Organic Chemistry 2 · Functional-group transformations
Organometallic carbon–carbon bonds: practice problems
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- 3-Butylcyclopentanone from cyclopent-2-enone and lithium dibutylcuprate
- Cyclohexanecarboxylic acid from cyclohexylmagnesium bromide and CO2
- Diphenylmethanol from ethyl formate and two phenylmagnesium bromide
- Add carbon, then work up
- When the proton wins
- Grignard addition — ethylmagnesium bromide and acetone (mechanism)
- Extend a vinyl fragment by one carbon
- A soft carbon reagent meets an enone
- Turn carbon dioxide into a carboxylic acid
Draw the mechanism 80
- Add carbon, then work upDraw carbonyl addition and a separately introduced protonation stage.
- When the proton winsDraw proton transfer that consumes a carbon nucleophile.
- Grignard addition — ethylmagnesium bromide and acetone (mechanism)Use the C–Mg bond electrons to add ethyl to acetone, then add water to turn the alkoxide into an alcohol.
- Extend a vinyl fragment by one carbonRetain an organolithium alkene while incorporating formaldehyde as a primary-alcohol carbon.
- A soft carbon reagent meets an enoneDistinguish organocuprate conjugate addition from hard-nucleophile carbonyl addition and complete enolate workup.
- Turn carbon dioxide into a carboxylic acidIncorporate CO₂ carbon and retain both oxygens through a genuinely acidic workup.
- Count both additions to an esterContinue ester addition through leaving-group loss, ketone capture, and both alkoxide protonations.
- Open a cyclic ester with excess carbon donorRetain the tethered leaving oxygen through lactone double addition and produce a diol rather than an alcohol plus a detached alkoxy group.
- Carry nitrile addition through hydrolysisTrack nitrile nitrogen all the way to ammonium and identify water as the ketone oxygen source.
- Extend a carbon donor through an epoxideCombine carbon-chain extension with less-hindered epoxide attack and distinguish it from carbonyl addition.
- Choose acid–base chemistry before additionRecognize a competing alcohol proton in a molecule that also contains a carbonyl electrophile.
- Select direct addition to a conjugated carbonylDistinguish a specified 1,2 organolithium addition from conjugate addition and retain the alkene.
- Make an amine by carbon additionApply carbon–metal addition to C=N and distinguish it from hydride-based reductive amination.
- Two equivalents of cyclohexylmagnesium bromide add to methyl acetateDraw the addition, methoxide loss and second addition of cyclohexylmagnesium bromide to methyl acetate, then protonate the alkoxide to give 1,1-dicyclohexylethan-1-ol.
- Phenylmagnesium bromide opens ethylene oxideDraw the SN2 ring opening of ethylene oxide by phenylmagnesium bromide and the workup protonation that gives 2-phenylethanol.
- Phenylmagnesium bromide and acetonitrile give acetophenoneDraw the single addition of phenylmagnesium bromide to acetonitrile and the acidic hydrolysis of the resulting imine to acetophenone.
- 1-Ethynylcyclohexanol from cyclohexanone and acetylideDraw acetylide addition to cyclohexanone and the ammonium workup that gives 1-ethynylcyclohexan-1-ol.
- Pent-2-yne from sodium propynide and bromoethaneDraw the SN2 attack of propynide on bromoethane that makes pent-2-yne.
- Pent-3-yn-1-ol from propynide and ethylene oxideDraw propynide opening oxirane by SN2 and the workup that gives pent-3-yn-1-ol.
- Sodium amide deprotonates propyneDraw the deprotonation of propyne by amide ion to form sodium propynide.
- 4-(4-Methylphenyl)morpholine by Buchwald–Hartwig aminationDraw one Buchwald–Hartwig cycle: oxidative addition of 4-bromotoluene, morpholine binding to palladium, deprotonation by tert-butoxide and C–N reductive elimination.
- Pentane from 1-bromobutane and lithium dimethylcuprateDraw lithium dimethylcuprate transferring one methyl group to 1-bromobutane with loss of bromide to give pentane.
- Hexan-2-one from acetyl chloride and lithium dibutylcuprateDraw lithium dibutylcuprate adding to acetyl chloride and the loss of chloride that gives hexan-2-one.
- Acetophenone from benzoyl chloride and Me2CuLiDraw lithium dimethylcuprate adding to benzoyl chloride and the loss of chloride that gives acetophenone without further addition.
- 3-Phenylbutanal from crotonaldehyde and Ph2CuLiDraw the 1,4-addition of lithium diphenylcuprate to (E)-crotonaldehyde and the carbon protonation of the enolate that gives 3-phenylbutanal.
- trans-2-Methylcyclohexanol: Me2CuLi opens cyclohexene oxideDraw lithium dimethylcuprate opening cyclohexene oxide by backside attack and the NH4Cl workup, and explain why the product is trans-2-methylcyclohexanol.
- 3-Methylcyclohexanone from cyclohexenone and Me2CuLiDraw the conjugate (1,4) addition of lithium dimethylcuprate to cyclohex-2-enone and the carbon protonation of the lithium enolate.
- 3-Butylcyclopentanone from cyclopent-2-enone and lithium dibutylcuprateDraw the 1,4-addition of lithium dibutylcuprate to cyclopent-2-enone and the carbon protonation of the enolate in the NH4Cl workup.
- 3-Vinylcyclohexanone from cyclohexenone and divinylcuprateDraw the 1,4-addition of lithium divinylcuprate to cyclohex-2-enone and the NH4Cl protonation of the enolate on carbon that gives 3-vinylcyclohexanone.
- Ethyl (E)-3-methylhept-2-enoate by syn carbocuprationDraw the syn addition of lithium dibutylcuprate across ethyl but-2-ynoate and the protonation of the vinylcopper with retention that gives ethyl (E)-3-methylhept-2-enoate.
- Toluene from iodobenzene and lithium dimethylcuprateAccount for the methyl–aryl bond formed when lithium dimethylcuprate couples with iodobenzene to give toluene, and explain why no backside attack is possible.
- (S)-5-Methylundecane by cuprate SN2 on octan-2-yl tosylateDraw lithium dibutylcuprate displacing tosylate from (S)-octan-2-yl tosylate by backside attack and show the inverted stereocentre of (S)-5-methylundecane.
- 2-Methyloct-2-ene from 3-bromo-3-methylbut-1-ene and Bu2CuLiDraw lithium dibutylcuprate attacking the alkene end of 3-bromo-3-methylbut-1-ene with allylic shift of the double bond and loss of bromide (SN2′) to give 2-methyloct-2-ene.
- (E)-But-2-ene from (E)-1-bromopropene and lithium dimethylcuprateAccount for the methyl–vinyl bond formed when lithium dimethylcuprate couples with (E)-1-bromopropene, and explain why the alkene geometry is retained.
- 2-Lithio-1,3-dithiane from 1,3-dithiane and n-BuLiDraw the removal of the C2–H proton of 1,3-dithiane by n-butyllithium that gives 2-lithio-1,3-dithiane and butane.
- Lithium dimethylcuprate from methyllithium and copper(I) iodideDraw the two transmetalation steps in which methyllithium transfers methyl groups to copper(I) iodide to form lithium dimethylcuprate.
- 4-Methoxyacetophenone from 4-methoxybenzonitrile and MeMgBrDraw the addition of methylmagnesium bromide to 4-methoxybenzonitrile and the acid hydrolysis of the imine to 4-methoxyacetophenone.
- Phenylmagnesium bromide destroyed by acetic acidDraw the proton transfer from acetic acid to phenylmagnesium bromide that gives benzene and bromomagnesium acetate.
- 1,1-Diphenylethanol from acetyl chloride and two PhMgBrDraw both phenylmagnesium bromide additions to acetyl chloride, the loss of chloride, and the workup that gives 1,1-diphenylethanol.
- Methylmagnesium bromide deprotonates propyneDraw how methylmagnesium bromide removes the terminal C–H proton of propyne to give an alkynyl Grignard reagent and methane.
- 2-Methylpent-4-en-2-ol from acetone and allyl GrignardDraw the cyclic six-membered addition of allylmagnesium bromide to acetone and the NH4Cl workup that gives 2-methylpent-4-en-2-ol.
- 1-Phenylpropan-1-ol from benzaldehyde and EtMgBrDraw the addition of ethylmagnesium bromide to benzaldehyde and the NH4Cl workup that gives 1-phenylpropan-1-ol.
- Propiophenone from benzonitrile and ethylmagnesium bromideDraw the single addition of ethylmagnesium bromide to benzonitrile and the acidic hydrolysis of the imine to propiophenone.
- Triphenylmethanol from benzophenone and PhMgBrDraw the addition of phenylmagnesium bromide to benzophenone and the NH4Cl workup that gives triphenylmethanol.
- Phenylacetic acid from benzylmagnesium chloride and CO2Draw benzylmagnesium chloride adding to carbon dioxide and the acidic workup that gives phenylacetic acid.
- Pentan-1-ol from butylmagnesium bromide and formaldehydeDraw butylmagnesium bromide adding to formaldehyde and the workup that gives pentan-1-ol.
- 1-Methylcyclohex-2-en-1-ol from cyclohex-2-enone and MeMgBrDraw the direct (1,2) addition of methylmagnesium bromide to the carbonyl carbon of cyclohex-2-enone and the NH4Cl workup.
- Cyclohexanecarboxylic acid from cyclohexylmagnesium bromide and CO2Draw cyclohexylmagnesium bromide adding to carbon dioxide and the acidic workup that gives cyclohexanecarboxylic acid.
- 1-Ethylcyclopentanol from cyclopentanone and EtMgBrDraw the addition of ethylmagnesium bromide to cyclopentanone and the NH4Cl workup that gives 1-ethylcyclopentan-1-ol.
- 3-Ethylpentan-3-ol from diethyl carbonate and three EtMgBrDraw the three ethylmagnesium bromide additions to diethyl carbonate, both losses of ethoxide, and the workup that gives 3-ethylpentan-3-ol.
- Benzaldehyde from DMF and phenylmagnesium bromideDraw the addition of phenylmagnesium bromide to N,N-dimethylformamide and the acid workup that releases benzaldehyde and dimethylamine.
- 2-Phenylpropan-2-ol from ethyl benzoate and two MeMgBrDraw both methylmagnesium bromide additions to ethyl benzoate, the loss of ethoxide, and the workup that gives 2-phenylpropan-2-ol.
- Ethyl benzoate from ethyl chloroformate and PhMgBrDraw the addition of phenylmagnesium bromide to ethyl chloroformate and the loss of chloride that gives ethyl benzoate.
- Diphenylmethanol from ethyl formate and two phenylmagnesium bromideDraw both phenylmagnesium bromide additions to ethyl formate, the loss of ethoxide, and the workup that gives diphenylmethanol.
- 3-Methylbutan-2-ol from isopropylmagnesium bromide and acetaldehydeDraw isopropylmagnesium bromide adding to acetaldehyde and the workup that gives 3-methylbutan-2-ol.
- MeMgBr adds to the ketone of methyl 4-acetylbenzoateDraw the selective addition of one equivalent of methylmagnesium bromide to the ketone of methyl 4-acetylbenzoate and the NH4Cl workup.
- Hexane-1,5-diol from tetrahydropyran-2-ol and MeMgBrDraw how excess methylmagnesium bromide deprotonates tetrahydro-2H-pyran-2-ol, opens it to the aldehyde, adds to it, and how the workup gives hexane-1,5-diol.
- N-Methyl-1-phenylpropan-1-amine from an imine and EtMgBrDraw the addition of ethylmagnesium bromide to the C=N carbon of N-methyl-1-phenylmethanimine and the NH4Cl workup that gives the secondary amine.
- p-Toluic acid from p-tolylmagnesium bromide and CO2Draw p-tolylmagnesium bromide adding to carbon dioxide and the acidic workup that protonates the carboxylate to give p-toluic acid.
- Butan-2-ol from methylmagnesium bromide and 2-methyloxiraneDraw methylmagnesium bromide opening 2-methyloxirane at the CH2 carbon and the acidic workup that gives butan-2-ol.
- Grignard reduction of diisopropyl ketone by i-PrMgBrDraw the β-hydride transfer from isopropylmagnesium bromide to 2,4-dimethylpentan-3-one and the workup that gives 2,4-dimethylpentan-3-ol.
- Phenylboronic acid from PhMgBr and trimethyl borateDraw phenylmagnesium bromide adding to the empty p orbital of trimethyl borate and the acidic hydrolysis of the borate to phenylboronic acid.
- Ethylmagnesium bromide is destroyed by waterDraw the proton transfer from water to the carbon of ethylmagnesium bromide that converts the reagent into ethane.
- Methyl (E)-cinnamate by the Heck reaction of iodobenzeneDraw one Heck cycle joining iodobenzene and methyl acrylate: oxidative addition, migratory insertion, β-hydride elimination to methyl (E)-cinnamate and base regeneration of Pd(0).
- (E)-Stilbene by the Heck reactionDraw one Heck cycle: oxidative addition of iodobenzene, migratory insertion of styrene, β-hydride elimination to (E)-stilbene and base-assisted regeneration of Pd(0).
- Phenyllithium from bromobenzene by lithium–halogen exchangeDraw the lithium–halogen exchange between bromobenzene and n-butyllithium that gives phenyllithium and 1-bromobutane.
- (Z)-Prop-1-enyllithium from (Z)-1-bromopropene and n-BuLiDraw the lithium–halogen exchange of (Z)-1-bromopropene with n-butyllithium and keep the Z geometry in the vinyllithium.
- Acetophenone from benzoic acid and two methyllithiumDraw how two equivalents of methyllithium turn benzoic acid into a dianion and how the acid workup converts it through the hydrate into acetophenone.
- 2-Butylpyridine by Negishi coupling of 2-bromopyridineDraw one Negishi cycle that joins butylzinc bromide to 2-bromopyridine and explain why the sp3 butyl group couples before β-hydride elimination.
- 4-Methoxybiphenyl by Negishi coupling of 4-bromoanisoleDraw one Negishi cycle: oxidative addition of 4-bromoanisole to Pd(0), transmetalation of phenyl from zinc and reductive elimination to 4-methoxybiphenyl.
- Ethyl 3-hydroxy-3-phenylpropanoate by the Reformatsky reactionDraw zinc insertion into ethyl bromoacetate, addition of the organozinc to benzaldehyde, and the acidic workup to the β-hydroxy ester.
- 1-(Hex-1-yn-1-yl)-4-methoxybenzene by Sonogashira couplingDraw one Sonogashira turnover joining 4-iodoanisole and hex-1-yne: oxidative addition, copper acetylide formation, transmetalation and reductive elimination.
- Diphenylacetylene by Sonogashira couplingDraw one Sonogashira turnover: oxidative addition of iodobenzene, copper acetylide formation, transmetalation to palladium and reductive elimination to diphenylacetylene.
- Styrene by Stille coupling of iodobenzene and vinyltinDraw one Stille cycle: oxidative addition of iodobenzene, transfer of the vinyl group from tributyl(vinyl)tin to palladium and reductive elimination to styrene.
- 4-Acetylbiphenyl by Suzuki coupling of 4-bromoacetophenoneDraw one Suzuki cycle that couples 4-bromoacetophenone with phenylboronic acid, including carbonate activation of boron, and explain why the ketone survives.
- Biphenyl by Suzuki couplingDraw one Suzuki catalytic cycle: oxidative addition of bromobenzene to Pd(0), boronate formation, transmetalation and reductive elimination to biphenyl.
- (E)-4-Methylstilbene by Suzuki coupling with retentionDraw one Suzuki cycle joining (E)-β-bromostyrene and 4-methylphenylboronic acid and show that the E alkene geometry is retained in (E)-4-methylstilbene.
- trans-2,3-Dimethylcyclohexanone by conjugate addition and enolate trappingDraw the 1,4-addition of lithium dimethylcuprate to cyclohex-2-enone and the trapping of the resulting enolate at C2 by iodomethane, trans to the new C3 methyl.
- Valerophenone from a benzoyl Weinreb amide and BuMgBrDraw butylmagnesium bromide adding once to N-methoxy-N-methylbenzamide and the acidic workup that collapses the tetrahedral intermediate to valerophenone.
- Acetophenone from a Weinreb amide and phenylmagnesium bromideDraw phenylmagnesium bromide adding once to N-methoxy-N-methylacetamide and the acidic workup that releases acetophenone.
Predict the product 20
- Grignard addition — two additions to an esterPredict repeated organometallic addition through a ketone intermediate.
- Grignard carboxylation — incorporate carbon dioxidePredict the functional group and connectivity produced by organometallic carboxylation.
- Alkylate propyne with bromoethanePredict the internal alkyne formed by deprotonating propyne and alkylating with a primary halide.
- Sodium acetylide adds to acetonePredict the propargylic alcohol formed when an acetylide anion adds to a ketone.
- Grignard on benzaldehydePredict the alcohol from methylmagnesium bromide and benzaldehyde.
- Carboxylation of cyclohexylmagnesium bromidePredict the acid formed when cyclohexylmagnesium bromide is poured onto dry ice and worked up.
- Lithium dibutylcuprate couples with 1-bromopropanePredict the alkane formed by Corey–House coupling of a Gilman reagent with a primary alkyl bromide.
- Lithium dimethylcuprate adds to cyclohex-2-enonePredict the 1,4-addition product of a Gilman reagent with cyclohex-2-enone.
- Lithium dimethylcuprate with (E)-1-bromopropenePredict the product and alkene geometry when a Gilman reagent couples with a vinyl bromide.
- Predict the Grignard product from ethylene oxidePredict the alcohol formed when a Grignard reagent opens ethylene oxide.
- Methylmagnesium bromide opens 2-methyloxiranePredict which epoxide carbon a Grignard reagent attacks in 2-methyloxirane and name the alcohol formed.
- Two equivalents on an esterPredict the product of excess phenylmagnesium bromide with methyl benzoate.
- Grignard on formaldehydePredict the alcohol from a Grignard reagent and formaldehyde.
- Methylmagnesium bromide adds to cyclohex-2-enonePredict the main product of a Grignard reagent with an α,β-unsaturated ketone.
- Heck reaction of iodobenzene with styrenePredict the regiochemistry and alkene geometry of a Heck reaction between an aryl iodide and styrene.
- Methylmagnesium bromide adds to N-benzylideneanilinePredict the amine formed when a Grignard reagent adds to the carbon of an N-aryl imine.
- Grignard on cyclohexanonePredict the alcohol from ethylmagnesium bromide and cyclohexanone.
- Ethylmagnesium bromide adds to benzonitrilePredict the ketone made from benzonitrile and ethylmagnesium bromide after hydrolysis.
- Sonogashira coupling of 4-iodoanisole and phenylacetylenePredict the aryl alkyne formed when an aryl iodide couples with a terminal alkyne under Pd/Cu catalysis.
- Suzuki coupling of 4-bromotoluene and phenylboronic acidPredict the biaryl formed in a Suzuki coupling from the positions of the C–Br and C–B bonds.
Classify 2
- Grignard addition — formaldehyde to a primary alcoholRecognize formaldehyde as the route to a primary alcohol from an organometallic reagent.
- Alcohol class from the carbonylClassify the alcohol formed from each carbonyl partner of a Grignard reagent.
Compare 3
- Grignard vs organocuprate addition — compare 1,2 and 1,4Compare conjugate and direct addition tendencies without treating all metals alike.
- Butanoyl chloride: cuprate or Grignard?Compare the products of an acid chloride with excess Grignard reagent and with a Gilman reagent.
- Rank protons a Grignard reagent removesRank O–H, N–H and alkyne C–H protons by pKa to predict which quenches a Grignard reagent most readily.
Calculate 2
- Equivalents of CH3MgBr for 4-hydroxypentan-2-oneCount the minimum equivalents of a Grignard reagent needed when the substrate carries an unprotected O–H.
- Grignard equivalents for methyl benzoateCount the equivalents of Grignard reagent an ester consumes on its way to a tertiary alcohol.
Find the error 3
- Grignard reagent compatibility — an unprotected alcoholDiagnose consumption of a Grignard reagent by an unprotected alcohol.
- Sodium propynide and tert-butyl bromide failDiagnose why an acetylide cannot be alkylated with a tertiary alkyl halide.
- Which group in 4-hydroxybutanal quenches a Grignard?Identify the functional group in 4-hydroxybutanal that destroys a Grignard reagent by proton transfer.
Interpret the evidence 1
- Polarity of the C–Mg bondInterpret the polarity of the carbon–magnesium bond.
Work backward 5
- Grignard addition — disconnect a tertiary alcoholSelect a ketone and nucleophile pair by matching three carbon substituents.
- Grignard routes to hexan-1-olChoose the Grignard and electrophile pairs that build a primary alcohol by one- or two-carbon extension.
- Disconnect 1-cyclohexylethanol to an aldehydeIdentify the aldehyde that pairs with methylmagnesium bromide to make a secondary alcohol.
- Ester route to 2-phenylpropan-2-olRecognise that two identical groups on a tertiary carbinol carbon can both come from a Grignard adding twice to an ester.
- Three Grignard disconnections of 3-methylhexan-3-olChoose a valid ketone and Grignard pair for a tertiary alcohol with three different alkyl groups.
Plan a synthesis 5
- Choose a two-carbon extensionPlan chain growth through attack on ethylene oxide.
- Make a Gilman reagentPlan the formation of a lithium dialkylcuprate.
- Make a GrignardChoose the conditions that convert an alkyl halide into a Grignard reagent.
- Make butyllithiumChoose the stoichiometry and reagents for making an organolithium.
- Protect 4-bromobutan-1-ol before making its GrignardOrder a protection, Grignard formation, addition and deprotection sequence for a bromo alcohol.
Explain why 2
- Put the operations in orderExplain why aqueous workup must follow carbon–carbon bond formation.
- Why ether solventExplain why Grignard reagents are made in ether solvents.
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