WITTIG WITTIG REACTIONREACTION

ByBy Suman BalyaniSuman Balyani

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Know About WITTIG REACTIONWITTIG REACTION

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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 ReagentsWittig Reagents

BrCH3 PCH3

Ph

Ph

Ph Br+

benzene or toluene

N2

(C6H5)3P+

:

Wittig reagent – i. Preparation of phosphonium salt:

Reaction is SN2! – 3° phosphine very nucleophilic.

- Compare with 3° amine: (CH3)3N + CH3Br (CH3)4N+ Br-

ii. Deprotonation of phosphonium salt:

PCH3

Ph

Ph

Ph Br PH2C

Ph

Ph

Ph Li Br+THF or ether

N2, 0 oCC4H9Li

+ +-+ C4H10 +

triphenylphosphine

methyltriphenylphosphoniumbromide

triphenylphosphoniumyl methylide:a 'zwitterion' – overall neutralThe 'ylide' is resonance hybrid:

PH2C

Ph

Ph

Ph PCH2

Ph

Ph

Ph+- methylidene

triphenylphosphorane

pKa ~ 22.4

Å 1.66

sp2sp2 dz dz

Wittig ReactionWittig Reactionii. 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:

P(Ph)3H2C

O

P(Ph)3O

CH2THF or ether

N2, 0 - 25 oC

+-+ +

triphenylphosphine oxide

P(Ph)3H

CH3

O

CH3

H

THF or ether

N2, 0 oC

+-

Other examples:

P(Ph)3CH3

CH3

O

CH3

CH3

THF or ether

N2, 0 oC

+-

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

Wittig Reaction-MechanismWittig Reaction-Mechanism

The Wittig reaction (and related reactions) is the most important reaction for making alkenes from carbonyl compounds

MgBrCH3CH2O CH2CH3

OH

CHCH3 CH2CH3ether, N2

2. NH4Cl/H2O

dehydrating agent

e.g. H2SO4,POCl3-pyridine, etc.

+

Comparison of regioselectivity with other alkene-forming reactions:

Mechanism:i. addition of 'complex' nucleophileii. elimination via oxaphosphetan

H2C PPh3

O

CH2

O PPh3

+-+

+-

betaine

oxaphosphetan

• syn elimination of Ph3P=O• overall reaction exothermic

(P-O bond dissociation energy 130-140 kcal mol-1)

O PPh3

CH2

CH2

OPPh3

+?

Classical mechanism

Wittig Reaction- Mechanism and StereoselectivityWittig Reaction- Mechanism and Stereoselectivity

Stereoselectivity - consider:

P(Ph)3H

CH3

CH3 O

H

P(Ph)3O

CH3

H

CH3

HCH3

H

H

CH3THF or ether

N2, 0 - 25 oC

+-+ +

(Z)- (E)

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!

i. The ylide –CH2-PPh3CH2=PPh3 which bears no EWG attached to C is

termed an 'unstabilized ylide'.ii. for unstabilized ylides, betaines may have very short lifetime, but equilibration

with oxaphosphetan may occur.ii. oxaphosphetans can be detected by 31P NMR

Wittig Reaction- Ylide Reactivity and StereochemistryWittig Reaction- Ylide Reactivity and Stereochemistry

CHRPh3P

CHPh3P CH CHR CHPh3P CH CHR

CHRPh3P

CHPh3P CH CHR

CHPh3P CHPh3P CHPh3P

CH2RPh3P

CH2Ph3P CH CHR

CH2Ph3P

+ -

+ - + -

+ - + - etc.

[pKa+

~ 22]

[pKa ~ 18]+

[pKa ~ 18]+

(R = alkyl group)

i. ‘Unstabilized' ylides

• 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 Wittig Reaction –Ylide Reactivity and Stereochemistry (cont.)Stereochemistry (cont.)

CHPh3P C N

CHPh3P C OR

O

CHPh3P C OR

O

CPh3P C OR

O

Ph3P Ph3P

CH2CNPh3P

CH2Ph3P COOCH2CH3

CHPh3P C N CHPh3P C N

Ph3P

Ph3P

CHPh3P C R

O

CHPh3P C R

O

CPh3P C R

O

CH2Ph3P COC6H5

+ -

+ - +

-

+-

+ -etc.

[pKa+

~ 11-12]

[pKa ~ 9.2]+

[pKa ~ 6]

+ -

+

+ - +

-

[pKa ~ 6]+

ii. ‘Stabilized' ylides ('relative' to unstabilized ylides)

• 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 - ExamplesWittig Reaction - ExamplesBr PPh3

PPh3

O

H

O

OCH3OCH3

O

toluene

N2, 25 oC

+

-

+ PPh3

Br-

NaH, DMF

N2, 25 oC

+

DMF

(Z)

• Completely regioselective, highly stereoselective!

• selective for aldehyde –'chemoselective'!

• DMF – 'dipolar aprotic solvent' – strongly solvates Na+,

• 'Salt free'-conditions – enhances amount of (Z)-alkene!

i.

71% yield; Z:E 95:5

H N

O

CH3

CH3 H N

O

CH3

CH3CH3

SCH3

O

CH3

SCH3

O

NP

N

O

CH3

CH3CH3

H3CN

CH3 CH3

NP

N

O

CH3

CH3CH3

H3CN

CH3 CH3

NP

N

O

CH3

CH3CH3

H3CN

CH3 CH3

-

+

DMF N,N-dimethyl formamide

-

+

DMSOdimethyl sulfoxide

-

+

HMPA or HMPT: hexamethylphosphoric triamide

-

+

etc.

Dipolar aprotic solvents

Wittig Reaction – Examples (cont.)Wittig Reaction – Examples (cont.)

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

ii. Synthesis of prostaglandin F2 (Introduction!)

RO

O

OH

OR'

O

Br OCH3

O

OCH3Ph3P

O

OCH3Ph3P

ROOR'

OH

COOCH3

OHOH'

OH

COOH

toluene

N2, 25 oC+ -

+ PPh3

Br- NaH, DMSO

N2, 25 oC

i. DMSO

ii. NH4Cl/H2O

+

[R, R' = alcohol protecting groups]

ROOR'

-O

OH

ROOR'

O

O H :B-

+ :BH

BrOHH

O

H

OHH

PPh3LiO

HPPh3

OH H

OHH

toluene

N2, 25 oC

+

-+ PPh3

Br- n-BuLi (2 equiv.)THF

N2, 0 oC

i. THF, N2, 0 oC

ii. NH4Cl/H2O

+

+

(Z)

iii. If ,-unsaturated aldehyde is used, stereoselectivity is much poorer!

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

(E)

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

O

H

OHH

PPh3LiO

HPPh3

OH H

OHH

+

-

Br-

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

tert-C4H9OH

N2, 25 oC

i.

tert-C4H9OH, N2, 25 oC

ii. NH4Cl/H2O

++

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

Wittig Reaction – Examples (cont.)Wittig Reaction – Examples (cont.)

iv. Synthesis of polyenes

• (Z)-alkene also formed, but is unstable – will isomerize rapidly in presence of light to the all (E)-alkene.

• Commercial preparation of -carotene!

PPh3

O

H

O

H

Ph3P

N2, 25 oC

-

THF

+-

+

-carotene: precursor to Vitamin A!

Wittig Reaction – Examples (cont.)Wittig Reaction – Examples (cont.)

v. Synthesis of polycyclic alkenes Cl

Cl

PPh3

PPh3

PPh3

PPh3

H

H

O

O

O PPh3

-

+

toluene

N2, 25 oC

+

-+ 2PPh3

Cl-

n-BuLi (2 equiv.)

THF

N2, 0 oC

THF, N2, 0 oC

+

Cl-+

+2

40% yield

ClCl

S

H

O O

H

O PPh3

S

PPh3Ph3P

S

PPh3Ph3PS -+

toluene

N2, 25 oC +

-

+ 2PPh3

Cl-

n-BuLi (2 equiv.)THF

N2, 0 oC

THF, N2, 0 oC

Cl-

+2

+ +

Wittig Reaction – Examples (cont.)Wittig Reaction – Examples (cont.)

Wittig Reaction - DifficultiesWittig Reaction - Difficulties

CH3O

CH3

P(Ph)3OCH3O

O

H

PPh3

O

H

CH3O CH3

CH3

>180 oC+ +

+-

To overcome low reactivity of stabilized ylide?- use a different phosphorus-based stabilizing group which has lower ability

to stabilize negative charge than –+PPh3!

i. Difficult to separate O=PPh3 [MW = 278] from product alkene; O=PPh3 is not

soluble in water. ii. Wittig Reactions do not work well with ketones and stabilized ylides –

very difficult reaction to carry out!

CHPh3P C R

O

CHPh3P C R

O

CPh3P C R

O

CH2Ph3P COC6H5

CP C R

OO

CH3O

CH3OH

CP C R

OO

CH3O

CH3OH

CP C R

OO

CH3O

CH3OH

CP C

OO

CH3O

CH3OH H

OCH3

+ - +-

[pKa ~ 6]+

-

[pKa

~ 19]

- -

Phosphonate! – note that the anion is not an ylide!

Horner Emmons ReactionHorner Emmons Reaction

PCH3O

OCH3

OCH3

O

H

BrOCH3

H

O

H

POCH3

HCH3O

CH3O

OCH3

O

H

POCH3

HCH3O

CH3O

OCH3 O

H

POCH3

HCH3O

CH3O

O

Br CH3

~80-100 oC+

liquid: b.p 110-112 oC

Br

Br

+

+

~80-100 oC+

SN2

trimethyl phosphonoacetate

-

-

Michaelis-Arbuzov Reaction - two steps

i. formation of phosphonium salt

ii. SN2 reaction

Preparation of Phosphonates: From -halo-esters and ketones and trimethyl or triethyl phosphite:

Deprotonate phosphonate to generate nucleophilic reagent:

O

H

POCH3

HCH3O

CH3O

O O

POCH3

HCH3O

CH3O

ONaH, THF

N2, 0-25 oC -

resonance-stabilized anion (Slide 17) – not

an ylide!

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

Horner Emmons Reaction (cont.)Horner Emmons Reaction (cont.)Reaction of Phosphonate anion with aldehydes and ketones: Horner-Emmons or Horner-Wadsworth-Emmons Reaction

Addition intermediate – not detectable

O

POCH3

HCH3O

CH3O

OO

O

P OCH3O

OCH3

O

CH3O

OP

OCH3O

OCH3

CH3O

OCH3O

O

O

POCH3

OOCH3

THF

N2, 0-25 oC-

+

-

-

-+

dimethyl phosphate

oxaphosphetan – not detectable

dimethyl phosphite – water soluble!

compare with Wittig reaction:

O

OCH3

H

Ph3P

OCH3O

O

O PPh310 hours

N2, 170 oC

-+ +

+

Horner Emmons Reaction - ExamplesHorner Emmons Reaction - Examples

O

P

OCH3

H

OCH3OCH3

O

O

H

C

H C8H17

HOCH3CH3O

O P

OCH3

O

OCH3

O

OCH3

H

H

C

H C8H17

HN2, 60 oC

3 hr

-+

-

+

i. Pheremone of the dried-bean beetle70% yield

ii. Prostaglandin analogue

PCH3O

OCH3

OCH3

O

BrC5H11

O

PC5H11CH3O

CH3O

O O

PC5H11CH3O

CH3O

O

O

H

O

OCH3

O

C5H11

O

H

O

O

OCH3

100 oC+NaH, THF

N2, 25 oC -

THF

Prostaglandinanalogue

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

(E)

(E)

Thank you