Chemistry of Carbonyl Compounds

•Nucleophilic addition (1,2-add) / substitution •Conjugate addition (1,4 add) •Robinson annulation (McM 23.12) Base δ- Electrophile •Alkylation of enolate anions O H •Enamines as enolate equivs. (McM 23.11) δ+ Nucleophile •Halogenation of enols / enolates

•Related react. in nature Chemistry of Carbonyl Compounds

Base δ- Electrophile O H δ+ Nucleophile Nucleophilic addition / substitution

Aldehydes / Ketones Acid catalyzed Addition reactions H H H O O HO Nu HO Nu O H O Nu HO Nu R R' R R' R R' R R' _ H R R' R R' R R' Nu-H Nu Better electrophile Weaker nucleophile R, R': H, alkyl, aryl - Not good leaving groups

Carboxylic acid derivatives

Substitution

O O Nu O R L R L R Nu May also be acid cat. Nu - L L - Good leaving groups

-X > -OCOR > -OR > -NR2 X: Halogen, R: H, alkyl, aryl Aldehydes / Ketones The Cannizzarro reaction

Addition reactions Hydride as leaving group!

O O Nu H HO Nu R R' R R' R R' H Nu O O OH O R, R': H, alkyl, aryl - Not good leaving groups O OH R H + HO H R H R H R OH R H

R: No acidic α-H ex -H, -Ph. -But 2 Aldehyde Carboxylic acid + prim. alcohol

Nicotinamid adenine dinucleotide

O H H O

NH2 NH2 N N Alchohol dehydrogenase O O O O (NAD cont.) R-OH aldehyde / ketone OH OH O HO O HO P P HO HO prim or sec. NH2 NH2 O N N O N N N N N N O P O O P O O O O OH OH Aldehyde dehydrogenase OR OR O HO HO R OH R H NADH R=H NAD

R=Phosphate: NADP+, NADPH Conjugate Addition

δ- O O O O O δ- δ+ R R R R 1,2-addition R δ+ Nu

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

1,2-addition, Ex: 1,4-addition, Ex: EWG •Alcohols •Amines

•Organolithium •Organocuprates O O O O O N R N S Identity of Nu Termodyn. prod, R OR O O

Sterical factors CN NO2 SO2R Michael reaction

O O H O R'' O R'' O O O O O R'' Base R R' R R' R R H H H R O R O NB! resonance forms Well stabilized enolate anion HSAB theory (not in McM) HSAB : Hard and soft acids and bases

Lewis bases / nucleophiles Lewis acids / electrophiles

Donor atom - hard bases: Acceptor atom - hard acid •high electroneg. •small •low polarizability •high positive charge •hard to oxidize •no unchared e- pair in valence shell •high electroneg. •low polarizability Donor atom - soft bases: •low electroneg. Acceptor atom - soft acid •high polarizability •large •easy to oxidize •low positive charge •unchared e- pair in valence shell •low electroneg. Hardness •high polarizability F- > Cl- >Br- >I- Hard acids prefer to bind to hard bases F- > OH- > NH - > CH - 2 3 Soft acids prefer to bind to soft bases Hardest electrophilic site O

R

Softest nucleophilic site

O O O HO Nu

R R

Nu Harder Nu 1,2 addition Softer Nu 1,4 addition

But also •Kin. / termodyn. control •Steric shielding Robinson Annulation (McM 23.12)

O O H H O O O O O O Base Base O R' R R' R R H H H R R O R O 1,5-diketone acidic α-H Michael react. O

O R Ring forming react. O R annulus (lat.) = ring Aldol condensation

O

OH R O R

- H2O

O

R

O R Base δ- Electrophile O H δ+ Nucleophile

Base O O O Enolate anion H Nucleophilic species

E O (React with hard E+) E

O

E

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

(React. with soft E+) Regioselectivity in enolate anion formation (not in McM)

Acidic protons

Kinetic control O O O sterically hidered base Low temp termodynamic control

O O Electrophilic addition to conjugated dienes

H sec, allylic cation H H Br Br 1,2-add. prod. H-Br kinetic prod.

+ H

prim. cat. Br

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

Termodyn prod: High activation barrier, most stable prod. Vigorous cond. (high temp), reversible Kinetic prod: Low activation barrier, less stable prod. Mils cond, (low temp,) irreversible EWG Michael acceptor

O O O O O N R N O S H EWG Enolizable R OR O

CN NO2 SO2R O O O H H H H CN H NO2 H SO2R R OR ca pKa: 17 19 25 25 10 30

Alkylation of enolate anions

O O O Base: Strong, sterical hindrance Base H

R-X Ketones, esters, nitriles N H + n-Bu-LI N Li + n-BuH (Aldehydes: condensation) O pKa ca 40 Litium Diisopropyl Amide R X Alkylation of 1,3-dicarbonyl compounds followed by decarboxylation

O O H OH O O O O + O O Base R-X H /H2O O O C + R RO OR RO OR OH OH RO OR O OH O R R R Base R-X

O O O R OH RO OR R R R

H O O O O + H /H2O O O O R RO R' RO R' O R R' ´- CO2 R R Enamines as enolate equivalents (McM 23.11, Lab ex. 11)

Synthesis of enamines

prim. amine H H R R O R-NH2 N N O NH2-R HO NH-R

- H ketone / aldehyde Iminium ion Imine

sec. amine R R' R R R' O NH N Base N R' H H

Enamine ketone / aldehyde Iminium ion

Neutral imine Reactivity of enamines

R R' R R' R N H O R H OH E N 2 HO N O H2O N R' E R' E E E E Enamine + RR'NH

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

•Monoalkylation •No strong base Halogenation of enolate anions

O O O H H OH R R R H H H H H

X-BX

O O O R X X R R X H X X OH H X X X Reacts further in the presence of base OH and halgen source

O Fairly good leaving group CX + 3 HO R

O HCX + 3 O R pKa X=I: 14 Halogenation of neutral enols

mainly monohalogenated prod. H H O O H O O X-X X + HX H X X H H H H Aldehyde or ketone E2 (acid, ester, amide - not enolization) - HX

O

α-Bromination of acids

Acid bromide generated in situ Enolize more easily than acid Br O P O Br O OH H Br H O Br P H Br2 Br OH O Br Br Br Br H

+ Br H2O cf McM 17.7 Br HO P R-OH + PBr3 R-Br Br O Br P-O bond Hell Volhart Zelinskii React. OH cf Wittig Intro of Cl also possible Carbonyl condensations in nature

Acyl-CoA Acetyl-CoA (Acetyl co-enzyme A)

NH2 N N Nature's Base N O OH O O O O N H H O N N P P O O O H3C S O O O or O O OH Cl O Nu PO3

Acetyl-CoA

Choline

OH N Synthesis of Acetylcholine O CoA (neurotransmittor) S Acetylcholine esterase

O N O

Acetylcholine Carbohydrates

Hydrol. Citrate O O ≈ Aldol OH Degradation / oxidation Acyl-CoA cycle Energy CoA + CO H CO2H of fatty acids S HO C 2 HO2C 2 CO2 Oxaloacetic acid OH O Citric acid

Metab. with little carbohydrates ≈ Claissen O O (Diabetes, starvation, diets) Degradation / oxidation condes. O O CoA CoA of fatty acids S S CoA Acetone S

Acetoacetyl-CoA

Biosynthesis Steroids, Lipids etc

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