Organic Chemistry 2 · Aromatic systems
Planning aromatic transformations: practice problems
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- 4-Methylaniline from 4-chlorotoluene via benzyne
- 4-Nitroanisole from 1-chloro-4-nitrobenzene
- Replace fluoride through an anionic ring intermediate
- Substitute an electron-poor heteroaromatic ring
- Replace an unactivated aryl chloride
- 4-Nitroaniline by hydrolysis of 4-nitroacetanilide
- 3-Methoxyaniline from 2-bromoanisole via benzyne
- 3-(Trifluoromethyl)aniline via benzyne from a CF3 aryl chloride
- m-Anisidine from 4-bromoanisole by cine substitution
Draw the mechanism 41
- Replace fluoride through an anionic ring intermediateDistinguish nucleophilic aromatic addition–elimination from EAS and trace stabilization into a para nitro group.
- Substitute an electron-poor heteroaromatic ringUse ring nitrogen to accept the addition-stage electron pair and account for deprotonation of a neutral nitrogen nucleophile.
- Replace an unactivated aryl chlorideDistinguish aryne elimination–addition from nitro-activated addition–elimination and follow the ortho hydrogen.
- 4-Nitroaniline by hydrolysis of 4-nitroacetanilideDraw acid-catalysed hydrolysis of the acetamide protecting group: carbonyl protonation, water addition, proton relays, loss of the aryl amine, and the base workup.
- 3-Methoxyaniline from 2-bromoanisole via benzyneDraw benzyne formation from 2-bromoanisole and the regioselective addition of amide that places the carbanion next to the methoxy group.
- 3-(Trifluoromethyl)aniline via benzyne from a CF3 aryl chlorideDraw the elimination of HCl from 2-chlorobenzotrifluoride to an aryne and the addition of amide that puts the aryl anion next to the CF3 group, giving the meta product.
- m-Anisidine from 4-bromoanisole by cine substitutionDraw benzyne formation from 4-bromoanisole and the addition of amide at the carbon next to the original C–Br carbon, the cine pathway to m-anisidine.
- 4-Methylaniline from 4-chlorotoluene via benzyneDraw the benzyne mechanism: E2-like loss of an ortho H and chloride, then amide addition to the aryne and protonation by ammonia.
- Benzyne from anthranilic acid trapped by furanDraw the diazotization of anthranilic acid with isoamyl nitrite, fragmentation of benzenediazonium-2-carboxylate to benzyne, N2 and CO2, and the Diels–Alder trapping of benzyne by furan.
- Grignard benzyne from 1-bromo-2-fluorobenzene + dimethylfuranStarting from the 2-fluorophenylmagnesium bromide that 1-bromo-2-fluorobenzene forms with Mg, draw β-elimination of Mg(Br)F to benzyne and its Diels–Alder trapping by 2,5-dimethylfuran.
- Benzonorbornadiene from a Kobayashi benzyne precursorDraw fluoride removing the trimethylsilyl group from 2-(trimethylsilyl)phenyl triflate, loss of triflate to benzyne and the Diels–Alder reaction with cyclopentadiene.
- Roberts 14C label scrambling: chlorobenzene to anilineDraw how [1-14C]chlorobenzene and KNH2 give both [1-14C]aniline and [2-14C]aniline through benzyne, showing why the label ends up on the ipso and ortho carbons in equal amounts.
- 2-Aminopyridine by the Chichibabin reactionDraw the Chichibabin amination: amide addition at C2, expulsion of hydride to restore aromaticity, H2 formation, and the aqueous workup.
- Toluene from 4-methylbenzenesulfonic acidDraw removal of a sulfonic acid blocking group: ipso protonation of the ring and loss of SO3 that restores the aromatic ring.
- 4-Nitrobenzenediazonium chloride from 4-nitroanilineDraw diazotization: nitrosonium ion formation from nitrous acid, N-nitrosation of the aryl amine, tautomerization to the diazohydroxide and loss of water to give the diazonium ion.
- 2-Bromo-4-methylaniline by hydrolysis of its acetanilideDraw acid-catalysed removal of the acetyl protecting group from 2-bromo-4-methylacetanilide, through the tetrahedral intermediate to the free aniline after the NaOH workup.
- 4-Bromoaniline by base hydrolysis of 4-bromoacetanilideDraw the NaOH hydrolysis that removes the acetyl protecting group from 4-bromoacetanilide: hydroxide addition, loss of the anilide nitrogen and the final proton transfer.
- Acetanilide: protecting aniline with acetic anhydrideDraw the acetylation of aniline by acetic anhydride, addition, collapse expelling acetate and deprotonation, and explain why the acetamide is a gentler ring activator than NH2.
- 2-Nitrotoluene by desulfonation of the blocked sulfonic acidDraw removal of the SO₃H blocking group from 4-methyl-3-nitrobenzenesulfonic acid: ipso protonation and loss of SO₃ to give 2-nitrotoluene.
- 3-Bromophenol by hydrolysis of 3-bromobenzenediazoniumDraw hydrolysis of 3-bromobenzenediazonium in hot aqueous acid: loss of N₂ to the aryl cation, capture by water and deprotonation to 3-bromophenol.
- Butyrophenone by Friedel–Crafts acylation of benzeneDraw Friedel–Crafts acylation of benzene with butanoyl chloride: acylium ion formation with AlCl3, ring attack and loss of the ring proton to butyrophenone.
- Nitration of 4-methylacetanilide ortho to NHAcDraw nitration of 4-methylacetanilide ortho to the acetamido group, showing the nitrogen lone pair that makes NHAc the stronger director.
- 1-Nitro-4-propylbenzene by nitration of propylbenzeneDraw nitronium formation and nitration of propylbenzene para to the propyl group, including the contributor with charge on the propyl-bearing carbon.
- Nitration of 4-methylbenzenesulfonic acid ortho to methylDraw nitration of 4-methylbenzenesulfonic acid ortho to the methyl group, where the methyl and sulfonic acid directing effects agree.
- 4-Methylbenzenesulfonic acid by sulfonation of tolueneDraw sulfonation of toluene with SO₃ para to the methyl group, giving the sulfonic acid that blocks the para position in later steps.
- 2-Nitroaniline from 1-chloro-2-nitrobenzene and ammoniaDraw ammonia displacing chloride from 1-chloro-2-nitrobenzene: addition ortho to the nitro group, the Meisenheimer complex, loss of chloride and deprotonation by a second ammonia.
- 2-Methoxypyridine from 2-chloropyridineDraw SNAr of 2-chloropyridine with methoxide, placing the negative charge of the addition intermediate on the ring nitrogen.
- 2-(Dimethylamino)pyrimidine from 2-chloropyrimidine by SNArDraw dimethylamine displacing chloride from 2-chloropyrimidine: addition at C2 with the charge on a ring nitrogen, loss of chloride and deprotonation by a second dimethylamine.
- 2-(Piperidin-1-yl)pyridine from 2-fluoropyridineDraw SNAr of 2-fluoropyridine with neutral piperidine: addition with the charge on the ring nitrogen, loss of fluoride, then deprotonation by a second piperidine.
- 4-Nitroanisole from 1-chloro-4-nitrobenzeneDraw nucleophilic aromatic substitution of chloride by methoxide through the Meisenheimer complex, showing how the para nitro group carries the negative charge.
- 4-(Ethylsulfanyl)pyridine from 4-chloropyridine by SNArDraw ethanethiolate adding to C4 of 4-chloropyridine with the negative charge pushed onto the ring nitrogen, then the loss of chloride.
- 4-Morpholinobenzonitrile from 4-fluorobenzonitrile by SNArDraw morpholine displacing fluoride from 4-fluorobenzonitrile: addition, delocalization of the charge onto the para nitrile nitrogen, loss of fluoride and deprotonation by carbonate.
- 4-Nitrophenol from 1-fluoro-4-nitrobenzene by SNArDraw hydroxide displacing fluoride from 1-fluoro-4-nitrobenzene through a Meisenheimer complex, then the phenoxide formed in base and its protonation in the workup.
- SNAr selectivity: 4-bromo-N-methyl-2-nitroanilineDraw methylamine displacing fluorine, not bromine, from 4-bromo-1-fluoro-2-nitrobenzene, and explain the choice through nitro-group position and leaving-group ability in SNAr.
- (2,4-Dinitrophenyl)hydrazine by SNAr with hydrazineDraw hydrazine displacing chloride from 1-chloro-2,4-dinitrobenzene to make Brady's reagent: addition, the nitro-stabilized intermediate, loss of chloride and deprotonation.
- N-Methyl-2,4-dinitroaniline from 1-chloro-2,4-dinitrobenzeneDraw SNAr of chloride by neutral methylamine, including the zwitterionic Meisenheimer complex and the final deprotonation by a second methylamine.
- 2,4-Dinitrophenyl phenyl sulfide by SNAr with thiophenolDraw the SNAr of 1-fluoro-2,4-dinitrobenzene with thiophenol: carbonate deprotonation, thiolate addition, the nitro-stabilized Meisenheimer complex and loss of fluoride.
- 4-Nitroanisole from 1,4-dinitrobenzeneDraw SNAr in which methoxide displaces one nitro group of 1,4-dinitrobenzene as nitrite while the other nitro group stabilizes the Meisenheimer complex.
- SNAr of pentafluoropyridine: 4-methoxy product at C4Draw methoxide adding to C4 of pentafluoropyridine, the ring-nitrogen anion that makes C4 the preferred site, and the loss of fluoride.
- N-Ethyl-2,4-dinitroaniline from Sanger's reagentDraw the SNAr of 1-fluoro-2,4-dinitrobenzene (Sanger's reagent) with ethylamine and explain why fluoride is the best leaving group here.
- 4-Nitrobenzyl phenyl sulfone by vicarious substitutionDraw the vicarious nucleophilic substitution of hydrogen in nitrobenzene: sulfonyl carbanion formation, addition para to the nitro group, β-elimination of HCl and protonation of the nitrobenzylic anion.
Predict the product 7
- Moderate an amino directorIdentify why N-acylation can improve an aromatic-substitution plan.
- Benzyne Products From 4-Bromotoluene and NaNH2Predict the regioisomer mixture from elimination–addition through a methyl-substituted benzyne.
- Sandmeyer Chlorination of BenzenediazoniumPredict the product of a Sandmeyer reaction of an arenediazonium salt with copper(I) chloride.
- Schiemann Fluorination of 4-Bromoaniline SaltPredict the aryl fluoride formed by heating an arenediazonium tetrafluoroborate.
- Warm Water on 4-MethylbenzenediazoniumPredict the phenol formed when an arenediazonium salt is heated in aqueous acid.
- Acylate anisolePredict the Friedel–Crafts acylation product of an activated ring.
- KMnO4 Oxidation of 4-NitrotoluenePredict the product of hot KMnO4 side-chain oxidation of a nitro-substituted toluene.
Classify 2
- A nitro group becomes an amino groupTrack how functional-group conversion changes the next EAS preference.
- Pathway for NaOH with 2,4-DinitrochlorobenzeneClassify the pathway when a nucleophile meets an aryl halide activated by ortho and para nitro groups.
Compare 1
- Friedel–Crafts route planning — acylation/reduction vs alkylationSelect acylation and reduction to avoid carbocation rearrangement.
Find the error 4
- Check whether oxidation has the needed handleDiagnose a benzylic-oxidation plan lacking a benzylic H.
- Friedel–Crafts acylation limitations — free-aniline incompatibilityDiagnose Lewis-acid incompatibility in a Friedel–Crafts proposal.
- Friedel–Crafts on m-dinitrobenzeneDiagnose why a Friedel–Crafts acylation fails on a strongly deactivated ring.
- Diagnosing a Route to 3-NitroacetophenoneDiagnose why nitration before Friedel–Crafts acylation fails and choose the corrected order.
Interpret the evidence 1
- A reversible substituent as a temporary obstacleInterpret the purpose and limits of reversible aromatic sulfonation.
Work backward 4
- A plausible route is not a purity certificateChoose an honest route claim when regioisomer separation remains necessary.
- Intermediate en Route to 3-Chlorobenzoic AcidIdentify the intermediate that sets up meta chlorination in a two-step route from toluene.
- Intermediate Nitrated en Route to 4-EthylnitrobenzeneIdentify the intermediate that is nitrated so the nitro group lands para to an ethyl group.
- Starting Material for a Diazonium Route to PhenolWork backward from phenol through a diazonium salt to identify the amine starting material.
Plan a synthesis 22
- Order two aromatic transformationsOrder oxidation and nitration to favor a meta relationship.
- Friedel–Crafts acylation — order acylation and nitrationChoose a route order compatible with Friedel–Crafts acylation.
- Order a blocking-group route to 2-bromotolueneSequence sulfonation, bromination and desulfonation so bromine goes ortho to methyl without the para isomer.
- Remove the acetyl group from 4-bromoacetanilideChoose conditions that hydrolyze an acetamide protecting group back to the free aryl amine.
- Reagents to Diazotize AnilineChoose the reagents and temperature that convert an aryl amine into an arenediazonium salt.
- H3PO2 Removal of an Amino DirectorRecognize diazotization then H3PO2 as the way to remove an amino group after it has directed substitution.
- Make propylbenzene without rearrangementPick the Friedel–Crafts route that keeps a straight propyl chain.
- Reduce valerophenone to pentylbenzeneChoose conditions that reduce an aryl ketone carbonyl all the way to a CH2 group.
- Make phenylacetonitrile from tolueneChoose a two-step side-chain sequence that adds a carbon to the benzylic position of toluene.
- Pick a reagent to reduce nitrobenzene to anilineChoose a reagent that reduces an aryl nitro group to an amino group.
- Route to 2-Bromo-4-nitrotoluene From TolueneChoose a step order where two existing substituents reinforce each other to place the third group.
- Ordering a Route From Toluene to PABAOrder nitration, side-chain oxidation and nitro reduction so both groups end up para and the amine survives.
- Ordering a Route to 4-BromoanilineOrder nitration, reduction, amide protection, bromination and deprotection to make a para-bromoaniline cleanly.
- Make 3-bromoanilineSequence three steps so the nitro group directs bromine meta before reduction.
- Make 3-bromonitrobenzeneChoose the step order that places Br and NO2 meta.
- Make 3-chloroacetophenoneOrder acylation and chlorination for a meta product.
- 3-Nitrobenzoic acid from toluenePlan the order that converts the methyl into a meta director first.
- Make 4-bromonitrobenzeneChoose the step order that places Br and NO2 para.
- Make 4-chloroacetophenoneOrder chlorination and acylation for a para product.
- 4-Nitrobenzoic acid from toluenePlan the order that keeps the para relationship from toluene.
- Order the acetanilide route to 4-nitroanilineSequence acetylation, nitration and amide hydrolysis so a protected amino group directs nitration para.
- Planning 4-Nitroanisole by SNArPick the aryl halide and nucleophile that make a nitro aryl ether by nucleophilic aromatic substitution.
Explain why 4
- Friedel–Crafts alkylation — repeated substitution riskExplain the risk of repeated Friedel–Crafts alkylation.
- Why SO3H makes a good aromatic blocking groupExplain which property of the sulfonic acid group lets it serve as a temporary blocking group.
- Why Aniline Leads to 1,3,5-TribromobenzeneExplain how a removable amino director gives the all-meta 1,3,5-tribromo pattern.
- Why protect phenol before nitrating it?Explain why the phenol OH is capped as an ester or ether before nitration with nitric acid.
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