrazolone synthesis from ethyl acetoacetate and phenylhydrazineDraw the Knorr pyrazolone synthesis: the terminal NH2 of phenylhydrazine forms a hydrazone with the ketone of ethyl acetoacetate, then the NH–phenyl nitrogen attacks the ester and ethanol leaves to close 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one.
- Paal–Knorr synthesis of 2,5-dimethylfuran from hexane-2,5-dioneDraw the acid-catalysed Paal–Knorr cyclisation of hexane-2,5-dione: enolise one ketone, let the enol oxygen attack the other protonated ketone, then dehydrate the cyclic hemiketal to 2,5-dimethylfuran.
- Paal–Knorr synthesis of 1,2,5-trimethylpyrrole from hexane-2,5-dione and methylamineDraw the Paal–Knorr condensation of hexane-2,5-dione with methylamine: form the hemiaminal, close the ring through nitrogen onto the second ketone, then remove two molecules of water to reach 1,2,5-trimethylpyrrole.
Classificar 1
- Where does each Hantzsch ring atom come from?Assign the six ring atoms of a Hantzsch 1,4-dihydropyridine to the three components.
Comparar 1
- Urea versus ammoniaCompare the rings that urea and ammonia build from the same aldehyde and ketoester.
Trabalhe de trás para frente 2
Design the disconnection
- Which dione gives 2,5-dimethylfuran?Choose the dicarbonyl precursor of a furan by counting the atoms between the carbonyls.
- Which partner gives 3,5-dimethylpyrazole?Choose the dicarbonyl partner for hydrazine that delivers a 3,5-disubstituted pyrazole.
Planeje uma síntese 1
- Plan an N-benzylpyrroleChoose the amine and dicarbonyl partners for a Paal–Knorr synthesis of an N-substituted pyrrole.
Explique por quê 1
- Why indoles cyclise easilyExplain why the Pictet–Spengler cyclisation needs an electron-rich arene.
Travou em sínteses de heterociclos e multicomponentes? Escaneie o problema.
Tire uma foto da reação da sua lista ou do livro e desenhe o mecanismo com cada seta corrigida. 1 scan grátis agora, sem cadastro; mais 1 com uma conta gratuita.
Depois, Scan Standard: /mês