Química Orgânica Avançada · Advanced synthesis
Grupos protetores, organolítios e quimiosseletividade
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O que você vai aprender
- Decide when a functional group must be protected, choose a silyl, THP, acetal or Boc group, and draw how it goes on and comes off.
- Use organolithium reagents as bases (ortho-lithiation, LDA enolates) or as nucleophiles (halogen exchange, acetylides) and predict which role they play.
- Choose a reagent that stops at the intended oxidation level or reacts at one carbonyl: Weinreb amides, DIBAL-H, Luche reduction, Wittig and HWE olefinations.
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Why protect
Try to make a Grignard reagent from 4-bromobutan-1-ol. The moment magnesium inserts into the C–Br bond, the new carbanion carbon meets an O–H proton (pKa about 16) on the same or a neighbouring molecule. Proton transfer is far faster than any addition, so the reagent destroys itself and gives butan-1-olate. The fix is to hide the acidic or electrophilic group in a form that survives the reaction and can be removed cleanly afterwards. A good protecting group goes on in high yield, is inert to the planned conditions, and comes off under conditions that leave the rest of the molecule untouched.
Silyl ethers on and off
A tert-butyldimethylsilyl (TBS) ether is made from the alcohol, TBSCl and imidazole: imidazole attacks silicon first, and the alcohol displaces it from the silylimidazolium ion. The bulky tert-butyl group shields silicon, so TBS ethers survive bases, Grignard and organolithium reagents, hydrides and mild oxidants. Removal uses fluoride, usually tetrabutylammonium fluoride: fluoride attacks silicon and the alkoxide departs, because the Si–F bond is much stronger than the Si–O bond. Unlike a THP acetal, a TBS ether adds no new stereocentre, and it survives the very mild acid (PPTS in ethanol) that removes a THP group, although stronger aqueous acid (acetic acid–water, HCl in methanol) also cleaves it.
Organolithiums: base or nucleophile
n-Butyllithium behaves as a butyl carbanion with a conjugate acid, butane, of pKa about 50, so it removes almost any proton it can reach. With anisole and TMEDA, lithium coordinates to the methoxy oxygen and the base removes the adjacent ring hydrogen: directed ortho-lithiation. With an aryl bromide at −78 °C, exchange at bromine is faster still and the aryl anion forms where bromine was. Bulky LDA is a base only and makes kinetic enolates. Whether the reagent acts as a base or a nucleophile depends on what it meets first; order of addition and temperature matter.
Stop at the ketone
Esters and acid chlorides take two equivalents of a Grignard reagent because the tetrahedral intermediate collapses in the flask, and the ketone it releases is itself attacked by the Grignard reagent (a ketone is even more electrophilic than the ester it came from). An N-methoxy-N-methylamide (Weinreb amide) avoids this: after one addition, magnesium is chelated by the alkoxide oxygen and the methoxy oxygen, and this five-membered chelate does not collapse in the flask. The ketone only appears during the acidic workup, after the organometallic has been destroyed. The same logic explains DIBAL-H stopping at aldehydes from esters and nitriles at −78 °C: the intermediate waits for water.
What to carry forward
Plan around what each reagent will meet first: protect acidic O–H and N–H groups and the more reactive carbonyl, pick organolithium conditions that make the reagent a base or a nucleophile on purpose, and use chelated or aluminium-bound intermediates to stop at the ketone or aldehyde.
Problemas de prática (20)
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Desenhe o mecanismo 14
Protecting groups
- Ethylene glycol acetal of ethyl 4-oxocyclohexane-1-carboxylateDraw the acid-catalysed conversion of the ketone in ethyl 4-oxocyclohexane-1-carboxylate into its ethylene glycol acetal while the ester is left untouched.
- TFA removes the Boc group from tert-butyl N-benzylcarbamateDraw how trifluoroacetic acid cleaves tert-butyl N-benzylcarbamate to the benzylammonium ion, isobutene and carbon dioxide.
- TBAF removes the TBS group from tert-butyldimethyl(3-phenylpropoxy)silaneDraw fluoride attacking silicon to release the alkoxide of 3-phenylpropan-1-ol, then the water workup that gives the free alcohol.
- TBS protection of 3-phenylpropan-1-ol with TBSCl and imidazoleDraw how imidazole activates tert-butyldimethylsilyl chloride and how 3-phenylpropan-1-ol then becomes its TBS ether.
- THP protection of cyclohexanol with dihydropyran and PPTSDraw the acid-catalysed addition of cyclohexanol to 3,4-dihydro-2H-pyran that gives the THP acetal, including where the enol ether is protonated.
Organolithium chemistry
- Lithium phenylacetylide opens 2-methyloxiraneDraw the phenylacetylide anion opening 2-methyloxirane and the ammonium chloride workup that gives 5-phenylpent-4-yn-2-ol.
- Kinetic enolate of 2-methylcyclohexanone and allylationDraw LDA forming the kinetic enolate of 2-methylcyclohexanone and the enolate alkylating allyl bromide to give 2-allyl-6-methylcyclohexanone.
- Lithium–halogen exchange of 4-bromoanisole and formylation with DMFDraw the lithium–halogen exchange that turns 4-bromoanisole into an aryl anion, its addition to DMF, and the acidic workup that releases 4-methoxybenzaldehyde.
- Ortho-lithiation of anisole and carboxylation to 2-methoxybenzoic acidDraw butyllithium removing the ring hydrogen ortho to the methoxy group of anisole, the aryl anion adding to carbon dioxide, and the acidic workup to 2-methoxybenzoic acid.
Chemoselective carbonyl tactics
- DIBAL-H reduces benzonitrile to benzaldehydeDraw DIBAL-H coordinating and delivering one hydride to benzonitrile, release of the imine on workup, and the acidic hydrolysis of that imine to benzaldehyde.
- Horner–Wadsworth–Emmons olefination of cyclohexanoneDraw sodium hydride forming the phosphonate carbanion of triethyl phosphonoacetate, its addition to cyclohexanone, and the oxaphosphetane fragmentation to ethyl 2-cyclohexylideneacetate.
- 1,2-Reduction of cyclohex-2-en-1-one with NaBH4/CeCl3Draw borohydride delivering hydride to the carbonyl carbon of cyclohex-2-en-1-one and methanol protonating the alkoxide to give the allylic alcohol cyclohex-2-en-1-ol.
- Ethylmagnesium bromide and N-methoxy-N-methylbenzamide give propiophenoneDraw the single addition of the ethyl Grignard to the Weinreb amide N-methoxy-N-methylbenzamide and the acidic workup that releases propiophenone.
- Stabilised Wittig: benzaldehyde and ethyl (triphenylphosphoranylidene)acetateDraw the oxaphosphetane formed from benzaldehyde and the ester-stabilised ylide and its collapse to ethyl cinnamate and triphenylphosphine oxide.
Classificar 1
- Classify functional groups toward LiAlH4Sort common functional groups into those that survive and those that are reduced by lithium aluminium hydride.
Comparar 1
- Compare TBS and THP protection of a chiral alcoholExplain why a THP ether of a chiral alcohol gives a mixture of diastereomers while a TBS ether does not.
Encontre o erro 1
- Diagnose a one-pot halogen exchange that went wrongFind the error in a procedure that adds n-BuLi to an aryl bromide and an aldehyde mixed together.
Trabalhe de trás para frente 1
- Choose the Weinreb amide for cyclohexyl phenyl ketoneWork backwards from a ketone to the Weinreb amide that, with phenylmagnesium bromide, delivers it.
Planeje uma síntese 1
- Order the steps of a Grignard route from 4-bromobutan-1-olPut protection, Grignard formation, addition, oxidation and deprotection in a workable order for a hydroxy ketone synthesis.
Explique por quê 1
- Explain why a Weinreb amide stops at the ketoneExplain how chelation of the tetrahedral intermediate prevents a second Grignard addition to a Weinreb amide.
Travou em grupos protetores, organolítios e quimiosseletividade? 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