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Química Orgânica Avançada · Named reactions atlas

Reações nomeadas em heteroátomos

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O que você vai aprender

  • Push arrows through the phosphorus-mediated Mitsunobu, Appel, Staudinger–aza-Wittig and Corey–Fuchs reactions and explain how P=O formation drives them.
  • Activate a carboxylic acid with a carbodiimide, a pyridinium salt or a mixed anhydride, and use DMAP acyl transfer to make hindered esters.
  • Draw activated-DMSO, chlorite, Pummerer and xanthate (Chugaev) reactions, and say which atom is oxidised and which is reduced.
  • Follow iminium and nitrilium ions through the Strecker, Eschweiler–Clarke, Pinner, Ritter, Ugi and Passerini reactions.
  • Build heteroaromatic and fused nitrogen rings by Vilsmeier–Haack formylation and Bischler–Napieralski cyclisation, and predict the regiochemistry of Fischer indole and Paal–Knorr syntheses.

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Phosphorus pulls oxygen out

Triphenylphosphine is a soft nucleophile that ends up as triphenylphosphine oxide, and the strong P=O bond (about 540 kJ/mol) pays for the reaction. In the Mitsunobu reaction PPh₃ adds to diethyl azodicarboxylate (DEAD), the betaine removes a proton from an acidic partner (pKa below about 11), and the alcohol oxygen bonds to phosphorus. The resulting alkoxyphosphonium ion, drawn here for (R)-butan-2-ol, is an alkyl group carrying the leaving group Ph₃P=O, so the carboxylate attacks the carbon by SN2 and the alcohol carbon is inverted. The Appel reaction uses the same alkoxyphosphonium idea with CBr₄ or CCl₄ as the halogen source and bromide or chloride as the nucleophile. In the Staudinger reaction PPh₃ adds to the terminal nitrogen of an organic azide, N₂ leaves through a four-membered transition state, and the iminophosphorane Ph₃P=NR remains; water turns it into the amine, and a ketone in the same molecule turns it into an imine (aza-Wittig). In the Corey–Fuchs reaction the ylide Ph₃P=CBr₂, made from CBr₄ and two equivalents of PPh₃, converts an aldehyde into a 1,1-dibromoalkene, and two equivalents of n-butyllithium then give the terminal alkyne with one more carbon.

Activating carboxylic acids

A carboxylic acid does not acylate an alcohol on its own, because OH⁻ is a poor leaving group. Named esterifications turn the OH into a good leaving group first. In the Steglich esterification dicyclohexylcarbodiimide (DCC) is protonated by the acid and the carboxylate adds to it, giving an O-acylisourea. Left alone, this intermediate slowly rearranges by O→N acyl transfer to an unreactive N-acylurea. A catalytic amount of 4-(dimethylamino)pyridine (DMAP) intercepts it first and forms the N-acylpyridinium ion drawn here, an acylating agent reactive enough to acylate even tert-butanol under neutral conditions. Dicyclohexylurea (DCU) is the by-product. In the Mukaiyama esterification the carboxylate adds to 2-chloro-1-methylpyridinium iodide and the leaving group is 1-methyl-2-pyridone. In the Yamaguchi esterification the carboxylate and 2,4,6-trichlorobenzoyl chloride give a mixed anhydride, and DMAP attacks its less hindered carbonyl.

Oxidation through sulfur and chlorine

DMSO oxidises alcohols once its oxygen has been made into a leaving group. Oxalyl chloride (Swern), DCC with a mild acid (Pfitzner–Moffatt) or SO₃·pyridine (Parikh–Doering) activates the oxygen. The alcohol then attacks sulfur, giving an alkoxysulfonium ion like the one drawn. A base forms the sulfur ylide, and its carbanion removes the carbinol hydrogen through a five-membered cyclic transition state. The products are the carbonyl compound and dimethyl sulfide. The reaction needs a hydrogen on the carbinol carbon and no water is present, so primary alcohols stop at the aldehyde. In the Pinnick oxidation chlorous acid (from NaClO₂ at pH about 3.5) adds to an aldehyde, and the chlorite ester fragments into the carboxylic acid and HOCl. 2-Methylbut-2-ene scavenges the HOCl. The Pummerer reaction also goes through a sulfonium ion: an acylated sulfoxide loses an α-proton and then the carboxylate, and the thionium ion formed captures the carboxylate at carbon. In the Chugaev elimination a methyl xanthate is heated. Its C=S sulfur removes a β-hydrogen on the same side as the C–O bond (syn elimination) through a six-membered cyclic transition state.

Iminium and nitrilium electrophiles

Many nitrogen named reactions are additions to C=N⁺ bonds. In the Strecker synthesis an aldehyde and ammonia give an iminium ion that cyanide traps, and the α-aminonitrile is hydrolysed to an α-amino acid. In the Eschweiler–Clarke methylation formaldehyde and an amine give an iminium ion, and formate delivers a hydride to it while losing CO₂. A tertiary amine cannot form a new iminium ion, so the reaction stops without quaternisation. Nitrilium ions, R–C≡N⁺–R′, are the triple-bond version. In the Ritter reaction a nitrile nitrogen traps a tertiary or benzylic carbocation, and water then gives an amide. In the Pinner reaction HCl protonates a nitrile and an alcohol adds to give an imidate salt. In the Ugi and Passerini reactions the terminal carbon of an isocyanide (drawn here as tert-butyl isocyanide) adds to an iminium ion or an activated carbonyl, a carboxylate traps the nitrilium ion, and a Mumm acyl transfer gives the final amide.

Heteroatom routes to rings

DMF and POCl₃ give the chloroiminium ion drawn here, the Vilsmeier reagent, Me₂N⁺=CHCl. It is a weak electrophile, so it formylates only electron-rich arenes and heteroarenes. Pyrrole reacts at C2, and aqueous work-up hydrolyses the iminium salt to the aldehyde. The Bischler–Napieralski reaction uses POCl₃ on a 2-arylethyl amide. The amide oxygen is phosphorylated and leaves, the nitrilium ion formed is attacked by the electron-rich ring, and a 3,4-dihydroisoquinoline results. Ring closure takes place para to a methoxy group. Two older ring syntheses depend on counting atoms. In the Paal–Knorr synthesis a 1,4-dicarbonyl compound and an amine, or acid alone, give a pyrrole or a furan. In the Fischer indole synthesis an arylhydrazone undergoes a [3,3] shift through the ene-hydrazine side of the ketone, and the nitrogen that was attached to the aryl ring becomes the indole nitrogen. The Gabriel synthesis, and its Mitsunobu variant with phthalimide, gives primary amines without over-alkylation.

What to carry forward

Find the atom that is activated: oxygen bonded to phosphorus, sulfur or an acyl group becomes a leaving group, and nitrogen as C=N⁺ or C≡N⁺ becomes an electrophile. Then let the named reagent do one job at a time. Phosphorus ends as Ph₃P=O, DMSO as dimethyl sulfide, the carbodiimide as a urea and the isocyanide as an amide. Check stereochemistry (Mitsunobu inversion, syn Chugaev elimination) and regiochemistry (C2 of pyrrole, para to methoxy) before you draw the product.

Problemas de prática (40)

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Desenhe o mecanismo 20

Phosphorus reagents

  • Appel bromination of geraniolDraw the Appel reaction that converts geraniol into geranyl bromide: halophilic attack of PPh₃ on CBr₄, deprotonation of the alcohol by CBr₃⁻, formation of the alkoxyphosphonium ion and SN2 displacement by bromide.
  • Corey–Fuchs alkyne formation from (2,2-dibromovinyl)cyclohexaneDraw how two equivalents of n-butyllithium convert (2,2-dibromovinyl)cyclohexane into the lithium acetylide, by E2 elimination of HBr and then bromine–lithium exchange, and how water gives ethynylcyclohexane.
  • Corey–Fuchs dibromo-olefination of cyclohexanecarbaldehydeDraw how CBr₄ and two equivalents of PPh₃ make the dibromomethylene ylide, and how the ylide converts cyclohexanecarbaldehyde into (2,2-dibromovinyl)cyclohexane by a Wittig reaction.
  • Mitsunobu esterification of (R)-butan-2-ol with 4-nitrobenzoic acidDraw the Mitsunobu reaction of (R)-butan-2-ol with 4-nitrobenzoic acid: betaine formation from PPh₃ and DEAD, proton transfer from the acid, formation of the alkoxyphosphonium ion, and SN2 attack of the carboxylate with inversion to give (S)-butan-2-yl 4-nitrobenzoate.
  • Intramolecular Staudinger–aza-Wittig reaction of 5-azidopentan-2-oneDraw how triphenylphosphine turns 5-azidopentan-2-one into the cyclic imine 5-methyl-3,4-dihydro-2H-pyrrole: phosphazide formation, loss of N₂ to the iminophosphorane, and an intramolecular aza-Wittig reaction through an oxazaphosphetidine.

Building heterocycles and arenes

  • Bischler–Napieralski cyclisation of N-[2-(3,4-dimethoxyphenyl)ethyl]acetamideDraw the Bischler–Napieralski reaction: activation of the amide oxygen by POCl₃, formation of the nitrilium ion, intramolecular electrophilic attack para to a methoxy group and rearomatisation to 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline.
  • Vilsmeier–Haack formylation of pyrroleDraw the Vilsmeier–Haack formylation of pyrrole: electrophilic attack at C2 on the chloroiminium ion, rearomatisation, loss of chloride to the iminium salt and its hydrolysis on aqueous work-up to pyrrole-2-carbaldehyde.
  • Formation of the Vilsmeier reagent from DMF and POCl₃Draw how DMF and phosphoryl chloride give the Vilsmeier reagent, the N,N-dimethylchloromethyleneiminium ion: O-phosphorylation of DMF, chloride addition to the iminium carbon and loss of dichlorophosphate.

Sulfur and chlorine reagents

  • Chugaev elimination of 2-methyl-1-phenylpropan-1-olDraw the conversion of 2-methyl-1-phenylpropan-1-ol into its S-methyl xanthate and the syn (Ei) Chugaev elimination that gives (2-methylprop-1-en-1-yl)benzene and S-methyl hydrogen dithiocarbonate, which decomposes to carbonyl sulfide and methanethiol.
  • Pfitzner–Moffatt oxidation of 2-phenylethanolDraw the Pfitzner–Moffatt oxidation of 2-phenylethanol: activation of DMSO by protonated DCC, formation of the alkoxysulfonium ion with release of dicyclohexylurea, ylide formation and the intramolecular hydrogen transfer that gives phenylacetaldehyde and dimethyl sulfide.
  • Pinnick oxidation of (E)-cinnamaldehydeDraw the Pinnick oxidation of (E)-cinnamaldehyde: addition of chlorous acid to the aldehyde and fragmentation of the chlorite ester to (E)-cinnamic acid and HOCl, and explain why a scavenger alkene is added.
  • Pummerer rearrangement of methyl phenyl sulfoxide with acetic anhydrideDraw the Pummerer rearrangement of methyl phenyl sulfoxide: O-acylation of the sulfoxide, formation of the sulfonium ylide, loss of acetate to the thionium ion and capture of the thionium ion by acetate to give (phenylthio)methyl acetate.

Iminium and nitrilium ions

  • Eschweiler–Clarke methylation of piperidineDraw the Eschweiler–Clarke methylation of piperidine: hemiaminal and iminium ion formation from formaldehyde, then hydride transfer from formate with loss of CO₂ to give 1-methylpiperidine.
  • Passerini reaction of acetone, acetic acid and tert-butyl isocyanideDraw the Passerini reaction: acid activation of acetone, isocyanide addition to give a nitrilium ion, trapping by acetate and the intramolecular acyl transfer that gives the α-acyloxy amide.
  • Pinner reaction of benzonitrile with ethanolDraw the Pinner reaction: protonation of benzonitrile by HCl, addition of ethanol to the nitrilium carbon, and the proton transfers that give ethyl benzimidate hydrochloride.
  • Ritter reaction of 1-methylcyclohexan-1-ol with acetonitrileDraw the Ritter reaction: ionisation of 1-methylcyclohexan-1-ol to the tertiary carbocation, capture by the nitrogen of acetonitrile to give a nitrilium ion, addition of water and tautomerisation to N-(1-methylcyclohexyl)acetamide.
  • Strecker synthesis of 2-amino-3-methylbutanenitrile from 2-methylpropanalDraw the Strecker reaction of 2-methylpropanal with ammonia and cyanide: hemiaminal formation, loss of water to the iminium ion and cyanide addition to give the α-aminonitrile that leads to valine.
  • Ugi four-component reaction: 2-methylpropanal, benzylamine, acetic acid and tert-butyl isocyanideDraw the Ugi reaction from the imine of 2-methylpropanal and benzylamine: protonation to the iminium ion, isocyanide addition to give a nitrilium ion, trapping by acetate and the Mumm acyl transfer that gives the bis-amide.

Activating acids

  • Mukaiyama esterification of benzoic acid with cyclohexanolDraw how 2-chloro-1-methylpyridinium iodide activates benzoic acid as a 2-acyloxypyridinium ion and how cyclohexanol then attacks it, releasing 1-methyl-2-pyridone.
  • Steglich esterification: tert-butyl phenylacetate from phenylacetic acidDraw the DCC/DMAP (Steglich) esterification of phenylacetic acid with tert-butanol: formation of the O-acylisourea, acyl transfer to DMAP, and attack of tert-butanol on the N-acylpyridinium ion, with dicyclohexylurea as the by-product.

Preveja o produto 4

Building heterocycles and arenes

  • Fischer indole synthesis with butan-2-onePredict the main indole from an unsymmetrical ketone in the Fischer indole synthesis from the preferred ene-hydrazine.

Phosphorus reagents

  • Mitsunobu ester from cis-4-tert-butylcyclohexanolPredict the relative configuration of the ester formed when a cyclohexanol undergoes Mitsunobu esterification.

Sulfur and chlorine reagents

  • Pinnick oxidation of a keto aldehydePredict the chemoselectivity of the Pinnick oxidation for an aldehyde in the presence of a ketone.

Iminium and nitrilium ions

  • Assemble an Ugi productPredict the connectivity of an Ugi four-component product from its four components.

Classificar 2

Sulfur and chlorine reagents

  • Which oxidation is not an activated-DMSO reaction?Classify common alcohol oxidations by whether they proceed through an alkoxysulfonium ion.

Iminium and nitrilium ions

  • Which alcohol works in a Ritter reaction?Classify alcohols by whether they can form the carbocation that a Ritter reaction needs.

Comparar 2

Phosphorus reagents

  • Rank Mitsunobu pronucleophiles by acidityRank four common Mitsunobu pronucleophiles by acidity and relate acidity to deprotonation by the PPh₃–DEAD betaine.

Building heterocycles and arenes

  • Rank arenes toward the Vilsmeier reagentRank substituted benzenes by their reactivity toward the weakly electrophilic Vilsmeier reagent using σp⁺ values.

Calcular 3

Phosphorus reagents

  • Atom economy of an Appel brominationCalculate the atom economy of the Appel bromination of geraniol from the balanced equation.
  • Enantiomeric excess after a Mitsunobu inversionCalculate the enantiomeric excess of a Mitsunobu product from the starting ee and the fractions of inversion and retention.
  • Gas evolved in a Staudinger reactionUse the Staudinger stoichiometry to calculate the volume of N₂ released from a known amount of azide.

Encontre o erro 2

Activating acids

  • A DCC esterification that stalledDiagnose N-acylurea formation in a carbodiimide esterification and choose the change that prevents it.

Sulfur and chlorine reagents

  • A Swern oxidation that was allowed to warmDiagnose the methylthiomethyl ether by-product of a Swern oxidation that warmed before the base was added.

Interprete as evidências 1

  • Follow the labelled nitrogenInterpret an isotope-labelling result to decide which hydrazine nitrogen becomes the indole nitrogen in the Fischer synthesis.

Trabalhe de trás para frente 2

Building heterocycles and arenes

  • Precursor for 2,5-diphenylfuranIdentify the dicarbonyl precursor of a 2,5-disubstituted furan by counting the atoms between the carbonyl groups.

Iminium and nitrilium ions

  • Which aldehyde gives phenylalanine?Work back from an α-amino acid to the aldehyde needed for its Strecker synthesis.

Planeje uma síntese 3

Iminium and nitrilium ions

  • A primary amine with inverted configurationPlan a Gabriel-type synthesis of a chiral primary amine with defined configuration from a secondary alcohol.

Activating acids

  • Make the acetate with the opposite configurationChoose between retentive acylation and Mitsunobu inversion to set the configuration of a secondary ester.
  • A tert-butyl ester next to an acetalChoose esterification conditions that make a tert-butyl ester without touching an acid-sensitive acetal.

Explique por quê 1

  • Which carbonyl does DMAP attack?Explain why DMAP transfers the aliphatic acyl group, not the aroyl group, from a Yamaguchi mixed anhydride.

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