Organic Chemistry 2 · Carboxyl and acyl chemistry
Hydrolysis and esterification: practice problems
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- Acid hydrolysis of acetonitrile to acetic acid
- Fischer esterification of benzoic acid to methyl benzoate
- Saponification — methyl acetate and hydroxide
- Fischer esterification — water departure and acid regeneration
- Trace an ester hydrolysis in acid
- Water replaces an acyl chloride
- Split an anhydride into two acids
- Open a five-membered lactone
- Open a lactam in aqueous acid
Draw the mechanism 73
- Saponification — methyl acetate and hydroxideAdd hydroxide to an ester, release the alkoxide, and transfer a proton to make carboxylate and alcohol.
- Fischer esterification — water departure and acid regenerationShow neutral water departure and catalyst regeneration from a supplied protonated intermediate.
- Trace an ester hydrolysis in acidComplete all addition, proton-shuttle, elimination and catalyst-regeneration stages of acid-catalyzed hydrolysis.
- Water replaces an acyl chlorideUse a neutral aqueous nucleophile and account for hydronium plus chloride in the final mixture.
- Split an anhydride into two acidsMap the bridging oxygen and incoming water oxygen into different acid molecules.
- Open a five-membered lactoneDistinguish ring-opening acyl–oxygen cleavage from breaking the tether alkyl–oxygen bond, with explicit solvent proton exchange.
- Open a lactam in aqueous acidActivate a ring nitrogen for departure and finish with the correct ammonium/carboxylic-acid speciation.
- Hydrolyze an N-substituted amideAvoid expelling an amide anion and distinguish catalyst regeneration from final amine protonation.
- Replace sulfur at an acyl centerKeep the C–S leaving-group bond distinct from the S–alkyl bond and track thiolate protonation.
- Hydrolyze an ester with a resonance-stabilized leaving groupDetermine why phenoxide can both depart and accept the carboxylic-acid proton without becoming the final charge carrier.
- Fischer esterification — complete acetic acid/methanol cycleComplete Fischer esterification from unactivated starting materials while tracking which oxygen leaves as water.
- An ester that loses its alkyl groupContrast tertiary alkyl–oxygen cleavage with acyl substitution and complete the carbocation elimination branch.
- Hydrate a nitrile under basic conditionsFollow hydroxide addition to a nitrile through the imidic acid and amide anion to the primary amide, including each proton transfer.
- 4-Nitrophenyl acetate hydrolysis to 4-nitrophenoxideDraw hydroxide cleaving 4-nitrophenyl acetate: addition to the carbonyl, loss of 4-nitrophenoxide from the tetrahedral intermediate, and deprotonation of acetic acid to acetate.
- Acid hydrolysis of acetamide to acetic acidDraw the acid hydrolysis of acetamide: protonation of the carbonyl oxygen, water addition, nitrogen protonation, loss of ammonia and its capture as ammonium beside acetic acid.
- Acid hydrolysis of acetanilide to anilinium chlorideDraw the acid-catalysed hydrolysis of acetanilide: carbonyl protonation, water addition, proton relay to nitrogen, loss of aniline and its protonation to anilinium.
- Acid hydrolysis of acetohydroxamic acid to hydroxylamineDraw the acid hydrolysis of acetohydroxamic acid to acetic acid and hydroxylammonium chloride.
- Acid hydrolysis of acetonitrile to acetic acidDraw the full acid hydrolysis of acetonitrile: water addition to the protonated nitrile, tautomerisation to acetamide, then acid hydrolysis of acetamide to acetic acid and ammonium.
- Esterase deacylation: hydrolysis of O-acetylserineDraw the deacylation half of a serine esterase: imidazole-assisted water attack on O-acetylserine, then collapse with the serine oxygen taking the proton from imidazolium, giving acetic acid and serine.
- Hydrolysis of acetylcholine to cholineDraw hydroxide addition to acetylcholine, loss of the choline alkoxide and proton transfer to give choline and acetate.
- Acid-catalysed hydrolysis of methyl acetate to acetic acidDraw the six proton-transfer, addition and elimination steps that convert methyl acetate and water into acetic acid and methanol with hydronium as catalyst (methyl acetate).
- Transesterification of ethyl acetate to methyl acetateDraw the acid-catalysed exchange of the ethoxy group of ethyl acetate for methoxy, giving methyl acetate and ethanol in methanol.
- Hydrolysis of aspirin to salicylic acidDraw aspirin hydrolysis at pH 7–9: deprotonation of the acid, carboxylate-assisted water addition to the acetyl group, loss of the phenoxide and proton transfer.
- LiI cleavage of methyl mesitoate to 2,4,6-trimethylbenzoateDraw the single SN2 step in which iodide removes the methyl group of methyl mesitoate, giving 2,4,6-trimethylbenzoate and iodomethane.
- Basic hydrolysis of benzamide to benzoateDraw hydroxide addition to benzamide, expulsion of amide ion by the oxide and the proton transfer that gives benzoate and ammonia.
- Basic hydrolysis of benzanilide to benzoate and anilineDraw the saponification of benzanilide: hydroxide addition to the amide carbonyl, loss of the anilide anion, and the proton transfer that gives benzoate and aniline.
- Acid hydrolysis of benzonitrile to benzoic acidDraw the complete acid hydrolysis of benzonitrile: water addition to the nitrilium ion, tautomerisation of the imidic acid to benzamide, and acid hydrolysis of benzamide to benzoic acid and ammonium.
- Hydroxide opens azetidin-2-one to 3-aminopropanoateDraw hydroxide addition to the β-lactam azetidin-2-one, ring opening by C–N cleavage and the proton transfer to 3-aminopropanoate.
- Methoxide-catalysed transesterification of triacetin to methyl acetateDraw one methoxide-catalysed ester exchange of triacetin: methoxide addition, loss of the glycerol alkoxide and regeneration of methoxide from methanol.
- TFA removes the Boc group from N-Boc-benzylamine to give benzylamineDraw Boc removal from tert-butyl N-benzylcarbamate with TFA: carbonyl protonation, loss of the tert-butyl cation, its deprotonation to isobutylene, and decarboxylation of the carbamic acid.
- Basic hydrolysis of butanenitrile to butanoateDraw the full basic hydrolysis of butanenitrile: hydroxide addition to the nitrile, proton transfers that give butanamide, then saponification of butanamide to butanoate and ammonia.
- Basic hydrolysis of ε-caprolactam to 6-aminohexanoateDraw hydroxide opening the ring of ε-caprolactam: addition to the lactam carbonyl, ring opening by loss of the nitrogen, and the proton transfers that give 6-aminohexanoate.
- Basic hydrolysis of methyl N-methylcarbamate to methylamineDraw hydroxide addition to methyl N-methylcarbamate, loss of methoxide, deprotonation, N-protonation and loss of CO2 that liberate methylamine.
- Chymotrypsin burst: 4-nitrophenyl acetate acylates serineDraw the fast acylation of chymotrypsin by 4-nitrophenyl acetate with serine and an imidazole model of His57: base-assisted serine attack, then loss of 4-nitrophenol protonated by imidazolium.
- Acid hydrolysis of DMF to formic acidDraw the acid hydrolysis of N,N-dimethylformamide: carbonyl protonation, water addition, N-protonation, loss of dimethylamine and its capture as dimethylammonium beside formic acid.
- Saponification of ethoxy-¹⁸O ethyl acetate to ¹⁸O-ethanolDraw the saponification of ethyl acetate carrying ¹⁸O in its ethoxy oxygen and follow the label: hydroxide addition, collapse with loss of labelled ethoxide, and the final proton transfer to acetate and ethanol.
- Bender ¹⁸O exchange: ethyl benzoate loses its carbonyl labelDraw how carbonyl-¹⁸O ethyl benzoate exchanges its label with water in base: hydroxide addition, the water-relayed proton transfer between the two oxygens, and loss of labelled hydroxide.
- Fischer esterification with ¹⁸O-methanol gives labelled methyl acetateFollow the ¹⁸O of labelled methanol through Fischer esterification of acetic acid and show that the water lost contains an oxygen from the acid.
- Fischer esterification of adipic acid to diethyl adipateDraw both Fischer esterification cycles that convert the two carboxyl groups of adipic acid into diethyl adipate.
- Fischer esterification of benzoic acid to methyl benzoateDraw protonation, addition, deprotonation, protonation, elimination and deprotonation (PADPED) for benzoic acid and methanol with sulfuric acid.
- Fischer synthesis of isoamyl acetate (banana oil)Draw the Fischer esterification that combines acetic acid and isoamyl alcohol into isoamyl acetate, the banana-scented ester.
- Fischer esterification to ethyl phenylacetateDraw the acid-catalysed esterification of phenylacetic acid with excess ethanol to ethyl phenylacetate.
- Fischer esterification to isopropyl propanoateDraw the six PADPED steps that join propanoic acid and isopropanol into isopropyl propanoate with sulfuric acid as catalyst.
- Fischer esterification to (S)-sec-butyl acetateDraw the Fischer esterification of acetic acid with (S)-butan-2-ol and show that (S)-sec-butyl acetate forms with retention.
- Fischer attempt with tert-butanol gives isobutyleneDraw why heating tert-butanol with acetic acid and sulfuric acid gives isobutylene by E1 instead of a Fischer ester.
- N-Acetylimidazole from 4-nitrophenyl acetate and imidazoleDraw imidazole acting as a nucleophilic catalyst on 4-nitrophenyl acetate: N3 addition to the carbonyl, loss of 4-nitrophenoxide, and the proton transfer that gives neutral N-acetylimidazole and 4-nitrophenol.
- Lactonization of 2-(hydroxymethyl)benzoic acid to phthalideDraw the acid-catalysed ring closure of 2-(hydroxymethyl)benzoic acid to the five-membered lactone phthalide.
- Acid-catalysed lactonization to δ-valerolactoneDraw the intramolecular Fischer esterification in which the hydroxyl of 5-hydroxypentanoic acid closes a six-membered lactone ring.
- Hydrolysis of methyl mesitoate to mesitoic acid via an acylium ionDraw protonation of the methoxy oxygen of methyl 2,4,6-trimethylbenzoate, loss of methanol to the acylium ion, and capture of the acylium by water on workup.
- Acid hydrolysis of methyl benzoate in H₂¹⁸ODraw the acid hydrolysis of methyl benzoate in ¹⁸O-labelled water and follow the label: carbonyl protonation, labelled water addition, proton transfers, and loss of unlabelled methanol.
- Glycine methyl ester hydrochloride from glycine, SOCl2 and methanolDraw esterification of glycine in methanol with HCl from SOCl2: amine protonation, carbonyl protonation, methanol addition, proton relay and loss of water.
- Acid hydrolysis of N,N-dimethylbenzamide to benzoic acidDraw the acid hydrolysis of N,N-dimethylbenzamide to benzoic acid and dimethylammonium chloride.
- Acid hydrolysis of trimethyl orthoacetate to methyl acetateDraw hydrolysis of trimethyl orthoacetate: protonation, loss of methanol to a dialkoxycarbenium ion, water addition, a second methanol loss and deprotonation to methyl acetate.
- Penicillin G acylates serine: β-lactam ring openingDraw how penicillin G inactivates a transpeptidase: base-assisted attack of the serine oxygen on the β-lactam carbonyl, then ring opening with the lactam nitrogen taking a proton, giving the penicilloyl–serine ester.
- Hydroxide opens phthalimide to 2-carbamoylbenzoateDraw hydroxide addition to one imide carbonyl of phthalimide, ring opening by C–N cleavage and the proton transfer to 2-carbamoylbenzoate.
- Acid hydration of propionitrile to propanamideDraw the controlled hydration of propionitrile: protonation by sulfuric acid, water addition to the nitrilium ion and the two proton transfers that turn the imidic acid into propanamide.
- Basic hydrolysis of 2-pyrrolidinone to 4-aminobutanoateDraw the hydroxide ring opening of 2-pyrrolidinone: tetrahedral addition, expulsion of the ring nitrogen, and the water-relayed proton transfers that leave 4-aminobutanoate (GABA anion).
- Labelled saponification gives ¹⁸O-acetateTrack an ¹⁸O label from hydroxide through addition, loss of ethoxide and proton transfer to show acyl–oxygen cleavage in saponification.
- Saponification of β-propiolactone to 3-hydroxypropanoateDraw hydroxide addition to β-propiolactone, ring opening by acyl–oxygen cleavage and the two proton transfers that give 3-hydroxypropanoate.
- Hydroxide opens coumarin to (Z)-coumarinateDraw hydroxide addition to coumarin, ring opening with phenoxide as the leaving group and the deprotonation that gives the (Z)-coumarinate dianion.
- Saponification of δ-valerolactone to 5-hydroxypentanoateDraw how hot aqueous hydroxide opens δ-valerolactone to 5-hydroxypentanoate: addition, ring opening, then the two proton transfers.
- Saponification of diethyl malonate to malonateDraw the two hydroxide addition–ethoxide loss cycles that convert diethyl malonate into the malonate dianion and ethanol.
- Saponification of dimethyl terephthalate to terephthalateDraw both hydroxide addition–methoxide loss cycles that turn dimethyl terephthalate into the terephthalate dianion and methanol.
- Saponification of ε-caprolactone to 6-hydroxyhexanoateDraw the BAC2 ring opening of ε-caprolactone by hydroxide and the proton transfers that end at 6-hydroxyhexanoate.
- Saponification of ethyl 4-nitrobenzoate to 4-nitrobenzoateDraw hydroxide addition to ethyl 4-nitrobenzoate, loss of ethoxide and the proton transfer that gives 4-nitrobenzoate and ethanol.
- Saponification of ethyl acetate to acetateDraw hydroxide addition to ethyl acetate, loss of ethoxide from the tetrahedral intermediate, and the proton transfer that makes acetate and ethanol.
- Saponification of methyl benzoate to benzoateDraw hydroxide addition to methyl benzoate, expulsion of methoxide and the acid–base step that gives benzoate and methanol.
- Saponification of (R)-sec-butyl acetate to (R)-butan-2-olDraw the saponification of (R)-sec-butyl acetate and show why (R)-butan-2-ol forms with retention of configuration.
- Saponification of vinyl acetate to acetaldehyde and acetateDraw how hydroxide cleaves vinyl acetate, then follow the enolate leaving group until it becomes acetaldehyde.
- Acetylcholinesterase: serine acylation by acetylcholineDraw the acylation half of acetylcholinesterase with serine and an imidazole model of histidine: general-base-assisted serine attack on acetylcholine, then collapse with the choline oxygen taking the proton back.
- tert-Butyl acetate in H₂¹⁸O: the label ends in tert-butanolDraw the AAL1 hydrolysis of tert-butyl acetate in ¹⁸O water: carbonyl protonation, ionisation to the tert-butyl cation and acetic acid, capture by labelled water and deprotonation to ¹⁸O-tert-butanol.
- Saponification of triacetin to glycerolDraw the three hydroxide additions, alkoxide losses and proton transfers that saponify all three esters of triacetin to glycerol.
- Acid hydrolysis of urea to ammonium and CO2Draw acid hydrolysis of urea: O-protonation, water addition, proton relay to nitrogen, loss of ammonia, then N-protonation and decarboxylation of carbamic acid.
Predict the product 15
- Name the product actually presentSeparate a basic reaction mixture from a later acidic workup.
- Open a cyclic ester without losing carbonMap lactone hydrolysis to a hydroxycarboxylate product.
- Benzoyl chloride and water: products of hydrolysisPredict the products when an acyl chloride is hydrolysed by water alone.
- Products of acid hydrolysis of methyl acetatePredict the products of acid-catalysed ester hydrolysis, including the protonation state of the acid formed.
- N-Methylacetamide heated in aqueous HCl: productsPredict the products, with their charge states, of hydrolysing a secondary amide in hot aqueous acid.
- N-Methylacetamide heated in aqueous NaOH: productsPredict the products, with their charge states, of hydrolysing a secondary amide in hot aqueous base.
- Propanoic anhydride and water: products of hydrolysisPredict the products and their amounts when a symmetrical carboxylic anhydride is hydrolysed.
- Fischer esterPredict the ester formed when propanoic acid is heated with methanol and catalytic acid.
- Ring opening of 2-pyrrolidone in hot aqueous HClPredict the ring-opened product, with its charge state, of hydrolysing a five-membered lactam in strong aqueous acid.
- Lactone formed from 5-hydroxypentanoic acid in acidPredict the ring size and structure of the lactone formed by intramolecular esterification of a hydroxy acid.
- Open a lactonePredict the product of saponifying a cyclic ester.
- NaOH on ethyl benzoatePredict the products of saponifying an ester, including the charge state of the acid.
- After acidificationPredict what the carboxylate from a saponification becomes on acidic work-up.
- Saponification of glyceryl tristearate: productsPredict the products of saponifying a triglyceride fat with excess hydroxide.
- Acid-catalysed transesterification of methyl benzoate in ethanolPredict the products when an ester exchanges its alkoxy group with a large excess of a different alcohol.
Classify 2
- Distinguish alcoholysis from hydrolysisPredict transesterification when the medium supplies alcohol rather than water.
- Classify biodiesel formation from glyceryl trioleateClassify the conversion of a vegetable-oil triglyceride to methyl esters and glycerol, and name the role of methoxide.
Compare 4
- Methyl benzoate hydrolysis: 1 M HCl or 1 M NaOH?Compare acid-catalysed hydrolysis and saponification of methyl benzoate by nucleophile strength and reversibility.
- Methyl acetate vs N-methylacetamide: which hydrolyses faster?Rank an ester against an amide for hydrolysis rate using resonance donation and leaving-group basicity.
- Ethyl trifluoroacetate vs ethyl acetate: hydrolysis rateExplain a rate difference in ester hydrolysis from the inductive effect of a substituent on the acyl carbon.
- Rank four methyl esters by saponification rateRank methyl esters by base hydrolysis rate from the crowding of the carbon next to the carbonyl.
Calculate 4
- Fischer esterification — calculate the reaction directionCalculate the reaction quotient for a reversible esterification.
- Yield from KCalculate the equilibrium yield of a Fischer esterification from its equilibrium constant.
- Base needed for a diesterCount the equivalents of hydroxide consumed when a diester is fully saponified.
- Moles of NaOH to saponify glyceryl tripalmitateCount the moles of hydroxide a triglyceride consumes when it is completely saponified.
Find the error 2
- Fischer esterification — repair leaving-group protonationRecognize necessary protonation before favorable hydroxyl departure.
- tert-Butanol failsExplain why Fischer esterification fails with a tertiary alcohol and name a better route.
Interpret the evidence 3
- Follow an ester oxygen labelUse specified acyl–oxygen cleavage to locate an isotope in a hydrolysis product.
- Which O leaves as water?Use the Fischer mechanism to track which oxygen ends up in the water by-product.
- Acid hydrolysis of ethoxy-¹⁸O ethyl acetate: where is the label?Use acyl–oxygen cleavage in acid-catalysed ester hydrolysis to predict where an alkoxy ¹⁸O label ends up.
Plan a synthesis 4
- Fischer esterification — shift the equilibrium toward esterDistinguish shifting composition from changing a catalyst concentration.
- Methyl ester of an acetal-bearing benzoic acid with diazomethaneChoose a mild esterification for a carboxylic acid that carries an acid-sensitive acetal.
- Fischer conditionsChoose conditions that give a high yield of ester from a carboxylic acid and an alcohol.
- Partial hydrolysis of benzonitrile to benzamideChoose conditions that hydrate a nitrile to the amide without carrying on to the carboxylic acid.
Explain why 4
- Audit the net role of hydroxideExplain why saponification consumes base overall.
- Why sodium stearate forms scum in hard waterExplain soap scum from the low solubility of calcium and magnesium fatty acid carboxylates.
- Why saponification is irreversibleExplain why ester hydrolysis in base goes to completion while acid hydrolysis is an equilibrium.
- How sodium stearate micelles remove greaseExplain soap action from the amphiphilic structure of a fatty acid carboxylate and micelle formation.
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