Organic Chemistry 2 · Nitrogen and biological molecules
Building and transforming amines: practice problems
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- Methyl yellow by azo coupling
- Aniline by Hofmann rearrangement of benzamide
- But-1-ene by Hofmann elimination of butan-2-amine
- Follow one alkylation event
- Transfer a hydride equivalent
- A primary amine from ammonia
- Closing a nitrogen heterocycle
- Menshutkin reaction — amine quaternization
- An amino alcohol without an alkyl halide
Draw the mechanism 69
- Follow one alkylation eventDraw SN2 alkylation and identify the immediate ammonium product.
- Transfer a hydride equivalentUse a real B–H bond as electron source while reducing an iminium π bond.
- A primary amine from ammoniaComplete the first alkylation branch through a neutral amine, distinguishing nucleophilic and base equivalents of ammonia.
- Closing a nitrogen heterocycleMap intramolecular substitution into a five-membered ring and complete ammonium deprotonation.
- Menshutkin reaction — amine quaternizationRecognize quaternization as a complete substitution with no N–H deprotonation available.
- An amino alcohol without an alkyl halideFollow neutral nitrogen ring opening and an intermolecular proton relay to an amino alcohol.
- Aza-Michael addition — dimethylamine and methyl vinyl ketoneTrack conjugate nitrogen addition, enolate resonance, and solvent proton transfers while preserving the ketone.
- Reductive amination — acetone and methylamineJoin carbinolamine formation and dehydration to a formal isolated-iminium hydride transfer, retaining carbonyl oxygen in water.
- Hofmann rearrangement — N-bromoamide to a shorter amineTrack carbon-to-nitrogen migration, hydrolytic proton transfers, and carbon dioxide loss in the Hofmann rearrangement.
- Gabriel synthesis — phthalimide alkylation and deprotectionCarry an imide nitrogen through alkylation and both hydrolytic acyl cleavages without confusing alkyl C–N retention with acyl C–N loss.
- Hinsberg reaction — secondary-amine sulfonylationComplete sulfonamide formation at an expanded-valence sulfur center and identify why the product has no N–H acidity.
- A nitrogen–nitrogen bond from a secondary amineGenerate a nitrosating electrophile from nitrous acid and distinguish secondary-amine nitrosation from primary-amine diazonium chemistry.
- Two nitrogen origins in an aryl diazonium ionCarry 4-ethylaniline through nitrosation, solvent-mediated tautomerization, and dehydration while conserving both nitrogens and showing why acid is consumed overall.
- Fischer indole synthesis: follow the two nitrogensTurn acetophenone and phenylhydrazine into 2-phenylindole through hydrazone formation, ene-hydrazine tautomerization, a [3,3] rearrangement, cyclization and ammonia loss, tracking both nitrogen atoms and every explicit proton.
- Reduce an amide all the way to an amineExplain why LiAlH₄ turns an amide into an amine rather than an alcohol by following the iminium ion that forms after the first hydride.
- Trimethylamine N-oxideDraw nucleophilic attack of trimethylamine on hydrogen peroxide and the deprotonation that gives trimethylamine N-oxide.
- 1-Amino-2-methylpropan-2-ol from 2,2-dimethyloxiraneDraw ammonia opening 2,2-dimethyloxirane at the less hindered carbon and the proton transfers that give 1-amino-2-methylpropan-2-ol.
- Benzyl azide from benzyl bromide by SN2Draw the one-step SN2 displacement of bromide from benzyl bromide by azide that gives benzyl azide.
- 1-Azidobutane from 1-bromobutaneDraw the one-step backside attack of azide on 1-bromobutane that makes 1-azidobutane, the first stage of an azide route to butan-1-amine.
- trans-2-Azidocyclopentanol by azide opening of an epoxideDraw the anti SN2 opening of cyclopentene oxide by azide and the protonation by ammonium that gives trans-2-azidocyclopentanol.
- Butan-1-amine from 1-azidobutaneDraw hydride delivery to the carbon-bound azide nitrogen with loss of N2, and protonation by water to give butan-1-amine.
- (S)-2-Azidobutane from (R)-butan-2-yl tosylate by SN2Draw the backside attack of azide on (R)-butan-2-yl tosylate and show the inversion that gives (S)-2-azidobutane.
- Methyl yellow by azo couplingDraw the para attack of N,N-dimethylaniline on the terminal nitrogen of benzenediazonium and the loss of the ring hydrogen to acetate, giving methyl yellow.
- Fluorobenzene by the Balz–Schiemann reactionDraw loss of N2 from benzenediazonium tetrafluoroborate to the phenyl cation and its capture by fluoride from tetrafluoroborate, giving fluorobenzene.
- Acetanilide by Beckmann rearrangement of acetophenone oximeDraw protonation of (E)-acetophenone oxime, the migration of the anti phenyl group to nitrogen as water leaves, capture of the nitrilium ion by water and the proton transfers that give acetanilide.
- Caprolactam by the Beckmann rearrangementDraw protonation of the oxime OH, the concerted ring-carbon migration to nitrogen as water leaves, capture of the nitrilium ion by water, and the proton transfers that give caprolactam.
- Dihydroisoquinoline by Bischler–Napieralski cyclizationDraw activation of N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide by POCl3, formation of the nitrilium ion, ring closure of the arene onto it and rearomatization to 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline.
- Butan-1-ol from butan-1-amine and nitrous acidDraw nitrosonium formation from nitrous acid, N-nitrosation of butan-1-amine, the proton transfers to the butyldiazonium ion, and displacement of N2 by water to give butan-1-ol.
- 3-Methylcyclohexene by Cope elimination (cis N-oxide)Draw the syn elimination of cis-N,N,2-trimethylcyclohexan-1-amine N-oxide, in which the oxide removes the C6 hydrogen on its own face, giving 3-methylcyclohexene.
- Cyclohexene by Cope elimination of an amine N-oxideDraw oxidation of N,N-dimethylcyclohexylamine to its N-oxide and the cyclic syn elimination in which the oxide oxygen removes a ring β-hydrogen, giving cyclohexene and N,N-dimethylhydroxylamine.
- But-1-ene by Cope eliminationDraw oxidation of N,N-dimethylbutan-2-amine to its N-oxide and the cyclic syn elimination in which the oxide oxygen removes a β-hydrogen, giving but-1-ene.
- Ethyl N-phenylcarbamate by Curtius rearrangementDraw the concerted phenyl migration of benzoyl azide with loss of N2, addition of ethanol to phenyl isocyanate, and the O-to-N proton relay that gives ethyl N-phenylcarbamate.
- Ethylamine by the Curtius rearrangementDraw formation of propanoyl azide, the concerted migration of ethyl to nitrogen with loss of N2, water addition to ethyl isocyanate, and decarboxylation to ethylamine.
- 4-Chlorophenol from 4-chlorobenzenediazonium in hot acidDraw loss of N2 from 4-chlorobenzenediazonium, capture of the aryl cation by water, and deprotonation of the oxonium ion to 4-chlorophenol.
- Triethylamine from diethylamineDraw the SN2 attack of diethylamine on bromoethane and the deprotonation of the triethylammonium ion by carbonate to give triethylamine.
- trans-2-(Dimethylamino)cyclohexanol from cyclohexene oxideDraw the anti opening of cyclohexene oxide by dimethylamine and the proton relay that gives trans-2-(dimethylamino)cyclohexanol.
- N,N-Dimethylbenzylamine by Eschweiler–Clarke methylationDraw both rounds of formaldehyde addition, iminium formation and hydride transfer from formate (with CO2 loss) that convert benzylamine into N,N-dimethylbenzylamine.
- N-Methylpiperidine by Eschweiler–Clarke methylationDraw piperidine adding to formaldehyde, the formic-acid proton transfers and loss of water to the iminium ion, and hydride transfer from formate with CO2 loss that gives N-methylpiperidine.
- Fmoc protection of glycine methyl esterDraw addition of the glycine methyl ester nitrogen to the carbonyl of Fmoc-Cl, loss of chloride, and deprotonation by bicarbonate to give the Fmoc carbamate.
- N-Butylphthalimide by Gabriel alkylation of 1-bromobutaneDraw the single SN2 step in which the phthalimide anion displaces bromide from 1-bromobutane, giving N-butylphthalimide.
- Butan-1-amine by hydrazinolysis of N-butylphthalimideDraw the two hydrazine acyl substitutions (Ing–Manske procedure) that cut N-butylphthalimide into butan-1-amine and phthalhydrazide.
- Biphenyl by Gomberg–Bachmann arylation of benzeneDraw addition of hydroxide to benzenediazonium, homolysis of benzenediazohydroxide to the phenyl radical and N2, addition of the radical to benzene, and hydrogen abstraction that gives biphenyl.
- Aniline by Hofmann rearrangement of benzamideDraw N-bromination of benzamide in base, migration of phenyl to nitrogen with loss of bromide to phenyl isocyanate, and hydrolysis with loss of CO2 to aniline.
- Cyclohexylamine by Hofmann rearrangement of an amideDraw N-bromination of cyclohexanecarboxamide in base, migration of the cyclohexyl group to nitrogen with loss of bromide, and hydrolysis with loss of CO2 to cyclohexylamine.
- (E)-1-Phenylpropene by Hofmann eliminationDraw the E2 of N,N,N-trimethyl-1-phenylpropan-2-aminium hydroxide in which hydroxide removes a benzylic hydrogen, giving conjugated (E)-1-phenylpropene and trimethylamine.
- But-1-ene by Hofmann elimination of butan-2-amineExcess CH3I/K2CO3 first converts butan-2-amine into N,N-dimethylbutan-2-amine. Draw the third SN2 methylation to the quaternary ammonium salt and the Hofmann E2 in which hydroxide removes a terminal methyl hydrogen as trimethylamine leaves, giving but-1-ene.
- N,N-Dimethylpent-4-en-1-amine by ring-opening HofmannDraw the ring-opening Hofmann E2 of N,N-dimethylpiperidinium hydroxide in which hydroxide removes a ring β-hydrogen and the ring C–N bond breaks, giving N,N-dimethylpent-4-en-1-amine.
- Pent-1-ene by Hofmann eliminationDraw the Hofmann E2 of N,N,N-trimethylpentan-2-aminium hydroxide in which hydroxide removes a terminal methyl hydrogen as trimethylamine leaves, giving pent-1-ene.
- 2-Methylbut-1-ene by Hofmann eliminationDraw the Hofmann E2 of N,N,N,2-tetramethylbutan-2-aminium hydroxide in which hydroxide removes a methyl hydrogen, giving 2-methylbut-1-ene and trimethylamine.
- Anthranilic acid by Hofmann rearrangement of phthalimideDraw hydroxide opening phthalimide, N-chlorination and aryl migration to the isocyanate, hydrolysis with loss of CO2, and the acid workup that gives anthranilic acid.
- N-Methylcyclohexylamine from an imineDraw hydride transfer from borohydride to the imine carbon of N-methylcyclohexanimine and protonation of the nitrogen anion by methanol.
- Aniline by Lossen rearrangement of a benzohydroxamateDraw deprotonation of O-acetylbenzohydroxamic acid, phenyl migration with loss of acetate to phenyl isocyanate, and the hydroxide addition and decarboxylation that give aniline.
- 2,5-Dimethylpyrrole by the Paal–Knorr synthesisDraw ammonia adding to one ketone, ring closure of the nitrogen onto the second ketone, and the two dehydrations and deprotonations that give 2,5-dimethyl-1H-pyrrole.
- 6,7-Dimethoxy-THIQ by Pictet–Spengler cyclizationDraw acid-catalysed iminium formation from 2-(3,4-dimethoxyphenyl)ethan-1-amine and formaldehyde, ring closure of the electron-rich arene onto the iminium carbon and rearomatization to 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
- 1-Methyl-tetrahydro-β-carboline by Pictet–SpenglerDraw TFA-catalysed iminium formation from tryptamine and acetaldehyde, attack of indole C2 on the iminium carbon and rearomatization to 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.
- N-Benzylpiperidine by SN2 alkylation of piperidineDraw the SN2 attack of piperidine on benzyl bromide and the deprotonation by carbonate that gives N-benzylpiperidine.
- N-Isopropylaniline by reductive amination of acetoneDraw aniline adding to acetone, the acetic-acid proton transfers and loss of water to the iminium ion, and hydride transfer from NaBH(OAc)3 that gives N-isopropylaniline.
- N-Benzyl-1-phenylethylamine by reductive aminationDraw benzylamine adding to acetophenone, the acetic-acid proton transfers, loss of water to the iminium ion and hydride transfer from NaBH3CN that gives N-benzyl-1-phenylethylamine.
- 4-Benzylmorpholine by reductive amination of benzaldehydeDraw morpholine adding to benzaldehyde, the amine-relayed proton transfer, loss of hydroxide to the iminium ion and hydride transfer from NaBH(OAc)3 that gives 4-benzylmorpholine.
- N,N-Dimethylcyclopentylamine by reductive aminationDraw dimethylamine adding to cyclopentanone, the proton transfers and loss of water to the iminium ion, and hydride transfer from NaBH3CN that gives N,N-dimethylcyclopentylamine.
- 2-Methylpyrrolidine by intramolecular reductive aminationDraw the amine of 5-aminopentan-2-one closing onto its own ketone, the proton transfers and loss of water to the cyclic iminium ion, and hydride transfer that gives 2-methylpyrrolidine.
- N-Benzyl-2-methylpropan-1-amine by reductive aminationDraw benzylamine condensing with isobutyraldehyde to the imine, hydride transfer from NaBH(OAc)3 and protonation of nitrogen that give N-benzyl-2-methylpropan-1-amine.
- Phenylalaninate by reductive amination of phenylpyruvic acidDraw ammonia deprotonating phenylpyruvic acid, adding to the ketone, the ammonium-relayed loss of water to the iminium ion, and hydride transfer that gives phenylalaninate.
- Cyclohexylamine by reductive aminationDraw ammonia adding to cyclohexanone, the proton relay to the carbinolamine, ammonium-assisted loss of water to the iminium ion, and hydride delivery from cyanoborohydride to cyclohexylamine.
- N-tert-Butylacetamide by the Ritter reactionDraw ionisation of tert-butanol to the tert-butyl cation, its capture by acetonitrile nitrogen, addition of water to the nitrilium ion, and the proton transfers to N-tert-butylacetamide.
- Anilinium ion from benzoic acid by the Schmidt reactionDraw the acylium ion from benzoic acid, addition of HN3, phenyl migration with loss of N2, and the hydration and decarboxylation that leave the anilinium ion.
- δ-Valerolactam from cyclopentanone by the Schmidt reactionDraw HN3 adding to protonated cyclopentanone, loss of water, ring-carbon migration with loss of N2 to the nitrilium ion, and the water addition and tautomerisation that give δ-valerolactam.
- Staudinger reduction to butan-1-amineDraw phosphine attack on the azide, N2 loss through a four-membered ring to the iminophosphorane, and its hydrolysis to butan-1-amine and triphenylphosphine oxide.
- N,N-Diethyl tosylamideDraw diethylamine attacking the sulfur of tosyl chloride with loss of chloride, and pyridine removing the N–H proton to give N,N-diethyl-4-methylbenzenesulfonamide.
Predict the product 19
- Map a nitrile reductionRetain the nitrile carbon when predicting a primary amine.
- Reduce N-ethylpropanamide with LiAlH4Predict the amine formed when LiAlH4 reduces the secondary amide N-ethylpropanamide.
- Azo coupling of benzenediazonium with phenolPredict the azo dye formed when a diazonium ion couples with phenol.
- Curtius rearrangement of butanoyl azidePredict the amine formed when an acyl azide undergoes Curtius rearrangement and hydrolysis.
- Phenol from benzenediazonium hydrogen sulfatePredict the product of warming an arenediazonium salt in water.
- Gabriel synthesis with benzyl bromidePredict the amine released by a Gabriel synthesis using benzyl bromide.
- Hofmann elimination of butan-2-aminePredict the major alkene from Hofmann elimination of a secondary-carbon amine.
- Order the steps of a Hofmann eliminationPut the reagent steps of a Hofmann elimination in the correct order.
- Hofmann rearrangement of hexanamidePredict the amine formed in the Hofmann rearrangement of hexanamide.
- Hofmann ring opening of N-methylpiperidinePredict the product of one Hofmann elimination on a cyclic amine.
- Reduce nitrobenzenePredict the product of reducing nitrobenzene with Fe/HCl.
- Nitrous acid with dimethylaminePredict the product of a secondary amine with nitrous acid.
- Ammonia with excess methyl iodidePredict the final product when ammonia is treated with excess iodomethane.
- Reduce cyclohexanone oxime with LiAlH4Predict the product when LiAlH4 reduces cyclohexanone oxime.
- Reductive amination of benzaldehydePredict the primary amine formed by reductive amination of benzaldehyde with ammonia.
- Secondary amine by reductive aminationPredict the secondary amine formed from cyclohexanone and methylamine.
- Sandmeyer bromination of benzenediazoniumPredict the product of a Sandmeyer reaction with copper(I) bromide.
- Sandmeyer cyanation of 4-methylbenzenediazoniumPredict the aryl nitrile from a Sandmeyer reaction with copper(I) cyanide.
- Tosylation of diethylamine to a sulfonamidePredict the sulfonamide formed from a sulfonyl chloride and a secondary amine.
Classify 4
- Reductive amination — classify the nitrogen substitutionDetermine amine degree from retained nitrogen substituents.
- Hinsberg test for a secondary amineClassify an amine from its behavior in the Hinsberg test.
- Which reductions give a primary amine?Classify the amines formed by reducing a nitro compound, a nitrile and an amide.
- Which halide works for SN2 amine synthesis?Classify alkyl halides as suitable or unsuitable for SN2 N-alkylation with azide.
Compare 1
- Compare two reduction routesDistinguish retained nitrogen substitution in amide and nitrile reduction.
Calculate 2
- Carbons in the amine from pentanenitrileCount the carbons in the primary amine formed by LiAlH4 reduction of pentanenitrile.
- Carbon count after Hofmann rearrangement of benzamideCount the carbons kept when an amide undergoes Hofmann rearrangement.
Find the error 1
- Diagnose an alkylation planRecognize the SN2 boundary for tertiary alkyl electrophiles.
Interpret the evidence 1
- Hofmann rearrangement vs amide reduction — carbon accountingContrast one-carbon-shortening rearrangement with carbon-retaining reduction.
Work backward 2
- Reductive amination — disconnect the carbonyl and amine partnersWork backward from an amine to reductive-amination partners.
- Pick the reductive-amination partnersIdentify carbonyl and amine partners that give N-ethylbutan-2-amine by reductive amination.
Plan a synthesis 9
- Reductive amination — plan N-ethylpiperidine formationChoose reductive amination when a single tertiary-amine product is desired.
- Clean primary amine from an alkyl bromideChoose the azide route to make a primary amine without overalkylation.
- Boc protection and removal on benzylamineChoose the conditions to install and to remove a Boc group on an amine.
- Removing a Cbz group from N-Cbz-alanine methyl esterChoose the conditions that remove a Cbz protecting group while leaving an ester intact.
- Diazotization reagents for anilineChoose the reagents that convert aniline into benzenediazonium chloride.
- Removing Fmoc in solid-phase peptide synthesisChoose the reagent that removes an Fmoc group while leaving Boc-type side-chain protection intact.
- Synthesis of 4-bromoaniline from nitrobenzeneOrder the steps of a protected route from nitrobenzene to 4-bromoaniline.
- Route to hexan-1-amine from 1-bromopentaneChoose a primary-amine route that also adds the needed carbon.
- Route to N,N-dimethylcyclohexanamineChoose a clean route to a specific tertiary amine.
Explain why 4
- Explain a product mixtureIdentify why direct amine alkylation lacks intrinsic single-alkylation control.
- Why Gabriel avoids overalkylationExplain why the Gabriel synthesis stops after a single N-alkylation.
- Why Hofmann elimination gives the less substituted alkeneExplain the anti-Zaitsev regiochemistry of Hofmann elimination.
- Why use NaBH3CN?Explain why NaBH3CN is chosen for one-pot reductive amination.
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