Ketones and Aldehydes - La Salle University

Ketones and Aldehydes - La Salle University

Ketones and Aldehydes Properties Nomenclature Preparation Reactions Synthesis Carbonyl Functional Groups Large Dipole Controls Properties and Reactivity Boiling Points Dipole-Dipole Interactions Adrogenic/Anabolic Steroids CH3 OH CH3 H CH3 O

H CH3 H O H H H O Testosterone Androstenedione Anabolic Steroids CH3 OH CH3 CH3 OH

H H CH3 H H N H N O Nandralone Stanozolol H H IUPAC Nomenclature Ketones

Cl O O 2-methyl-3-pentanone Cl 2,7-dichlorocycloheptanone O Br Br O 1-phenyl-1-propanone (R) 6,6-dibromo-5-cyclopentyl-2-heptanone propiophenone (common)

OH Cl O (E) 5(S)-hydroxy-1-(m-chlorophenyl)-3-hexen-2-one O O trans 1,3-diacetylcyclohexane IUPAC Nomenclature Aldehydes H O O H octanal (E) 3-isopropyl-3-hexenal O

Br H CH O cis 4-bromocyclohexane-1-carbaldehyde O 5-oxohexanal Classical Aldehyde Nomenclature Prefix form HCHO acet CH3CHO

propion butyr valer CHO CHO CHO CHO Prefix

capro CHO CHO enanth capryl CHO CHO pelargon capr CHO CHO example: Cl Cl

classical: -dichloro--methylenanthaldehyde IUPAC: 4,4-dichloro-2-methylheptanal Preparation of Ketones and Aldehydes Friedel-Crafts Acylation (ketones) Gatterman-Koch Formylation (aldehydes) Hydration of Alkynes (ketones with oxymercuration, aldehydes with hydroboration) Ozonolysis of Alkenes (aldehydes and ketones depending on substitution) 1,3-Dithiane alkylations (aldehydes and ketones) Reduction of acids, acid chlorides and nitriles Gilman Reaction (ketones) Friedel-Crafts Acylation Isoflavones Highly Sought After Natural Products

Jamaicin Piscidia erythrina L. CH3 CH3 O O O O CH3O O CH3 CH3 O O OH

ClCCH2 O CH3O O + Friedel-Crafts Acylation A Convergent Synthesis of Flavonoids TiCl 4 CH2Cl2 CH3 CH3 O

OH + HCl O no rxn here O CH3O Price, W.A.; Schuda, P.F. J.Org. Chem., 1987, 52, 1972-1979 O Acylation occurs ortho to OH possible complexation via H bond CH3 CH3 O

O H O CH3O O O Gatterman-Koch Formylation O

CH CO, HCl AlCl3/CuCl benzene or activated benzene needed in situ preparation of formyl chloride C O + HCl O HCCl Oxymercuration Hydration Markovnikov CH3CH2C CH HgSO4, H2SO4 H 2O

OH CH3CH2C=CH2 an enol O CH3CH2CCH3 a ketone Hydroboration Hydration Anti-Markovnikov CH3CH2C CH B H (sia)2BH 1) disiamyl borane 2) H2O2, NaOH OH

CH3CH2CH=CH2 an enol O CH3CH2CH2CH an aldehyde Ozonolysis Alkene Cleavage CH3 CH3 C=C CH3 H CH3 CH3

1) O3 in CH2Cl2 C 2) CH3SCH3 or Zn/HOAc O +O C CH3 H DMS O CH3 H O C=C

O CH3 CH3 O H O O O O H O ozonide + DMSO Gilman Reagent with Acid Chlorides

DIBAH Diisobutyl Aluminum Hydride Reduction of an Ester to an Aldehyde O O COCH2CH3 1) DIBAH in toluene + 2) H3O CH + CH3CH2OH H DIBAH (CH3)2CHCH2 Al

CH2CH(CH3)2 Nucleophilic Addition Reactions: Strong Nucleophiles O O H 3O + OH Nu:

Nu Nu Basic nucleophiles: RMgX, RLi, LiAlH4, NaBH4, RC Nonbasic nucleophiles: CN CNa Carbonyl Reactivity O H

C O > H R C O > H R C O > R'

R C decreasing rate of reaction with nucleophile OR Cyanohydrin Formation O OH CH C HCN, (KCN trace amt.) H CN

+ enant. O H CH CN Mandelonitrile in defense glands of millipede A. corrugata Nucleophilic Addition Reactions: Weak Nucleophiles O O + H , H 2O

H OH OH2 H O H H2O H3O + -H2O OH OH a hydrate

Acetal Formation O + H , CH3OH HO OCH3 + H , CH3OH CH3O OCH3 acetal hemiacetal

O + excess CH3CH2OH, H CH3CH2O OCH2CH3 + H2O Acetal Mechanism O + H , CH3OH HO OCH3

+ H , CH3OH CH3O OCH3 acetal hemiacetal + -H + -H OH2 O

H HO HOCH3 H OCH3 H HO H2 O OCH3 -H2O OCH3 H CH3O HOCH3 OCH3

Propose a Mechanism O + S S H3O H S S H + Use of Ethylene Glycol to Protect Ketones and Aldehydes

CH2 CH2 O HOCH2CH2OH, H3O O + O O + H2O O ? CO2H CH2OH Synthesis

O 1) HOCH2CH2OH, H 2) LiAlH4 3) H3O + O + CO2H CH2OH LiAlH4 will reduce the ketone preferentially, therefore, protection of the ketone is necessary. Aldehydes React Preferentially O O

HC O CCH3 HC HOCH2CH2OH + H O HC O O 1) NaBH4 CCH3

2) H3O + OH CHCH3 Imine Formation Imines and Enamines O N o R 1 amine RNH2 H3O

+ H2O + pH = 4-5 o 2 amine R2NH H3O imine NR2 + H2O + enamine CH3 N

O CH3NH2 + H2O + H3O , pH = 4-5 H2O H3O O NH2CH3 intermolec. + H transfer HO

H + NHCH3 carbinolamine CH3 N -H2O H2O NHCH3 Imine Derivatives Wolff-Kishner Reduction O H

NH2NH2, KOH DMSO N NH2 a hydrazone H + N2 Mechanism from Hydrazone Deoxygenation Enamine Mechanism (same as imine mech. until last step) CH3 O

CH3 N (CH3)2NH + H3O , pH = 4-5 CH3 N CH3 H OH2 Wittig Reaction: C=O into C=C Ylide Synthesis (C6H5)3P

(C6H5)3P + CH3Br SN2 (C6H5)3P CH3 + CH3CH2CH2CH2Li CH3 Br (C6H5)3P CH2 phosphorous ylide (C6H5)3P CH2 methylene triphenylphosphorane

Mechanism (C6H5)3P CH2 O (C6H5)3P CH2 + HC (C6H5)3P O CH2 C H

methylene triphenylphosphorane (C6H5)3 P CH2=CH (C6H5)3PO + O CH2 C H an oxaphosphetane CH3 O (CH3)2CHCH2CCH3 (C6H5)3P=C(CH3)2 CH3 C (CH3)2CHCH2CCH3

+ (C6H5)3P=O Pure Alkene is Formed in Wittig Rxn CH3 CH2 1) CH3MgBr O + 2) POCl3, pyr. 9 : 1 CH2 (C6H5)3P=CH2

methylenecyclohexane exclusively (Methoxymethylene)-triphenylphosphorane an Aldehyde Prep H O (C6H5)3P CHOCH3 O OCH3 H3O CH + Propose a Sequence of Steps O

CHCH3 O H O H Provide a Mechanism O OCH3 + H , H2*O O *OH *O is O-18

same conditions HO * O H + CH3OH + O OCH3 H O H , H2*O +

*OH same conditions HO * O *O is O-18 H + CH3OH H O OCH3 H O *OH

2 + H H2O - CH3OH O H * OH * O HO H2O H

O *OH H Conjugate Addition to ,-Unsaturated C=O groups O O O O 2 electrophilic sites

1,2- vs. 1,4-Addition CH3 OH 1) CH3MgBr O 2) H3O + O

1) Li(CH3)2Cu 2) H3O H + CH3 Gilman Reagents add 1,4 CH3CH2 O 1) Li(CH3CH2)2Cu H 2) H3O CH3CH2 O

+ H H CH3CH2 O Li H H Synthesis O OH ?? CN

CH3CH2CH2 Carry Out Conjugate Addition 1st O OH 1) Li(CH3CH2CH2)2Cu + 2) H3O CH CH CH 3 2 2 3) HCN, (KCN) CN MCAD Deficiency, a Genetic Disease

Children with any of these enzyme deficiencies have a significant risk (20%) of death during the first, clinical episode of hypoglycemia (low blood glucose). Those patients affected show episodes of acute, life-threatening attacks that are symptomatically consistent with Reyes Syndrome and sometimes misdiagnosed as S.I.D.S. The most common of these in-born errors is MCAD Deficiency. (Medium Chain Acyl-CoA Dehydrogenase) ~1/50 Caucasians carry the gene. MCAD Enzyme (MCAD) is one of the enzymes involved in mitochondrial fatty acid -oxidation, which fuels hepatic ketogenesis, a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. Typically, a previously healthy child with MCAD deficiency presents with hypoketotic hypoglycemia, vomiting, liver dysfunction, skeletal muscle weakness

and lethargy triggered by a common illness. On average, this occurs between 3 and 24 months of age. Ackee Fruit (Bligia Sapida) from Jamaica Ingestion of the unripe seeds from the fruit of the Jamaican Ackee tree causes a disruption of the dehydrogenase enzymes needed to metabolize fatty acids. This vomiting sickness is a result of the enzyme inhibitor Hypoglycin A. CO H 2 NH2 (R)(-) MCPA is the Toxic

Metabolite of Hypoglycin-A CO2H H NH2 Hypoglycin-A from Bligia sapida metabolism OH H O (R)(-) MCPA binds irreversibly to medium-chain acyl-CoA dehydrogenase enzymes Wittig Approach to Both Enantiomers

1) Ph3P=CH2 O Cl H (R)(-) 2) KOC(CH3)3 3) n-BuLi, HCHO HO (S )(+) MCPA (S) via initial S N2 HO (R)(-) MCPA (R) via initial epoxide opening

Wittig Approach to (S)(+)-MCPA Start with (R)(-) Epichlorohydrin SN2 on 1o Alkyl Chloride? O (C6H5)3P=CH2 O P(C6H5)3 Cl H (R)(-) O H P(C6H5)3 H

KOC(CH3)3 Cl (S) O O P(C6H5)3 P(C6H5)3 (R,R) (R,R) Wittig Sequence Affords (S) (Methylenecyclopropyl)methanol O P(C6H5)3 O

P(C6H5)3 (R,R) (R,R) O P(C6H5)3 H C O n-butyl Li paraformaldehyde OH O P(C6H5)3 H

CH2O - (C6H5)3PO OH (S) P(C6H5)3 O Homologation to (S)(-)-MCPA OH CH3SO 2Cl (S) KCN DM F pyridine hydrolysis or

1) DIBAH 2) CrO3, H2SO 4 CN OSO2CH3 (S) HO2C (S) (S) Approach to (R)-(+)-MCPA Same Wittig Approach with Ylide Opening the Epoxide First? O O Cl

Cl (C6H5)3P H (R) H2C=P(C6H5)3 H O O (C6H5)3P (R) H KOC(CH3)3 (C6H5)3P (S,S)

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