Organic Chemistry Fifth Edition

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Organic Chemistry II (Chem 234)Professor Duncan
J. Wardrop
Spring 2004
University of Illinois at Chicago
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18.9The Aldol Condensation
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Aldol Condensation
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Aldol Condensation of Butanal
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Dehydration of Aldol Addition Product

• dehydration of ?-hydroxy aldehyde can
  becatalyzed by either acids or bases

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Dehydration of Aldol Addition Product
NaOH

• in base, the enolate is formed

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Dehydration of Aldol Addition Product
NaOH

• the enolate loses hydroxide to form the
  ?,?-unsaturated aldehyde

8
Aldol reactions of ketones

• the equilibrium constant for aldol addition
  reactions of ketones is usually unfavorable

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Intramolecular Aldol Outpaces Intermolecular
Process
even ketones give good yields of aldol
condensation products when the process is
intramolecular
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Conformational Picture
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18.10Mixed Aldol Condensationsa.k.a.Crossed-Con
densations a.k.a.Claisen Schmidt Reaction
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Mixed Aldol Reactions - A Complex Situation!

• There are four possible aldol products because
  the reaction mixture contains the two aldehydes
  plus the enolate of each aldehyde.

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What Nucleophiles and Electrophiles are Present?
Electrophiles
Nuleophiles
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All Combinations of Enolates and Aldehydes
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Keys to Successful Crossed Aldol Reactions
In order to carry out practically useful crossed
aldol reactions, the following rules must be
observed 1. Only one of the two carbonyl
components can undergo enolization - one
enolate will be present during reaction 2.
Second carbonyl compound must not undergo
enolization and be more electrophilic than the
enolizable compound - prevents self-condensation
of enolizable carbonyl compound since any enolate
is immediately trapped by the electrophilic
carbonyl compound
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Formaldehyde No Alpha Protons - No Enolization!
Formaldehyde has no a-protons and therefore
cannot form an enolate Formaldehyde is
extremely reactive toward nucleophilic addition -
consider the size of Khydration
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Crossed Aldol Reaction with Formaldehyde
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Aldehydes Which Do Not Have Alpha Protons

• These aldehydes cannot form enolates

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Crossed Aldol Reaction with Aromatic Aldehydes
One possible enolate anion. Self condensation is
slower than reaction with aromatic aldehyde
Electrophilic and unable to enolize
Dehydration is favorable because of conjugated
nature of product
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18.11Effects of Conjugation in ???-Unsaturated
Aldehydes and Ketones
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Nucleophilic (and not so nucleophilic) Alkenes
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Relative Stability of Unsaturated Carbonyl
Compounds

• aldehydes and ketones that contain a
  carbon-carbon double bond are more stable when
  the double bond is conjugated with the carbonyl
  group than when it is not
• compounds of this type are referred to as ?,?
  unsaturated aldehydes and ketones

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Relative Stability of a,b and g,d-Carbonyl
Compounds
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Acrolein - An Orbital Picture
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Acrolein - An Orbital Picture
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Acrolein - An Orbital Picture
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Acrolein - An Orbital Picture
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Acrolein - A Resonance Description
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a,b-Carbonyl Compounds are Ambient Electrophiles

• ???-Unsaturated aldehydes and ketones are more
  polar than simple aldehydes and ketones.
• ???-Unsaturated aldehydes and ketones contain
  two possible sites for nucleophiles to attack
• carbonyl carbon
• ?-carbon

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A Comparison of Dipole Moments
?
?
?
?
?

Butanal
trans-2-Butenal

• greater separation of positive and negative
  charge

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Electrophilic Alkenes
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Termite Self-Defense!
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18.12Conjugate Addition to ???-Unsaturated
Carbonyl Compounds
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Nucleophilic Addition to a,b-Unsaturated Carbonyl
Compounds

• 1,2-addition (direct addition)
• nucleophile attacks carbon of CO
• 1,4-addition (conjugate addition)
• nucleophile attacks ?-carbon

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• attack is faster at CO
• attack at ?-carbon gives the more stable product

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1,2-addition

• formed faster
• major product under conditions of kinetic
  control (i.e. when addition is not readily
  reversible)

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1,4-addition

• enol
• goes to keto form under reaction conditions

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1,4-addition

• keto form is isolated product of 1,4-addition
• is more stable than 1,2-addition product

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1,2-addition
1,4-addition
CO is stronger than CC
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1,2-Addition to a,b-Unsaturated Carbonyl Compounds

• observed with strongly basic nucleophiles
• Grignard reagents
• LiAlH4
• NaBH4
• Sodium acetylide
• strongly basic nucleophiles add irreversibly

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Acetylenic Grignard Reagents Undergo 1,2-Addition
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1,4-Addition to a,b-Unsaturated Carbonyl Compounds

• observed with weakly basic nucleophiles
• cyanide ion (CN)
• thiolate ions (RS)
• ammonia and amines
• azide ion (N3)
• weakly basic nucleophiles undergo
• reversible addition

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Example
(93-96)
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Example
O
C6H5CH2SH
HO, H2O
(58)
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18.13Addition of Carbanions to???-Unsaturated
Carbonyl CompoundsThe Michael Reaction
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1,4-Addition of Enolates to a,b-Unsaturated Carbon
yl Compounds - The Michael Reaction

• Stabilized carbanions, such as those derived
  from ?-diketones undergo conjugateaddition to
  ?,?-unsaturated ketones.

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The Michael Reaction - An Example
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Michael Addition is a Useful Process!

• The Michael reaction is a useful method
  forforming carbon-carbon bonds.
• It is also useful in that the product of the
  reaction can undergo an intramolecularaldol
  condensation to form a six-membered ring. One
  such application is called the Robinsonannelation
  .

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Robinson Annelation - A Type of Michael Addition
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Robinson Annelation - The Big Picture
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18.14Conjugate Addition of Organocopper
Reagentsto ???-Unsaturated Carbonyl Compounds
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Addition of Organocopper Reagents
to???-Unsaturated Aldehydes and Ketones

• The main use of organocopper reagents is toform
  carbon-carbon bonds by conjugate addition to
  ?,?-unsaturated ketones.

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Addition of Organocopper Reagents
to???-Unsaturated Aldehydes and Ketones
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Information Suggested Problems
Suggested Problems 18.39-18.42
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