Organic Chemistry 2 · Functional-group transformations
Ethers and epoxide opening: practice problems
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- Williamson ether synthesis — ethyl methyl ether
- Open and protonate a three-membered ring
- Separate alkyl and aryl ether bonds
- Change the ether-cleavage mechanism
- Open an unstrained cyclic ether with acid
- Epoxide opening — acid-catalysed, with methanol
- Epoxide opening — with cyanide
- Preserve the backside-opening geometry
- Williamson ether synthesis — halohydrin-to-epoxide cyclization
Draw the mechanism 80
- Williamson ether synthesis — ethyl methyl etherExecute an SN2 ether formation with complete ion accounting.
- Open and protonate a three-membered ringCouple nucleophilic ring opening to an explicit proton-transfer step.
- Separate alkyl and aryl ether bondsCleave anisole at methyl while preserving an unreactive aryl–oxygen bond.
- Change the ether-cleavage mechanismUse tertiary ionization rather than assigning universal methyl-site SN2 cleavage.
- Open an unstrained cyclic ether with acidTrack a single ether ring opening without losing either end of the four-carbon chain.
- Epoxide opening — acid-catalysed, with methanolProtonate the epoxide, then add methanol at the tertiary carbon while the ring oxygen stays on CH₂.
- Epoxide opening — with cyanideUse the carbon end of cyanide to open the epoxide and add a carbon to the chain. This is ring opening, not addition to a carbonyl.
- Preserve the backside-opening geometryRepresent an actual above/below projection and retain trans oxygen substituents through workup.
- Williamson ether synthesis — halohydrin-to-epoxide cyclizationConnect selective O–H removal to intramolecular SN2 ring formation.
- Williamson ether synthesis — five-membered ring closureMap a five-membered ring from a preformed haloalkoxide rather than an intermolecular methylation.
- Install sulfur next to an alcoholTrack a polarizable sulfur donor and distinguish neutral thioether from alkoxide charge after opening.
- Resolve oxygen provenance in epoxide hydrolysisComplete water attack and acid regeneration while distinguishing the two final alcohol oxygens.
- Lanosterol biosynthesis — oxidosqualene cyclization cascadeFollow the oxidosqualene cyclization cascade: epoxide opening, four ring closures with a ring-C expansion, then the hydride and methyl shifts that finish lanosterol.
- HCl opens cyclohexene oxide to the trans-chlorohydrinDraw the protonation of cyclohexene oxide by HCl and the backside attack of chloride that opens the ring to trans-2-chlorocyclohexan-1-ol.
- Hydroxide opens cyclohexene oxide to trans-cyclohexane-1,2-diolDraw the backside attack of hydroxide on cyclohexene oxide and the protonation of the alkoxide by water that gives trans-cyclohexane-1,2-diol.
- HBr cleaves tert-butyl propyl ether by SN1Draw the protonation of tert-butyl propyl ether, its ionisation to the tert-butyl cation and propan-1-ol, and the capture of the cation by bromide.
- HBr opens tetrahydropyran to 5-bromopentan-1-olDraw the protonation of tetrahydropyran and the SN2 attack of bromide on a ring CH2 that opens the ring to 5-bromopentan-1-ol.
- Pent-4-yn-2-ol from propylene oxide and sodium acetylideDraw amide deprotonating acetylene, the acetylide opening 2-methyloxirane at its CH2 carbon, and hydronium protonating the alkoxide to give pent-4-yn-2-ol.
- 2-Methoxy-2-phenylethan-1-ol from styrene oxide in acidic methanolDraw protonation of 2-phenyloxirane, methanol attacking the benzylic carbon, and deprotonation to 2-methoxy-2-phenylethan-1-ol.
- (Tetrahydrofuran-2-yl)methanol by 5-exo epoxide cyclizationDraw NaH deprotonating 3-(oxiran-2-yl)propan-1-ol, the alkoxide opening the epoxide at its inner carbon to close a five-membered ring, and water protonating the new alkoxide.
- 1-Methoxy-1-methylcyclohexane by alkoxymercurationDraw mercury(II) adding to 1-methylcyclohexene, methanol attacking the more substituted carbon, loss of the O–H proton, and replacement of mercury by hydrogen with NaBH4.
- trans-2-Aminocyclohexan-1-ol from cyclohexene oxideDraw ammonia opening cyclohexene oxide by backside SN2 attack, then proton transfers through a second ammonia that give trans-2-aminocyclohexan-1-ol.
- trans-2-Azidocyclohexan-1-ol from cyclohexene oxideDraw azide opening cyclohexene oxide by backside attack and ammonium chloride protonating the alkoxide, giving trans-2-azidocyclohexan-1-ol.
- 1-Oxaspiro[2.5]octane from cyclohexanone by Corey–ChaykovskyDraw hydride forming dimethylsulfonium methylide from trimethylsulfonium, the ylide adding to cyclohexanone, and the alkoxide displacing dimethyl sulfide to give 1-oxaspiro[2.5]octane.
- 3-Hydroxy-3-phenylpropanenitrile from styrene oxideDraw cyanide opening styrene oxide at the terminal CH2 by SN2, then water protonating the benzylic alkoxide to give 3-hydroxy-3-phenylpropanenitrile.
- Ethyl trans-3-phenylglycidate by Darzens condensationDraw ethoxide forming the enolate of ethyl chloroacetate, its addition to benzaldehyde, and the alkoxide displacing chloride to give ethyl trans-3-phenyloxirane-2-carboxylate.
- 1-(Dimethylamino)propan-2-ol from propylene oxideDraw dimethylamine opening propylene oxide at the CH2 carbon by SN2, then proton transfers through a second dimethylamine that give 1-(dimethylamino)propan-2-ol.
- Dimethyl sulfoxide from dimethyl sulfide and hydrogen peroxideDraw the sulfur of dimethyl sulfide attacking an oxygen of hydrogen peroxide, breaking the O–O bond, then hydroxide removing the O–H proton to give dimethyl sulfoxide.
- 2-(Ethylthio)ethanol from 2-chloroethyl ethyl sulfideDraw sulfur of 2-chloroethyl ethyl sulfide displacing chloride to form a thiiranium ion, water opening that ring, and water removing the proton to give 2-(ethylthio)ethan-1-ol.
- cis-2,3-Dimethyloxirane from (Z)-but-2-eneDraw the concerted epoxidation of (Z)-but-2-ene by mCPBA and show that the cis relationship of the methyl groups is kept.
- Cyclohexene oxide from cyclohexene and mCPBADraw the one-step transfer of oxygen from mCPBA to cyclohexene, giving cyclohexene oxide and 3-chlorobenzoic acid.
- trans-2,3-Dimethyloxirane from (E)-but-2-eneDraw the concerted epoxidation of (E)-but-2-ene by mCPBA and show that the trans relationship of the methyl groups is kept.
- 1-Ethoxy-2-methylpropan-2-ol from 2,2-dimethyloxiraneDraw ethoxide opening 2,2-dimethyloxirane at the CH2 carbon by SN2, then ethanol protonating the tertiary alkoxide to give 1-ethoxy-2-methylpropan-2-ol.
- trans-2-Methylcyclohexan-1-ol via Me2CuLi epoxide openingDraw lithium dimethylcuprate delivering a methyl group to the back face of cyclohexene oxide and the workup acid protonating the alkoxide to give trans-2-methylcyclohexan-1-ol.
- 2-Methylbutan-2-ol from 2,2-dimethyloxirane and methylmagnesium bromideDraw the methyl group of methylmagnesium bromide opening 2,2-dimethyloxirane at the CH2 carbon and the acidic workup protonating the alkoxide.
- Racemic butane-2,3-diol from cis-2,3-dimethyloxiraneDraw hydronium protonating cis-2,3-dimethyloxirane, water opening it from the back face, and loss of the proton to give one enantiomer of chiral butane-2,3-diol.
- trans-2-Bromocyclohexan-1-ol from cyclohexeneDraw bromonium-ion formation from cyclohexene, backside opening by water, and deprotonation to trans-2-bromocyclohexan-1-ol.
- Cyclohexene oxide from trans-2-bromocyclohexan-1-olDraw hydroxide deprotonating trans-2-bromocyclohexan-1-ol and the alkoxide displacing bromide from the neighbouring carbon by backside attack to close cyclohexene oxide.
- 2-Bromo-2-methylpropan-1-ol from 2,2-dimethyloxiraneDraw HBr protonating 2,2-dimethyloxirane, then bromide opening the protonated epoxide at the tertiary carbon to give 2-bromo-2-methylpropan-1-ol.
- Phenol and bromomethane from anisole and HBrDraw HBr protonating the ether oxygen of anisole, then bromide attacking the methyl carbon by SN2 to release phenol and bromomethane.
- Benzyl bromide from benzyl methyl ether and HBrDraw HBr protonating benzyl methyl ether, loss of methanol to give the benzylic cation, and capture of that cation by bromide to give benzyl bromide.
- 1-Bromopropane from dipropyl ether and excess HBrDraw protonation of dipropyl ether, bromide displacing propan-1-ol by SN2, then protonation of propan-1-ol and a second SN2 that gives a second 1-bromopropane.
- 1-Bromopropan-2-ol from 2-methyloxirane and HBrDraw HBr protonating 2-methyloxirane and bromide opening the protonated ring at the CH2 carbon to give 1-bromopropan-2-ol.
- Iodoethane from diethyl ether and excess HIDraw both SN2 cleavages: HI protonates diethyl ether and iodide releases ethanol, then a second HI converts that ethanol into a second iodoethane.
- Iodoethane and propan-2-ol from ethyl isopropyl etherDraw HI protonating ethyl isopropyl ether, then iodide attacking the primary ethyl carbon by SN2 to release iodoethane and propan-2-ol.
- Cyclohexanol from methoxycyclohexane and HIDraw protonation of methoxycyclohexane and iodide attacking the methyl carbon by SN2, releasing cyclohexanol and iodomethane.
- (R)-Butan-2-ol from (R)-2-methoxybutane and HIDraw HI protonating (R)-2-methoxybutane, then iodide attacking the methyl carbon by SN2 so that (R)-butan-2-ol is released with its stereocentre untouched.
- 2-Iodo-2-methylpropane from MTBE and HIDraw protonation of 2-methoxy-2-methylpropane, ionization to the tert-butyl cation and methanol, then capture of the cation by iodide.
- (R)-1-Phenylethane-1,2-diol from (R)-styrene oxide and NaOHDraw hydroxide opening (R)-2-phenyloxirane at the CH2 carbon and water protonating the alkoxide, keeping the benzylic stereocentre unchanged in (R)-1-phenylethane-1,2-diol.
- cis-2-Methyl-3-phenyloxirane by Jacobsen epoxidationDraw the Mn(V)-oxo species of the Jacobsen catalyst delivering its oxygen to both carbons of cis-β-methylstyrene on one face and releasing cis-2-methyl-3-phenyloxirane.
- 1-Methylcyclohexan-1-ol from 1-methylcyclohexene oxide + LiAlH4Draw hydride from LiAlH4 opening 1-methylcyclohexene oxide at its secondary ring carbon and water protonating the tertiary alkoxide to give 1-methylcyclohexan-1-ol.
- 1-Phenylethan-1-ol from styrene oxide and LiAlH4Draw hydride from LiAlH4 opening 2-phenyloxirane at the CH2 carbon and water protonating the alkoxide to give 1-phenylethan-1-ol.
- 1-Methylcyclohexene oxide from 1-methylcyclohexene and mCPBADraw the concerted transfer of the terminal peroxy oxygen of mCPBA to 1-methylcyclohexene, giving 1-methylcyclohexene oxide and 3-chlorobenzoic acid.
- mCPBA epoxidation of (E)-stilbene to trans-stilbene oxideDraw the one-step oxygen transfer from mCPBA to (E)-stilbene and show that the two phenyl groups stay trans in trans-stilbene oxide.
- trans-2-Methoxy-2-methylcyclohexan-1-ol in acidic methanolDraw sulfuric acid protonating 1-methylcyclohexene oxide, methanol opening it at the tertiary carbon from the back face, and methanol removing the proton to give trans-2-methoxy-2-methylcyclohexan-1-ol.
- trans-2-Methoxycyclopentan-1-ol from cyclopentene oxideDraw methoxide opening cyclopentene oxide from the back face and methanol protonating the alkoxide to give trans-2-methoxycyclopentan-1-ol.
- 2-Methoxy-1-phenylethan-1-ol from styrene oxide and methoxideDraw methoxide opening 2-phenyloxirane at the CH2 carbon and methanol protonating the resulting alkoxide.
- 2-Methoxy-2-methylpropane (MTBE) from 2-methylpropeneDraw protonation of 2-methylpropene to the tert-butyl cation, capture by methanol, and deprotonation of the oxonium ion to MTBE.
- 1-Bromo-2-methylbutan-2-ol from 2-methylbut-1-ene and NBSDraw NBS transferring bromine to 2-methylbut-1-ene as a bromonium ion, water opening it at the tertiary carbon, and the succinimide anion removing the proton to give 1-bromo-2-methylbutan-2-ol.
- 2-Phenylethan-1-ol from PhMgBr and ethylene oxideDraw the C–Mg bond of phenylmagnesium bromide opening ethylene oxide by SN2, then acidic workup protonating the alkoxide to give 2-phenylethan-1-ol.
- (Phenylthio)methyl acetate by Pummerer rearrangementDraw methyl phenyl sulfoxide being acylated on oxygen by acetic anhydride, elimination to a thionium ion, and acetate adding to it to give (phenylthio)methyl acetate.
- But-1-ene from butyl phenyl sulfoxide by syn eliminationDraw the concerted five-membered-ring syn elimination in which the sulfoxide oxygen of butyl phenyl sulfoxide removes a β-hydrogen, giving but-1-ene and benzenesulfenic acid.
- Cyclohexanol from tert-butoxycyclohexane and TFADraw trifluoroacetic acid protonating tert-butoxycyclohexane, ionisation to the tert-butyl cation and cyclohexanol, then E1 loss of a proton to give 2-methylpropene.
- 4-Chlorobutyl acetate from THF and acetyl chlorideDraw the oxygen of tetrahydrofuran adding to acetyl chloride, loss of chloride to give an acyloxonium ion, then chloride opening the ring by SN2 to give 4-chlorobutyl acetate.
- Diethyl sulfide from ethanethiol and bromoethaneDraw hydroxide deprotonating ethanethiol and the thiolate displacing bromide from bromoethane to give diethyl sulfide.
- Trimethyl(phenoxy)silane from anisole and TMSIDraw the ether oxygen of anisole attacking silicon to displace iodide, then iodide removing the methyl group by SN2 to give trimethyl(phenoxy)silane and iodomethane.
- Trimethylsulfonium iodide from dimethyl sulfideDraw a sulfur lone pair of dimethyl sulfide displacing iodide from iodomethane to give trimethylsulfonium iodide.
- 2-Methylpropane-1,2-diol from 2,2-dimethyloxiraneDraw protonation of 2,2-dimethyloxirane, water attacking the tertiary carbon, and deprotonation to 2-methylpropane-1,2-diol.
- 4-Nitroanisole from 4-nitrophenol and iodomethaneDraw carbonate deprotonating 4-nitrophenol, then the 4-nitrophenoxide ion displacing iodide from iodomethane to give 4-nitroanisole.
- 2-Methyltetrahydrofuran from 5-chloropentan-2-olDraw hydride deprotonating 5-chloropentan-2-ol, then the alkoxide closing a five-membered ring by intramolecular SN2 to give 2-methyltetrahydrofuran.
- Ethoxycyclopentane from cyclopentanol and iodoethaneDraw sodium hydride deprotonating cyclopentanol, then the cyclopentoxide ion displacing iodide from iodoethane to give ethoxycyclopentane.
- 2-Methylpropene from ethoxide and tert-butyl bromideDraw ethoxide forming with NaH, then show why it acts as a base on 2-bromo-2-methylpropane, removing a β-hydrogen in an E2 step instead of making an ether.
- Allyl ethyl ether from ethanol and allyl bromideDraw sodium hydride deprotonating ethanol, then ethoxide displacing bromide from allyl bromide by SN2 to give allyl ethyl ether.
- Benzyl ethyl ether from ethanol and benzyl bromideDraw sodium hydride deprotonating ethanol, then ethoxide displacing bromide from benzyl bromide by SN2.
- 2-(Benzyloxy)ethanol by monobenzylation of ethylene glycolDraw one equivalent of hydride deprotonating one OH of ethylene glycol, then that alkoxide attacking benzyl bromide by SN2 to give 2-(benzyloxy)ethanol.
- Tetrahydrofuran from 4-bromobutan-1-olDraw sodium hydride deprotonating 4-bromobutan-1-ol, then the alkoxide attacking its own CH2Br carbon to close tetrahydrofuran.
- Propene by E2 from isopropoxide and 2-bromopropaneDraw hydride deprotonating propan-2-ol, then the isopropoxide ion removing a β-hydrogen of 2-bromopropane in one E2 step to give propene.
- (S)-2-Phenoxybutane from phenol and (R)-2-butyl tosylateDraw hydride deprotonating phenol, then phenoxide attacking (R)-2-butyl tosylate from the backside to give (S)-2-phenoxybutane with inversion.
- Benzyl phenyl ether from phenol and benzyl bromideDraw carbonate deprotonating phenol, then phenoxide attacking benzyl bromide by SN2 to give benzyl phenyl ether.
- Ethoxybenzene from phenol and bromoethaneDraw hydroxide deprotonating phenol, then phenoxide displacing bromide from bromoethane by SN2 to give ethoxybenzene.
Predict the product 22
- Select the site of basic openingPredict the connectivity of methoxide opening of an unsymmetrical epoxide.
- Symmetric ether from alcoholPredict the product of heating a primary alcohol with sulfuric acid at 140 °C.
- Major product of HBr with 2-methyloxiranePredict the major regioisomer when HBr opens an epoxide with only primary and secondary carbons.
- Acidic methanol opens 2,2-dimethyloxiranePredict the regiochemistry of acid-catalysed methanol opening of a 2,2-disubstituted epoxide.
- Alkoxymercuration of 1-methylcyclohexenePredict the ether formed when 1-methylcyclohexene undergoes alkoxymercuration–demercuration in methanol.
- Stereochemistry of cis-2,3-dimethyloxirane hydrolysisPredict the stereoisomers formed when a meso epoxide is opened by water under acid.
- Stereochemistry of azide opening of cyclohexene oxidePredict the relative and absolute stereochemistry of azide opening of cyclohexene oxide.
- Ethanolamine from ethylene oxide and ammoniaPredict the product when ammonia opens ethylene oxide.
- Methylmagnesium bromide opens 2,2-dimethyloxiranePredict the alcohol formed when a Grignard reagent opens a 2,2-disubstituted epoxide.
- Methoxide opening of 2-methyloxirane in methanolPredict the regiochemistry of methoxide opening 2-methyloxirane under basic conditions.
- Products of anisole cleavage by HIPredict which C–O bond of an aryl methyl ether breaks when it is heated with HI.
- Dipropyl ether with excess HBrPredict the products of cleaving a symmetric dialkyl ether with excess hot HBr.
- Which C–O bond of MTBE breaks?Predict which C–O bond of tert-butyl methyl ether breaks with HI and why the mechanism is SN1.
- 3-Hydroxypropanenitrile from ethylene oxidePredict the product when cyanide opens ethylene oxide.
- Epoxide from (Z)-but-2-ene and mCPBAPredict the stereochemistry of the epoxide formed from (Z)-but-2-ene with mCPBA.
- Stereochemistry of (E)-but-2-ene epoxidationDescribe the stereoisomer mixture formed when (E)-but-2-ene is epoxidized with mCPBA.
- Which alkene of 1-methyl-4-vinylcyclohexene reacts?Predict which of two alkenes in one molecule is epoxidized first by one equivalent of mCPBA.
- LiAlH4 reduces 1,2-epoxyhexanePredict the alcohol formed when LiAlH4 opens a terminal epoxide.
- Butyl methyl sulfide from methanethiolatePredict the product of a thiolate with a primary alkyl bromide.
- Diol from hydrolysis of cyclohexene oxidePredict the relative stereochemistry of the diol formed by acid hydrolysis of cyclohexene oxide.
- Ring closurePredict the product of an intramolecular Williamson reaction.
- Williamson productPredict the ether formed from a phenoxide and a primary alkyl halide.
Classify 4
- Name the etherName an unsymmetrical ether with IUPAC alkoxy-alkane rules.
- Common name of an etherGive the common (alkyl alkyl ether) name of a symmetrical ether.
- THF, dioxane, oxaneMatch common cyclic ethers to their ring structures.
- Name the epoxideIdentify the structure of 2-methyloxirane (propylene oxide).
Compare 3
- Compare activation of a tertiary-substituted epoxideExplain substrate-dependent regioselectivity while retaining the original epoxide oxygen.
- Reagents for cis- or trans-cyclohexane-1,2-diolMatch dihydroxylation reagents to the cis or trans diol they give from cyclohexene.
- Ether vs alkane vs alcoholRank similar-mass compounds by boiling point using intermolecular forces.
Find the error 2
- Williamson ether synthesis — anisole route planningDistinguish phenoxide nucleophilicity from aryl-halide SN2 impossibility.
- Why mostly elimination?Explain why a Williamson synthesis with a tertiary alkyl halide gives an alkene.
Interpret the evidence 5
- Read the anti requirementInfer relative stereochemistry from backside epoxide opening.
- Distinguish opening from eliminationIdentify the bond changes in epoxide hydration without inventing a new π bond.
- Site of attack in acid-catalysed epoxide openingExplain why acid-catalysed opening of an epoxide with a tertiary carbon occurs at that carbon.
- Markovnikov ether without rearrangementExplain why alkoxymercuration of 3,3-dimethylbut-1-ene gives the unrearranged Markovnikov ether.
- Site of attack in basic epoxide openingState the rule for where strong nucleophiles open unsymmetrical epoxides under basic conditions.
Work backward 1
- Identify the first cleavage productApply SN2 selectivity to acid cleavage of an unsymmetrical ether.
Plan a synthesis 3
- Williamson ether synthesis — choose a viable methyl electrophileChoose the viable direction of a Williamson disconnection.
- Cyclohexene oxide via the bromohydrin routeOrder the events that convert cyclohexene into cyclohexene oxide through a bromohydrin.
- Choose the Williamson pairChoose the alkoxide/alkyl halide pair that gives tert-butyl ethyl ether by SN2.
Explain why 3
- Track the retained oxygenUse an isotope to identify the unbroken C–O bond during opening.
- Why ethers make good inert solventsExplain why ethers resist most reagents but are cleaved by strong HBr or HI.
- Why 18-crown-6 activates potassium fluorideExplain how 18-crown-6 makes potassium fluoride a useful nucleophile in an organic solvent.
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