Synthesis of Stilbene by the Wittig and Horner-Wadsworth-Emmons Reactions

Part A (p. 606)(p.590 4th ed.) - Wittig reaction for the synthesis of stilbene. Part B (p. 610)(p.594 4th ed.) - Wadsworth-Emmons reaction for the synthesis of stilbene.

Important Concepts • Synthetic methods for making double bonds (olefins) • Phosphonium salt, ylide, phosphonate ester • Transition state controls Wittig stereochemistry (cis) • Ring closure controls Wadsworth-Emmons stereochemistry (trans) • cis-trans photoisomerization with iodine

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 1 The Wittig Reaction

Step 1 - Formation of the ylide.

Cl- R + Base R' R' Ph3P H Ph3P Ph3P H H H Phosphonium salt ylide ylene

Step 2 - Addition to the carbonyl (aldehyde or ketone).

R R' R R' R H † O + Ph3P + + Ph P O H 3 H H H H R' Georg Wittig (1897 - 1987) Triphenylphosphine Born in Berlin Germany cis trans Oxide (TPPO) University of Heidelberg Nobel Prize - 1979 major

Our Reaction. Ph cis trans - Ph Ph Ph H Cl + Ph Ph O NaOH + Ph3P H Ph3P H H H H H H Ph

Ph H trans-Stilbene Iodine H Ph hν

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC Photosource: † NobelPrize.org 2 The Wittig Reaction Mechanism

(1) Ph Why cis stereochemistry? Ph3P H Ph Ph3P H H O H O R' Ph3P Ph3P R' H B H R H R R'

R (2) Ph O Ph P Ph3P O R' 3 H Ph3P O Ph P H H = 3 H H R' R H H R' R H O Ph Ph R Ph Oxaphosphetane ring The transition states control stereochemistry

(3) Ph3P O + H H Ph3P O Ph Ph Ph Ph

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 3 Procedural Details - Wittig

Week 1 - For the Wittig reaction follow the procedure in the book. - Do not evaporate solvent after initial workup. - Save a small amount of crude for TLC analysis. - Add iodine to flask and stopper with a rubber septum. Label flask and place in hood, with light on, until next week.

Why wash with aq. NaHSO3? Why wash with aq. NaCl? O aq. NaHSO HO - + 3 SO3 Na - to remove water from solvent R H R H

Week 2 - Add solvent if necessary and follow workup procedure. - Recrystallize once from 95% ethanol. There is no need to recrystallize a second time. - No Bromine or Bayer tests for unsaturation. - Get TLC of cis/trans, plus final Wittig and Wadsworth-Emmons products on same plate.

- Get data from Wadsworth-Emmons and include in your report (e.g. as if you had performed both reactions). The procedure section should only have your reaction, not your partners. Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 4 Determining the cis/trans ratio from NMR spectra

Integrate the vinylic protons to determine the cis:trans ratio

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 5 The Horner-Wadsworth-Emmons Reaction

†

O R' O R' O R' (1) EtO P H Base EtO P H EtO P EtO H EtO EtO H Phosphonate ester

R O R' R H O O + EtO P H + EtO P O-K+ (1911 - 2005) (2) Leopold Horner H EtO H R' EtO Born in Kehl am Rhein Germany University of Mainz trans William S. Wadsworth & William D. Emmons (1924 - 2001) Born in Minnesota, BS - U. MN, Ph.D. - U. IL Rohm & Haas

Our reaction Ph O Ph O Ph O Ph H O KOtBu EtO - + EtO P H EtO P H H + P O K EtO EtO H DMF EtO H Ph O E-Stilbene H N Remove in aqueous wash

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC Photosource: † Wiley Interscience 6 The Horner-Wadsworth-Emmons Reaction Mechanism

O Ph O Ph (1) EtO P H EtO P H EtO H -O EtO

O- EtO O EtO O Ph - O P O P O (2) EtO P H EtO EtO H Ph H Ph EtO H Ph Ph H Ph H

O- EtO O P O Ph H EtO EtO - + (3) + P O K H Ph H Ph EtO Ph H

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 7 Why is the trans Product Favored for Horner-Wadsworth-Emmons?

EtO EtO O Rapid EtO H Rapid O P P O R' P EtO EtO EtO R' Equilibrium Equilibrium R' R R O R O - O -

Fast Ring Slow Ring Closure Closure

- O- O EtO EtO P O EtO P O EtO H R' H H R H R R' The cis pathway is much slower than the trans.

R'

R R' R

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 8 Procedural Details - Wadsworth-Emmons

Week 1 - Put a stir bar in the 25 ml RB flask and place in oven at beginning of class for 20 minutes and let it cool in the dessicator cabinet. No flame or heat-gun is required for drying.

- Place a rubber septum over the RB flask immediately after removing from dessicator cabinet.

- Assemble apparatus with CaCl2 drying tube connected to needle, which penetrates rubber septum.

- Use a plastic syringe to add reagents through the septum.

- Be very careful with the needles.

- After workup you do not need to save any of the crude for NMR analysis.

- Recrystallize from 95% ethanol.

Week 2 - Get data from Wittig and include in your report (e.g. as if you had performed both reactions). The procedure section should only have your reaction, not your partners.

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 9 Required Data

Wittig - m.p. of purified product. - TLC with crude, pure Wittig and pure Wadsworth-Emmons on same plate. - Weight, %Yield - IR and 1H NMR of starting materials and final product. - 1H NMR of crude cis/trans mixture.

Horner-Wadsworth-Emmons - m.p. of purified product. - TLC with crude, pure Wittig and pure Wadsworth-Emmons on same plate. - Weight, %Yield - IR and 1H NMR of starting materials and final product.

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 10 Photoisomerization with Iodine

R R' I2 H R' ν H H h R H

(1) I I 2 eq. I (free radical)

R R' R R' H R' (2) H H H H H I R I I Rotation about single bond

H R' H R' (3) H + I2 R I R H I catalyst

Chem 343 - Wittig/Wadsworth-Emmons, Copyright - D.J. Dyer & SIUC 11