Organic Chemistry 2 · Synthesis planning
Synthesis roadmaps: reagents, protecting groups and multistep planning: practice problems
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- Acetonide protection of propane-1,2-diol with 2,2-dimethoxypropane
- BBr₃ removes the methyl group from 4-methylanisole
- Boc protection of 4-aminobutan-1-ol with Boc₂O
- DMAP-catalysed acetylation of 2-phenylethanol
- Cyclohexylmagnesium bromide and formaldehyde give cyclohexylmethanol
- Acid hydrolysis of 2-methyl-2-phenyl-1,3-dioxolane releases acetophenone
- Acid-catalysed hydration of pentanenitrile to pentanamide
- tert-Butyl benzoate from benzoic acid and isobutylene
- Protected Grignard reagent plus acetone gives 5-hydroxy-5-methylhexanal
Draw the mechanism 33
- Acetonide protection of propane-1,2-diol with 2,2-dimethoxypropaneDraw the acid-catalysed transfer of the isopropylidene group from 2,2-dimethoxypropane to propane-1,2-diol, through two oxocarbenium ions and with loss of two methanol molecules, that closes the five-membered acetonide ring.
- BBr₃ removes the methyl group from 4-methylanisoleDraw the Lewis acid–base adduct of 4-methylanisole with boron tribromide, the bromide SN2 at the methyl carbon, and the aqueous workup that releases 4-methylphenol, the deprotection of a phenol methyl ether.
- Boc protection of 4-aminobutan-1-ol with Boc₂ODraw how the amine of 4-aminobutan-1-ol attacks di-tert-butyl dicarbonate, how the tetrahedral intermediate collapses, and how the leaving group breaks down to CO₂ and tert-butoxide, which removes the last N–H proton to give the Boc carbamate while the alcohol is left free.
- DMAP-catalysed acetylation of 2-phenylethanolDraw how 4-(dimethylamino)pyridine turns acetic anhydride into an N-acetylpyridinium ion, how 2-phenylethanol is acetylated by that ion, and how the catalyst is released to protect the alcohol as its acetate ester.
- Cyclohexylmagnesium bromide and formaldehyde give cyclohexylmethanolDraw the addition of cyclohexylmagnesium bromide to formaldehyde and the acidic workup, and recognise this as the way to lengthen a chain by one carbon ending in CH₂OH.
- Acid hydrolysis of 2-methyl-2-phenyl-1,3-dioxolane releases acetophenoneDraw the acid-catalysed hydrolysis that removes an ethylene ketal protecting group: ring opening to the oxocarbenium ion, capture by water, and loss of ethane-1,2-diol to give acetophenone.
- Acid-catalysed hydration of pentanenitrile to pentanamideDraw how aqueous acid adds water across the C≡N bond of pentanenitrile, through the nitrilium ion and the imidic acid, to give pentanamide, and recognise that mild conditions stop at the amide while prolonged heating in aqueous acid continues to pentanoic acid.
- tert-Butyl benzoate from benzoic acid and isobutyleneDraw the acid-catalysed addition of benzoic acid to 2-methylpropene through the tert-butyl cation, the way a carboxylic acid is protected as its tert-butyl ester.
- Protected Grignard reagent plus acetone gives 5-hydroxy-5-methylhexanalAdd a dioxolane-protected Grignard reagent to acetone, then unmask the aldehyde by acid hydrolysis of the acetal.
- Acetonide protection of cis-cyclohexane-1,2-diolProtect cis-cyclohexane-1,2-diol as its acetonide by drawing two oxocarbenium ions from 2,2-dimethoxypropane and their capture by each OH.
- Propynide alkylation gives pent-2-yne, the Lindlar precursorBuild pent-2-yne from propyne by acetylide formation and SN2 with bromoethane, the first stage of a route to (Z)-pent-2-ene.
- Methylation of phenylacetylide: 1-phenylpropyneExtend phenylacetylene by one carbon: deprotonate with sodium amide and draw the acetylide SN2 on iodomethane to 1-phenylpropyne.
- BBr3 demethylation of 2-methoxynaphthalene: 2-naphtholCleave the methyl ether of 2-methoxynaphthalene with BBr3 by drawing the O–B adduct, SN2 of bromide on methyl and the hydrolysis of the aryloxyborane.
- Benzoic acid to methyl benzoate through benzoyl chlorideConvert benzoic acid to methyl benzoate by drawing acyl chloride formation with SOCl2 and its methanolysis.
- Boc protection of (S)-1-phenylethylamine: Boc carbamateProtect (S)-1-phenylethylamine with Boc2O, showing the tert-butyl carbonate leaving group fall apart to CO2 and the (S) centre unchanged.
- TFA removes the Boc group: benzylamineRemove a Boc group with TFA by drawing tert-butyl cation loss, its E1 to isobutylene and the decarboxylation of the carbamic acid.
- TFA removes the Boc group from N-Boc-piperidine: piperidineDeprotect N-Boc-piperidine with TFA by drawing tert-butyl cation loss, isobutylene formation and decarboxylation of the carbamic acid.
- Cbz protection of benzylamine: benzyl benzylcarbamateProtect benzylamine as a Cbz carbamate by addition–elimination at benzyl chloroformate.
- Cbz protection of cyclohexylamine: benzyl carbamateProtect cyclohexylamine as its Cbz carbamate by drawing addition to benzyl chloroformate, chloride loss and deprotonation by carbonate.
- DMAP acetylation of (R)-1-phenylethanol: (R)-acetateAcetylate (R)-1-phenylethanol with Ac2O through the N-acetylpyridinium ion from DMAP, keeping the (R) centre.
- Piperidine removes the Fmoc group: benzylamineRemove an Fmoc group with piperidine by drawing fluorenyl deprotonation, E1cB loss of the carbamate and decarboxylation.
- Piperidine removes Fmoc: cyclohexylamineRemove an Fmoc group from cyclohexylamine by drawing fluorenyl deprotonation, E1cB loss of the carbamate and decarboxylation.
- Phenylmagnesium bromide and formaldehyde: benzyl alcoholAdd one carbon to a benzene ring by drawing phenylmagnesium bromide adding to formaldehyde and the acidic workup to benzyl alcohol.
- Hydrolysis of cyclohexanone ethylene ketal: cyclohexanoneRemove an ethylene ketal protecting group with aqueous acid, drawing both oxocarbenium ions and every proton transfer to cyclohexanone.
- MOM protection of benzyl alcohol: [(methoxymethoxy)methyl]benzeneProtect benzyl alcohol as a methoxymethyl ether by SN2 at the CH2 of MOMCl and amine deprotonation.
- Acid hydration of phenylacetonitrile: 2-phenylacetamideHydrate phenylacetonitrile to 2-phenylacetamide in sulfuric acid, drawing the nitrilium ion, water addition and the imidic acid tautomerisation.
- TBAF removes the TBS group: 3-phenylpropan-1-olDeprotect a TBS ether with fluoride and protonate the released alkoxide to give 3-phenylpropan-1-ol.
- TBS protection of cyclohexanol: tert-butyldimethyl(cyclohexyloxy)silaneProtect cyclohexanol as its TBS ether by drawing substitution at silicon and the imidazole deprotonation.
- TBS protection of (R)-butan-2-ol: (R)-TBS etherProtect (R)-butan-2-ol as its TBS ether and show why the stereocentre keeps its (R) configuration.
- TBAF removes the TBS group: cyclohexanolRemove a TBS protecting group with fluoride and protonate the released cyclohexoxide.
- tert-Butyl ester of phenylacetic acid from isobutyleneProtect phenylacetic acid as its tert-butyl ester by drawing the tert-butyl cation from isobutylene and its capture by the acid.
- THP protection of benzyl alcohol: 2-(benzyloxy)oxaneProtect benzyl alcohol as a THP acetal through an oxocarbenium ion formed from dihydropyran.
- THP protection of cyclohexanol: 2-(cyclohexyloxy)oxaneProtect cyclohexanol as a THP acetal by protonating dihydropyran to an oxocarbenium ion and trapping it with the alcohol.
Predict the product 7
- Benzyl chloride to a one-carbon-longer acidPredict the carboxylic acid formed when a Grignard reagent is carboxylated with CO₂.
- Boc and Cbz on the same diaminePredict which of two carbamate protecting groups on the same molecule is removed by catalytic hydrogenolysis.
- A five-step road from bromobenzenePredict the product of a multistep sequence that adds a carbon and then converts it through acid, acid chloride and amide to an amine.
- Choosing the less substituted alkenePredict the major E2 product when a bulky base is used to make a less substituted alkene from a tertiary halide.
- Hydroboration–oxidation of hex-1-enePredict the anti-Markovnikov alcohol formed by hydroboration–oxidation of a terminal alkene.
- Ozonolysis of a ring alkenePredict the open-chain dicarbonyl compound formed when ozonolysis cleaves a C=C bond inside a ring.
- Follow a three-step sequencePredict the product of an oxidation, Grignard addition and E1 dehydration carried out in sequence.
Classify 4
- Which aryl bromide needs no protection?Classify functional groups as compatible or incompatible with formation of a Grignard reagent.
- Which step needs an oxidant?Classify functional-group interconversions as oxidations, reductions or neither by comparing bonds to oxygen and hydrogen.
- Functional-group interconversion vs disconnectionIdentify which retrosynthetic arrow is a functional-group interconversion rather than a disconnection.
- What is a synthon in retrosynthesis?Define a synthon and distinguish it from the reagent that serves as its synthetic equivalent.
Compare 2
- Remove one protecting group, keep the otherCompare deprotection conditions to pick the reagent that removes a silyl ether while a benzyl ether stays.
- The one-carbon oxidation ladderRank one-carbon compounds by the oxidation state of carbon to see which interconversions need an oxidant or a reductant.
Calculate 5
- Convergent versus linearCalculate the overall yield of a convergent route along its longest linear sequence and compare it with a linear route.
- Count the carbons after an epoxide openingCount the carbons in the product of a Grignard reagent opening ethylene oxide.
- How much Grignard reagent?Count the equivalents of Grignard reagent consumed by an acidic O–H and an ester in the same molecule.
- Overall yield of a four-step routeCalculate the overall yield of a linear synthesis by multiplying the step yields.
- Overall yield of a three-step synthesisCalculate the overall yield of a linear three-step synthesis by multiplying the step yields.
Find the error 4
- A protecting group that does not protectDiagnose why an ester protecting group fails in a Grignard step and choose a compatible alternative.
- A route that stallsDiagnose a failed aromatic synthesis caused by the Friedel–Crafts limitation and reorder the steps.
- Fix the route to trans-2-methylcyclohexanolDiagnose a regiochemical error in a proposed alkene hydration and replace it with the reagent that gives the required regio- and stereochemistry.
- Wrong order: LiAlH4 after ester formationDiagnose a route that forms an ester before a LiAlH4 reduction and fix it by reducing first and esterifying last.
Work backward 2
- Which ester makes 3-ethylpentan-3-ol?Work backwards from a tertiary alcohol with two identical groups to the ester that supplies the third group.
- Disconnect pentan-3-oneChoose a nitrile and Grignard reagent pair that gives a target ketone after acidic hydrolysis.
Plan a synthesis 20
- Benzene to 3-bromoanilineOrder aromatic substitutions and a functional-group interconversion so that the directing effects give a meta-disubstituted product.
- Hex-1-yne to hexan-2-oneChoose the reagent that hydrates a terminal alkyne to a methyl ketone rather than an aldehyde.
- Benzoic acid to benzaldehydePlan a reduce-then-reoxidise sequence when no single common reagent stops at the needed oxidation level.
- But-1-yne to (Z)-hex-3-enePlan a C–C bond formation followed by a stereoselective alkyne reduction, in the right order, to reach a cis alkene.
- Acetylene to hex-3-ynePlan two sequential acetylide alkylations to place one ethyl group on each end of an alkyne.
- Reduce the ester, keep the ketoneOrder protection, reduction and deprotection steps so that a hydride reagent reduces only the less reactive carbonyl group.
- Markovnikov hydration without rearrangementChoose a hydration method that gives the Markovnikov alcohol of an alkene whose carbocation would rearrange.
- Butan-1-ol to butanalChoose the oxidant that converts a primary alcohol into an aldehyde without over-oxidation.
- 1-Bromobutane to hexan-1-olPlan a two-carbon chain extension that ends in a primary alcohol.
- 4-Aminophenol from phenolOrder nitration, separation and reduction to make 4-aminophenol.
- Cyclohexanone to cyclohexylamine: two routesRecognise two valid routes from a ketone to a primary amine: one-step reductive amination and oxime formation then LiAlH4 reduction.
- Oxidize one of two OHUse a selective protecting group to oxidise only a secondary alcohol in a diol.
- Aldehyde + bromide in same moleculeSequence protection, Grignard formation and deprotection for a bifunctional substrate.
- Amine during FCPlan protection of an aniline before Friedel–Crafts acylation.
- Mild oxidationChoose a chemoselective oxidant for an aldehyde in the presence of an alkene.
- trans-DiolChoose reagents for anti dihydroxylation of an alkene.
- Fix the alkene positionChoose a route that places a C=C at a defined position without isomer mixtures.
- 1,5-Dicarbonyl via MichaelChoose a C–C bond-forming reaction that builds a 1,5-dicarbonyl.
- +1 C to acidConvert an alkyl bromide into the carboxylic acid with one more carbon.
- Ketone from alkyneOrder the steps that build a methyl ketone from acetylene.
Explain why 3
- Why acetals are good ketone protecting groupsExplain why acetals survive basic and nucleophilic reagents but are removed by aqueous acid.
- Why acetylate aniline before nitrating?Explain why an amine is converted to an amide before electrophilic nitration in a route to a para-substituted aniline.
- Why acylate, then reduce?Explain why a straight-chain alkylbenzene is made by Friedel–Crafts acylation followed by carbonyl reduction.
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