Organic Chemistry 2 · Carboxyl and acyl chemistry
Acyl substitution and derivative choice: practice problems
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- Butanal from butanenitrile with DIBAL-H
- Trace an activated acyl transfer
- Complete a specified aminolysis stage
- A neutral alcohol and an acid chloride
- Amide formation — acetyl chloride and methylamine
- Alcohol capture by an anhydride
- Anhydride capture by ammonia
- From an ester to a primary amide
- An amine tether closes onto an acyl chloride
Draw the mechanism 85
- Trace an activated acyl transferConstruct addition and elimination snapshots for an anionic oxygen nucleophile.
- Complete a specified aminolysis stageChoose bond cleavage during collapse of a deprotonated aminolysis intermediate.
- A neutral alcohol and an acid chlorideComplete neutral oxygen acylation including acid scavenging, rather than starting with an alkoxide.
- Amide formation — acetyl chloride and methylamineAdd methylamine to an acid chloride, then remove one nitrogen proton to give a neutral amide with one N–H bond.
- Alcohol capture by an anhydrideFollow acyl–oxygen cleavage and use the carboxylate coproduct to resolve an oxonium ion.
- Anhydride capture by ammoniaDistinguish the nitrogen valence changes of ammonolysis from oxygen acylation and retain the acid coproduct.
- From an ester to a primary amideComplete ester aminolysis including the proton transfer missing from an isolated tetrahedral-collapse exercise.
- An amine tether closes onto an acyl chlorideConstruct a five-membered lactam while tracking the tether and the remaining N–H bond.
- An alcohol tether closes onto an acyl chlorideConstruct a lactone by intramolecular acyl substitution, not carbon substitution or simple acid–base neutralization.
- Make a thioester with a sulfur donorTransfer an acyl group to sulfur and distinguish its lone-pair bookkeeping from neutral thiol attack.
- Use a carboxylate as the acyl acceptorBuild an anhydride through the carboxylate oxygen while retaining both carbonyl groups.
- Exchange an ester alkoxy groupFollow reversible acyl substitution and explicitly regenerate an alkoxide catalyst from the alcohol solvent.
- Reduce an ester through two hydride deliveriesFollow two distinct Al–H transfers through an aldehyde, then map both ester oxygens into alcohols at a separate workup.
- Make an acid chloride with thionyl chlorideConvert a carboxylic acid OH into a leaving group at sulfur, then complete chloride addition and fragmentation to SO₂.
- Acetic acid by acid hydrolysis of acetamideHydrolyse acetamide in hot aqueous acid: protonate the carbonyl, add water, shuttle protons onto nitrogen, expel ammonia and capture it as ammonium.
- N-(2-Hydroxyethyl)acetamide from Ac2O and 2-aminoethanolAcetylate the nitrogen of 2-aminoethanol selectively with acetic anhydride, using the acetate released to remove the N–H proton.
- Paracetamol by N-acetylation of 4-aminophenol in waterSynthesize paracetamol by N-acetylation of 4-aminophenol with acetic anhydride, with acetate as leaving group and as base.
- Acetanilide from acetic anhydride and anilineAcetylate aniline with acetic anhydride: nitrogen adds, acetate leaves, and acetate takes the N–H proton to give acetanilide and acetic acid.
- Phenyl acetate from acetic anhydride and phenolAcetylate phenol with acetic anhydride: the phenol oxygen adds, acetate leaves, and pyridine removes the oxonium proton to give phenyl acetate.
- Aspirin from salicylic acid and acetic anhydrideDraw the sulfuric acid–catalyzed acetylation of the phenol OH of salicylic acid by acetic anhydride, with only neutral or protonated intermediates, to give aspirin.
- N,N-Dimethylacetamide from acetyl chloride and dimethylamineMake the tertiary amide N,N-dimethylacetamide: dimethylamine adds to acetyl chloride, chloride leaves, and a second dimethylamine takes the N–H proton.
- Isopropyl acetate from acetyl chloride and propan-2-olAcylate propan-2-ol with acetyl chloride by addition–elimination, then let pyridine remove the oxonium proton to give isopropyl acetate.
- Phenyl acetate from acetyl chloride and sodium phenoxideAcetylate phenoxide ion at oxygen with acetyl chloride: addition to the carbonyl, then loss of chloride to give phenyl acetate.
- Acetaldehyde from acetyl chloride with LiAlH(OtBu)3Draw the single hydride delivery from LiAlH(OtBu)3 to acetyl chloride and the loss of chloride that gives acetaldehyde.
- Ethyl benzoate by acid-catalysed transesterification of methyl benzoateExchange the methoxy group of methyl benzoate for ethoxy under acid catalysis: protonate, add ethanol, transfer protons, lose methanol, deprotonate (PADPED).
- Methyl acetate from 1-acetylimidazole and methanolDraw the methanolysis of 1-acetylimidazole, showing how protonating the ring nitrogen lets neutral imidazole leave.
- Acetonitrile by dehydrating acetamide with thionyl chlorideDehydrate acetamide to acetonitrile: activate the amide oxygen on sulfur, remove both N–H protons, and let the chlorosulfite leave as SO2 and chloride.
- Benzamide from benzoyl chloride and ammoniaConvert benzoyl chloride into benzamide: ammonia adds, chloride leaves, and a second ammonia removes the extra N–H proton.
- N-Hydroxybenzamide from benzoyl chloride and hydroxylamineAcylate hydroxylamine on nitrogen with benzoyl chloride and use bicarbonate to remove the N–H proton, giving the hydroxamic acid N-hydroxybenzamide.
- Benzoyl azide from benzoyl chloride and sodium azideDraw azide ion substituting for chloride on benzoyl chloride by addition–elimination, stopping at benzoyl azide.
- tert-Butyl benzoate from benzoyl chloride with DMAPShow DMAP acting as a nucleophilic catalyst: form the N-benzoylpyridinium ion, add tert-butanol, release DMAP and deprotonate with Et3N to give tert-butyl benzoate.
- Bisphenol A phenyl carbonate by melt transesterificationDraw the base-catalysed transesterification of diphenyl carbonate by bisphenol A: phenoxide formation, addition–elimination at the carbonate and proton transfer that releases phenol.
- Bisphenol A chloroformate from phosgene and bisphenol ADraw the first acylation of interfacial polycarbonate synthesis: hydroxide forms a bisphenol A phenoxide, which adds to phosgene and expels chloride to give the chloroformate.
- Boc protection of benzylamine with Boc2OProtect benzylamine as its Boc carbamate: amine addition to Boc2O, loss of tert-butyl carbonate, its fragmentation to CO2, and the final proton transfer.
- Benzyl N-methylcarbamate from benzyl chloroformateDraw the Cbz protection of methylamine: addition to benzyl chloroformate, loss of chloride and deprotonation by carbonate.
- 1-Benzoylimidazole from benzoic acid and CDIActivate benzoic acid with CDI: form the mixed carbonic anhydride, transfer the benzoyl group to imidazole and release CO2 to give 1-benzoylimidazole.
- 4-(Phenylacetyl)morpholine from phenylacetic acid via CDICouple phenylacetic acid with morpholine through CDI: build 1-(phenylacetyl)imidazole with loss of CO2, then let morpholine displace imidazole.
- 2-Chloro-N-phenylacetamide from chloroacetyl chlorideShow why aniline acylates the acyl chloride carbon of chloroacetyl chloride rather than displacing the CH2Cl chlorine, giving 2-chloro-N-phenylacetamide.
- N,N-Diethylcyclohexanecarboxamide from its acid chlorideMake N,N-diethylcyclohexanecarboxamide from cyclohexanecarbonyl chloride, using one diethylamine as the nucleophile and the second as the base.
- N-Acetyl-N,N'-dicyclohexylurea from DCC and acetic acidShow how acetic acid and DCC give the O-acylisourea and why, with no amine present, it rearranges by O→N acyl transfer to the N-acylurea side product.
- N-Methylacetamide from acetic acid and methylamine with DCCCouple acetic acid with methylamine using DCC: protonate DCC, form the O-acylisourea, add the amine, and release dicyclohexylurea.
- NHS ester of benzoic acid from DCC and N-hydroxysuccinimideMake the NHS active ester of benzoic acid with DCC: form the O-acylisourea, transfer the benzoyl group to N-hydroxysuccinimide, and release DCU.
- Ethyl acetoacetate from diketene and ethanolOpen diketene with ethanol and catalytic Et3N: addition to the lactone carbonyl, ring opening to an enolate and carbon protonation to ethyl acetoacetate.
- 2-Methyl-N-phenylpropanamide from dimethylketene and anilineDraw the addition of aniline to dimethylketene: N–C bond formation at the central carbon, proton relay by a second aniline and carbon protonation to the amide.
- Methanolysis of 2,2-dimethylsuccinic anhydridePredict which carbonyl of 2,2-dimethylsuccinic anhydride methanol attacks and draw the ring opening to 4-methoxy-2,2-dimethyl-4-oxobutanoic acid.
- N-Benzylbenzamide by EDC/HOBt couplingCouple benzoic acid and benzylamine with EDC and HOBt: form the O-acylisourea, convert it into the OBt active ester, then acylate the amine to give N-benzylbenzamide.
- Acetohydrazide from ethyl acetate and hydrazineConvert ethyl acetate into acetohydrazide: hydrazine adds to the ester carbonyl, ethoxide leaves, and the ethoxide takes the N–H proton.
- 5-(Benzylamino)-5-oxopentanoic acid from glutaric anhydrideOpen glutaric anhydride with benzylamine and relay the N–H proton to the carboxylate to form the amide–acid 5-(benzylamino)-5-oxopentanoic acid.
- N-Phenylpropanamide by HATU couplingCouple propanoic acid with aniline using HATU: form the acyloxy uronium salt, convert it into the OAt active ester and let aniline displace OAt.
- First urethane link from HDI and ethylene glycolForm the first carbamate link of a polyurethane: ethylene glycol adds to one isocyanate of hexamethylene diisocyanate, then a second glycol relays the proton to nitrogen.
- Mixed carbonic anhydride from propanoic acidActivate propanoic acid with isobutyl chloroformate and N-methylmorpholine: deprotonate the acid, add the carboxylate to the chloroformate and expel chloride.
- Benzyl isobutyrate from isobutyryl chlorideEsterify benzyl alcohol with isobutyryl chloride: alcohol addition, chloride loss and deprotonation by pyridine give benzyl isobutyrate.
- Methyl N-methylcarbamate from methyl isocyanate and methanolDraw the addition of methanol to methyl isocyanate and the proton relay that gives methyl N-methylcarbamate.
- 1,3-Dimethylurea from methyl isocyanate and methylamineDraw the addition of methylamine to methyl isocyanate and the proton transfers that give 1,3-dimethylurea.
- Diketene from ketene dimerizationShow how two ketene molecules combine into diketene: the C=C of one ketene adds across the C=O of the other to close a four-membered β-lactone.
- Methyl acetate from ketene and methanolDraw the addition of methanol to ketene, including protonation of the enolate carbon, to give methyl acetate.
- Kevlar first amide bond from terephthaloyl chlorideForm the first amide bond of Kevlar: p-phenylenediamine adds to one acyl chloride of terephthaloyl chloride, chloride leaves and the NMP solvent takes the proton.
- Piperidin-2-one from 5-aminopentanoic acidDraw the thermal ring closure of 5-aminopentanoic acid to piperidin-2-one through a tetrahedral intermediate.
- γ-Butyrolactone from 4-hydroxybutanoic acidDraw the acid-catalysed ring closure of 4-hydroxybutanoic acid to γ-butyrolactone, with every proton transfer.
- 4-Methylbenzylamine from 4-methylbenzonitrile and LiAlH4Reduce 4-methylbenzonitrile to 4-methylbenzylamine with LiAlH4: two hydride additions to the nitrile carbon, then protonation of nitrogen in the aqueous workup.
- Maleanilic acid from maleic anhydride and anilineOpen maleic anhydride with aniline and relay the proton to the carboxylate, keeping the Z alkene, to give maleanilic acid.
- Methyl N-benzylcarbamate from methyl chloroformateMake the carbamate methyl N-benzylcarbamate from methyl chloroformate and benzylamine, choosing chloride as the group that leaves.
- Acetic benzoic anhydride from acetyl chloride and benzoateDraw the attack of benzoate on acetyl chloride and loss of chloride that give acetic benzoic anhydride.
- N-Methylbenzamide from NHS benzoate and methylamineDraw the aminolysis of NHS benzoate by methylamine: addition to the ester carbonyl, loss of the N-hydroxysuccinimide anion and the final proton transfer.
- Butanal from butanenitrile with DIBAL-HDraw the DIBAL-H reduction of butanenitrile to the aluminium imine and its aqueous hydrolysis to butanal.
- Pentanenitrile from 1-bromobutane and cyanideExtend 1-bromobutane by one carbon: cyanide carbon displaces bromide in one SN2 step to give pentanenitrile, a nitrile precursor of acids, amides and amines.
- First amide bond of nylon 6,6 from adipoyl chloride and hexane-1,6-diamineDraw the addition–elimination that joins adipoyl chloride and hexane-1,6-diamine by the first amide bond of nylon 6,6.
- Benzoyl chloride from benzoic acid with oxalyl chloride and DMFMake the Vilsmeier chloroiminium ion from DMF and oxalyl chloride, use it to activate benzoic acid, and let chloride give benzoyl chloride while DMF is regenerated.
- Methyl 2-hydroxyethyl terephthalate by transesterificationDraw the exchange of one methoxy group of dimethyl terephthalate for ethylene glycol, the first step toward PET.
- Aniline and CO2 from phenyl isocyanate and waterDraw how water converts phenyl isocyanate into aniline and CO2: addition to N=C=O, proton relay to the carbamic acid and decarboxylation.
- Monoethyl phthalate from phthalic anhydride and ethanolOpen phthalic anhydride with ethanol and relay the oxonium proton to the carboxylate through a second ethanol, giving monoethyl phthalate.
- Phthalimide from phthalic anhydride and ammoniaTurn phthalic anhydride into phthalimide: ammonia opens the anhydride to the amide-acid, then heating closes the imide ring with loss of water.
- Ethyl benzimidate hydrochloride by Pinner reactionDraw the Pinner reaction of benzonitrile with ethanol and dry HCl: nitrilium ion formation, ethanol addition and proton relay to the imidate salt.
- Methyl propanoate from propanenitrile by Pinner hydrolysisConvert propanenitrile to methyl propanoate: form the Pinner imidate salt with methanol and HCl, then add water and expel ammonia.
- Phenylacetonitrile by POCl3 dehydration of 2-phenylacetamideDehydrate 2-phenylacetamide to phenylacetonitrile with POCl3 and pyridine: activate the amide oxygen on phosphorus, then remove both N–H protons as the phosphate leaves.
- S-Ethyl propanethioate from propanoyl chlorideAcylate the sulfur of ethanethiol with propanoyl chloride by addition–elimination, then let pyridine take the sulfonium proton to give S-ethyl propanethioate.
- N-(1-Methylcyclohexyl)acetamide by Ritter reactionDraw the Ritter reaction of 1-methylcyclohexanol with acetonitrile: tertiary carbocation, nitrilium ion, water addition and tautomerisation to the amide.
- N-tert-Butylbenzamide by Ritter reaction of isobutyleneDraw the Ritter reaction of isobutylene with benzonitrile: Markovnikov protonation, nitrilium ion, water addition and tautomerisation to the amide.
- Benzanilide by Schotten–Baumann benzoylation of anilineBenzoylate aniline under Schotten–Baumann conditions: nitrogen addition, chloride loss, and hydroxide removing the N–H proton to give benzanilide.
- tert-Butyl phenylacetate by Steglich esterificationDraw the Steglich esterification of phenylacetic acid with tert-butanol, showing DMAP intercepting the O-acylisourea and DCU forming at the end.
- Monomethyl succinate from succinic anhydride and methanolOpen succinic anhydride with methanol: addition, ring-opening loss of the carboxylate, then proton relay through methanol gives the half-ester monomethyl succinate.
- N-Methylacetamide from S-ethyl ethanethioate and methylamineDraw the aminolysis of S-ethyl ethanethioate by methylamine through a tetrahedral intermediate, with ethanethiolate as the leaving group.
- 3-Amino-2-methylpent-2-enenitrile by Thorpe condensationDraw the Thorpe self-condensation of propanenitrile with sodium ethoxide: α-deprotonation, carbanion addition to the second nitrile and tautomerisation to the enaminonitrile.
- 2-Aminocyclohex-1-ene-1-carbonitrile by Thorpe–ZieglerDraw the Thorpe–Ziegler cyclisation of heptanedinitrile: α-deprotonation, ring closure onto the second nitrile and tautomerisation to the cyclic enaminonitrile.
- Cyclohexyl benzoate by Yamaguchi esterificationFollow the Yamaguchi esterification of benzoic acid with cyclohexanol: build the mixed anhydride, let DMAP pick the benzoyl carbonyl, and transfer it to the alcohol.
Predict the product 17
- Track the leaving fragmentIdentify both organic fragments from alcoholysis of a symmetric anhydride.
- Product of acetyl chloride with isopropanol and pyridinePredict the ester formed when an alcohol reacts with an acid chloride in the presence of pyridine.
- Benzoyl chloride + methylamine productPredict the amide formed when benzoyl chloride reacts with excess methylamine.
- Acetyl chloride + sodium propanoate productPredict the mixed anhydride formed from an acid chloride and a carboxylate salt.
- Products of propanoyl chloride with waterPredict the products when an acid chloride reacts with water.
- Heating ammonium benzoatePredict the product of strongly heating an ammonium carboxylate salt.
- LiAlH4 reduction of N-methylbenzamidePredict the amine formed when a secondary amide is reduced with LiAlH4.
- Acetic anhydride + ethanol productsIdentify both products when a symmetric anhydride reacts with an alcohol.
- Succinic anhydride + methylamine productPredict the ring-opened amide-acid from a cyclic anhydride and a primary amine.
- Methyl acetate + ammonia productPredict the amide formed when an ester is treated with ammonia.
- Sodium benzoate + iodomethane productPredict the ester formed by SN2 alkylation of a carboxylate salt.
- LiAlH4 reduction of ethyl benzoateIdentify both alcohols formed when an ester is reduced with LiAlH4.
- 4-Hydroxybutanoic acid in acidPredict the lactone formed when a γ-hydroxy acid is treated with acid.
- Benzonitrile in hot aqueous acidPredict the final product of complete acid hydrolysis of a nitrile.
- Acetonitrile + phenylmagnesium bromidePredict the ketone formed by Grignard addition to a nitrile followed by hydrolysis.
- Product of benzoic acid with thionyl chloridePredict the acid chloride formed when a carboxylic acid is heated with thionyl chloride.
- Ethyl benzoate in methanol/methoxidePredict the product of base-catalysed transesterification in excess alcohol.
Classify 9
- Identify when substitution is unavailableDistinguish ordinary carbonyl addition from acyl substitution by connectivity.
- Routes to an esterRecognise which reagent pairs give an ester and which do not.
- Name CH3CH2COClName an acyl chloride from its parent carboxylic acid.
- N-substituted amideName an amide with alkyl groups on nitrogen using N locants.
- Name an anhydridePick the structure that matches the name propanoic anhydride.
- Ester namingName an ester by putting the alkoxy group first and the acid-derived part second.
- Cyclic namesRecognise lactones and lactams and name γ-butyrolactone.
- Nitrile namingName a nitrile counting the nitrile carbon in the parent chain.
- Amine for a tertiary amideChoose the amine that gives a tertiary amide (no N–H) with an acid chloride.
Compare 3
- Compare two acyl donorsUse leaving-group basicity to compare acid chlorides and esters.
- Rank derivativesOrder carboxylic acid derivatives by reactivity toward nucleophilic acyl substitution.
- Where does a thioester sit?Place thioesters on the acyl-substitution reactivity ladder and justify it.
Calculate 2
- Count nucleophile and acid captureSeparate amine incorporation from its use as a stoichiometric base.
- Amine equivalents for acid chloride amidationCalculate the minimum equivalents of amine needed to convert an acid chloride fully into an amide without another base.
Find the error 2
- Audit a neutral nucleophile’s first adductAssign charges after neutral ammonia adds without deprotonation.
- Methyl benzoate to benzoyl chloride with NaCl: does it work?Diagnose why an acyl substitution that climbs the reactivity ladder, ester to acid chloride, does not occur.
Interpret the evidence 2
- Two steps of nucleophilic acyl substitutionIdentify the two stages of nucleophilic acyl substitution and the tetrahedral intermediate that links them.
- Tetrahedral intermediate from methoxide and acetyl chlorideRecognise the tetrahedral alkoxide intermediate formed when methoxide adds to acetyl chloride.
Work backward 3
- Work backward from an esterAssign which fragment comes from the acyl donor versus the alcohol.
- Monomers of nylon 6,6Identify the two monomers of a polyamide from its repeat unit.
- Monomers of PETIdentify the two monomers of poly(ethylene terephthalate) from its repeat unit.
Plan a synthesis 5
- Choose a route to an amideSelect acyl activation rather than relying on acid–amine salt formation.
- Reagent to acetylate anilineChoose the reagent that converts aniline into acetanilide.
- Stopping at the ketone from benzoyl chlorideChoose the organometallic reagent that converts an acid chloride into a ketone without over-addition.
- Reagent to dehydrate benzamideChoose a reagent that dehydrates a primary amide to a nitrile.
- Making pentanenitrile from 1-bromobutaneChoose the reagent that converts a primary alkyl bromide into a nitrile with one more carbon.
Explain why 5
- Explain an amide’s persistenceConnect nitrogen donation and poor leaving-group ability to amide stability.
- Why amides are planarExplain the planarity and restricted C–N rotation of amides through resonance.
- Why DCC is used for amide couplingExplain how DCC enables amide formation from a carboxylic acid and an amine.
- Leaving group vs pKaConnect the pKa of a leaving group's conjugate acid to acyl substitution rates.
- Role of pyridine in acid chloride esterificationExplain why pyridine is added when an acid chloride is converted into an ester.
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