Ketones and Aldehydes

Properties Nomenclature Preparation Reactions Synthesis

Carbonyl Functional Groups

Large Dipole Controls Properties and Reactivity

Boiling Points Dipole-Dipole Interactions

O

Adrogenic/Anabolic Steroids

CH 3 OH CH 3 H H H

Testosterone

O CH 3 O CH 3 H H H

Androstenedione

Anabolic Steroids

O CH 3 OH H H H H N N

Nandralone

CH 3 H

Stanozolol

H CH 3 OH CH 3 H

O

IUPAC Nomenclature Ketones

Cl

2-methyl-3-pentanone

O Cl

2,7-dichlorocycloheptanone

O

1-phenyl-1-propanone propiophenone

(common) Br Br O

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

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

Br O CH

cis 4-bromocyclohexane-1-carbaldehyde

O O

5-oxohexanal

H

Prefix

form acet propion butyr valer

Classical Aldehyde Nomenclature

HCHO CH 3 CHO CHO      CHO CHO CHO

Prefix

capro enanth capryl pelargon CHO CHO CHO CHO 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 aldehydes ( ketones with hydroboration) with oxymercuration, Ozonolysis of Alkenes ( aldehydes depending on substitution ) and ketones 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

CH 3

Piscidia erythrina L.

CH 3 O O O O CH 3 O O

CH 3 CH 3 O

Friedel-Crafts Acylation A Convergent Synthesis of Flavonoids

CH 3 CH 3 O OH O ClCCH 2 + CH 3 O TiCl 4 CH 2 Cl 2 OH no rxn here O CH 3 O Price, W.A.; Schuda, P.F.

J.Org. Chem.

,

1987

,

52

, 1972-1979 + H Cl O O O O

Acylation occurs ortho to OH

CH 3 CH 3 O possible complexation via H bond   O H O   O O CH 3 O

Gatterman-Koch Formylation

O CH CO, HCl AlCl 3 /CuCl benzene or activated benzene needed

in situ

preparation of formyl chloride C O + HCl O HCCl

Oxymercuration Hydration Markovnikov

CH 3 CH 2 C CH HgSO 4 , H 2 SO 4 H 2 O OH CH 3 CH 2 C=CH 2

an enol

O CH 3 CH 2 CCH 3

a ketone

Hydroboration Hydration Anti-Markovnikov

CH 3 CH 2 C CH 1) disiamyl borane 2) H 2 O 2 , NaOH OH CH 3 CH 2 CH=CH 2

an enol

B H

(sia) 2 BH

O CH 3 CH 2 CH 2 CH

an aldehyde

Ozonolysis Alkene Cleavage

CH 3 H C=C CH 3 CH 3 1) O 3 in CH 2 Cl 2 2) CH 3 SCH 3 or Zn/HOAc CH 3 O O O CH 3 H C=C CH 3 O O O CH 3 H C O + O DMS CH 3 C CH 3 + DMS O H O O H O ozonide

Gilman Reagent with Acid Chlorides

DIBAH

D i i so b utyl A luminum H ydride

Reduction of an Ester to an Aldehyde

O COCH 2 CH 3 1) DIBAH in toluene 2) H 3 O + O CH + CH 3 CH 2 OH H

DIBAH

Al (CH 3 ) 2 CHCH 2 CH 2 CH(CH 3 ) 2

Nu:

Nucleophilic Addition Reactions: Strong Nucleophiles

  O   O H 3 O + OH Nu Nu

Basic nucleophiles:

RMgX, RLi, LiAlH

Nonbasic nucleophiles:

CN 4 , NaBH 4 , RC CNa

Carbonyl Reactivity

H   O   C H > R O C H > R O C R' > R O C OR decreasing rate of reaction with nucleophile

Cyanohydrin Formation

O CH H CN , (KCN trace amt.) O CH H CN O H C H CN + enant.

Mandelonitrile

in defense glands of millipede

A. corrugata

Nucleophilic Addition Reactions:

O

Weak Nucleophiles

H H + , H 2 O O OH OH 2 H O H H 2 O H 3 O + OH -H 2 O OH a hydrate

Acetal Formation

O H + , CH 3 OH HO OCH 3

hemiacetal

H + , CH 3 OH CH 3 O OCH 3

acetal

O excess CH 3 CH 2 O H, H + CH 3 CH 2 O OCH 2 CH 3 + H 2 O

Acetal Mechanism

O O H H + , CH 3 OH HO OCH 3

hemiacetal

H + , CH 3 OH HO -H + OH 2 H OCH 3 H HO OCH 3 -H 2 O HOCH 3 CH 3 O OCH 3

acetal

-H + OCH 3 H 2 O H CH 3 O OCH 3 HOCH 3

Propose a Mechanism

S S H 3 O + H S S H + O

Use of Ethylene Glycol to Protect Ketones and Aldehydes

O CH 2 O CH 2 O H OCH 2 CH 2 O H, H 3 O + + H 2 O O O ?

CO 2 H CH 2 OH

Synthesis

O 1) HOCH 2 CH 2 OH, H + 2) LiAlH 4 3) H 3 O + O CO 2 H LiAlH 4 will reduce the ketone preferentially, CH 2 OH therefore,

protection

of the ketone is necessary.

O HC

Aldehydes React Preferentially

O CCH 3 O HC OH CHCH 3 HOCH 2 CH 2 OH H + O HC O O CCH 3 1) NaBH 4 2) H 3 O +

Imine Formation

O

Imines and Enamines

N R o 1 amine RNH 2 H 3 O +

pH = 4-5

o 2 amine R 2 NH H 3 O +

imine

NR 2 + H 2 O + H 2 O

enamine

O CH 3 NH 2 H 3 O + , pH = 4-5 H 2 O N CH 3 + H 2 O H N CH 3 O NH 2 CH 3 HO H 3 O + NHCH 3 intermolec.

H + transfer

carbinolamine

H 2 O -H 2 O NHCH 3

Imine Derivatives

O

Wolff-Kishner Reduction

H H NH 2 NH 2 , KOH DMSO + N 2 N NH 2 a hydrazone

Mechanism from Hydrazone

Deoxygenation

O

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

CH 3 N CH 3 (CH 3 ) 2 NH H 3 O + , pH = 4-5 CH 3 N CH 3 H OH 2

Wittig Reaction: C=O into C=C

(C 6 H 5 ) 3 P + CH 3 Br

Ylide Synthesis

S N 2 (C 6 H 5 ) 3 P CH 3 Br (C 6 H 5 ) 3 P CH 3 + CH 3 CH 2 CH 2 CH 2 Li (C 6 H 5 ) 3 P CH 2

phosphorous ylide

(C 6 H 5 ) 3 P CH 2 methylene triphenylphosphorane

Mechanism

(C 6 H 5 ) 3 P CH 2 (C 6 H 5 ) 3 P CH 2 + O HC (C 6 H 5 ) 3 P O CH 2 H C methylene triphenylphosphorane (C 6 H 5 ) 3 PO + CH 2 =CH (C 6 H 5 ) 3 P O CH 2 H C an oxaphosphetane

O (CH 3 ) 2 CHCH 2 CCH 3 (C 6 H 5 ) 3 P =C(CH 3 ) 2 CH 3 C CH 3 (CH 3 ) 2 CHCH 2 CCH 3 + (C 6 H 5 ) 3 P =O

Pure Alkene is Formed in Wittig Rxn

CH 3 CH 2 O 1) CH 3 MgBr 2) POCl 3 , pyr.

+ (C 6 H 5 ) 3 P=CH 2 9 : 1 CH 2 methylenecyclohexane exclusively

(Methoxymethylene)-triphenylphosphorane an Aldehyde Prep

O H OCH 3 O CH (C 6 H 5 ) 3 P CHOCH 3 H 3 O +

O

Propose a Sequence of Steps…

O H CHCH 3 O H

Provide a Mechanism

O OCH 3 H + , H 2 * O *O is O-18 O * OH same conditions HO + CH 3 OH H * O

O OCH 3 H + , H 2 * O *O is O-18 O H OCH 3 O - CH 3 OH * OH 2 O H + * OH same conditions HO + CH 3 OH HO H + O H 2 O H * OH H O * OH H * O H 2 O H * O H

Conjugate Addition to



,



-Unsaturated C=O groups

O O O O     2 electrophilic sites

O 

1,2

- vs.

1,4

-Addition

CH 3 O H 1) CH 3 MgBr 2) H 3 O +   O H 1) Li( CH 3 ) 2 Cu 2) H 3 O + CH 3

Gilman Reagents add 1,4

CH 3 CH 2 CH 3 CH 2 O H 1) Li( CH 3 CH 2 ) 2 Cu 2) H 3 O + CH 3 CH 2 H O H O Li H H

O

Synthesis

??

CH 3 CH 2 CH 2 OH CN

Carry Out Conjugate Addition 1st

O 1) Li(CH 3 CH 2 CH 2 ) 2 Cu 2) H 3 O + 3) HCN, (KCN) CH 3 CH 2 CH 2 OH 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 Reye’s Syndrome and sometimes misdiagnosed as S.I.D.S.

The most common of these in-born errors is MCAD Deficiency. ( M edium C hain A cyl-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 2 H NH 2

(R)(-) MCPA

is the Toxic Metabolite of Hypoglycin-A CO 2 H H NH 2

Hypoglycin-A

from

Bligia sapida

metabolism OH H O

(R)(-) MCPA binds irreversibly to medium-chain acyl-CoA dehydrogenase enzymes

O H (R)(-) Cl

Wittig Approach to Both Enantiomers

1) Ph 3 P=CH 2 2) KOC(CH 3 ) 3 3) n-BuLi, HCHO HO (S) via initial S N 2

(S )(+) MCPA (R)(-) MCPA

HO (R) via initial epoxide opening

Wittig Approach to (S)(+)-MCPA

Start with (R)(-) Epichlorohydrin S N 2 on 1 o Alkyl Chloride?

O H (R)(-) Cl (C 6 H 5 ) 3 P=CH 2 O H (S) P(C 6 H 5 ) 3 Cl KOC(CH 3 ) 3 O H P(C 6 H 5 ) 3 O (R,R) P(C 6 H 5 ) 3 O P(C 6 H 5 ) 3 (R,R)

O Wittig Sequence Affords (S) (Methylenecyclopropyl)methanol O O n-butyl Li P(C 6 H 5 ) 3 P(C 6 H 5 ) 3 (R,R) (R,R) OH P(C 6 H 5 ) 3 paraformaldehyde O H C H O - (C 6 H 5 ) 3 PO OH P(C 6 H 5 ) 3 CH 2 O P (C 6 H 5 ) 3 O (S)

Homologation to (S)(-)-MCPA

CN OH OSO 2 CH 3 CH 3 SO 2 Cl pyridine KCN DM F (S) (S) (S) hydrolysis or 1) DIBAH 2) CrO 3 , H 2 SO 4 HO 2 C (S)

Approach to (R)-(+)-MCPA

Same Wittig Approach with Ylide Opening the Epoxide First?

O Cl H (R) H 2 C=P(C 6 H 5 ) 3 (C 6 H 5 ) 3 P O H Cl (C 6 H 5 ) 3 P (R) H O KOC(CH 3 ) 3 (C 6 H 5 ) 3 P O (S,S)