CHEM 2445 - Aldol

DR. EDDY

The Experiment
Aldol condensation of benzaldehyde and acetone
Chapter 37, p. 484
Macroscale procedure p. 486

Aldol Condensation
Reaction between 2 carbonyls under basic conditions
Basic conditions generate enolate

Active nucleophile

Intermediate aldol product can be dehydrated under

thermodynamic conditions

Mechanism

General Features
Catalytic with hydroxide
Equilibrium established

pKa difference between enolate and hydroxide <4 unit

Thermodynamic equilibrium, goes to more substituted alkene

Stereochemistry for intermediate

Syn aldol
Anti aldol

Some pKa values

Controlling the Aldol

Formation of enolate

Thermodynamic enolate
Kinetic enolate

Base (-OH, -OR, -H, -NR2)

Thermodynamic conditions
Kinetic conditions

See: J. Org. Chem., 1963, 28, 3362; J. Org. Chem., 1965, 30, 1341;
J. Org. Chem., 1965, 30, 2502; J. Org. Chem., 1969, 34, 2324

Kinetic versus Thermodynamic Enolate

E and Z Enolates

OMe

95

OtBu

95

Et

77

23

iPr

40

60

tBu

100

Ph

100

NEt2

100

General Features of Enolate Equilibrium

Equilibrium position determined by: solvent, base,

cation, temperature
Kinetic Enolate

Thermodynamic Enolate

Aprotic solvents (Et2O,

THF)

Protic Solvents (ROH)

Strong bases (LDA, LTMP)

Weaker bases (RO-, H-)

Oxophilic cations (Li+, Ti4+,

B3+, Al3+)
Low Temperature (-78 C)

Higher temperature (>0C)

Short reaction time

Long reaction time

Base Effect on Enolate Geometry

Acyl Addition Models

Felkin-Anh

J. Chem. Soc., 1959, 112; Tetrahedron Letters, 1968,

2199; Tetrahedron Letters, 1976, 155

Anti Felkin-Anh
Cram
Cram Chelate

J. Am. Chem. Soc., 1952, 74, 5828; J. Am. Chem. Soc., 1953, 75,
6005; J. Am. Chem. Soc., 1963, 85, 1245

Zimmerman-Traxler model

J. Am. Chem. Soc., 1957, 79, 1920

General Observations
Reaction sometimes highly stereospecific
Stereospecific when R large
Some equilibration or isomerization
Z-enolate more selective than E-enolate
When stereospecific Z-enolate gives syn; E-enolate

gives anti

Examples
Z-enolate

E-enolate

The Main Problem

-Hydroxy carbonyls dehydrate to form ,-

unsaturated carbonyls

Thermodynamically more stable product

Happens through E1 elimination of the conjugate base (E1cb)

The Investigated Reaction

Procedure
Mix 5.3 g benzaldehyde with 1.45 g acetone
Add half to solution of 5 g NaOH in 50 mL water/40 mL ethanol
Stir 15 minutes
Add remainder of benzaldehyde/acetone solution
Stir 30 minutes
Vacuum filter crystals
Wash crystals with 100 mL water
Repeat 3x
Press dry while vacuum applied
Record weight, mp, IR, % yield
Recrystalize with ethanol if necessary

Pre-Lab Things
Include

Reactions
Mechanism
Hazards
Densities
Molecular weights of starting material and product

Post-Lab Things
Things to think on

Kinetic or thermodynamic conditions

What would happen if you ran this reaction under the other
conditions?
How would you run the reaction under the opposite conditions?

Is product trans,trans, cis,trans, or cis,cis?

How do you tell?

How would you form the intermediate aldol product

without dehydration?

Getting Out on Time

Work in pairs
Switch between vacuum flasks when 2/3 full
Dry product thoroughly on vacuum for mp and IR