Ch. 18 Lect. 2 Complex Carbonyl Reactions

I. Aldol CondensationA. Two aldehyde molecules can react to form an -unsaturated aldehyde product

1) This reaction allow C—C bond formation between 2 carbonyl compounds

2) It is base catalyzed

3) Condensation = when 2 molecules combine and give off H2O

4) This reaction works for all aldehydes and some ketones

5) Mechanism

a) Enolate formation is the initial step

b) Nucleophilic carbon of the enolate attacks the carbonyl of the second aldehyde

C

O

CH3HC

O

CH3H

+ OH-, H2OCHH3C

OH

CH2 C

O

H5 oC

C C

H

H3C

CH

O

Hacetaldehyde 3-hydroxybutanal

-unsaturated aldehydetrans-2-butenal

c) The reaction can be stopped at this point at low temperature

d) At higher temperature, dehydration follows

B. Using the Aldol Condensation

1) C—C bond formation is always important for synthesis

2) This is the first example of carbonyl—carbonyl addition

3) Product functional groups are flexible depending on temperature

C

O

CH2H HOH-

C

O

CH2H

C

O

CH3H C

O

CH2H C

H

OH

CH3

H OH

Enolatesmall concentration

Aldol

C

O

CHH C

H

OH

CH3

H OH-

C

O

CHH C

H

OH

CH3-H2O C

O

CHH CH CH3

-unsaturated aldehyde

4) Low temperature example:

5) High temperature example

C. Ketones can undergo Aldol Condensation

1) Aldehyde carbonyls are not stabilized very much by single R group, so the Aldol Condensation is exothermic (more stable product)

2) Ketone Carbonyls are more stable; the Aldol condensation is generally endothermic

CH3CHCH

O

CH35 oC

OH-, H2OCH3CH C

OHCH3

H

C

CH3

CH3

CH

O

+ CH3CHCH

O

CH3

Aldol

H

O H

O

K2CO3, H2O, H

O

H

-unsaturated aldehyde

3) We can force the reaction towards completion by removing product or H2O

D. Crossed Aldol Condensation

1) Reaction of two different aldehydes or ketones is called Crossed Aldol

2) Crossed Aldol Condensations gives product mixtures

C

O

CH3H3C

C

O

CH3H3C

OH-

CH3C

OH

CH3

CH2 C

O

CH3

Aldol 6%

-H2O C

H3C

H3C

CH C

O

CH3

-unsaturated ketone 80%

CH3C

OH

H

CH C

O

H

CH3

C

O

HH3C

C

O

HCH3CH2

+ NaOH

CHCH3CH2

OH

CH2 C

O

H+

+ +CHH3C

OH

CH2 C

O

H CHCH3CH2

OH

CH C

O

H

CH3

2) Crossed Aldol Condensations are only selective if one carbonyl has no -H’s

E. Intramolecular Aldol Condensations give cyclic products

1) Low concentrations ( < 0.001 M) of the linear molecule are used to prevent intermolecular interactions = High Dilution Reaction

NaOH+ C

O

HCH3CH2

C

O

HCH3C

CH3

CH3

CC

OH

H

CH C

O

H

CH3

H3C

CH3

CH3

-H2OCC

H

C CH

O

CH3

H3C

CH3

CH3

HCCH2CH2CH2CH2CH

O ONaOH

OHH

HC

O

H -H2O

H

C

O

H

2) 5- and 6-membered rings are most favored due to low ring strain

3) Intramolecular Ketone Aldol Condensations are more likely than the intermolecular reaction

a) G = H – TS is endothermic for ketone aldol condensation partly due to unfavorable entropy (2 particles 1 particle)

b) The Intramolecular reaction is less endothermic because entropy does not disfavor a 1 particle 1 particle reaction

II. Other routes to -Unsaturated Aldehydes and KetonesA. Base mediated Dehydrohalogenation

H3CCCH2CH2CCH3

O ONaOH

H3C OH

CH3

O

0%

O

OHH3C

+

100%

-H2O

O

H3C

O

Cl2, CCl4

O

Cl

H

OH-

E2O

B. Wittig Reaction

1) Carbonyl Substituted Ylides are stabilized by resonance

2) These stable Ylides will react with Aldehydes to give -Unsaturated aldehydes

C. Oxidation of Allylic Alcohols by MnO2

CH CH

O

(C6H5)3P CH CH

O

(C6H5)3P CH CH

O

(C6H5)3P

CH CH

O

(C6H5)3P + H

O

O

H

CHH2C CH2OHMnO2 CHH2C CH

O

III. Properties of -Unsaturated Aldehydes and KetonesA. -Unsaturated Aldehydes and Ketones (also known as Enones) are

difunctional: alkene and a carbonyl

1) Sometimes they react at a single functional group in normal alkene or carbonyl reactions

2) Sometimes the reactivity is over the whole enone functional group

B. Conjugated Enones are Stabilized

1) Resonance forms of conjugated enone 2-butenal

2) “Moving Into Conjugation” of nonconjugated enones

a) Isomerization to a more stable form can occur in basic conditions

b) Example:

CHH3C CH CH

O

CHH3C CH CH

O

CHH3C CH CH

O

CHH2C CH2 CH

O

not conjugated

OH-

H2OCHH3C CH CH

O

conjugated

c) Mechanism

C. Enone reactions are often typical of alkene and carbonyl chemistry

1) Alkene Hydrogenation

2) Electrophilic Addition to C=C system

CHH2C CH2 CH

OOH-

H2O

CHH3C CH CH

OCHH2C CH CH

O

CHH2C CH CH

O

CHH2C CH CH

O

H2O

+ OH-

O

H2, Pd/C

O

CH3CH=CHCCH3

OBr2, CCl4 CH3CHCHCCH3

O

Br Br

3) Conjugate Reduction

a) Selective for conjugated C=C in presence of other C=C bonds

b) Similar mechanism to alkyne trans-alkene

4) Addition Reactions to the Carbonyl

IV. Addition to -Unsaturated Aldehydes and KetonesA. 1,4 Additions are to the entire Enone functional group

1) 1,2 Additions to either alkene or carbonyl are just like single group cases

CH3

O C

CH3

CH2

CH3

1. Li, NH3 (l)2. NH4Cl, H2O

CH3

O C

CH3

CH2

CH3H

CH=CHCCH3

O

NH2OH, H+

-H2O

CH=CHCCH3

NOH

oxime

C CH C

OA B

C CH C

O

B A

or C CH C

OA

B

2) 1,4 Additions are similar to those of 1,4-butadiene; they involve both of the functional groups = Conjugate Addition

1) Nu- part adds to the -carbon

2) E+ part adds to the carbonyl oxygen

3) Initial product is an enol if the electrophile is H+

4) Tautomerization then leads to a ketone product

5) The result looks like a 1,2 addition to the C=C bond

B. Oxygen and Nitrogen Nucleophile Conjugate Additions

1) ROH, HOH, RNH2 all react similarly with enones

C CH C

ONu H

C CH C

O

Nu

H

C CH C

O

Nu H

C CH C

O

CH3H

H

OH H

C CH C

O

CH3H

H

OH

H

C CH C

O

CH3

H

H

H2O

2) Why do the reactions go 1,4 instead of 1,2 ?

a) Both types of additions are reversible

b) The carbonyl products of 1,4 addition are generally more stable than the hydrate, hemiacetal, and hemiaminal products of 1,2 addition to the carbonyl

c) Exceptions: hydroxylamines, semicarbazides, and hydrazines lead to precipitates that drive the 1,2 addition

3) HCN also adds 1,4 to enones

C. Organometallic Reagent Additions to Enones

1) Organolithium Reagents add 1,2 at the carbonyl

CH3CCH=CH2

OHCN

CH3CCH2CN

O

CH3CCH=CH2

O1. CH3Li, Et2O

2. H+, H2OCH3CCH=CH2

OH

CH3

2) Organocuprate reagents add 1,4 to enones

3) The organocuprate intermediate is an enolate capable of attacking another electrophilic carbon. This results in two alkylations of the C=C bond.

D. The Michael Addition

1) Enolate Ions are good nucleophiles that can perform conjugate (1,4) addition on enones

2) The most reactive enolates are derived from a -dicarbonyl

1. (CH3)2CuLi, Et2O

2. H+, H2OCH3CCH=CH2

O

CH3CCH

O

CH2

H CH3

CH3CCH

O

CH2

CH3CH3CH2

CH3CCH=CH2

O1. (CH3)2CuLi, Et2O2. CH3CH2Br

CH3CCH2CCH3

O O

+ H2C=CHCH

Opyridine

CH2CH2CH

O

CH

CH3C

CH3C

O

O

3) Other enolates can do the reaction as well

4) Mechanism

a) -Carbon of enolate is the Nucleophile

b) -Carbon of the enone is the Electrophile

O

CH3+ H2C=CHC

O

EtO-K+, EtOH

OCH3

CH2CH2C

O

C C

O

+C C

C

O

C C

O

C CC O

H+

C C

O

C CC OH C C

O

C C C

O

H

5) Robinson Annulation

a) Sometimes, the Michael Addition product can undergo an intramolecular aldol condensation

b) This sequence is called the Robinson Annulation

H3C

O

C CC

H

H

H

CH3

O

3-butene-2-one

+EtO-K+, EtOH, Et2OMichael Addition

H3C

OO

CH3

AldolCondensation

OOH

CH3

, OH-

O

CH3

54% 86%

+ H2O-H2O

O

CH

CO

+

CH2O