Wittig Reaction

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Wittig Reaction

Surbhi Goyal

Abstract: The Wittig Reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide.

The reaction was given by George Wittig in 1950. He was awarded with Nobel Prize in 1979. The importance of Wittig reaction is that it provides a method for making carbon - carbon double bond formation in which the position of double bond formation is unambiguous. Otherwise, if we are using Grignard reagent positional isomers are formed. Hence the yield of the reaction decreases.

Keywords: Wittig Reaction, Phosphonium ylide, Grignard Reagent, George Witig

I. INTRODUCTION

The reaction between an aldehyde or ketone and phosphonium ylide to form an alkene and a phosphine oxide is known as Wittig reaction.

O

R

1

R

2

Ph

3

P

R

3

R

4

Ph

3

P O

R

1

R

2

R

3

R

4

Aldehyde

or Ketone

Phosphonium

Ylide

Alkene

Phosphine

Oxide

+ +

The importance of Wittig reaction is that it provides a method for making carbon - carbon double bond formation in which the position of double bond formation is unambiguous. For example- cyclohexane react with phosphonium ylide to form methylene cyclohexane exclusively.

O

H

₂

C PPh

₃

CH

₂

methylene

cyclohexane

cyclohexanone

+

Otherwise, if we are using Grignard reagent positional isomers are formed. Hence the yield of the reaction decreases.

O

HO CH

3

CH

3

CH

2

CH

₃

MgBr

H

cyclohexanone

methylene

cyclohexane

1-methylcyclohex-1-ene

A. Phosphonium Ylide

Ylide is a species in which positive and negative charge are located on the adjacent atoms as in H2C PPh3 _{the “yl” part of the}

name ylide refers to the covalent bond in the substructure P CH2_{. The “ide “part indicates that it also contain the ionic bond.}

OR

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B. Preparation Of Phosphonium Ylide

Phosphonium ylides are prepared from phosphonium salt. Phosphonium salt is prepared by reaction of triphenylphosphine with alkyl halide. Then phosphonium salt is deprotonated with strong base giving phosphonium ylide.

P Ph

Ph Ph

H3C I P

Ph Ph

Ph

CH₃

P Ph Ph

Ph C H₂

I

P Ph Ph

Ph

CH₂ Bu Li

Phosphonium ylide I

Phosphonium salt

H

Phosphonium ylide is also called Wittig reagent. For Wittig reaction, we always prefer a path in which Wittig reagent is derived from less hindered alkyl halide. For example we can prefer 3-Methyl hept-3-ene by two ways.

3-methy l hept-3-ene

butanal

O Ph3P

PPh3

O butan-2-one

a

b

+

Path b is more preferred than path a. because in path b, phosphonium ylide is derived from less hindered alkyl halide.

C. Classification Of Phosphonium Ylides

Phosphonium ylide are classified into three types on the basis of their reactivity.

Table: Triphenyl phosphonium ylides: nomenclature, preparation and stereoselectivity of their Wittig reactions.

“Stabilized ylide” have strongly conjugating substituent’s (e.g -COOMe, -CN, -SO2Ph) on the ylidic carbon and usually favour the formation of (E)-alkene. “Semistablized” ylides contain mildly conjugating substituents (Ph or allyl) and give mixture of cis and trans alkene.

“Nonstablized” ylides contain alkyl substituents on the ylidic carbon and usually favour (Z)-alkenes. The three R groups present on S.No. P-Ylide Ylide type Ylide is

prepared

prepared from

PPh3 CHR Hal

and

1,2-disubstituted alkene

1.

PPh3 CHAlkyl Non-

stablized ylide

in situ n-BuLi or

Na CH₂S( O)CH₃

or

K O tert-Bu

with ≥ 90% cis -selectivity

2.

PPh3 CHAryl

Semi-stablized ylide

in situ

NaOEt or aq.NaOH _as _cis,trans

mixture 3.

PPh3 CHCOOR Stablized

ylide

in prior

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D. Mechanism of Wittig Reaction

1) Betaine Mechanism: It is two step mechanism in which firstly betaine is formed when carbonyl compound and phosphonium ylides are approach towards each other after this oxaphosphetane is formed from betaine which is then fragment into phosphine oxide and alkene.

R'

R

O

B

PPh

₃

A

O PPh

₃

R

R'

B

A

O PPh

₃

R'

R

A

B

Ph

₃

P O

Betaine

Oxaphosphitane

Alkene

phosphine

oxide

+

2) Concerted Mechanism: It is one step mechanism in which directly oxaphosphetane is formed when carbonyl compound and phosphonium ylide approach towards each other.

R'

R

O

B

PPh

3

A

O PPh

3

R'

R

A

B

Ph

3

P O

Alkene

Phosphine

oxide

Oxaphosphitane

+

After this, oxaphosphetane fragment into alkene and phosphine oxide. The driving force for the fragmentation of oxaphosphetane into alkene and phosphine oxide is being provided by the formation of very strong phosphorous – oxygen bond.

Some reactions proceed through via betaine mechanism and some reactions proceed through via concerted mechanism depending upon the nature of the substrate.

E. Evidence For The Existence Of Intermediate

Evidence for the existence of betaine intermediate from some experimental observations are

1) The formation of stable adducts between betaine and lithium halide in situ.

2) The trapping of betaine as β-hydroxy phosphonium salts by addition of acid at low temperature.

3) The prominent effect of lithium salt on the alkene stereochemistry.

But in first time in 1973, Veejs reported that oxaphosphetanes are the only observable intermediates by P31 NMR spectroscopy in conventional reactions of non-stabilized ylides at low temperature -30o to 0oC.

In the case of Semistablized ylides, oxaphosphetanes have generally have not been detected even at low temperature -100 to -80oC. Hence there is little hope for oxaphosphetanes formed from stabilized ylides.

F. Stereoselectivity In Wittig Reaction

The general rule is that stabilized ylide (R1=Ar, COR, C=C etc) react with aldehyde or ketone to give mostly (E)-isomer. While unstabilized ylide give (Z)-isomer.

Ph

₃

P

R

1

O

R

2

H

R

1

R

2

R

1

R

2

(E)-Alkene

R

1

=COOMe, SO

₂

Ph

CN etc.

(Z)-Alkene

R

1

=Alkyl

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When reaction takes place between carbonyl compound and phosphonium ylide. Then they just approach to each other perpendicularly so that bulky groups are away from each other and (2π-2π) cycloaddition takes place in (supra + antara) mode in thermal condition to form four member puckered oxaphosphetane which is equivalent to syn oxaphosphetane. Since oxygen is more electronegative than carbon so the HOMO of the carbonyl group have larger orbital coefficient at oxygen while the LUMO will have a larger orbital coefficient at carbon the situation is similar with ylide. Since carbon is more electronegative than phosphorous .The HOMO of the ylide group have larger orbital coefficient at carbon. The ylidic carbon is act as nucleophile so the primary interaction will be between its HOMO and LUMO of the electrophillic carbonyl group. Since the orbital interact best where coefficients are large. This primary interaction will be in favour of forming C-C bond. For secondary interactions, the phosphorous have vacant d- orbital which act as LUMO and interact with HOMO of the carbonyl group which has its biggest coefficient on oxygen. So this bonding interaction will be in favour of forming P-O bond.

HOMO

LUMO

The biases in the primary and secondary orbital interactions will lead to some distortions from the pure perpendicular approach which will become more pronounced the nearer two species get to each other. So, the ylide might rotate a bit so that its carbon atom will be closer to the carbonyl ‘s carbon atom and its phosphorous atom will be closer to the carbonyl’s oxygen atom in order to maximize the bonding overlap and of course the perpendicular approach of ylide and carbonyl group will proceed in such a way that their respective biggest substituent’s are as far away from each other as possible.

If R = alkyl group, then phosphonium ylide is non-stabilized and more reactive. It reacts with carbonyl compound rapidly and form syn oxaphosphetane which is fragment into (Z)-alkene and phosphine oxide. The reaction is irreversible in this case.

O H

R1

PR₃ H R2

H R1

R₃ P

H R2

O _H O PR3

R1

H R2

R1 H

R2 H

(R2= alkyl group) f our member puckered ring structure

syn

oxaphosphitane

(Z)-alkene

+

O H

R1

PR₃

H R2

H

R1

R₃

P

H R2

O _H O PR3

R1

H

R2

f our member puckered ring structure

syn

oxaphosphitane

O PR₃

H

R1

R2

R1

H

R2

(E)-alkene H

anti

oxaphosphetane

(R2=COCH₃)

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G. Stereoselectivity In Case Of Salt Free Conditions

The stereoselectivity of the Wittig reaction depends not only on the substituents but also on the presence of salt. In absence of lithium salts ( “salt free” ), there is stereoselective synthesis of alkene from non-stabilized ylide so the reaction in which (Z)-alkene is desired are often carried out using sodium or potassium bases. For example, by using NaNH2, KO-tert-Bu, and KHMDS etc.

Under salt free conditions, the cis oxaphosphetane formed from non stabilized ylides can be kept from participating in the stereochemical drift (i.e. the initially obtained cis-oxaphosphetane can subsequently isomerize irreversibly to a trans-oxaphosphetane with the rate constant kdrift × [ktrans / (ktrans +kcis )]. This isomerization is referred to as stereochemical drift.) and left intact until they decompose to give the alkene in the terminating step. This alkene is then a pure cis isomer. In other words, salt free Wittig reactions of non-stabilized ylides represent stereoselective synthesis of cis-alkenes.

O H R₁

PR₃ H R2

H R₁

R₃ P

H R₂

O H O PR3 R1

H R2

R₁ H

R2

H (R2= alkyl group) four member

puckered ring structure

syn

oxaphosphitane (Z)-alkene +

Example

Br

PPh

3

Br

PPh

3

Ph

O

Ph

H

1-bromo-2-methylpropane

1-((

Z

)-5-methylhex-3-enyl)benzene

H. Stereoselectivity In Case Of Non-Salt Free Conditions

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O PPh

₃

R

1

R

2

R

1

H

O

H

R

2

PPh

₃

O PPh

₃

R

1

R

2

Li O

PPh

₃

H

R

2

R

1

H

Li O

PPh

₃

H

R

1

Li O

PPh

₃

H

R

1

R

2

R

2

Li Hal

O

PPh

₃

R

1

R

2

O PPh

₃

R

1

R

2

R

1

R

2

O PPh

₃

k

_trans

k

_cis

k

_trans

trans lithiobetaine

an oxide ylide

cis lithiobetaine

end of the reaction

start of

the reaction

HCl

A

B

C

D

E

O PPh

₃

R

1

R

2

R

1

H

O

H

R

2

PPh

₃

O PPh

₃

R

1

R

2

Li O

PPh

₃

H

R

2

R

1

H

Li O

PPh

₃

H

R

1

Li O

PPh

₃

H

R

1

R

2

R

2

Li Hal

O

PPh

₃

R

1

R

2

O PPh

₃

R

1

R

2

R

1

R

2

O PPh

₃

k

_trans

k

_cis

k

_trans

an oxide ylide

end of the reaction

start of

the reaction

HCl

A

B

C

D

E

O PPh

₃

R

1

R

2

R

1

H

O

H

R

2

PPh

₃

O PPh

₃

R

1

R

2

Li O

PPh

₃

H

R

2

R

1

H

Li O

PPh

₃

H

R

1

Li O

PPh

₃

H

R

1

R

2

R

2

Li Hal

O

PPh

₃

R

1

R

2

O PPh

₃

R

1

R

2

R

1

R

2

O PPh

₃

k

_trans

k

_cis

k

_trans

an oxide ylide

end of the reaction

start of

the reaction

HCl

KOtert-Bu (-LiOtert-Bu)

A

B

C

D

E

PhLi

+

II. ACKNOWLEDGEMENT

It is our proud privilege and duty to acknowledge the kind of help and guidance received from several people in preparation of this paper. It would not have been possible to prepare this paper in this form without their valuable help, cooperation and guidance. A special gratitude I give to Dr. Anju, Dr. Meenakshi, Miss Sapna whose contribution in stimulating suggestions and encouragement helped me to writing his paper. Last, but not the least, I wish to thank my parents for financing my studies as well as foronstantly encouraging me.

REFERENCES

[1] B. E. Maryanoff, Allen B. Reitz. Chem. Rev. 1989, 863-927. [2] J. Boutagy, Richard Thomas. Chem. Rev. 1974, 74, 87-99. [3] [Synth] snypa.co.uk 19-2-2016.

[4] Chemistry.stackexchange.com 19-2-2016.

[5] Warren, S., Organic Synthesis: The Disconnection Approach Wiley Publication, Nisha Enterprises, Sahibabad, UP. 2014, 3, 120-124. [6] Carruthers, W., Coldham, I.,Modern Methods of Organic Synthesis, Cambridge university Press, U.K., 2004, 4, 132-139.