Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 27, 2011 Topic: _Experiment 6__ page 1 of 3.

Experiment 6. The Aldol Reaction (or Condensation) [see: Ege’s 17.4A, pp 701-705]

The original aldol reaction: NaOH H H H O+ workup H H H3C H H2O 3 H C β H H C β H 2 3 α + 3 α 5 °C, 1 h O HO H O H OH O ~50% Aldol products [aldehyde + ol] Note these specfic reaction conditions. (β-hydroxy-aldehyde) Often difficult to stop at the stage of a β-hydroxy-aldehyde or ketone.

Aldol condensation reaction

H H NaOH H3C + O + H2O O 95% EtOH O O rt H O

H In this combination, H C H H O H3C O O O O this is the only "acidic" H (pKa ~18). orthogonal: no orbital overlap Note: not acidic H base x C O O O The resulting carbanion is not stabilized by the C=O π-electrons.

Comments:

HO 1. H H H H C H O H O H O α-hydrogens O O O (resonance stabilized) pKa of H-OH is 15.7

- - 2. Whenever a nucleophilic base (e.g., HO , H3CO ) is used, the base adds to the C=O carbon.

HO HO OH H OH H H3C H3C O O O O O O

However, these adducted compounds are less stable than the original C=O compounds and do not undergo any other reactions but to go back to the original aldehyde/ketone. Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 27, 2011 Topic: _Experiment 6__ page 2 of 3.

The reaction mechanism:

HO H H H O C O H O H O O O O A H C H--OR (R = H or C2H5) O B - HO or OC2H5 H H H H O O O H O HO O HO O α,β-unsaturated ketone a highly resonance-stabilized class of compound

Comments: (1) The conjugated ketone produced is primarily the morestable trans-stereoisomer. (2) The reaction of the ketone enolate with benzaldehyde takes place exclusively at the α-carbon.

α-carbon H O O H O H O O H H O H not O-alkylation O C-alkylation O- O because of the high C=O bond energy in the T.S.

(3) The last dehydration step should go through the ketone enolate intermediate as shown above. The alternative E process should require a higher energy of activation than the pathway that goes through the enolization by deprotonation (acid-base reaction)

- HO or OC2H5

H H O OH O An E2 process less likely.

(4) The last dehydration step is thermodynamics driven. Especially, when aromatic ketones/aldehydes are used for the reaction, the resulting α,β-unsaturated ketones are stabilized by extensive resonance involving the alkenic C=C and the two aromatic rings. This is also evident from the extremely low C=O stretching vibration IR absorption bands (~1650 cm-1).

Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 27, 2011 Topic: _Experiment 6__ page 3 of 3.

(4) (continued).

νC=O absorption bands: O O O 1695 cm-1 1715 cm-1 1685 cm-1 Aldol condensation product:

H H H H

H O 1655 cm-1 H O H O H O

H H H H O H O H O

H H

H O H O

All of these resonance structures have the single-bonded C-O. lowering the νC=O

Questions: (1) Calculate how many mol equiv of NaOH is used in Experiment 5. (2) Why does the enolate, C, from ketone A shown above selectively attack benzaldehyde (B) even though a large concentration of non-enolized ketone A is available?

(3) Show the structures of the starting carbonyl compounds for the aldol condensation reaction that provides the α,β-unsaturated ketones indicated.

NaOH/C2H5OH H + O H O

KOt-Bu (base) O