Química Orgânica 2 · Synthesis planning
Rotas de síntese: reagentes, grupos protetores e planejamento em várias etapas
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Prática grátis de setas curvas: escolha um mecanismo
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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
O que você vai aprender
- Choose the reagent that carries out a functional-group interconversion with the required oxidation level, regiochemistry and stereochemistry.
- Plan carbon–carbon bond formations that lengthen a chain by a known number of carbons and work backwards from a target to its starting materials.
- Select, install and remove protecting groups for alcohols, diols, ketones, amines, carboxylic acids and phenols, and draw how each one goes on and comes off.
- Put the steps of a multistep route in a working order and calculate overall yields of linear and convergent routes.
Lição gratuita
O texto da lição resolvida. No Arrow Lab, cada etapa vem com as estruturas e as setas desenhadas.
Ler a aula gratuita (5 partes)
Read the change first: oxidation level and position
Before choosing a reagent, compare the starting carbon with the target carbon. Count the bonds from that carbon to O, N or halogen: an alkane carbon has none, an alcohol, halide or amine carbon one, an aldehyde, ketone or acetal carbon two, a carboxylic acid, ester, amide or nitrile carbon three, and CO₂ four. Moving up the scale needs an oxidant; moving down needs a reductant; staying level needs neither. PCC in CH₂Cl₂ stops a primary alcohol at the aldehyde, while Jones reagent (CrO₃, H₂SO₄, water) continues to the carboxylic acid. Secondary alcohols give ketones and tertiary alcohols are not oxidised. NaBH₄ reduces aldehydes and ketones but not esters or acids; LiAlH₄ reduces esters and acids to primary alcohols and amides and nitriles to amines. Then check where the new group goes: aqueous acid hydrates an alkene with Markovnikov orientation and may rearrange the carbocation; Hg(OAc)₂ then NaBH₄ gives the Markovnikov alcohol without rearrangement; BH₃ then H₂O₂/NaOH gives the anti-Markovnikov alcohol by syn addition. A terminal alkyne gives the methyl ketone with HgSO₄ in aqueous H₂SO₄ and the aldehyde with a bulky borane, and O₃ then Me₂S cleaves a C=C bond into two carbonyl groups. Butan-1-ol, butanal and butanoic acid are drawn here.
Count the carbons: reactions that build the skeleton
Count the carbons in the target and in the starting material; the difference tells you which carbon–carbon bond must be made. A Grignard reagent RMgBr adds one carbon with formaldehyde (RCH₂OH), two carbons with ethylene oxide (RCH₂CH₂OH) and one carbon with CO₂ (RCO₂H). With an aldehyde it gives a secondary alcohol, with a ketone a tertiary alcohol, and with an ester two equivalents add, so the tertiary alcohol carries two identical groups from the Grignard reagent. With a nitrile it adds once, and acidic hydrolysis of the imine gives a ketone. Cyanide displaces a methyl or primary halide to add one carbon as a nitrile, which LiAlH₄ turns into a primary amine and acid hydrolysis into a carboxylic acid; the amide is the intermediate, and mild conditions (concentrated aqueous HCl, gentle warming, short time) stop at it, whereas heating under reflux in aqueous acid continues to the acid. NaNH₂ makes an acetylide from a terminal alkyne; the acetylide alkylates methyl and primary halides, and the alkyne can then be reduced with H₂ and Lindlar's catalyst (cis alkene), Na in NH₃ (trans alkene) or H₂ on Pd/C (alkane). Cyclohexylmagnesium bromide and formaldehyde give the cyclohexylmethanol drawn here.
Protecting groups: on, survive, off
A group that would react with a reagent must be masked, carried through the step, and released afterwards. Ketones and aldehydes become ethylene acetals (ethane-1,2-diol, TsOH, water removed), which survive bases, hydrides and Grignard reagents and come off in aqueous acid. A 1,2-diol becomes an acetonide with 2,2-dimethoxypropane and TsOH. Alcohols become TBS ethers (TBSCl, imidazole; removed by fluoride, TBAF), benzyl ethers (NaH, BnBr; removed by H₂ on Pd/C) or acetate esters (Ac₂O with a little DMAP; removed by methoxide or hydroxide); an acetate does not survive a Grignard reagent or LiAlH₄. Amines become carbamates: Boc (Boc₂O; removed by trifluoroacetic acid) or Cbz (benzyl chloroformate; removed by H₂ on Pd/C). A carboxylic acid becomes a tert-butyl ester (isobutylene, H₂SO₄; removed by TFA), and a phenol a methyl ether (removed by BBr₃). Groups removed by different conditions are orthogonal: a TBS ether comes off with TBAF while a benzyl ether stays, and a Cbz group comes off by hydrogenolysis while a Boc group stays. The Boc-protected amino alcohol and the acetonide of propane-1,2-diol are drawn.
Put the steps in order, and count the yield
On a benzene ring the order of substitutions decides the pattern: install a meta director (NO₂, C=O, SO₃H) first when the target is meta, and an ortho/para director first when it is ortho or para. Friedel–Crafts reactions fail on rings that carry NO₂ or other strong deactivators, and primary alkyl halides rearrange under Friedel–Crafts alkylation, so a straight chain is introduced by acylation followed by Clemmensen or Wolff–Kishner reduction. NH₂ is converted to an acetamide before nitration so that the ring is neither oxidised nor protonated to the meta-directing anilinium ion. A nitro group reduced to NH₂ at the end (Sn or Fe with HCl) changes a meta director into an ortho/para director, which is why 3-bromoaniline (drawn as its nitro precursor, 1-bromo-3-nitrobenzene) is made by nitration, bromination, then reduction. Yields multiply: four steps of 85%, 70%, 90% and 60% give 0.85 × 0.70 × 0.90 × 0.60 = 32% overall. A convergent route that makes two fragments separately and joins them is measured along its longest linear sequence, so it usually gives a higher overall yield than a linear route with the same total number of steps.
What to carry forward
Work from the target backwards: compare oxidation levels, carbon counts and positions; pick the reagent whose selectivity matches; protect any group the reagent would attack, using a protecting group that comes off under conditions the rest of the molecule tolerates; and order the steps so that every reagent meets only the groups it should change. Shorter and convergent routes lose less material.
Problemas de prática (80)
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Desenhe o mecanismo 33
Protecting groups
- 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.
- 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.
- 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.
- 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.
- Cbz protection of benzylamine: benzyl benzylcarbamateProtect benzylamine as a Cbz carbamate by addition–elimination at benzyl chloroformate.
- Piperidine removes the Fmoc group: benzylamineRemove an Fmoc group with piperidine by drawing fluorenyl deprotonation, E1cB loss of the carbamate and decarboxylation.
- MOM protection of benzyl alcohol: [(methoxymethoxy)methyl]benzeneProtect benzyl alcohol as a methoxymethyl ether by SN2 at the CH2 of MOMCl and amine deprotonation.
- TBS protection of cyclohexanol: tert-butyldimethyl(cyclohexyloxy)silaneProtect cyclohexanol as its TBS ether by drawing substitution at silicon and the imidazole deprotonation.
- TBAF removes the TBS group: cyclohexanolRemove a TBS protecting group with fluoride and protonate the released cyclohexoxide.
- THP protection of benzyl alcohol: 2-(benzyloxy)oxaneProtect benzyl alcohol as a THP acetal through an oxocarbenium ion formed from dihydropyran.
Building the carbon skeleton
- 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-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.
- 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.
Grupos protetores
- Proteção do cis-ciclo-hexano-1,2-diol como acetonídeoProteja o cis-ciclo-hexano-1,2-diol como acetonídeo desenhando os dois íons oxocarbênio formados a partir do 2,2-dimetoxipropano e sua captura por cada OH.
- Desmetilação do 2-metoxinaftaleno com BBr3: 2-naftolClive o éter metílico do 2-metoxinaftaleno com BBr3 desenhando o aduto O–B, a SN2 do brometo na metila e a hidrólise do ariloxiborano.
- Proteção Boc da (S)-1-feniletilamina: carbamato BocProteja a (S)-1-feniletilamina com Boc2O, mostrando o grupo abandonador carbonato de terc-butila se decompondo em CO2 e o centro (S) inalterado.
- O TFA remove o grupo Boc da N-Boc-piperidina: piperidinaDesproteja a N-Boc-piperidina com TFA desenhando a perda do cátion terc-butila, a formação de isobutileno e a descarboxilação do ácido carbâmico.
- Proteção Cbz da ciclo-hexilamina: carbamato de benzilaProteja a ciclo-hexilamina como carbamato Cbz desenhando a adição ao cloroformato de benzila, a perda de cloreto e a desprotonação pelo carbonato.
- Acetilação do (R)-1-feniletanol com DMAP: acetato (R)Acetile o (R)-1-feniletanol com Ac2O por meio do íon N-acetilpiridínio formado pelo DMAP, mantendo o centro (R).
- A piperidina remove o Fmoc: ciclo-hexilaminaRemova um grupo Fmoc da ciclo-hexilamina desenhando a desprotonação do fluorenila, a perda do carbamato por E1cB e a descarboxilação.
- Hidrólise do etilenocetal da ciclo-hexanona: ciclo-hexanonaRemova um grupo protetor etilenocetal com ácido aquoso, desenhando os dois íons oxocarbênio e cada transferência de próton até a ciclo-hexanona.
- O TBAF remove o grupo TBS: 3-fenilpropan-1-olDesproteja um éter TBS com fluoreto e protone o alcóxido liberado para obter o 3-fenilpropan-1-ol.
- Proteção TBS do (R)-butan-2-ol: éter (R)-TBSProteja o (R)-butan-2-ol como éter TBS e mostre por que o estereocentro mantém a configuração (R).
- Éster terc-butílico do ácido fenilacético a partir do isobutilenoProteja o ácido fenilacético como éster terc-butílico desenhando o cátion terc-butila formado a partir do isobutileno e sua captura pelo ácido.
- Proteção THP do ciclo-hexanol: 2-(ciclo-hexilóxi)oxanoProteja o ciclo-hexanol como acetal THP protonando o di-hidropirano a um íon oxocarbênio e capturando-o com o álcool.
Construção do esqueleto carbônico
- Metilação do fenilacetileto: 1-fenilpropinoAumente o fenilacetileno em um carbono: desprotone com amideto de sódio e desenhe a SN2 do acetileto no iodometano até o 1-fenilpropino.
- Brometo de fenilmagnésio e formaldeído: álcool benzílicoAcrescente um carbono a um anel benzênico desenhando a adição do brometo de fenilmagnésio ao formaldeído e o tratamento ácido até o álcool benzílico.
- Hidratação ácida da fenilacetonitrila: 2-fenilacetamidaHidrate a fenilacetonitrila a 2-fenilacetamida em ácido sulfúrico, desenhando o íon nitrílio, a adição de água e a tautomerização do ácido imídico.
Reagents and functional-group maps
- Benzoic acid to methyl benzoate through benzoyl chlorideConvert benzoic acid to methyl benzoate by drawing acyl chloride formation with SOCl2 and its methanolysis.
Preveja o produto 7
Building the carbon skeleton
- Benzyl chloride to a one-carbon-longer acidPredict the carboxylic acid formed when a Grignard reagent is carboxylated with CO₂.
Protecting groups
- Boc and Cbz on the same diaminePredict which of two carbamate protecting groups on the same molecule is removed by catalytic hydrogenolysis.
Ordering multistep routes
- 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.
- Follow a three-step sequencePredict the product of an oxidation, Grignard addition and E1 dehydration carried out in sequence.
Reagents and functional-group maps
- 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.
Classificar 4
Protecting groups
- Which aryl bromide needs no protection?Classify functional groups as compatible or incompatible with formation of a Grignard reagent.
Reagents and functional-group maps
- Which step needs an oxidant?Classify functional-group interconversions as oxidations, reductions or neither by comparing bonds to oxygen and hydrogen.
Vocabulário de retrossíntese
- Interconversão de grupo funcional vs desconexãoIdentifique qual seta retrossintética é uma interconversão de grupo funcional, e não uma desconexão.
- O que é um sínton na retrossíntese?Defina sínton e diferencie-o do reagente que serve como seu equivalente sintético.
Comparar 2
Protecting groups
- Remove one protecting group, keep the otherCompare deprotection conditions to pick the reagent that removes a silyl ether while a benzyl ether stays.
Reagents and functional-group maps
- The one-carbon oxidation ladderRank one-carbon compounds by the oxidation state of carbon to see which interconversions need an oxidant or a reductant.
Calcular 5
Ordering multistep routes
- Convergent versus linearCalculate the overall yield of a convergent route along its longest linear sequence and compare it with a linear route.
- Overall yield of a four-step routeCalculate the overall yield of a linear synthesis by multiplying the step yields.
Building the carbon skeleton
- Count the carbons after an epoxide openingCount the carbons in the product of a Grignard reagent opening ethylene oxide.
Protecting groups
- How much Grignard reagent?Count the equivalents of Grignard reagent consumed by an acidic O–H and an ester in the same molecule.
Ordenação de rotas em várias etapas
- Rendimento global de uma síntese em três etapasCalcule o rendimento global de uma síntese linear em três etapas multiplicando os rendimentos de cada etapa.
Encontre o erro 4
Protecting groups
- A protecting group that does not protectDiagnose why an ester protecting group fails in a Grignard step and choose a compatible alternative.
Ordering multistep routes
- A route that stallsDiagnose a failed aromatic synthesis caused by the Friedel–Crafts limitation and reorder the steps.
Reagents and functional-group maps
- 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.
Ordenação de rotas em várias etapas
- Ordem errada: LiAlH4 depois da formação do ésterDiagnostique uma rota que forma um éster antes de uma redução com LiAlH4 e corrija-a reduzindo primeiro e esterificando por último.
Trabalhe de trás para frente 2
Building the carbon skeleton
- 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.
Planeje uma síntese 20
Ordering multistep routes
- Benzene to 3-bromoanilineOrder aromatic substitutions and a functional-group interconversion so that the directing effects give a meta-disubstituted product.
- 4-Aminophenol from phenolOrder nitration, separation and reduction to make 4-aminophenol.
Reagents and functional-group maps
- 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.
- 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.
- 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.
Building the carbon skeleton
- 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.
- 1-Bromobutane to hexan-1-olPlan a two-carbon chain extension that ends in a primary alcohol.
- 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.
Protecting groups
- Reduce the ester, keep the ketoneOrder protection, reduction and deprotection steps so that a hydride reagent reduces only the less reactive carbonyl group.
- 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.
Ordenação de rotas em várias etapas
- Da ciclo-hexanona à ciclo-hexilamina: duas rotasReconheça duas rotas válidas de uma cetona a uma amina primária: aminação redutiva em uma etapa e formação de oxima seguida de redução com LiAlH4.
Explique por quê 3
Protecting groups
- Why acetals are good ketone protecting groupsExplain why acetals survive basic and nucleophilic reagents but are removed by aqueous acid.
Ordering multistep routes
- 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.
Travou em rotas de síntese: reagentes, grupos protetores e planejamento em várias etapas? Escaneie o problema.
Tire uma foto da reação da sua lista ou do livro e desenhe o mecanismo com cada seta corrigida. 1 scan grátis agora, sem cadastro; mais 1 com uma conta gratuita.
Depois, Scan Standard: /mês