Ketones and Aldehydes

Properties

Nomenclature

Preparation

Reactions

Synthesis

Carbonyl Functional Groups

Large Dipole Controls Properties and Reactivity

Boiling PointsDipole-Dipole Interactions

Adrogenic/Anabolic Steroids

CH3

O

CH3OH

H

H

H

Testosterone

CH3

O

CH3

H

H

H

O

Androstenedione

Anabolic Steroids

O

CH3OH

H

H

H

CH3

CH3

H

H

HN

N

CH3

OH

H

Nandralone Stanozolol

IUPAC NomenclatureKetones

O

2-methyl-3-pentanone

O

Cl

Cl2,7-dichlorocycloheptanone

O

1-phenyl-1-propanonepropiophenone (common)

OBr Br

(R) 6,6-dibromo-5-cyclopentyl-2-heptanone

OH

O

Cl

(E) 5(S)-hydroxy-1-(m-chlorophenyl)-3-hexen-2-one

O

O

trans 1,3-diacetylcyclohexane

IUPAC NomenclatureAldehydes

O

H

octanal

H

O

(E) 3-isopropyl-3-hexenal

CH

O

Br

cis 4-bromocyclohexane-1-carbaldehyde

O

H

O

5-oxohexanal

Classical Aldehyde Nomenclature

HCHO

CH3CHO

CHO

CHO

CHO

Prefix

form

acet

propion

butyr

valer

CHO

IUPAC: 4,4-dichloro-2-methylheptanal

CHO

CHO

CHO

capro

enanth

capryl

CHOpelargon

CHOcapr

example:CHO

Cl Cl

classical: -dichloro--methylenanthaldehyde

Prefix

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

IsoflavonesHighly Sought After Natural Products

OCH3

CH3

O

OCH3O O

O

Jamaicin

Piscidia erythrina L.

O

CH3

CH3OH

+O

O

ClCCH2

O

CH3O

TiCl4CH2Cl2

O

CH3

CH3OH

O

O

CH3OO

+ HCl

no rxn here

A Convergent SynthesisFriedel-Crafts Acylation

of Flavonoids

Price, W.A.; Schuda, P.F. J.Org. Chem., 1987, 52, 1972-1979

Acylation occurs ortho to OH

OH

O

OCH3

CH3

CH3O

O

O

possible complexationvia H bond

Gatterman-Koch Formylation

CO, HCl

AlCl3/CuCl

CH

O

benzene or activated benzene needed

HCCl

O

C O + HCl

in situ preparation of formyl chloride

Oxymercuration HydrationMarkovnikov

CH3CH2C CHHgSO4, H2SO4

H2OCH3CH2C=CH2

OH

an enol

CH3CH2CCH3

O

a ketone

Hydroboration HydrationAnti-Markovnikov

2) H2O2, NaOH

1) disiamyl borane

O

CH3CH2CH2CH

CHCH3CH2C

an enol

OH

CH3CH2CH=CH2

an aldehyde(sia)2BH

B

H

OzonolysisAlkene Cleavage

C=C

CH3

CH3

CH3

H

O3 in CH2Cl2C O

H

CH3

C

CH3

CH3

O+

H

CH3

CH3

CH3

C=C

OO

O

1)

2) CH3SCH3or Zn/HOAc

OO

O

H O

OO

H

ozonide

DMS

+ DMSO

Gilman Reagent with Acid Chlorides

DIBAHDiisobutyl Aluminum Hydride

Reduction of an Ester to an Aldehyde

COCH2CH3

O

1) DIBAHin toluene

CH

O

+ CH3CH2OH

Al

H

CH2CH(CH3)2(CH3)2CHCH2

DIBAH

2) H3O+

Nucleophilic Addition Reactions:

Strong Nucleophiles

O

Nu:

O

Nu

H3O+ OH

Nu

Basic nucleophiles: RMgX, RLi, LiAlH4, NaBH4, RC CNaNonbasic nucleophiles: CN-

Carbonyl Reactivity

C

O

HH R H

O

CR R'

O

CR OR

O

C> > >

decreasing rate of reaction with nucleophile

Cyanohydrin Formation

CH

O

HCN, (KCN trace amt.)C

OH

HCN

+ enant.

Mandelonitrilein defense glands of millipede A. corrugata

CH

OH

CN

Nucleophilic Addition Reactions:Weak Nucleophiles

O OH

H+, H2O

OH2O

OH

HH

OH

OH

a hydrate

-H2O

H2O

H3O+

Acetal Formation

OH+, CH3OH HO OCH3

hemiacetal

H+, CH3OH OCH3CH3O

acetal

O

excess CH3CH2OH, H+OCH2CH3CH3CH2O

+ H2O

H2O

HOCH3

OCH3CH3O

H

-H2O OCH3HO OCH3

HOH2

HO OCH3

H

HOCH3

OH

acetal

OCH3CH3OH+, CH3OH

hemiacetal

HO OCH3H+, CH3OHO

-H+-H+

Acetal Mechanism

Propose a Mechanism

SS SSH H

O

+H3O+

Use of Ethylene Glycol to Protect Ketones and Aldehydes

O

HOCH2CH2OH, H3O+OO

CH2CH2

+ H2O

?

O

CO2H

O

CH2OH

Synthesis

O

CO2H

O

CH2OHLiAlH4 will reduce the ketone preferentially,

1) HOCH2CH2OH, H+

2) LiAlH4

3) H3O+

therefore, protection of the ketone is necessary.

Aldehydes React Preferentially

CCH3

O

HC

O

CHCH3HC

O OH

HC

OO

CCH3

O

HOCH2CH2OHH+

1) NaBH4

2) H3O+

Imine Formation

Imines and Enamines

O

RNH2

NR

+ H2O

R2NH

NR2

+ H2O

pH = 4-5imine

enamine

1 amine

2 amine

o

o

H3O+

H3O+

-H2O

H2O NCH3H

H2O NHCH3

H3O+

H3O+, pH = 4-5

carbinolamine

intermolec.H+ transfer

HO NHCH3O NH2CH3

+ H2O

NCH3

CH3NH2

O

Imine Derivatives

Wolff-Kishner ReductionO

NH2NH2, KOH

NNH2

a hydrazone

HH

DMSO+ N2

Mechanism from Hydrazone

Deoxygenation

Enamine Mechanism (same as imine mech. until last step)

OH2

NCH3CH3O

(CH3)2NH

H3O+, pH = 4-5

NCH3CH3

H

Wittig Reaction:C=O into C=C

Ylide Synthesis

SN2(C6H5)3P + CH3Br (C6H5)3P CH3

CH3(C6H5)3P + CH3CH2CH2CH2Li (C6H5)3P CH2

CH2(C6H5)3P

phosphorous ylide

Br

methylene triphenylphosphorane

Mechanism

an oxaphosphetane

methylene triphenylphosphorane

+(C6H5)3PO

CH2=CH

(C6H5)3

C

O

CH2

P

H

(C6H5)3

C

O

CH2

P

H

HC

O

+ (C6H5)3P CH2

CH2(C6H5)3P

(CH3)2CHCH2CCH3

O(C6H5)3P=C(CH3)2

(CH3)2CHCH2CCH3

CCH3CH3

+ (C6H5)3P=O

Pure Alkene is Formed in Wittig Rxn

O

CH3

+

CH2

9 : 1

1) CH3MgBr

2) POCl3, pyr.

(C6H5)3P=CH2

CH2

methylenecyclohexane exclusively

(Methoxymethylene)-triphenylphosphoranean Aldehyde Prep

OOCH3H

(C6H5)3P CHOCH3 H3O+

CH

O

Propose a Sequence of Steps…

O O

H H

OCHCH3

Provide a Mechanism

O OCH3H+, H2O

+ CH3OH

O OHHO O

H

**

*O is O-18

* sameconditions

O OCH3H+, H2O

+ CH3OH

O OHHO O

H

**

*O is O-18

* sameconditions

O OCH3

H

O OH2

O OH

H

*

- CH3OHH2O

O OH

H*

H+

H+

HO O

HH

*

H2O

*

Conjugate Addition to,-Unsaturated C=O groups

O O O

O

2 electrophilic sites

1,2- vs. 1,4-Addition

O

1) CH3MgBr

2) H3O+

OHCH3

1) Li(CH3)2Cu

2) H3O+

CH3

O

H

Gilman Reagents add 1,4

O

H

1) Li(CH3CH2)2Cu

2) H3O+

CH3CH2

H

OCH3CH2

H

CH3CH2

H

O

H

Li

Synthesis

O

CN

OH

CH3CH2CH2

??

Carry Out Conjugate Addition 1st

O

CN

OH

CH3CH2CH2

1) Li(CH3CH2CH2)2Cu

2) H3O+

3) HCN, (KCN)

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 Reye’s 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.

CO2H

NH2

(R)(-) MCPA is the Toxic Metabolite of Hypoglycin-A

CO2H

NH2H

metabolism

Hypoglycin-A

OH

H O

(R)(-) MCPA

from Bligia sapida binds irreversibly to

medium-chain acyl-CoA dehydrogenase enzymes

Wittig Approach to Both Enantiomers

O

Cl

H

1) Ph3P=CH2

(R)(-)

3) n-BuLi, HCHO2) KOC(CH3)3 HO

(S) via initial S N2

HO

(R) via initial epoxide opening

(S)(+) MCPA

(R)(-) MCPA

Wittig Approach to (S)(+)-MCPAStart with (R)(-) Epichlorohydrin

SN2 on 1o Alkyl Chloride?

O

Cl

H

(C6H5)3P=CH2 KOC(CH3)3O

H

P(C6H5)3

(R)(-)

O

H

P(C6H5)3

Cl

O

P(C6H5)3

(S)

P(C6H5)3

O

(R,R) (R,R)

Wittig Sequence Affords (S) (Methylenecyclopropyl)methanol

O

P(C6H5)3P(C6H5)3

O

(R,R) (R,R)

n-butyl Li

O

P(C6H5)3paraformaldehyde

CH

O

H

O

P(C6H5)3

CH2O

O

P

OH

(C6H5)3

- (C6H5)3POOH

(S)

Homologation to (S)(-)-MCPAOH

(S) (S)

OSO2CH3

CH3SO2Cl

pyridineKCN

DMF(S)

CN

hydrolysisor

1) DIBAH2) CrO3, H2SO4

(S)

HO2C

Approach to (R)-(+)-MCPA Same Wittig Approach with Ylide

Opening the Epoxide First?

O

Cl

H

H2C=P(C6H5)3

ClO

(C6H5)3PH

O(C6H5)3P

H(R)

(R)

KOC(CH3)3

O(C6H5)3P

(S,S)