The Horner-Wadsworth-Emmons (HWE) reaction involves reacting a phosphonate with an aldehyde or ketone in the presence of a strong base to form an alkene. The reaction proceeds through a three step mechanism: 1) deprotonation of the methylene group of the phosphonate by the base, 2) reaction of the carbanion intermediate with the carbonyl group to form a tetrahedral intermediate, and 3) elimination of the phosphate group to form the alkene product. The HWE reaction is useful for synthesizing alkenes from carbonyl compounds and has advantages over the Wittig reaction such as producing E-alkene products and having an easier

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2. HORNER-WADSWORTH-EMMONS REACTION
Dr. Shahid Rasool Horner-Wadsworth-Emmons reaction CHEM5128
Advanced Named Reactions
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3. Key Concepts
• Introduction to Horner-Wadsworth-Emmons reaction
• Discussion of reacting species, bases, solvents
• Mechanism of reaction
• Explanation of mechanism step by step
• Synthetic applications
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4. Horner-Wadsworth-Emmons (HWE) Reaction:
• In 1959, L. Horner modified Wittig reaction (1954)
• In 1961, W.S. Wadsworth and W.D. Emmons worked on it.
• Phosphonates react aldehydes or ketones to produce alkene
• NaH or LiH is used as base (proton remover)
• A way to prepare olefins from aldehydes or ketones
• Overall reaction,

5. Phosphonates:
• Organo-phosphorus compounds
• Phosphonates are derived from phosphonic acids
• Phosphonates for HWE reaction should bear EWG
• EWG = Strong anion stabilizing group (CO2Me, COMe, CHO,
CN, SO2R, SOR, vinyl, phenyl)
HO P
O
OH
R RO P
O
OR
R
Phophonic acids Phosphonates
RO P
O
OR
CH2
Phosphonates for HWE
EWG
RO P
O
OR
CH C
O
OR RO P
O
OR
CH C
O
OR

6. Phosphonates:
• Phosphonates without anion stabilizing groups can be converted to
nucleophiles through strong bases like LiNiPr2 or n-BuLi
• Aldehydes and ketones are converted to β-hydroxy phosphonates
• Elimination to form olefins tends to be very slow, and in some
cases cannot be achieved.
H3CO P
O
OCH 3
CH3
n-BuLi
H3CO P
O
OCH 3
CH2 Li
R C
O
HH3CO P
O
OCH 3
CH2 CH R
OH

7. Synthesis of Phosphonates:
• Simple keto- and ester-substituted phosphonates are prepared by
the Arbusov reaction - alkylation of a trialkyl phosphite with an
alkyl bromide or iodide.

8. Aldehydes or Ketones:
• Aldehydes and ketones both can be used.
• Aldehydes are more reactive than ketones for nucleophillic
addition reactions due to less steric hindrance.
• Why aldehydes & ketones show nucleophillic addition instead of
nucleophillic substitution? (no good leaving group)
• All type of aldehydes are known to show HWE reaction.
• Methy ketones or ketones with small groups are known to show
HWE reaction.
• Ketones bearing bulky groups are inert for HWE reaction
R C
Aldehyde group
H
O
R C
Ketone group
R
O

9. Bases and Solvent:
• Lithium hydride (LiH) or Sodium hydride (NaH)
• Due to sensitivity of substrates towards these hydrides, the bases
used are lithium chloride with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), lithium/magnesium halide with triethylamine (NEt3)
• Potassium carbonate (K2CO3) or Cesium carbonate (Cs2CO3) are
used as bases in solvent free synthesis
• One of the liquid reactants is in excess acting as solvent.
• Different solvents have also been reported including
dimethoxyethane (DME), tetrahydrofuran (THF) etc.
DBU

10. Complete Mechanism:

11. Step-1, Deprotonation of phosphonate:
• Deprotonation by LiH or NaH is shown below.
• Why the proton of methylene is so acidic? (due to EWG)
• Why double bond is created towards carbonyl and not the
phosphoryl group?
• Carbonyl is strong EWG bearing one ethoxy group.
C
H
Li H
+
-
+ -
P
H
OEt
O
O
OEtEtO
C
Li
P
H
OEt
O
O
OEt
EtO
- H2
C
H
H
+
-P
H
OEt
O
O
OEt
EtO
- +
- +
- H2
C
Na
P
H
OEt
O
O
OEtEtO

12. Step-2, Reaction with aldehyde:
• Phosphonate stabilized carbanions reacts with aldehyde to form an
intermediate.
• Phosphonate stabilized carbanions is a strong nucleophile and less
basic.
• What is the difference between a nucleophile and a base?
+
-
C
Na
P
H
OEt
O
O
OEtEtO
H
O
R
C
P
OEt
O
O
OEt
EtO
H
O
H
R
Na

13. Step-3, Olefin formation:
• The intermediate moves forward through a cyclic mechanism to
form olefin.
C
P
OEt
O
O
OEtEtO
H
O
H
R
Na
O P
H
R
H
O
OEt
O
OEt
OEt
O P
H
R
H
O
OEt
O
OEt
OEt
H
R
H
O
OEt
O P
O
OEt
OEt
Na
Na
Na

14. Stereochemistry:
• erythro means identical group on same side (kinetic adduct)
• threo means identical group on opposite side (thermodynamically
favorable means requires high energy or temperature)

15. Comparison of E-Alkene and Z-Alkene:
• Increasing steric bulk of the aldehyde favors E-alkene
• Aromatic aldehydes favor E-alkene
• Higher reaction temperatures (23 °C over −78 °C) favors E-alkene
• Using the solvent dimethoxyethane (DME) over tetrahydrofuran
(THF) favors E-alkene
• Bulky phosphonate and bulky electron-withdrawing groups favor
E-alkene

16. Comparison of E-Alkene and Z-Alkene:
• Solvent free synthesis in Potassium carbonate (K2CO3) or Cesium
carbonate (Cs2CO3) as bases favors Z-alkene
• Phosphonates with electron-withdrawing groups (trifluoroethyl)
together with strongly dissociating conditions i.e. Potassium
bis(trimethylsilyl)amide (KHMDS, ((CH3)3Si)2NK as strong base,
18-crown-6 as hygroscopic solid and tetrahydrofuran (THF) as
solvent favors Z-alkene (Still Modification)

17. Effect of EWG of phosphonates on rate:
• EWG on phosphonate increases the rate of reaction because it
forms stabilized intermediate.

18. Comparison of HWE and Wittig Reactions:
• HWE uses more nucleophillic and reactive phosphonate-stabilized
carbanions than phosphonium ylide
• Phosphonium ylide bears a neutral form and neutral species are
less reactive than charged species
• HWE byproduct dialkylphosphate salt is easily removed by water
during workup than triphenylphosphine oxide (Wittig reaction)
• HWE produces E-alkenes and Wittig reaction produces Z-alkenes.
RO P
O
OR
CH C
O
OR RO P
O
OR
CH C
O
OR
phosphonate-stabilized carbanions

19. Examples of HWE Reaction:
Antibiotic
Alkaloid

20. Examples of HWE Reaction: