Chemistry of Carbonyl Compounds

•Nucleophilic addition (1,2-add) / substitution•Conjugate addition (1,4 add)•Robinson annulation (McM 23.12)

•Alkylation of enolate anions•Enamines as enolate equivs. (McM 23.11)

•Halogenation of enols / enolates

•Related react. in nature

OH

δ+

δ-

Nucleophile

ElectrophileBase

Chemistry of Carbonyl Compounds

OH

δ+

δ-

Nucleophile

ElectrophileBase

Nucleophilic addition / substitutionAldehydes / Ketones

O

R'R

R, R': H, alkyl, aryl - Not good leaving groups

NuR R'O Nu H

R R'HO Nu

Addition reactions

O

R R'

HO

R'RNu-H

H

R R'HO Nu

H

HR R'HO Nu

_

Acid catalyzed

Better electrophileWeaker nucleophile

Carboxylic acid derivatives

Substitution

O

LR

L - Good leaving groups

Nu

-X > -OCOR > -OR > -NR2X: Halogen, R: H, alkyl, aryl

R LO Nu

- L

O

NuR May also be acid cat.

Aldehydes / Ketones

O

R'R

R, R': H, alkyl, aryl - Not good leaving groups

NuR R'O Nu H

R R'HO Nu

Addition reactions

The Cannizzarro reaction Hydride as leaving group!

O

R H

R: No acidic α-Hex -H, -Ph. -But

OH

R H

O OH

O

R HO

R OH

H

+RHO

H

H

2 Aldehyde Carboxylic acid + prim. alcohol

N

N N

NNH2

O

ORHO

OP

O

OOH

P

OO

OHHO

N

OHO

O

NH2

N

N N

NNH2

O

ORHO

OP

O

OOH

P

OO

OHHO

N

OHO

O

NH2

NADH

H H

Nicotinamid adenine dinucleotide

NADR=H

R=Phosphate: NADP+, NADPH

R-OH

prim or sec.

Alchohol dehydrogenase(NAD cont.)

aldehyde / ketone

R

O

H

Aldehyde dehydrogenaseR

O

OH

Conjugate Addition

O

R

O

R

O

R

O

R

1,2-addition, Ex: •Alcohols•Organolithium

1,4-addition, Ex: •Amines•Organocuprates

Termodyn. prod,

O

Rδ+

δ+

δ-

δ-

Nu

1,2-addition

1,4-addition(conjugate addition / MIchael addition)

Michael reaction

Michael acceptorEWG

O O

R

O

ORN S

ONO

O OR

CN NO2 SO2R

R' R

O OBase

R' R

O O

H H H

NB! resonance formsWell stabilized enolate anion

O

R''O

R''

HO

R''

OR

O

ROR

O

R

Identity of NuSterical factors

HSAB theory (not in McM)

HSAB : Hard and soft acids and bases

Lewis bases / nucleophiles Lewis acids / electrophiles

Donor atom - hard bases:•high electroneg.•low polarizability•hard to oxidize

Donor atom - soft bases:•low electroneg.•high polarizability•easy to oxidize

Hardness

F- > Cl- >Br- >I-

F- > OH- > NH2- > CH3

-

Acceptor atom - hard acid•small•high positive charge•no unchared e- pair in valence shell•high electroneg.•low polarizability

Acceptor atom - soft acid•large•low positive charge•unchared e- pair in valence shell•low electroneg.•high polarizability

Hard acids prefer to bind to hard basesSoft acids prefer to bind to soft bases

O

R

Hardest electrophilic site

Softest nucleophilic site

O

R

Harder Nu

HO Nu

1,2 addition

O

R

Softer Nu

O

Nu

1,4 addition

But also•Kin. / termodyn. control•Steric shielding

Robinson Annulation (McM 23.12)

R' R

O OBase

R' R

O O

H H H

O O

OR

O

R

H H

1,5-diketoneacidic α-H

Michael react.

Base

O

OR

O

R

O

OR

O R

- H2O

O

OHR

O R

O

O R

R

Aldol condensation

Ring forming react.annulus (lat.) = ring

OH

δ+

δ-

Nucleophile

ElectrophileBase

OH

BaseO O Enolate anion

Nucleophilic species

O

E

O E

E

OE

E: - Alkyl halides- Carbonyl compounds (Aldol, Claissen condens.)- Halides

(React with hard E+)

(React. with soft E+)

Regioselectivity in enolate anion formation (not in McM)

O

Acidic protons

Kinetic control

sterically hidered base

Low temp

O

termodynamiccontrol

O

O

O

Electrophilic addition to conjugated dienes

Termodyn prod: High activation barrier, most stable prod. Vigorous cond. (high temp), reversibleKinetic prod: Low activation barrier, less stable prod. Mils cond, (low temp,) irreversible

H-Br

sec, allylic cation

prim. cat.

BrBr

H

H H

1,2-add. prod.kinetic prod.

+H

Br

1,4-add. prod.termodyn. prod.

EWG

O O

R

O

ORN S

ONO

O OR

CN NO2 SO2R

Michael acceptor

Enolizable

Alkylation of enolate anions

OHBase

O O

R-X

OR

X

Ketones, esters, nitriles(Aldehydes: condensation)

Base: Strong, sterical hindrance

N H + n-Bu-LI N Li + n-BuH

Litium Diisopropyl AmidepKa ca 40

EWG

O O

R

O

ORCN NO2 SO2R

H

HHHHHH

1019 2517 25ca pKa: 30

Alkylation of 1,3-dicarbonyl compounds followed by decarboxylation

O O

ORROBase O O

ORROR-X O O

ORRORBaseR-X

O O

ORROR R

H+/H2O O O

OHOR

H OCO

OH

OHR

+OOHR

OOHR

R

O O

R'RO

O O

R'ROR

H+/H2O O O

ROR

H

´- CO2

OR'R

Enamines as enolate equivalents (McM 23.11, Lab ex. 11)

Synthesis of enamines

O

ketone / aldehyde

R-NH2

prim. amine

O NH2-R HO NH-R

H

N RH

- H

N R

ImineIminium ion

O

ketone / aldehyde

sec. amine

N RR'

Iminium ion

RNHR'

HHBase NR R'

Enamine

Neutral imine

Reactivity of enamines

•Alkylation (alkyl halides)•Conjugate addition (Michael acceptors)•Acylation (acid halides)

•Monoalkylation•No strong base

NR R'

Enamine

E NE

R R'

O E OE

H2OH2O N R'

RHO N R'

R H OH

+ RR'NH

O

E EEE

Halogenation of enolate anions

O

RH

H

O

RH

O

RH

X-BX

O

RX

HX

Reacts further in the presence of base and halgen source

H H

H

H

OH

O

RX

XX

OH

OHX

XX

O R

O

HO RCX3Fairly good leaving group +

O

O RHCX3 +

pKa X=I: 14

Halogenation of neutral enols

OH

H O HX-X O

X

H

X

OX + HX

Aldehyde or ketone

(acid, ester, amide - not enolization)

H H HH

E2- HX

O

mainly monohalogenated prod.

α-Bromination of acids

O

OHH

PBrBr

BrO

OH P

Br

BrH

Br

O

BrH

+

HO PBr

Br

P-O bondcf Wittig

OH

Br

Acid bromide generated in situEnolize more easily than acid

Br2 O

BrBr

H2O

O

OHBr

cf McM 17.7

Hell Volhart Zelinskii React.Intro of Cl also possible

R-OH + PBr3 R-Br

Carbonyl condensations in nature

Acetyl-CoA (Acetyl co-enzyme A)

N

N N

NNH2

O

OHPO3

OPOPOHN

O OO OOH

O

HNSH3CO

O

Acetyl-CoA

Nu

BaseNature's

O

Clor

O

O

O

Synthesis of Acetylcholine (neurotransmittor)

NOH

Choline

Acetylcholineesterase

CoAS

O

NO

O

Acetylcholine

Acyl-CoA

CoAS

ODegradation / oxidation of fatty acids +

O

HO2CCO2H

Oxaloacetic acid

≈ Aldol Hydrol.Acyl-CoA

OH

HO2CCO2H

OOH

Citric acid

Citrate cycle Energy

CO2

Carbohydrates

* +

CoAS

ODegradation / oxidation of fatty acids

Metab. with little carbohydrates(Diabetes, starvation, diets)

CoAS

OO O

S CoA

Acetoacetyl-CoA

BiosynthesisSteroids, Lipids etc

Acetone

≈ Claissencondes.