A SMALL PRESENTATION ON

WITTIG REACTION
By Suman Balyani

Let your phones take some rest while you are going to

Let your phones take some rest while you are going to

Know About WITTIG REACTION

Synthesis of Alkenes
1. Wittig reaction 2. Julia reaction 3. Alkene metathesis 4. Heck reaction 5. Partial reduction of alkynes Unlike above reactions, the Wittig reaction proceeds via a one step process and is therefore far more direct hence more commonly employed

The Wittig Reaction

The Wittig Reaction is one of the premier methods for the synthesis of alkenes. It uses a carbonyl compound as an electrophile, which is attacked by a phosphorus ylide (the Wittig reagent).

Important characteristics of the Wittig Reaction

Pure alkene of known structure No regioisomers of alkenes E/Z isomers of alkene (this could be also controlled) C=C double bond in the product is always exactly where the C=O group in the reactant

Wittig Reagents
Wittig reagent i. Preparation of phosphonium salt:
H3C Br + (C6H5)3P:
benzene or toluene N2

+ H3C P

Ph Ph Br Ph

triphenylphosphine

methyltriphenylphosphonium bromide

Reaction is SN2! 3 phosphine very nucleophilic. - Compare with 3 amine: (CH3)3N + CH3Br (CH3)4N+ Brii. Deprotonation of phosphonium salt:
+ H3C P Ph Ph Br Ph + C4H9Li
THF or ether N2, 0 oC

- + H2C P

Ph Ph + C4H10 + Li Br Ph

pKa ~ 22.4

The 'ylide' is resonance hybrid:

- + H2C P Ph sp2 dz Ph Ph H2C P Ph sp2 dz Ph
Ph 1.66

triphenylphosphoniumyl methylide: a 'zwitterion' overall neutral

methylidene triphenylphosphorane

Wittig Reaction
ii. Deprotonation (cont.) Other bases: K+ -O-C(CH3)3 [pKa HO-C(CH3)3 ~ 19] NaH - sodium hydride ['pKa' H2 ~ 35] Li+ -N[Si(CH3)3]2 lithium hexamethyldisilazide [pKa HN [Si(CH3)3]2 ~ 30-35 Li+ -N[CH(CH3)]2 lithium di-iso-propylamide [pKa HN [CH(CH3)2 ]2 ~ 37-40. Reaction with carbonyl compounds The Wittig Olefination Reaction:
O - + THF or ether + H2C P(Ph)3
N2, 0 - 25 oC

CH2 + O P(Ph)3

Other examples:
H3C O H
THF or ether N2, 0 oC

+ P(Ph)3

CH3

H3C O H3C

triphenylphosphine oxide
+ P(Ph)3 CH3 CH3

THF or ether N2, 0 oC

Completely regioselective!- defines position of double bond in the product!

Wittig Reaction-Mechanism
Comparison of regioselectivity with other alkene-forming reactions:
O
CH3CH2 MgBr ether, N2 2. NH4Cl/H2O

CH2CH3 dehydrating OH
agent e.g. H2SO4, POCl3-pyridine, etc.

CHCH3 +

CH2CH3

The Wittig reaction (and related reactions) is the most important reaction for making alkenes from carbonyl compounds Mechanism: i. addition of 'complex' nucleophile ii. elimination via oxaphosphetan
O PPh3 CH2 CH2 + O PPh3
O - + + H2C PPh3 O + PPh3 CH2

oxaphosphetan

betaine syn elimination of Ph3P=O overall reaction exothermic (P-O bond dissociation energy 130-140 kcal mol-1)

Classical mechanism

Wittig Reaction- Mechanism and Stereoselectivity

i. ii. ii. The ylide CH2-PPh3CH2=PPh3 which bears no EWG attached to C is termed an 'unstabilized ylide'. for unstabilized ylides, betaines may have very short lifetime, but equilibration with oxaphosphetan may occur. oxaphosphetans can be detected by 31P NMR

Stereoselectivity - consider:
H H3C H3C - + THF or ether + P(Ph)3 O N2, 0 - 25 oC H3C H H H + HC 3 H CH3

(Z)- CH3
O

(E) H
P(Ph)3

The Wittig reaction is not completely stereoselective! -unstabilized prochiral ylides with prochiral carbonyl compound gives the (Z)-alkene as the major product. - exact amount depend upon reaction conditions!

Wittig Reaction- Ylide Reactivity and Stereochemistry

i. Unstabilized' ylides
+ Ph3P CHR Ph3P CHR + [pKa Ph3P CH2R ~ 22] (R = alkyl group) + Ph3P CH CH CHR

+ Ph3P CH CH CHR Ph3P CH CH CHR + [pKa Ph3P CH2 CH CHR ~ 18] + Ph3P CH + [pKa Ph3P CH2 Ph3P CH ~ 18]

+ Ph3P CH

etc.

also others where R = electron donating group (e.g. -OR', -NR'2 R' = alkyl group) react rapidly with aldehydes and ketones react rapidly with O2 generation and reaction must be carried out under N2! with prochiral carbonyl compound, (Z)-alkene is major product!

Wittig Reaction Ylide Reactivity and Stereochemistry (cont.)

ii. Stabilized' ylides ('relative' to unstabilized ylides)
+ Ph3P CH C N Ph3P CH C N + [pKa Ph3P CH2CN ~ 11-12] O O + Ph3P CH C OR Ph3P CH C OR + [pKa Ph3P CH2 COOCH2CH3 ~ 9.2] + Ph3P CH C R Ph3P CH C R + [pKa Ph3P CH2 COC6H5 ~ 6] + Ph3P Ph3P ~ 6] + Ph3P O O + Ph3P CH C N O

+ Ph3P C C OR O R

+ Ph3P C C

etc.

+ [pKa Ph3P

react slowly with aldehydes, only react with ketones under extreme conditions! generally stable in air! with prochiral carbonyl compound, (E)-alkene is major product!

Wittig Reaction - Examples

i.
Br + Br- PPh3
toluene N2, 25 oC NaH, DMF N2, 25 oC

+ PPh3

+ PPh3

(Z) 71% yield; Z:E 95:5

O
H

O OCH3
DMF

OCH3

Dipolar aprotic solvents

O H N CH3 H O

N+ CH3 H3C

O S CH3

OS H3C + CH3

CH3

DMF N,N-dimethyl formamide

CH3

DMSO dimethyl sulfoxide

O H3C N P

CH3 H3C P + CH3 N N N N N H3C CH H3C CH H3C CH3 3 H C CH 3

3 3

H3C + P CH3 N N N H3C CH H3C CH3 3

etc.

HMPA or HMPT: hexamethylphosphoric triamide

Completely regioselective, highly stereoselective! selective for aldehyde 'chemoselective'! DMF 'dipolar aprotic solvent' strongly solvates Na+, 'Salt free'-conditions enhances amount of (Z)alkene!

Wittig Reaction Examples (cont.)

ii. Synthesis of prostaglandin F2 (Introduction!)
O Br
toluene OCH3 + PPh3 o N2, 25 C

O + Ph3P
[R, R' = alcohol protecting groups]

Br-

O
NaH, DMSO

OCH3 COOCH3

N2, 25 oC

+ Ph3P
OH

OCH3

COOH

O i. DMSO

HO

HO
RO OR'
ii. NH4Cl/H2O

HO

RO OH'
O H :B-

OR'

The hemiacetal provides the 'free' aldehyde under the reaction conditions:

H O -O

O + :BH

RO

OR'

RO

OR'

Wittig Reaction Examples (cont.)

iii. If ,-unsaturated aldehyde is used, stereoselectivity is much poorer!
H HO Br + PPh 3
toluene N2, 25
oC

H HO HO

Br+ PPh3

n-BuLi (2 equiv.) THF

H LiO

N2, 0 oC i.

O
THF, N2, 0 oC

+ PPh3

HO

H +

H
ii. NH4Cl/H2O

(Z)

(E)

75% yield; Z:E ~1:3!

To enhance amount of (E)-isomer, conduct reaction in a protic solvent, or use excess of 'salt' (e.g. LiBr) in reaction mixture!
O

HO

H HO

Br+ PPh3

Li+ -O-t-C4H9 (2 equiv.) tert-C4H9OH

i.

H LiO

N2, 25

oC

+ PPh3

H tert-C4H9OH, N2, 25 oC
ii. NH4Cl/H2O

HO

+ H

69% yield; Z:E ~1:10!

Wittig Reaction Examples (cont.)

iv. Synthesis of polyenes
H

- +

PPh3

O H
THF N2, 25 oC

+ Ph3P

-carotene: precursor to Vitamin A!

(Z)-alkene also formed, but is unstable will isomerize rapidly in presence of light to the all (E)-alkene. Commercial preparation of -carotene!

Wittig Reaction Examples (cont.)

v. Synthesis of polycyclic alkenes
Cl
toluene N2, 25 oC

+ Cl- PPh + 2PPh3

n-BuLi 3 (2 equiv.) THF N 2 , 0 oC

+ PPh3

PPh + 3

Cl

40% yield

PPh Cl- + 3

O O

2 O PPh3 +

H
THF, N2, 0 oC

S
toluene

S + 2PPh3 Cl
N2, 25 oC

Cl

+ Ph3P Cl-

Cl-

+ PPh3

n-BuLi (2 equiv.) THF N2, 0 oC

S + Ph3P
O

+ PPh3

O H H

2 O PPh3

+
THF, N2, 0 oC

Wittig Reaction - Difficulties

i.

ii.

Difficult to separate O=PPh3 [MW = 278] from product alkene; O=PPh3 is not soluble in water. Wittig Reactions do not work well with ketones and stabilized ylides very difficult reaction to carry out!
O CH3O + - PPh3 H CH3 + O CH3 O
>180 oC

CH3 CH3 + H O P(Ph)3

CH3O

To overcome low reactivity of stabilized ylide? - use a different phosphorus-based stabilizing group which has lower ability to stabilize negative charge than +PPh3!
+ Ph3P CH C R O O O O Ph3P CH C R OO O + + Ph3P C C R [pKa Ph3P CH2 COC6H5 ~ 6] O -

-O

[pKa

CH3O P C R C CH3O H

CH3O P C R C CH3O H

CH3O P C R C CH3O H

CH3O P C OCH3 C CH3O H H ~ 19]

Phosphonate! note that the anion is not an ylide!

Horner Emmons Reaction

Preparation of Phosphonates: From -halo-esters and ketones and trimethyl or triethyl phosphite:
O Br H H BrH3C
trimethyl phosphonoacetate

OCH3 OCH3

Br OCH O 3
~80-100 oC

+ P CH3O OCH3

liquid: b.p 110-112 oC

CH3O P + CH3O

OCH3 H H

O
~80-100 oC

O OCH3 H H + Br CH3

Michaelis-Arbuzov Reaction - two steps i. formation of phosphonium salt ii. SN2 reaction

CH3O P + CH3O H H

OCH3

SN2

CH3O P CH3O

Deprotonate phosphonate to generate nucleophilic reagent:

O CH3O P CH3O O
NaH, THF

O OCH3
N2, 0-25
oC

O OCH3

H H

CH3O P CH3O H

resonance-stabilized anion (Slide 17) not an ylide!

also use diethyl ether, DMF, DMSO, HMPT as solvents!

Horner Emmons Reaction (cont.)

Reaction of Phosphonate anion with aldehydes and ketones: Horner-Emmons or Horner-Wadsworth-Emmons Reaction
O CH3O P CH3O H O OCH3 + O
THF

O O

OCH3 P OCH3 O

Addition intermediate not detectable

N2, 0-25 oC CH3O

O
dimethyl phosphate

- OCH3 O OCH3 P O

CH3O +

O O CH3O

OCH3 P

OCH3

oxaphosphetan not detectable

dimethyl phosphite water soluble! compare with Wittig reaction:

+ Ph3P O H OCH3 + O
N2, 170

O CH3O
oC

10 hours

O PPh3

Horner Emmons Reaction - Examples

i. Pheremone of the dried-bean beetle
OCH3 O O P O H + H C H H
CH3O OCH3

O H

OCH3 H

70% yield
H C OO P OCH3 OCH3 C8H17

OCH3 OCH3

N , 60 oC C8H17 2 3 hr

(E)
H

ii. Prostaglandin analogue

O Br + C5H11 CH3O OCH3 P O
100 oC

O
NaH, THF

O C5H11
O

O C5H11

OCH3

CH3O P CH3O O

CH3O P N2, 25 oC CH3O

O

O
Prostaglandin analogue

OCH3

OCH3

O H

(E)
C5H11 H O

THF

Completely regioselective, highly (E)-stereoselective, chemoselective for aldehyde!

Thank you