Organic Chemistry 2 · Carbonyl and enolate chemistry
Acetals, imines and related equilibria: practice problems
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- N-Methylbenzylamine by reductive amination
- Follow alcohol capture of a cationic intermediate
- Follow the nitrogen condensation stage
- Acetal formation — ethanal and methanol
- Recover a ketone from its acetal
- A diol protects an aldehyde
- Imine formation — ethanal and ammonia
- Water releases an amine from an imine
- A bifunctional nitrogen reagent
Draw the mechanism 76
- Follow alcohol capture of a cationic intermediateDraw alcohol attack and deprotonation in the closing stages of acetal formation.
- Follow the nitrogen condensation stageDraw concerted lone-pair donation/water loss and distinguish iminium from imine.
- Acetal formation — ethanal and methanolAdd two methanol molecules to an aldehyde and regenerate the acid catalyst.
- Recover a ketone from its acetalFollow both leaving alcohols and identify the water-derived carbonyl oxygen.
- A diol protects an aldehydeDistinguish intermolecular first capture from intramolecular second capture in a cyclic acetal.
- Imine formation — ethanal and ammoniaAdd ammonia to an aldehyde, then lose water to form a C=N bond.
- Water releases an amine from an imineComplete imine hydrolysis and represent the acidic ammonium endpoint.
- A bifunctional nitrogen reagentUse the nitrogen end of hydroxylamine while preserving its N–O and O–H bonds.
- Keeping a nitrogen–nitrogen bond intactForm a hydrazone through nitrogen without treating hydrazine as an oxygen reagent.
- A secondary amine changes the condensation endpointChoose alpha-carbon deprotonation when the iminium nitrogen has no removable proton.
- Hydrolyzing an enamine carbon skeletonRelate carbon protonation to iminium hydrolysis and the secondary-ammonium endpoint.
- An aminoaldehyde closes its own ringForm a five-membered cyclic imine while distinguishing ring atoms from the expelled oxygen.
- Enamine from acetone and N-methylcyclopentanamineDraw the acid-catalysed condensation of N-methylcyclopentanamine with acetone to the iminium ion and its deprotonation at the α-carbon to the enamine.
- Imine from acetone and cyclopentylamineDraw the acid-catalysed condensation of cyclopentylamine with acetone through the carbinolamine and iminium ion to N-cyclopentylpropan-2-imine.
- 5-Hydroxyhexan-2-one closes to a cyclic hemiacetalDraw the acid-catalysed attack of the hydroxyl group of 5-hydroxyhexan-2-one on its own ketone, forming the five-membered cyclic hemiacetal 2,5-dimethyloxolan-2-ol.
- (Diethoxymethyl)benzene from benzaldehydeDraw the full acid-catalysed path from benzaldehyde through the hemiacetal and the oxocarbenium ion to (diethoxymethyl)benzene.
- Aldehyde-selective dioxolane from 4-oxopentanalDraw the TsOH-catalysed acetalization of the aldehyde of 4-oxopentanal with one equivalent of ethylene glycol, leaving the ketone untouched.
- 2,2-Dimethyl-1,3-dioxolane by acetal exchangeDraw TsOH-catalysed exchange of both methoxy groups of 2,2-dimethoxypropane for the oxygens of ethylene glycol via two oxocarbenium ions.
- Benzaldehyde from (dimethoxymethyl)benzeneDraw acid hydrolysis of (dimethoxymethyl)benzene: loss of methanol to an oxocarbenium ion, capture by water, and a second loss of methanol to benzaldehyde.
- Acetonide of meso-butane-2,3-diolDraw the TsOH-catalysed acetonide formation from meso-butane-2,3-diol and acetone, keeping both stereocentres of the diol, to cis-2,2,4,5-tetramethyl-1,3-dioxolane.
- N,N,N′,N′-Tetramethylmethanediamine from formaldehydeDraw addition of dimethylamine to formaldehyde, ammonium-catalysed proton transfers to the hemiaminal, loss of water to an iminium ion and capture by the second dimethylamine.
- Acetone azine from acetone and hydrazineDraw two successive condensations of hydrazine with two acetone molecules, each by addition, proton transfers and loss of water, to acetone azine.
- 1-Methylcyclohexene by Bamford–Stevens reactionDraw the protic Bamford–Stevens reaction of 2-methylcyclohexanone tosylhydrazone through the diazo compound, the carbocation and a hydride shift to 1-methylcyclohexene.
- Benzanilide by Beckmann rearrangement of benzophenone oximeDraw activation of benzophenone oxime by PCl5, anti phenyl migration to the nitrilium ion, and water capture and tautomerization to benzanilide.
- 2-Methyl-1-pyrroline from 5-aminopentan-2-oneDraw the acid-catalysed intramolecular condensation of 5-aminopentan-2-one through the cyclic carbinolamine to 5-methyl-3,4-dihydro-2H-pyrrole.
- 2-Methoxyoxane from 3,4-dihydro-2H-pyranDraw pyridinium protonation of 3,4-dihydro-2H-pyran at carbon to the oxocarbenium ion, capture by methanol and deprotonation to the THP ether 2-methoxyoxane.
- 2,2-Dimethoxypropane from acetone and methanolDraw the TsOH-catalysed addition of two methanols to acetone, with loss of water through an oxocarbenium ion, to 2,2-dimethoxypropane.
- 2-Phenyl-1,3-dioxane from benzaldehydeDraw the TsOH-catalysed reaction of benzaldehyde with propane-1,3-diol through the hemiacetal and oxocarbenium ion to 2-phenyl-1,3-dioxane.
- Acetophenone from its ethylene ketalDraw the acid-catalysed hydrolysis of 2-methyl-2-phenyl-1,3-dioxolane: ring opening to an oxocarbenium ion, water addition and loss of ethylene glycol to acetophenone.
- 2-Methyl-1,3-dithiane from 1,3-dithianeDraw deprotonation of 1,3-dithiane at C2 by n-butyllithium and SN2 methylation of the 2-lithio-1,3-dithiane carbanion by iodomethane.
- 1,4-Dithiaspiro[4.5]decane from cyclohexanoneDraw the BF3-promoted condensation of cyclohexanone with ethane-1,2-dithiol through a thionium ion to the cyclic thioketal 1,4-dithiaspiro[4.5]decane.
- Acetone 2,4-dinitrophenylhydrazoneDraw addition of the terminal NH2 of 2,4-dinitrophenylhydrazine to acetone, proton transfers, loss of water and deprotonation to acetone 2,4-dinitrophenylhydrazone.
- 1-(6-Methylcyclohex-1-en-1-yl)pyrrolidine from 2-methylcyclohexanoneDraw iminium formation from 2-methylcyclohexanone and pyrrolidine and removal of the α-hydrogen on the less substituted side to 1-(6-methylcyclohex-1-en-1-yl)pyrrolidine.
- 1-(3-Methylbut-1-en-2-yl)pyrrolidine from 3-methylbutan-2-oneDraw iminium formation from 3-methylbutan-2-one and pyrrolidine, then removal of a methyl α-hydrogen to give the less substituted enamine 1-(3-methylbut-1-en-2-yl)pyrrolidine.
- Pyrrolidine enamine of 4-tert-butylcyclohexanoneDraw the TsOH-catalysed condensation of 4-tert-butylcyclohexanone with pyrrolidine through the iminium ion to 1-(4-tert-butylcyclohex-1-en-1-yl)pyrrolidine.
- 1-(Cyclohex-1-en-1-yl)pyrrolidine from cyclohexanoneDraw TsOH-catalysed addition of pyrrolidine to cyclohexanone, loss of water to the iminium ion and removal of an α-hydrogen to 1-(cyclohex-1-en-1-yl)pyrrolidine.
- 4-(Cyclopent-1-en-1-yl)morpholine from cyclopentanoneDraw the TsOH-catalysed condensation of cyclopentanone with morpholine to the iminium ion and its α-deprotonation to 4-(cyclopent-1-en-1-yl)morpholine.
- Cyclohexanone from its morpholine enamineDraw the acid hydrolysis of 4-(cyclohex-1-en-1-yl)morpholine: protonation at the β-carbon, water addition to the iminium ion and loss of morpholine to cyclohexanone.
- 1-(2-Methylprop-1-en-1-yl)piperidine from isobutyraldehydeDraw the condensation of 2-methylpropanal with piperidine, without added acid, through the iminium ion to 1-(2-methylprop-1-en-1-yl)piperidine.
- (E)-4-(Prop-1-en-1-yl)morpholine from propanalDraw the base-medium condensation of propanal with morpholine, with hydroxide pushed out by nitrogen, to (E)-4-(prop-1-en-1-yl)morpholine.
- Acetaldehyde from methyl vinyl etherDraw protonation of methyl vinyl ether at the terminal carbon to an oxocarbenium ion, addition of water to a hemiacetal, and loss of methanol to acetaldehyde.
- N,N-Dimethyl-2-phenylethylamine by Eschweiler–ClarkeDraw both rounds of Eschweiler–Clarke methylation of 2-phenylethylamine: iminium formation with formaldehyde and hydride transfer from formate, giving N,N-dimethyl-2-phenylethylamine.
- (S)-N,N-Dimethyl-1-phenylethylamine by Eschweiler–ClarkeDraw both Eschweiler–Clarke methylations of (S)-1-phenylethylamine with formaldehyde and formic acid, keeping the stereocentre, to give (S)-N,N-dimethyl-1-phenylethylamine.
- 1-Ethoxyethanol from acetaldehyde and ethanolDraw acid activation of acetaldehyde, addition of ethanol to the protonated carbonyl and loss of the oxonium proton to give the hemiacetal 1-ethoxyethanol.
- (E)-Imine from 4-nitrobenzaldehyde and anilineDraw the uncatalysed condensation of 4-nitrobenzaldehyde with aniline in ethanol through the carbinolamine to (E)-N-(4-nitrobenzylidene)aniline.
- (E)-Imine from acetophenone and benzylamineDraw the acid-catalysed condensation of acetophenone with benzylamine through the carbinolamine and iminium ion to (E)-N-benzyl-1-phenylethan-1-imine.
- (E)-N-Benzylideneaniline from benzaldehyde and anilineDraw addition of aniline to benzaldehyde, the proton transfers to the carbinolamine, acid-assisted loss of water to the iminium ion and deprotonation to (E)-N-benzylideneaniline.
- N-Methylcyclohexanimine from cyclohexanoneDraw addition of methylamine to cyclohexanone, proton transfers to the carbinolamine, loss of water to the iminium ion and deprotonation to N-methylcyclohexanimine.
- N-Benzylcyclopentanimine from cyclopentanoneDraw the acetic acid-catalysed condensation of cyclopentanone with benzylamine, through the carbinolamine and iminium ion, to N-benzylcyclopentanimine.
- N-tert-Butyl imine of isobutyraldehydeDraw the condensation of 2-methylpropanal with tert-butylamine, without added acid, through the carbinolamine and iminium ion to (E)-N-tert-butyl-2-methylpropan-1-imine.
- Iminium salt from benzaldehyde and pyrrolidineDraw the condensation of benzaldehyde with pyrrolidine under perchloric acid through the carbinolamine to the 1-benzylidenepyrrolidin-1-ium ion.
- 1,4-Dioxaspiro[4.5]decane from cyclohexanoneDraw TsOH-catalysed addition of ethylene glycol to cyclohexanone, loss of water to an oxocarbenium ion and ring closure by the second OH to the ethylene ketal.
- Neopentyl glycol ketal of cyclohexanoneDraw the TsOH-catalysed condensation of cyclohexanone with 2,2-dimethylpropane-1,3-diol to the six-membered 3,3-dimethyl-1,5-dioxaspiro[5.5]undecane.
- 1,4-Dioxaspiro[4.4]nonane from cyclopentanoneDraw the TsOH-catalysed protection of cyclopentanone with ethylene glycol: hemiketal, oxocarbenium ion and ring closure to 1,4-dioxaspiro[4.4]nonane.
- MacMillan iminium ion from (E)-cinnamaldehydeDraw acid-catalysed condensation of (E)-cinnamaldehyde with the MacMillan imidazolidinone catalyst to the conjugated iminium ion, keeping the catalyst stereocentre and the E alkene.
- 2-Methoxyoxolane from 4-hydroxybutanalDraw the HCl-catalysed ring closure of 4-hydroxybutanal to the cyclic hemiacetal and its conversion, via a cyclic oxocarbenium ion, to 2-methoxyoxolane.
- MOM ether of cyclohexanol from dimethoxymethaneDraw the acid-promoted acetal exchange in which dimethoxymethane loses methanol to a methoxymethyl cation that cyclohexanol captures, giving (methoxymethoxy)cyclohexane.
- N-Methyl-C-phenylnitrone from benzaldehydeDraw addition of N-methylhydroxylamine to benzaldehyde, proton transfers, acid-assisted loss of water to an N-hydroxyiminium ion and deprotonation of N–OH to the nitrone.
- (E)-Acetophenone oxime from acetophenoneDraw hydroxylamine addition to acetophenone, proton transfers and loss of water to give (E)-acetophenone oxime with the OH anti to the phenyl group.
- Cyclohexanone oxime from cyclohexanoneDraw addition of hydroxylamine nitrogen to cyclohexanone, proton transfers, acid-assisted loss of water and deprotonation to cyclohexanone oxime.
- Cyclohexanone by acid hydrolysis of cyclohexanone oximeDraw acid hydrolysis of cyclohexanone oxime: N-protonation, water addition, proton transfer to nitrogen and loss of hydroxylamine to give cyclohexanone.
- Cyclohexanone phenylhydrazone from cyclohexanoneDraw addition of phenylhydrazine to cyclohexanone with acetic acid catalysis and loss of water to give cyclohexanone phenylhydrazone.
- L-Proline enamine of acetoneDraw condensation of acetone with L-proline to the enamine, using the proline carboxylic acid as the proton shuttle and keeping the proline stereocentre.
- 4-Isopropylmorpholine by reductive amination of acetoneDraw iminium ion formation from acetone and morpholine with acetic acid and its reduction by NaBH(OAc)3 to 4-isopropylmorpholine.
- 4-Methoxy-N,N-dimethylbenzylamine by reductive aminationDraw iminium ion formation from 4-methoxybenzaldehyde and dimethylamine at pH 6 and its reduction by NaBH3CN to 4-methoxy-N,N-dimethylbenzylamine.
- N-Methylbenzylamine by reductive aminationDraw iminium formation from benzaldehyde and methylamine in a pH 5 buffer, then hydride transfer from NaBH3CN to give N-methylbenzylamine.
- N-Benzylcyclohexanamine by reductive aminationDraw iminium formation from cyclohexanone and benzylamine with acetic acid, then hydride delivery from NaBH(OAc)3 to give N-benzylcyclohexanamine.
- 2-Methylpiperidine by intramolecular reductive aminationDraw ring closure of 6-aminohexan-2-one to the cyclic iminium ion at pH 6 and its reduction by NaBH3CN to 2-methylpiperidine.
- Benzaldehyde from (E)-N-benzylideneanilineDraw acid hydrolysis of (E)-N-benzylideneaniline: N-protonation, water addition, proton transfers and expulsion of aniline to give benzaldehyde.
- Acetone semicarbazoneDraw addition of the hydrazine-type NH2 of semicarbazide to acetone, proton transfers, loss of water and deprotonation to acetone semicarbazone.
- 3-Methylcyclohexene by Shapiro reactionDraw the Shapiro reaction of 2-methylcyclohexanone tosylhydrazone, with α-deprotonation at the CH2 carbon, to give 3-methylcyclohexene.
- Cyclohexene from cyclohexanone tosylhydrazone (Shapiro)Draw the Shapiro reaction of cyclohexanone tosylhydrazone: two n-BuLi deprotonations, loss of sulfinate and N2 to a vinyllithium, and protonation to cyclohexene.
- 2-Aminopropanenitrile from acetaldehydeDraw ammonia addition to acetaldehyde, proton transfers with HCN/cyanide, loss of water to the iminium ion and cyanide addition to 2-aminopropanenitrile.
- 2-Phenyl-1,3-dithiane from benzaldehydeDraw BF3 activation of benzaldehyde, addition of propane-1,3-dithiol, loss of the oxygen as HOBF3⁻ to a thionium ion, and ring closure to 2-phenyl-1,3-dithiane.
- Cyclohexanone tosylhydrazone from cyclohexanoneDraw acid-catalysed addition of p-toluenesulfonyl hydrazide to cyclohexanone and loss of water to give cyclohexanone tosylhydrazone, the Shapiro reaction substrate.
- (Hydroxymethyl)urea from urea and formaldehydeDraw addition of a urea nitrogen to formaldehyde, removal of the N–H proton by hydroxide and protonation of the alkoxide by water to give (hydroxymethyl)urea.
Predict the product 12
- Shift a reversible condensationUse the reaction quotient to predict the effect of removing water.
- Acetal of benzaldehyde and ethanolPredict the acetal formed from benzaldehyde and excess ethanol under acid catalysis with water removal.
- Acetal in aqueous basePredict that an acetal survives basic conditions.
- Enamine from cyclohexanone and pyrrolidinePredict the enamine formed from cyclohexanone and pyrrolidine under acid catalysis.
- Enamine regiochemistry: 2-methylcyclohexanonePredict which enamine regioisomer forms from 2-methylcyclohexanone and pyrrolidine.
- Phenylhydrazone of benzaldehydePredict the product of benzaldehyde with phenylhydrazine.
- Products of N-butylpropan-2-imine hydrolysisPredict the carbonyl compound and amine released when an imine is hydrolysed in aqueous acid.
- Imine from cyclohexanone and methylaminePredict the condensation product of cyclohexanone with a primary amine under mild acid catalysis.
- Oxime from acetone and hydroxylaminePredict the oxime formed from acetone and hydroxylamine.
- Reductive amination: cyclohexanone + benzylaminePredict the amine from reductive amination of cyclohexanone with benzylamine.
- Dithiane from cyclohexanone and propanedithiolPredict the cyclic thioacetal formed from cyclohexanone and 1,3-propanedithiol.
- Raney nickel desulfurization of acetophenone dithiolanePredict the product of Raney nickel desulfurization of a ketone thioacetal.
Classify 10
- Name a mixed oxygen addition productClassify a carbon bearing OH and OR using explicit connectivity.
- What a positive 2,4-DNP test showsInterpret a positive 2,4-dinitrophenylhydrazine (Brady) test.
- Methyl glucoside anomeric carbon is an acetalClassify the anomeric carbon of methyl β-D-glucopyranoside.
- Spot the acetalRecognize an acetal carbon bearing two OR groups and no OH.
- Name a cyclic ketalName the spiro ketal from cyclohexanone and ethylene glycol.
- Naming the benzaldehyde–aniline Schiff baseName the imine (Schiff base) formed from benzaldehyde and aniline.
- Which amine gives an imine?Identify the amine class that condenses with a ketone to give a neutral imine.
- PLP and amino acids: the external aldimineIdentify the bond that joins pyridoxal phosphate to an amino acid substrate.
- Amine class from reductive aminationClassify the amine formed by reductive amination of a ketone with a secondary amine.
- Rhodopsin: retinal–lysine protonated imineIdentify how 11-cis-retinal is attached to opsin in rhodopsin.
Compare 2
- Distinguish nitrogen-condensation endpointsPredict the difference between primary- and secondary-amine condensation products.
- Hemiacetal versus hydrateDistinguish a hemiacetal from a carbonyl hydrate by its substituents.
Calculate 2
- Removing water shifts the acetal equilibriumCalculate how halving [H2O] changes the acetal-to-ketone ratio.
- Ring size of a cyclic hemiacetalCount ring atoms when a hydroxy aldehyde cyclizes.
Find the error 1
- Separate equilibrium from catalytic speedDistinguish acid catalysis from changes in water activity.
Interpret the evidence 3
- Read an intramolecular oxygen additionIdentify the product class when a tethered alcohol adds once to an aldehyde.
- Oxocarbenium ion in acetal formationIdentify the oxocarbenium ion intermediate in acid-catalyzed acetal formation.
- Isotope label in acetal hydrolysisTrack an 18O label through acid-catalyzed hydrolysis of a ketal.
Work backward 1
- Recover a masked carbonylInfer the parent carbonyl from an acetal’s carbon substituents.
Plan a synthesis 6
- Plan selective use of a protected carbonylChoose protection and deprotection conditions around a base-compatible transformation.
- Conditions for a dimethyl acetalChoose conditions that drive acetal formation to completion.
- Remove an acetalChoose conditions that hydrolyze an acetal back to the carbonyl.
- Reduce the ester, keep the ketoneSequence acetal protection around a LiAlH4 reduction of a keto ester.
- Choosing a reductive amination reductantChoose the reducing agent for one-pot reductive amination of a ketone.
- Hydrazone to alkane: Wolff–KishnerChoose conditions that convert a ketone hydrazone into a CH2 group.
Explain why 6
- Explain why acid can inhibit an amineBalance carbonyl activation against loss of free amine nucleophile.
- Why hemiacetals are rarely isolatedExplain the equilibrium that keeps acyclic hemiacetals from being isolated.
- Why acetals form only with acid, not baseExplain why acetal formation requires acid and cannot be base-catalyzed.
- Dithiane anion as an acyl anion equivalentExplain why 2-lithio-1,3-dithiane acts as an acyl anion equivalent (umpolung).
- Why secondary amines give enamines, not iminesExplain why a ketone and a secondary amine give an enamine rather than an imine.
- Why imine formation is fastest near pH 4–5Explain the rate maximum of imine formation near pH 4–5 from the two opposing roles of acid.
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