organic chemistry : third stage/ college of science ...§لكيمياء...

Organic chemistry : third stage/College of science /Baghdad

university By: Ass.prof.Dr.Muna A-heeti

Ref..Morrison and Boyd

α,β-Unsaturated Carbonyl Compounds

C OCC conjugated system

CH2=CHCH=Oacrolein

CH2=CHCOOH

acrylic acid

H2C CHC N

acrylonitrile

H2C CCH3

COOH

methacrylic acid

CH3CH=CHCH=O

crotonaldehyde

O

mesityl oxide

CH

CH

CH=O

cinnamaldehyde

CH

CH

CO

benzalacetophenone chalcone

CC

C

CH

HO

O

OH

OH

maleic acid

CC

C

HC

HO

OH

OHO

fumaric acid

O

O

O

maleic anhydride

α,β-Unsaturated Carbonyl Compounds, reactions:

1. electrophilic addition

deactivated

2. nucleophilic addition

activated

3. Michael Addition

4. Diels-Alder Reaction


The carbonyl group is an electron withdrawing group when conjugated with a double bond. This decreases the electron density and deactivates the double bond to electrophilic addition.

C C C O + HZ C C C OHZ

H2C CH

CH

OHCl

CH2CH2CHOCl

O CH3OH

H2SO4

O

OCH3

H2C CH

COOHH2O,H+

H2CH2C COOH

OH

C C C O + H C C C OH

electrophilic addition mechanism:

C C C OH

H

C C C O C C C OH H

more stable

C C C O + H C C C OH

electrophilic addition mechanism:

C C C OH

Z

C C C OH

C C C OHZ

Zunstable

enol

C C C OZ H


The carbonyl group is an electron withdrawing group when conjugated with a double bond. This decreases the electron density and activates the double bond to nucleophilic addition.

C C C O + Z- C C C OHZ

H2O

CH

CH

COOHNH2OH

CHCH2COOHNHOH

O O

NHCH3

CH

CH

COOEtNaCN,aq. H

CH2C COOEt

CNH3C H3C

CH3NH2

C C C O C C C O

nucleophilic addition mechanism:

C C C O C C C OZ Z

more stable

+ Z

Z

Z

C C C O

nucleophilic addition mechanism:

C C C O C C C OZ Z

ZH

C C C O C C C OHZ ZH

keto-enol tautomers

3. Michael Addition.

Carbanions as the nucleophiles in nucleophilic addition to α,β-usaturated carbonyls. (The enolate anion must be in reasonably high concentration for the Michael Addition to take place. Such enolates can be obtained from removal of alpha-hydrogens that are next to two electron withdrawing groups.)

CH

CH

CO

+COOEtCH2COOEt

piperidine HC

H2C C

O

CHEtOOC COOEt

benzalacetophenone diethylamalonate

H2C CCH3

COOEt +COOEtCH2C N

OEtH2C C

H

CH3COOEt

CHCOOEtCN

HC C

HCO

CH3 +COOEtCH2CO

CH3

base HC

H2C C

OCH3

CHC COOEtO

H3C

G+

G

mechanism: (concerted)

G G

4. Diels-Alder reaction: diene + dienophile cyclohexene

+CH=O

O

1,3-butadiene acrolein

+ O

O

O

O

O

O1,3-butadiene maleic anhydride

+

1,3-butadiene

O

O

O

Op-benzoquinone

O

O

+ O

O

OO

O

O

endo is preferred over the exo productany unsaturated groups in the dienophiletend to lie near the developing double bondin the diene rather than farther away (exo).

O

O

O

endo

exo

α,β-Unsaturated Carbonyl Compounds, reactions:


deactivated


activated

3. Michael Addition

4. Diels-Alder Reaction

C C C O + HZ C C C OZ H

+CO

CO

Amines, reactionsAmines are similar to ammonia in their reactions.

Like ammonia, amines are basic.

Like ammonia, amines are nucleophilic and react with alkyl halides, acid chlorides, and carbonyl compounds.

The aromatic amines are highly reactive in electrophilic aromatic substitution.

Amine, reactions:

1. As bases

2. Alkylation

3. Reductive amination

4. Conversion into amides

5. EAS

6. Hofmann elimination from quarternary ammonium salts

7. Reactions with nitrous acid

1. As bases

a) with acids

b) relative base strength

c) Kb

d) effect of groups on base strength

with acids

NH2 + HCl NH3+Cl-

(CH3CH2)2NH + CH3COOH (CH3CH2)2NH2+, -OOCCH3

anilinium chloride

diethylammonium acetate

relative base strength

RNH2 > NH3 > ArNH2

Kb ionization of the base in water

:Base + H2O H:Base+ + OH-

Kb = [ H:Base+ ] [ OH- ] / [ :Base ]

Kb

aliphatic amines 10-3 – 10-4

ammonia 1.8 x 10-5

anilines 10-9 or less

Why are aliphatic amines more basic than ammonia?

NH3 + H2O NH4+ + OH-

R-NH2 + H2O R-NH3+ + OH-

The alkyl group, -R, is an electron donating group. The donation of electrons helps to stabilize the ammonium ion by decreasing the positive charge, lowering the ΔH, shifting the ionization farther to the right and increasing the basicity.

Why are aromatic amines less basic than aliphatic amines?

R-NH2 + H2O R-NH3+ + OH-

NH2

+ H2O

NH3

+ OH

NH2 NH2 NH3 NH3

NH2 NH2 NH2 resonance stabilization of the free base, increases the ΔH, shifts the ionization to the left, decreasing base strength.

Effect of substituent groups on base strength:

NH2

+ H2O

NH3

+ OH

G G

Electron donating groups will stabilize the anilinium ion, decreasing the ΔH, shifting the ionization farther to the right and making the compound a stronger base.

Electron withdrawing groups destabilize the anilinium ion, increasing the ΔH, shifting the ionization towards the reactants, making the compound a weaker base.

Common substituent groups:

-NH2, -NHR, -NR2-OH-OR-NHCOCH3 electron donating-C6H5 groups-R-H-X-CHO, -COR-SO3H electron withdrawing-COOH, -COOR groups-CN-NR3

+

-NO2

Number the following in decreasing order of base strength (let #1 = most basic, etc.

NH3

NH2 NH2 NH2 NH2

NO2 OCH3

4 1 5 3 2

2. Alkylation (ammonolysis of alkyl halides)

RNH2R-X R2NH

R-XR3N

R-XR4N+X-

1o 2o 3o 4o salt

SN2: R-X must be 1o or CH3

CH3CH2CH2CH2BrNH3

CH3CH2CH2CH2NH2n-butylamine

CH3CH2CH2NH2CH3Cl

CH3CH2CH2NHCH3n-propylamine methyl-n-propylamine

NH22 CH3CH2Br

NEt

Et

aniline N,N-diethylaniline

H2C NH2

benzylamine

(xs) CH3I H2C N

CH3CH3

CH3 Ibenzyltrimethylammonium iodide


C OH2, Ni

or NaBH3CNCH NHR+ RNH2

C OH2, Ni

or NaBH3CNCH NR2+ R2NH 3o amine

2o amine

CCH2CH3

O

propiophenone

+ CH3CH2NH2NaBH3CN

CHCH2CH3

NHCH2CH3

1-(N-ethylamino)-1-phenylpropane

O

cyclohexanone

CH3NH2, H2/Ni NHCH3

cyclohexylmethylamine


R-NH2 + RCOCl RCONHR + HCl

1o N-subst. amide

R2NH + RCOCl RCONR2 + HCl

2o N,N-disubst. amide

R3N + RCOCl NR

3o

NH2 + (CH3CO)2OHN C CH3

O

N-phenylacetamide

CO

Cl(CH3CH2)2NH + C

O

N CH2CH3CH2CH3

N.N-diethyl-m-toluamide

N CH3CH3

+ CH3CO

ClNR

H3C H3C

DEET

Conversion into sulfonamides

R-NH2 + ArSO2Cl ArSO2NHR + HCl

1o N-subst.sulfonamide

R2NH + ArSO2Cl ArSO2NR2 + HCl

2o N,N-disubst.sufonamide

R3N + ArSO2Cl NR

Schotten-Baumann technique: reactions of aromatic acid chlorides are sped up by the addition of base.

R-NH2 + ArSO2Cl + KOH ArSO2NHR

1o acidic

ArSO2NR

water soluble salt

R2NH + ArSO2Cl + KOH ArSO2NR2 + HCl

2o N,N-disubst.sufonamide

water insoluble

Hinsberg Test:unknown amine + benzenesulfonyl chloride, KOH (aq)

Reacts to produce a clear solution and then gives a ppt upon acidification primary amine.

Reacts to produce a ppt secondary amine.

Doesn’t react tertiary amine.

NH2 N

N CH3CH3

+ SO2Cl SO

O

KOH

(CH3CH2)2NH SO2ClKOH

+ SO2ClKOH

+ SO

ON

CH2CH3

CH2CH3

NR

water sol.

ppt

sulfanilamide “magic bullet” antibiotic

NH2

SO2NH2

N

N N

NOH

H2N

H2C

HN C

O HN CH

COOH

CH2CH2COOH

folic acid

H2N COOH

p-aminobenzoic acd

H2N SO2NH2

sulfanilamide

5. EAS

-NH2, -NHR, -NR2 are powerful activating groups and ortho/para directors

a) nitration

b) sulfonation

c) halogenation

d) Friedel-Crafts alkylation

e) Friedel-Crafts acylation

f) coupling with diazonium salts

g) nitrosation

a) nitration

NH2

HNO3

H2SO4

TAR!

(CH3CO)2O

NHCOCH3

HNO3

H2SO4

NHCOCH3

NO2

+ ortho-

H2O,OH-

NH2

NO2

b) sulfonation

NH2

+ H2SO4

NH3

SO3

cold H2SO4

NH3 HSO4

c) halogenation

NH2

+ Br2, aq.

NH2Br Br

Brno catalyst neededuse polar solvent

Br2,Fe

Br

HNO3

H2SO4

Br

NO2

+ ortho-

H2/Ni

Br

NH2

polyhalogenation!

NH2

Cl2 (aq.)NH2

CH3

Cl

ClCH3

o-toluidine

bright yellow!

Swimming pool test kit for chlorine:

e) Friedel-Crafts alkylation

NR with –NH2, -NHR, -NR2

NH2CH3

+ CH3CH2Br, AlCl3 NR

Do not confuse the above with the alkylation reaction:

NH2CH3

+ CH3CH2Br

NHCH2CH3CH3

f) Friedel-Crafts acylation

NR with –NH2, -NHR, -NR2

NH2CH3

+ NR

Do not confuse the above with the formation of amides:

NH2CH3

NHCCH3CH3

H3C CO

Cl

AlCl3

+ H3C CO

Cl

O

g) nitrosation

NH3C CH3

NaNO2, HCl

NH3C CH3

NO

The ring is sufficiently activated towards EAS to reactwith the weak electrophile NO+

h) coupling with diazonium salts azo dyes

NH2CH3

+

N2 Cl

benzenediazoniumchloride

CH3

NH2

NN

an azo dye

6. Hofmann elimination from quarternary hydroxides

step 1, exhaustive methylation 4o salt

step 2, reaction with Ag2O 4o hydroxide + AgX

step 3, heat to eliminate alkene(s) + R3N

CH3CH2CH2CH2

(xs) CH3ICH3CH2CH2CH2NH2 N

CH3

CH3

CH3 I-

CH3CH2CH2CH2 NCH3

CH3

CH3 I-Ag2O

CH3CH2CH2CH2 NCH3

CH3

CH3 OH- + AgI

CH3CH2CH2CH2 NCH3

CH3

CH3 OH CH3CH2CH=CH2 + (CH3)3N

CH3CH2CHCH3NH2

+ (xs) CH3I CH3CH2CHCH3NCH3

CH3H3C I-

CH3CH2CHCH3NCH3

CH3H3C I-Ag2O CH3CH2CHCH3

NCH3

CH3H3C OH + AgI

CH3CH2CHCH3NCH3

CH3H3C OH CH3CH2CH=CH2 + CH3CH=CHCH3

+ (CH3)3Nchief product

Hofmann orientation


NH2 + HONO N N diazonium salt

R-NH2 + HONO N2 + mixture of alchols & alkenes

primary amines

secondary amines

HN R + HONO N R

N O

N-nitrosamine

tertiary amines

N RR

+ HONO N RR

NO

p-nitrosocompound

note: 90% of all tested nitrosamines are carcinogenic in man. Many nitrosamine cancers are organ specific. For example, dimethylnitrosamine causes liver cancer while the nitrosamines in tobacco smoke cause lung cancer.

Sodium nitrite (“cure”) is used as a preservative in meats such as bacon, bologna, hot dogs, etc. to kill the organism responsible for botulism poisoning. In the stomach, the nitrous acid produced from sodium nitrite can react with secondary and tertiary amines to form nitrosamines. To reduce the formation of nitrosamines, ascorbic acid (Vitamin C) is now added to foods cured with sodium nitrite.

Nitrosamines are also found in beer!

Amines, reactionsAmines are similar to ammonia in their reactions.

Like ammonia, amines are basic.

Like ammonia, amines are nucleophilic and react with alkyl halides, acid chlorides, and carbonyl compounds.

The aromatic amines are highly reactive in electrophilic aromatic substitution.

Amine, reactions:

1. As bases

2. Alkylation



5. EAS

6. Hofmann elimination from quarternary ammonium salts


Aryl Halides Ar-X

Organic compounds with a halogen atom attached to an aromatic carbon are very different from those compounds where the halogen is attached to an aliphatic compound. While the aliphatic compounds readily undergo nucleophilic substitution and elimination reactions, the aromatic compounds resist nucleophilic substitution, only reacting under severe conditions or when strongly electron withdrawing groups are present ortho/para to the halogen.

Aryl halides, syntheses:

1. From diazonium salts

Ar-N2+ + CuCl Ar-Cl

Ar-N2+ + CuBr Ar-Br

Ar-N2+ + KI Ar-I

Ar-N2+ + HBF4 Ar-F

2. Halogenation

Ar-H + X2, Lewis acid Ar-X + HX

X2 = Cl2, Br2

Lewis acid = FeCl3, AlCl3, BF3, Fe…

reactions of alkyl halides Ar-X

1. SN2 NR

2. E2 NR

3. organo metallic compounds similar

4. reduction similar

C C X

X

aryl halide

vinyl halide

Ag+

-OH

-OR

NH3

-CN

ArH

AlCl3

NO REACTION

Bond Lengths (Å)

C—Cl C—Br

CH3—X 1.77 1.91

C2H5—X 1.77 1.91 sp3

(CH3)3C—X 1.80 1.92

CH2=CH—X 1.69 1.86

C6H5—X 1.69 1.86sp2

In aryl halides, the carbon to which the halogen is attached is sp2 hybrizided. The bond is stronger and shorter than the carbon-halogen bond in aliphatic compounds where the carbon is sp3 hybridized. Hence it is more difficult to break this bond and aryl halides resist the typical nucleophilic substitution reactions of alkyl halides.

The same is true of vinyl halides where the carbon is also sp2 hybridized and not prone to nucleophilic substitution.

In a manner analogous to the phenols & alcohols, we have the same functional group in the two families, aryl halides and alkyl halides, but very different chemistries.

Aryl halides, reactions:

1. Formation of Grignard reagent

2. EAS

3. Nucleophilic aromatic substitution (bimolecular displacement)

(Ar must contain strongly electron withdrawing groups ortho and/or para to X)

4. Nucleophilic aromatic substitution (elimination-addition)

(Ring not activated to bimolecular displacement)

1) Grignard reagent

Br

Cl

Mg

Mg

anhyd. Et2O

THF

MgBr

MgCl

2) EAS The –X group is electron-withdrawing and deactivating in EAS, but is an ortho/para director.

BrHNO3, H2SO4

H2SO4,SO3

Br2,Fe

CH3CH2-Br, AlCl3

+

+

+

+

Br Br

Br

Br Br

Br

NO2

SO3H

Br

CH2CH3

Br

NO2

Br SO3H

Br CH2CH3

3) Nucleophilic aromatic substitution (bimolecular displacement)

Ar must contain strongly electron withdrawing groups ortho and/or para to the X.

ClNO2

NO2

+ NH3

NH2NO2

NO2

BrNO2

NO2

+ NaOCH3

OCH3NO2

NO2

O2N O2N

Cl

NO2

OH

NO2

ClNO2

NO2

OHNO2

NO2

O2N O2N

Cl

+ NaOH NR

350oC, 4500 psi H+OH

15% NaOH, 160oC H+

warm water

Cl

NO2

NH2

NO2

ClNO2

NO2

NH3NO2

NO2

O2N O2N

Cl NH2

NH3, 170oC

NH3, room temp.

NH3, Cu2O, 200oC, 900 psi

NO2 NO2

bimolecular displacement (nucleophilic aromatic substitution)

mechanism:

1) + :ZXX

ZRDS

X

Z2) Z + :X

X

Z

Z

X

Z

X

Z

X

Z

X

Z

X

G

G

If G is an electron withdrawing group in the ortho andpara positions, it will stabilize the intermediate anion.

evidence for the bimolecular displacement mechanism:

no element effect : Ar-I Ar-Br Ar-Cl Ar-F

(the C—X bond is not broken in the RDS)

4) Elimination-Addition, nucleophilic aromatic substitution.

When the ring is not activated to the bimolecular displacement and the nucleophile is an extremely good one.

Br

+ NaNH2, NH3

NH2

F

+

Li

LiH2O

Elimination-Addition mechanism (nucleophilic aromatic substitution)

1)

XH

+ :NH2

X

+ NH3

2)

X

+ :X

benzyne

3) + :NH2

NH2

NH24) + NH3

NH2

H

+ :NH2

elimination

addition

:

:

:

:

While the concept of “benzyne” may appear to be strange, there is much evidence that this mechanism is correct.

Cl

*

* = 14C

NaNH2

NH3

NH2

* *+NH2

47% 53%

OCH3

BrH3C NaNH2

NH3

NR

ClD

+ :NH2

ClH

+

benzyne intermediate has been trapped in a Diels-Alder condensation:

Carbanions

|— C: –

|

The conjugate bases of weak acids,strong bases, excellent nucleophiles.

1. Alpha-halogenation of ketones

CCH

O+ X2

OH- or H+

CCX

O+ HX

X2 = Cl2, Br2, I2

-haloketone

H3CC

CH3

O+ Br2, NaOH H3C

CCH2Br

O+ NaBr

acetone -bromoacetone

O

+ Cl2, H+

OCl

+ HCl

2-chlorocyclohexanone

C CH3

O+ Br2, NaOH C CH2Br + NaBr

O

-bromoacetophenone

cyclohexanone

acetophenone

Alpha-hydrogens: 1o > 2o > 3o

CH3CH2CH2CCH3

O

2-pentanone

+ Br2, NaOH CH3CH2CH2CCH2Br + NaBr

O

1-bromo-2-pentanone

Hydrogens that are alpha to a carbonyl group are weakly acidic:

H3CC

CH3

O

H3CC

CH2

O+ OH + H2O

RC

CH2

O

RC

CH2

O

"enolate" anion

Hydrogens that are alpha to a carbonyl are weaklyacidic due to resonance stabilization of the carbanion.

The enolate anion is a strong base and a good nucleophile

Mechanism for base promoted alpha-bromination of acetone:

H3CC

CH3

O

H3CC

CH2

O+ OH + H2O

RDS

H3CC

CH2

O+ Br Br

H3CC

CH2Br

O+ Br

1)

2)

Rate = k [acetone] [base]

Mechanism for acid catalyzed halogenation of ketones. Enolization.

H3CC

CH3

O

H3CC

CH3

OH+ H+

H3CC

CH3

OH+ :B

H3CC

CH2

OH+ H:B

H3CC

CH2

OH+ Br Br

H3CC

CH2Br

OH+ :Br

H3CC

CH2Br

OH

H3CC

CH2Br

O+ H

“enol”

1)

2)

3)

4)

RC

CH3

O

Oxidation of "methyl" ketones. Iodoform test.

+ (xs) OI R CO

O+ CHI3

NaOH + I2

RC

CH2I

O

RC

CHI2

O

RC

CI3

O+ OH

R C CI3

O

OH

goodleavinggroup

Carbanions. The conjugate bases of weak acids; strong bases, good nucleophiles.

1. enolate anions

2. organometallic compounds

3. ylides

4. cyanide

5. acetylides

Aldehydes and ketones: nucleophilic addition

Esters and acid chlorides: nucleophilic acyl substitution

Alkyl halides: SN2

CO

+ YZ COY

Z

CW

O+ Z C

Z

O+ W

R X + Z R Z + X

Carbanions as the nucleophiles in the above reactions.

2. Carbanions as the nucleophiles in nucleophilic addition to aldehydes and ketones:

a) aldol condensation

“crossed” aldol condensation

b) aldol related reactions (see problem 21.18 on page 811)

c) addition of Grignard reagents

d) Wittig reaction

Carbanions as the nucleophiles in nucleophilic addition to aldehydes and ketones:


Grignard reagents are examples of organo metallic carbanions.

CO

+ RMgX COMgX

R

a) Aldol condensation. The reaction of an aldehyde or ketone with dilute base or acid to form a beta-hydroxycarbonyl product.

CH3CH=Odil. NaOH

CH3CHCH2CH OOH

acetaldehyde 3-hydroxybutanal

CH3CCH3

O dil. NaOHCH3CCH2CCH3

OOH

CH3acetone4-hydroxy-4-methyl-2-pentanone

CH3CH=Odil. NaOH

CH3CHCH2CH OOH


OH

CH2CH=O CH3CH+ O CH3CHCH2CH OO

+ H2O

+ H2O

nucleophilic addition by enolate ion.

H3CC

CH3

O

OH

H3CC

CH2

O

H3CC

CH3

O

H3CCO

CH2

CO

CH3

CH3

+ H2O

+ H2O

H3CCO

CH2

COH

CH3

CH3dil. NaOH

CH3CH2CH=O + dil. NaOH CH3CH2CHCH2CH2CHOH

O

CH3CHCH Oalpha!

CH3CH2CH CH3CH2CHCHCHOH

CH3

OO

O

dil. OH-

O

OH

OH

O

O

O

O + HOH

dil. H+

O

+ H2O

O

With dilute acid the final product is the α,β-unsaturated carbonyl compound!

CH2CH O

phenylacetaldehyde

dil NaOHCH2 C

HCH

OHCH=O

dilute H+

CH2 CH

C CH=O

note: double bond is conjugatedwith the carbonyl group!

+ H2O

NB: An aldehyde without alpha-hydrogens undergoes the Cannizzaro reaction with conc. base.

CHO

benzaldehyde

conc. NaOH COO- CH2OH+

Crossed aldol condensation:

If you react two aldehydes or ketones together in an aldol condensation, you will get four products. However, if one of the reactants doesn’t have any alpha hydrogens it can be condensed with another compound that does have alpha hydrogens to give only one organic product in a “crossed” aldol.

CH3CH2CH + H2C OO CH3CHCH2 OHCH ONaOH

N.B. If the product of the aldol condensation under basic conditions is a “benzyl” alcohol, then it will spontaneouslydehydrate to the α,β-unsaturated carbonyl.

CH=O + CH3CH2CH2CH=Odil OH-

CH=CCH=OCH2CH3

CHCHCH=OOH

CH2CH3

-H2O

A crossed aldol can also be done between an aldehyde and a ketone to yield one product. The enolate carbanion from the ketone adds to the more reactive aldehyde.

C CH3

O

acetophenone

+ CH3CH=O

acetaldehyde

dil OH-CCH2

OCH

OHCH3

b) Aldol related reactions: (see problem 21.18 page 811 of your textbook).

CH=O + CH3NO2KOH

CH=CHNO2 + H2O

CH2NO2

CH=O + CH2C NNaOEt

CH=C CN

CHC N

+ H2O

Perkin condensation

CH=O + (CH3CO)2OCH3COONa

CH=CHCOOH

H2C CO

OCCH3

O

CHOH

CH2 CO

OCCH3

O

+ H2OHC C

HC

O

OCCH3

O

hydrolysis ofanhydride

+ CH3COOH

d) Wittig reaction (synthesis of alkenes)

1975 Nobel Prize in Chemistry to Georg Wittig

C O + Ph3P=C R'

R

ylide

CO

C R'R

PPh3

C CR

R' + Ph3PO

CH2CH=O + Ph3P=CH2 CH2CH=CH2 + Ph3PO

Ph = phenyl

CO

C R'R

PPh3

C CR

R' + Ph3PO

PPh

PhPh

CR

R' CO

ylide

nuclephilic addition by ylide carbanion, followed by loss of Ph3PO (triphenylphosphine oxide)

O + Ph3PCHCH=CH2 CHCH CH2 + Ph3PO

3. Carbanions as the nucleophiles in nucleophilic acyl substitution of esters and acid chlorides.

a) Claisen condensation

a reaction of esters that have alpha-hydrogens in basic solution to condense into beta-keto esters

CH3COOEtethyl acetate

NaOEtCH3CCH2COOEt

O+ EtOH

ethyl acetoacetate

CH3COOEtNaOEt

CH3CCH2COOEtO

+ EtOH

CH3 COEt

OCH3 C OEt

O

CH2COOEt

nucleophilic acyl substitution by enolate anion

OEt

CH2COOEt

Mechanism for the Claisen condensation:

ethyl propionate

CH3CH2CCHCOOEt

CH3

O

ethyl 2-methyl-3-oxopentanoate

OEtCH3CH2COOEt

OEt

CH3CHCOOEt CH3CH2CO

OEt CH3CH2CO

OEtCHCOOEtCH3

CH2COOEt

NaOEtCH2C

OCHCOOEt

ethyl phenylacetate

CHCOOEt CH2CO

OEtCH2C

O

CHCOOEtOEt

OEt

Crossed Claisen condensation:

COOEt + CH3COOEtNaOEt

CO

CH2COOEt

ethyl benzoate

HCOOEt + CH3CH2COOEt

ethyl formate

H CO

CHCOOEtCH3

OEt

COOEt

COOEtCH3CH2COOEt

OC2H5+ C

O

CO

OEtCHCOOEtCH3

COOEt

COOEt2 CH3CH2COOEt

NaOC2H5+ C

O

CO

CHCOOEtCH3

CHCOOEtCH3

ethyl oxalate

EtOCOEtethyl carbonate

+

COOEt

CH2COOEt

ethyl malonate

NaOEtC CHO COOEt

COOEtEtO

CH3CH2COOEt

ethyl propionate

+O

cyclohexanone

NaOEtCH3CH2C

OO

enolate from ketone in nucleophilic acyl substitution on ester

O

b) Coupling of lithium dialkyl cuprate with acid chloride

R CCl

O+ R'2CuLi R C

R'

O

nucleophile = R'

4. Carbanions as nucleophiles in SN2 reactions with R’X:

a) Corey-House synthesis of alkanes

R2CuLi + R’X R-R’

b) metal acetylide synthesis of alkynes

RCC-M+ + R’X RCCR’

c) Malonate synthesis of carboxylic acids

d) Acetoacetate synthesis of ketones

5. Michael Addition to α,β-unsaturated carbonyl compounds

Carbanions are the conjugate bases of weak acids and are therefore strong bases and excellent nucleophiles that can react with aldehydes/ketones (nucleophilic addition), esters/acid chlorides (nucleophilic acyl substitution), and alkyl halides (SN2), etc.

Reactions involving carbanions as nucleophiles:


2. Nucleophilic addition to aldehydes/ketones

a) aldol and crossed aldol

b) aldol related reactions

c) Grignard synthesis of alcohols

d) Wittig synthesis of alkenes

3. Nucleophilic acyl substitution with esters and acid chlorides

a) Claisen and crossed Claisen

b) R2CuLi + RCOCl

(next slide)

4. SN2 with alkyl halides

a) Corey-House

b) metal acetylide

c) Malonate synthesis

d) Acetoacetate synthesis


Carbanions

|— C: –

|

The conjugate bases of weak acids,strong bases, excellent nucleophiles.


CCH

O+ X2

OH- or H+

CCX

O+ HX

X2 = Cl2, Br2, I2

-haloketone

H3CC

CH3

O+ Br2, NaOH H3C

CCH2Br

O+ NaBr

acetone -bromoacetone