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‫שלבית‬-‫ – סינתזה דו‬6 '‫נסוי מס‬
‫ סיפוח מיכאל‬+ ‫דחיסת אלדול‬
.‫ ביצוע תגובות עוקבות של דחיסה אלדולית וסיפוח מיכאל‬- ‫מטרות הניסוי‬
- ‫חומר רקע‬
Aldol Reaction (Condensation)
R. Kane, Ann. Phys. Chem., Ser. 2, 44, 475 (1838); idem, J. Prakt. Chem. 15, 129 (1838).
Traditionally, it is the acid- or base-catalyzed condensation of one carbonyl compound
with the enolate/enol of another, which may or may not be the same, to generate a βhydroxy carbonyl compound—an aldol. The method is compromised by selfcondensation, polycondensation, generation of regioisomeric enols/enolates, and
dehydration of the aldol followed by Michael addition, q.v. The development of methods
for the preparation and use of preformed enolates or enol derivatives, that dictate specific
carbon-carbon bond formation, have revolutionized the coupling of carbonyl compounds:
Historical perspective:
C. H. Heathcock, Comp. Org. Syn. 2, 133-179 (1991).
General review: T. Mukaiyama, Org. React. 28, 203-331 (1982).
Application of lithium and magnesium enolates: C. H. Heathcock, Comp. Org. Syn. 2,
181-238 (1991);
of boron enolates: B. M. Kim et al., ibid. 239-275;
of transition metal enolates: I. Paterson, ibid. 301-319.
Stereoselective reactions of ester and thioester enolates: M. Braun, H. Sacha, J. Prakt.
Chem. 335, 653-668 (1993).
Review of asymmetric methodology: A. S. Franklin, I. Paterson, Contemp. Org. Syn. 1,
317-338 (1994).
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Michael Reaction (Addition)
A. Michael, J. Prakt. Chem. [2] 35, 349 (1887).
Base-promoted conjugate addition of carbon nucleophiles (donors) to activated
unsaturated systems (acceptors):
Reviews:
E. D. Bergmann et al., Org. React. 10, 179-555 (1959);
H. O. House, Modern Synthetic Reactions (W. A. Benjamin, Menlo Park, California, 2nd
ed., 1972) pp 595-623;
M. E. Jung, Comp. Org. Syn. 4, 1-67 (1991).
Review of organometallic nucleophiles: D. A. Hunt et al., Org. Prep. Proced. Int. 21,
705-749 (1989);
V. J. Lee, Comp. Org. Syn. 4, 69-137, 139-168 (1991); J. A. Kozlowski, ibid. 169-198.
Reviews of stereoselective synthesis: H.-G. Schmalz, ibid. 199-236; D. A. Oare, C. H.
Heathcock, Top. Stereochem. 20, 87-170 (1991);
J. d'Angelo et al., Tetrahedron Asymmetry 3, 459-505 (1992);
J. Leonard et al., Eur. J. Org. Chem. 1998, 2051-2061.
Procedure:
Aldol:
Place 0.02 mol of 4-methylbenzaldehyde, or 4-chlorobenzaldehyde, or p-anisaldehyde or
benzaldehyde into a 100ml Erlenmeyer flask (calculate before the laboratory the quantity
needed for each). Add 0.02 mol of acetophenone and 16.0 ml of ethanol 95%. Make
sure all solids are dissolved before proceeding. At room temperature add 4 ml of 60%
sodium hydroxide. Swirl the flask until the mixture solidifies or becomes very hazy.
Add ice to the mixture and swirl vigorously. Use a spatula to help break up the solid
lumps if needed. If an oil is present it should solidify, you might need to scratch the oil
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with a glass rod to help the crystallization process. Add 30ml of ice cold water, stir the
mixture and filter with a Büchner funnel. Let the solid dry on the funnel for about 30
minutes (use the time to clean up!). Recrystallize the chalcone (be careful not to touch the
compound – it can go into your gloves) using ethanol 95% or methanol (check which
solvent is better for your compound, but don’t throw any sample away!). Weigh the
product and measure the melting point. If the compound is not pure enough you will need
to recrystallize it a second time. If you don’t have at least 1g compound then repeat the
reaction.
Michael:
To a 100ml two-necked round-bottom flask with a magnet and a condenser, add 1.2g of
finely ground trans-chalcone, 0.75g of ethyl acetoacetate, and 25 ml of 95% ethanol.
Add approximately 100mg sodium hydroxide (quickly before it starts absorbing water)
and gently heat the mixture to reflux for at least 1 hour. If excessive bumping occurs you
may need to lower the temperature of the heating plate. Allow the mixture to cool to
room temperature and add 10 ml of water. Induce crystallization by cooling in an ice
bath and scratching the oil (be extremely careful not to break the flask while scratching
and add a glass container underneath the flask just in case you are not). Filter the crystals
on a Büchner funnel and rinse them with a small amount of ice cold water. Rinse the
flask with 3 ml of ice cold ethanol to transfer the remaining solid from the flask to the
Büchner. Remove the crystals from the Büchner and put them in a beaker, triturate them
with warm acetone (about 30 ml) and gravity filter into a round-bottom flask, then use the
rotavap to remove the solvent. Recrystallize your product with a suitable solvent. After
appropriately drying the crystals, measure the melting point and compare it to the
literature value. Consult with your laboratory assistant about obtaining spectroscopic data
on the compound (IR and/or 1H-NMR).
*Note
All recrystalizations should be done with gently warm solvents. Excessive heat will cause
side reactions.
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