Organic Chemistry 2 · Exam review
Acyl substitution, amines and diazonium salts: practice problems
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- Azo coupling of benzenediazonium with 2-naphthoxide
- Balz–Schiemann: 4-fluorotoluene from 4-methylbenzenediazonium tetrafluoroborate
- Boc protection of benzylamine with di-tert-butyl dicarbonate
- Phenol from benzenediazonium and warm water
- DMAP-catalysed acetylation of cyclohexanol
- Releasing benzylamine from N-benzylphthalimide with hydrazine
- Hinsberg test: propan-1-amine and benzenesulfonyl chloride
- Hofmann elimination opens the piperidine ring
- Acid-catalysed lactonisation of 2-(hydroxymethyl)benzoic acid
Draw the mechanism 37
- Azo coupling of benzenediazonium with 2-naphthoxideDraw the attack of C1 of 2-naphthoxide on the terminal nitrogen of benzenediazonium and the deprotonation that restores aromaticity, and explain why coupling occurs at C1.
- Balz–Schiemann: 4-fluorotoluene from 4-methylbenzenediazonium tetrafluoroborateDraw the loss of N₂ from 4-methylbenzenediazonium and the transfer of fluoride from tetrafluoroborate to the aryl cation that gives 4-fluorotoluene.
- Boc protection of benzylamine with di-tert-butyl dicarbonateDraw the addition of benzylamine to di-tert-butyl dicarbonate, the loss of tert-butyl carbonate, the proton transfer that gives the Boc carbamate, and the breakdown of tert-butyl hydrogen carbonate to CO₂ and tert-butanol.
- Phenol from benzenediazonium and warm waterDraw the loss of N2 from the benzenediazonium ion, the capture of the aryl cation by water and the final deprotonation that gives phenol.
- DMAP-catalysed acetylation of cyclohexanolDraw how DMAP acts as a nucleophilic catalyst: it is acylated by acetic anhydride to an N-acetylpyridinium ion, which transfers the acetyl group to cyclohexanol and releases DMAP again.
- Releasing benzylamine from N-benzylphthalimide with hydrazineDraw the two acyl substitutions by hydrazine that free benzylamine from N-benzylphthalimide and trap both carbonyls in the six-membered ring of phthalhydrazide.
- Hinsberg test: propan-1-amine and benzenesulfonyl chlorideDraw the sulfonylation of a primary amine and the two deprotonations by hydroxide that leave the N-propylbenzenesulfonamide anion dissolved in aqueous base.
- Hofmann elimination opens the piperidine ringDraw the N-methylation of N-methylpiperidine and the Hofmann E2 elimination of the 1,1-dimethylpiperidinium ion that opens the six-membered ring to N,N-dimethylpent-4-en-1-amine.
- Acid-catalysed lactonisation of 2-(hydroxymethyl)benzoic acidDraw the acid-catalysed ring closure of 2-(hydroxymethyl)benzoic acid to the five-membered lactone phthalide, with hydronium and water as the only acid and base.
- Hydration of benzonitrile to benzamide in aqueous acidDraw the acid-catalysed addition of water to benzonitrile through the nitrilium ion and the imidic acid, and the tautomerisation that gives benzamide.
- Reductive amination of benzaldehyde with morpholineDraw how benzaldehyde and the secondary amine morpholine form an iminium ion through a carbinolamine, with acetic acid and acetate moving the protons, and how cyanoborohydride reduces it to 4-benzylmorpholine.
- Saponification of phenyl acetateDraw the hydroxide addition and phenoxide loss that cleave phenyl acetate, and the two proton transfers that leave acetate and phenoxide, consuming two equivalents of hydroxide.
- Phenyl benzoate by the Schotten–Baumann methodDraw how aqueous hydroxide turns phenol into phenoxide and how phenoxide adds to benzoyl chloride and expels chloride to give phenyl benzoate.
- Ring opening of succinic anhydride by ammoniaDraw how ammonia opens the five-membered ring of succinic anhydride by addition–elimination, with the second ammonia as the base, to give ammonium succinamate.
- Diazoaminobenzene from benzenediazonium and anilineDraw the attack of aniline's nitrogen on the terminal nitrogen of benzenediazonium and the deprotonation by acetate that give 1,3-diphenyltriazene.
- N-Acetylation of 4-aminobenzyl alcohol with acetic anhydrideDraw the chemoselective N-acetylation of 4-aminobenzyl alcohol by acetic anhydride, ending with acetate removing the N–H proton.
- Acid hydrolysis of N-methylbenzamide to benzoic acidDraw the acid-catalysed hydrolysis of N-methylbenzamide to benzoic acid, including the protonation that turns the methylamino group into a leaving group.
- Phenyl acetate by pyridine-catalysed acetylation of phenolDraw pyridine attacking acetyl chloride to form the N-acetylpyridinium ion, phenol acylation by that ion, and deprotonation that gives phenyl acetate.
- 3-(Methylamino)propanenitrile by aza-Michael additionDraw the conjugate addition of methylamine to the β-carbon of acrylonitrile and the proton transfers through methanol that give 3-(methylamino)propanenitrile.
- Azo coupling of 4-nitrobenzenediazonium with phenolDraw the azo coupling of phenoxide with 4-nitrobenzenediazonium at the para position and the rearomatization that gives (E)-4-[(4-nitrophenyl)diazenyl]phenol.
- Base hydrolysis of phenylacetonitrile to phenylacetateDraw the hydroxide-promoted hydrolysis of phenylacetonitrile through phenylacetamide to phenylacetate and ammonia.
- N,N-Diethylbenzamide from benzoyl chloride and diethylamineDraw the addition–elimination of diethylamine on benzoyl chloride and the proton transfer to a second equivalent of amine that gives N,N-diethylbenzamide.
- Aniline from benzoyl chloride by the Curtius rearrangementDraw benzoyl azide formation, its Curtius rearrangement to phenyl isocyanate with loss of N2, and the hydrolysis and decarboxylation that release aniline.
- DCC coupling of 3-phenylpropanoic acid with morpholineDraw how DCC turns 3-phenylpropanoic acid into an O-acylisourea and how morpholine then forms 4-(3-phenylpropanoyl)morpholine with loss of dicyclohexylurea.
- Diazotization of 4-methoxyaniline with nitrous acidDraw how nitrous acid and HCl convert 4-methoxyaniline into 4-methoxybenzenediazonium chloride through the nitrosonium ion and an N-nitrosamine.
- Gabriel alkylation of phthalimide with ethyl bromoacetateDraw the deprotonation of phthalimide by carbonate and the SN2 attack of the imide anion on ethyl bromoacetate.
- Pent-1-ene by Hofmann elimination of pentan-2-amineExcess CH3I with NaOH first converts pentan-2-amine into N,N-dimethylpentan-2-amine. Draw the third SN2 methylation to the quaternary ammonium salt and the Hofmann E2 of the quaternary ammonium hydroxide that gives pent-1-ene, the less substituted alkene.
- Hofmann rearrangement of 3-methylbutanamide to isobutylamineDraw the Hofmann rearrangement of 3-methylbutanamide to 2-methylpropan-1-amine, from N-bromination through the isocyanate to loss of CO2.
- Hydroxide ring opening of N-methylsuccinimideDraw how one equivalent of hydroxide opens N-methylsuccinimide to 4-(methylamino)-4-oxobutanoate and explain why the amide that forms survives.
- LiAlH4 reduction of piperidin-2-one to piperidineDraw the LiAlH4 reduction of the lactam piperidin-2-one to piperidine, showing why oxygen, not nitrogen, leaves the tetrahedral intermediate.
- Benzamide by ammonolysis of methyl benzoateDraw ammonia adding to methyl benzoate, the proton transfer to a second ammonia, loss of methoxide, and proton return that gives benzamide.
- N-Acetylglycine from glycine and acetic anhydrideDraw the acetylation of glycine by acetic anhydride: amine addition to an anhydride carbonyl, loss of acetate, and deprotonation by acetate to give N-acetylglycine.
- 1-Propanoylpyrrolidine from propanoyl chlorideDraw the addition–elimination of pyrrolidine on propanoyl chloride and the deprotonation by triethylamine that gives 1-propanoylpyrrolidine.
- Reductive amination of acetophenone with methylamineDraw the iminium ion formation from acetophenone and methylamine in acetic acid and its reduction by cyanoborohydride to N-methyl-1-phenylethan-1-amine.
- N-Cyclohexylaniline by reductive amination of cyclohexanone with anilineDraw iminium formation from cyclohexanone and aniline under acetic acid catalysis and its reduction by cyanoborohydride to N-cyclohexylaniline.
- Saponification of γ-butyrolactone with sodium hydroxideDraw the hydroxide ring opening of γ-butyrolactone and the proton transfers that end at 4-hydroxybutanoate.
- Butanoyl chloride from butanoic acid and thionyl chlorideDraw how thionyl chloride converts butanoic acid into butanoyl chloride through a chlorosulfite leaving group that falls apart into SO2 and chloride.
Predict the product 8
- Acetylating 2-aminoethanolPredict which nucleophile of an amino alcohol is acylated first by an anhydride.
- Which conversion runs directly?Use the reactivity ladder to decide which acyl substitution occurs on simple mixing.
- Which group does mild base cleave?Predict which acyl group of an ester–amide is hydrolysed by mild aqueous base and in what protonation state the product exists.
- Diazotisation then potassium iodidePredict the product when an arenediazonium salt is treated with potassium iodide and keep the other ring substituent unchanged.
- Product of a Sandmeyer reaction with CuCNPredict the product of a Sandmeyer cyanation and place the new group at the former diazonium carbon.
- Anhydride + aminePredict both products when an acid anhydride acylates a primary amine.
- Hofmann elimination of pentan-2-aminePredict the major alkene from a Hofmann elimination.
- Open a lactone with hydroxidePredict the ring-opened product of saponifying a lactone.
Classify 2
- What the Gabriel synthesis cannot makeRecognise that the Gabriel synthesis needs an SN2-capable alkyl halide.
- Which nitrogen of nicotine is protonated first?Identify the more basic nitrogen in a molecule with an sp³ amine and an sp² pyridine nitrogen.
Compare 6
- Rank acetyl derivatives by reactivityOrder an amide, an ester, an anhydride and an acid chloride by their reactivity toward nucleophilic acyl substitution.
- Rank four nitrogen compounds by basicityOrder an amide, an arylamine, a benzylic amine and an alkylamine by basicity from where the nitrogen lone pair is.
- Rank para-substituted anilines by basicityOrder para-substituted anilines by basicity from the resonance and inductive effects of the substituent.
- Rank four nitrogen heterocycles by basicityRank pyrrole, pyridine, imidazole and piperidine by basicity.
- Ester or Weinreb amide for a ketone?Compare how an ester and a Weinreb amide react with one equivalent of a Grignard reagent.
- Thioester or ester: which acylates faster?Explain why a thioester is a better acyl donor than the corresponding oxoester.
Calculate 5
- Hydroxide consumed by 4-acetoxybenzoic acidCount every acidic proton and ester cleavage to find how much hydroxide a multifunctional compound consumes on saponification.
- pKb of methylamineConvert the pKa of an ammonium ion into the pKb of the amine.
- How much of an amine drug is protonated in blood?Use Henderson–Hasselbalch to find what percentage of an amine is protonated at a given pH.
- Neutral fraction of an amine at pH 7.8Calculate the percentage of an amine present as the neutral base at a given pH.
- Hydroxide for a triesterCount the hydroxide equivalents consumed by complete saponification of a triglyceride model.
Find the error 1
- Find the error in an acid hydrolysis mechanismIdentify the step in a proposed acid-catalysed ester hydrolysis that is impossible in the stated medium.
Interpret the evidence 3
- Follow the labelled oxygen from waterUse acyl–oxygen cleavage to predict where an oxygen label from the solvent ends up after saponification.
- Use IR to tell a primary amide from an esterAssign an IR spectrum to a primary amide using the C=O position and the number of N–H stretches.
- Identify the group behind a sharp 2250 cm⁻¹ IR bandAssign a sharp IR band at 2250 cm⁻¹ to a nitrile C≡N group.
Work backward 1
- Choose partners for a reductive aminationWork backward from a secondary amine to the carbonyl compound and amine that give it by reductive amination.
Plan a synthesis 5
- Choose the amide for a LiAlH₄ routeChoose the amide whose LiAlH₄ reduction gives a specified secondary amine, keeping track of which carbon becomes CH₂.
- Plan a route to 1,3,5-tribromobenzeneUse an amino group as a removable directing group in a multistep arene synthesis.
- Conditions to hydrolyze an amideChoose conditions that actually hydrolyze an unactivated amide.
- Route to 2-phenylethan-1-amineChoose a route to a primary amine that also adds one carbon.
- Choose the reagent that makes an aryl fluorideChoose the reagent sequence that replaces a diazonium group by fluorine.
Explain why 9
- Why is an acid chloride so much more reactive than an amide?Explain the reactivity gap between an acid chloride and an amide from π donation and leaving-group ability.
- Why amides resist hydroxideExplain why a tertiary amide survives conditions that saponify an ester.
- Why aryl diazonium salts can be usedExplain why arenediazonium ions are useful intermediates while alkyldiazonium ions are not.
- Why DMAP is a much stronger base than pyridineExplain how resonance donation from a para amino group raises the basicity of a pyridine nitrogen.
- Why the Gabriel synthesis stops at one alkyl groupExplain how the phthalimide nitrogen prevents the over-alkylation seen with ammonia.
- Why trimethylamine breaks the trend in waterExplain the basicity order of the methylamines in water from solvation of their ammonium ions.
- Why saponification goes to completionExplain why ester hydrolysis in base is irreversible while acid-catalysed hydrolysis is an equilibrium.
- Why a diazotization is run at 0–5 °CExplain why arenediazonium salts are prepared and kept at 0–5 °C.
- Why reductive amination beats alkylation for aminesExplain why reductive amination gives a clean secondary amine where direct alkylation with an alkyl halide does not.
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