Organic Lecture 4/11

Enol and Keto Forms

• Equilibrium Direction:

  • The equilibrium between the enol and keto form lies to the left, meaning there are more carbonyl compounds present.

• Acidity:

  • pKa values for alpha hydrogens in carbonyls range from 19 to 20.

  • Hydroxide ions can abstract these protons, but not efficiently, leaving a significant amount of carbonyl intact.

Mechanism Overview

• Reaction Conditions:

  • The reaction can be conducted under basic or acidic conditions, with considerations for dehydration.

• Temperature Effect:

  • Heating is necessary in basic conditions to promote dehydration since hydroxide is a poor leaving group.

  • In acidic conditions, the reaction proceeds to dehydration almost inevitably.

Aldol Reaction: Doing reaction with alpha hydrogen (next to carbonyl)

• Formation of Larger Molecules:

  • Removal of alpha hydrogen creates an enolate ion (anion of an enol)

  • Enolates can act as nucleophiles to form larger molecules through aldol reactions, especially in five- to six-membered rings.

  • Enolate stabilized by resonance and formation is an equilibrium process

• Cross Aldol Reactions:

  • Focus on minimizing self-aldol reactions by choosing reactants without alpha hydrogens, e.g., acetone for a formaldehyde reaction.

  • Works best if the carbonyl being attacked is an aldehyde

• Using Strong Bases:

  • LDA (Lithium diisopropylamide) is a super strong base (pKa ~36) often chosen to promote enolate formation without competing self-aldol reactions.

  • If excess of the agent we’re attacking, we can do a double reaction (adding to each side). Minimize by using LDA to use 1:1 ratio, only getting single addition.

Enolate Reactions

• Sn2

• Carbonyl Addition (Aldol)

• Basic conditions= require heat to get dehydration

• Acidic conditions= hard not to do the dehydration

Wittig Reaction: Converts aldehydes and ketones to alkenes

• Phosphonium Ylids:

  • The reaction involves a phosphonium ylide reacting with aldehydes or ketones to form alkenes.

  • The process replaces oxygen in the carbonyl with a double bond to the alkyl component from the ylide.

  • Written as CH3I —> 1. P(Ph3), 2. n-BuLi

• Mechanistic Steps:

  • Start with triphenylphosphine for ylide creation through nucleophilic attack (Sn2) on primary/methyl/allyl alkyl halides.

  

  • A strong base abstracts a proton, leading to the formation of the phosphonium ylide, which is resonance-stabilized.

Reaction Dynamics and Intermediates

• Intermediate Formation:

  • The proposed beta-aimine intermediates are highly controversial, as actual isolation has not been achieved.

• Mechanism Alternative Views:

  • Some chemists advocate for a direct pathway to the product rather than a two-plus-two cycloaddition scenario.

  • Mechanically, this reaction does not follow typical two-plus-two cycloaddition rules due to its lack of light requirement.

• Low temperatures and don’t have electron withdrawing group on ylide= z product

• Heat up and ylide has a electron withdrawing product= e product

Horner-Emmons-Wadsworth Modification: similar to Wittig, but uses phosphonate ester instead of ylide

• different solubility to make soluble in more polar substances

• Almost exclusive to E selectivity due to EWG

Enolate Stability and Product Outcomes

• Temperature Influence on Product:

  • Low temperatures yield the Z product, while higher temperatures favor E product formation unless an electron-withdrawing group is present.

• Historical Context:

  • The Wittig reaction was discovered in the 1950s, with a Nobel Prize awarded in 1979, highlighting its prominence in organic chemistry synthesis.

• Ongoing Developments:

  • The field of organic synthesis is continually evolving, with thousands of new reactions being discovered yearly.