Aldol Reactions PDF

Aldol Reactions Reactions at the a Carbon of Carbonyl Compounds: Enols and Enolates − O Nu O R + R' R Nu...

Aldol Reactions Reactions at the a Carbon of Carbonyl Compounds: Enols and Enolates − O Nu O R + R' R Nu R' O R' R a Hydrogens are weakly H acidic (pKa = 19 – 20) © 2014 by John Wiley & Sons, Inc. All rights reserved. The Acidity of the a Hydrogens of Carbonyl Compounds: Enolate Anions © 2014 by John Wiley & Sons, Inc. All rights reserved. O H C C R B: O O C C C C R R Resonance structures for the delocalized enolates © 2014 by John Wiley & Sons, Inc. All rights reserved.  H+ O H+ C C R Enolate HO O H C C C R R Enol form Keto form © 2014 by John Wiley & Sons, Inc. All rights reserved.  Keto and Enol Tautomers ❖ Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization © 2014 by John Wiley & Sons, Inc. All rights reserved. © 2014 by John Wiley & Sons, Inc. All rights reserved.  O O OH O Pentane-2,4-dione Enol form (24%) (76%) Hydrogen bond H H : : : :O :O: O :O: Resonance stabilization of the enol form © 2014 by John Wiley & Sons, Inc. All rights reserved. 4. Aldol Reactions: Addition of Enolates and Enols to Aldehydes and Ketones O OH O 10% NaOH 2 H H2O, 5 oC H  contains both an aldehyde and an alcohol functional group  aldol addition © 2014 by John Wiley & Sons, Inc. All rights reserved. 4A. Aldol Addition Reactions ❖ Mechanism of the aldol addition O O O H + H2O H H H HO O H OH O O O HO H H H + HO © 2014 by John Wiley & Sons, Inc. All rights reserved. 4B. The Retro-Aldol Reaction OH O O HO 2 H2O ❖ Mechanism H O O O O O HO + O HO H O HO + © 2014 by John Wiley & Sons, Inc. All rights reserved. 4C. Aldol Condensation Reactions: Dehydration of the Aldol Addition Product ❖ Dehydration of the aldol addition product Aldol condensation OH O O + H2O + OH H H H OH © 2014 by John Wiley & Sons, Inc. All rights reserved. 4D. Acid-Catalyzed Aldol Condensations O + O H3O 2 + H2O © 2014 by John Wiley & Sons, Inc. All rights reserved. ❖ Mechanism H H OH2 O O O + H O H H H H O H O O OH2 O OH H2O: + H2O H + + H3O © 2014 by John Wiley & Sons, Inc. All rights reserved. 4E. Synthetic Applications of Aldol Reactions ❖ Aldol additions and aldol condensations Important methods for carbon- carbon bond formation Useful for the synthesis of ⧫ b-hydroxyl carbonyl compounds ⧫ a,b-unsaturated carbon compounds © 2014 by John Wiley & Sons, Inc. All rights reserved.  R R H H H R R R base NaBH 4 O OH O OH OH Aldehyde Aldol 1,3-diol HA, -H2O H2/Ni high R R pressure H LiAlH 4 R R a,b-unsaturated O R aldehyde Allylic OH H2, Pd-C alcohol R R Saturated OH H alcohol R Aldehyde O © 2014 by John Wiley & Sons, Inc. All rights reserved. 5. Crossed Aldol Condensations © 2014 by John Wiley & Sons, Inc. All rights reserved. 5A. Crossed Aldol Condensations Using Weak Bases O O H + HO aldol addition OH O O dehydration H © 2014 by John Wiley & Sons, Inc. All rights reserved.  O O Na2CO3 (aq) + H H H OH O H H H © 2014 by John Wiley & Sons, Inc. All rights reserved. 5B. Crossed Aldol Condensations Using Strong Bases: Lithium Enolates and Directed Aldol Reactions O O LDA, THF -78 oC H O H O OH O O Li H2O © 2014 by John Wiley & Sons, Inc. All rights reserved. ❖ The use of a weaker base under protic conditions Formation of both kinetic and thermodynamic enolates Results in mixture of crossed aldol products © 2014 by John Wiley & Sons, Inc. All rights reserved. O O O HO + protic solvent (Kinetic (Thermodynamic enolate) enolate) O 1. H O O OH 2. H2O OH © 2014 by John Wiley & Sons, Inc. All rights reserved. ❖ Suggest a synthesis of the following compound using a directed aldol synthesis O OH Retrosynthetic analysis O OH O O + disconnection © 2014 by John Wiley & Sons, Inc. All rights reserved. ❖ Synthesis O O O Li LDA O OH O 1. H 2. H2O © 2014 by John Wiley & Sons, Inc. All rights reserved. 6. Cyclizations via Aldol Condensations ❖ Intramolecular Aldol condensation Useful for the synthesis of five- and six-membered rings Using a dialdehyde, a keto aldehyde, or a diketone e.g. O O HO H O © 2014 by John Wiley & Sons, Inc. All rights reserved.  O O (Ha) 8 7 6 5 4 3 2 1 H (path a) Ha Hb Hc O O H2O 1 8 6 4 2 5 3 7 H OH O 8 1 O 7 2 (-H2O) 6 3 5 4 (not formed) © 2014 by John Wiley & Sons, Inc. All rights reserved.  O O (Hb) 8 7 6 5 4 3 2 1 H (path b) Ha Hb Hc O O H2O 1 8 6 4 2 7 5 3 H O O 8 7 OH 6 1 (-H2O) 5 2 4 3 © 2014 by John Wiley & Sons, Inc. All rights reserved.  O O (Hc) 8 7 6 5 4 3 2 1 H (path c) Ha Hb Hc O O H2O 7 8 6 5 4 3 1 2 H 8 O O HO 7 1 6 2 H (-H2O) H 5 3 4 (not formed) © 2014 by John Wiley & Sons, Inc. All rights reserved.  Although three different enolates are formed, cyclization usually occurs with an enolate of the ketone adding to the aldehyde − − O O < R + R R + H (Ketones are (Aldehydes are less reactive more reactive toward nucleophiles) toward nucleophiles)  Path c is least favorable © 2014 by John Wiley & Sons, Inc. All rights reserved.  Path b is more favorable than path a because six-membered rings are thermodynamically more favorable to form than eight-membered rings Likewise, five-membered rings form far more readily than seven- membered rings © 2014 by John Wiley & Sons, Inc. All rights reserved.  END OF CHAPTER 