GRIGNARD REAGENTSGRIGNARD REAGENTS

ORGANOMETALLICS FROMORGANOMETALLICS FROM DIVALENT METALSDIVALENT METALS

+ Mgether

X

R = 1°, 2°, 3°, aryl

R X R Mg

This reaction was discovered by the Frenchman, Victor Grignard -- Nobel Prize in 1912

Formation of Grignard ReagentsFormation of Grignard Reagents

HALIDE REACTIVITIESHALIDE REACTIVITIES

R-I > R-Br > R-Cl

expensive,not readilyavailable

RX + Mg R-Mg-X

less reactive,but easy toprepare or buy

goodcompromise

RELATIVE RATES :

FAST SLOW

FORMATION OF A GRIGNARD REAGENTFORMATION OF A GRIGNARD REAGENT

Ethers are obligatory solvents for the Grignard Reaction.The reaction doesn’t work without an ether solvent.

Typical ether solvents are:

Diethyl ether (b.p. 35o C)

Tetrahydrofuran (b.p. 65o C)

Dioxane (b.p. 101o C)

CH3 C

CH3

H

Cl

Mg CH3 C

CH3

H

MgClether

+

CH3CH2 O CH2CH3

O O

O

THF

Consider two different leaving groups:

The second reaction is too slow at 35 °C,

Why might you need different Why might you need different solvents?solvents?

Bromine is more reactive than chlorine.

therefore we use a higher boiling solvent.

Br + Mgether

35 °CMgBr

Cl + Mg65 °C

MgClTHF

R

Mg

X

CH3 CH2

O

CH2

CH3CH2

O

CH2CH3 CH3

Formation of this complex is exothermic; the reaction is sufficiently exothermic to boil the solution without having to add external heat!

Ethers stabilize the Grignard ComplexEthers stabilize the Grignard Complex

Mg: [Ne]3s2

3s 3p

3s 3p

Mg. .

3s 3p

R-Mg-X

R X. .+RX

two etherscoordinate

ETHERS COORDINATE INTO EMPTY 3p ORBITALSETHERS COORDINATE INTO EMPTY 3p ORBITALS

two bondsform

promotion

R Mg X

OEtEt ..

..

O

Et

Et ..:

ether moleculescoordinate intoempty 3p orbitalson magnesium

THE GRIGNARD THE GRIGNARD COMPLEXCOMPLEX

Ethers stabilize the Grignard ComplexEthers stabilize the Grignard Complex

The complete structure of the Grignard reagent is quite complex. It is probably an equilibrium mixture of the type:

2 R-MgX R2Mg + MgX2

While this complex picture may be more correct, it is easier to treat the Grignard reagent as if it were simply R-Mg-X, which is what we shall do in this course.

R-Mg-X IS A USEFUL SIMPLICATIONR-Mg-X IS A USEFUL SIMPLICATION

….. and the actual reactive species may be a complex dimer.

CHEMISTS HAVE BEEN ARGUING ABOUT THE STRUCTURE OF THE GRIGNARD REAGENT FOR YEARS AND STILL CANNOT AGREE

We can view the Grignard as a hybrid reagent.

R MgX R: MgX

RMgX is a source of a carbanion ( R:- ) just like RLi.

Therefore we expect Grignard reagents to be both a strong base and good nucleophile.

R MgX

C Mg C Mg+:-

covalent ionic

PERCENT IONIC CHARACTERPERCENT IONIC CHARACTERcarbanion

- +

C-K 51C-Na 47C-Li 43C-Mg 35C-Zn 18C-Cd 15C-Cu 9

strongest base

best nucleophile

percent ionicbondmost reactive

least reactive

Less ionic characterthan organolithiumcompounds.More covalent.

Grignard Reagents give all the same reactions as alkyllthium compounds.

R-Mg-X R-Li

Grignard reagents are strong bases and react readily with any slightly acidic hydrogen ( compare R-Li).

R MgX + R H + MgX+

R Li + R H + Li+

H+

H+

Any source of H+ will bring about this reaction:

wateracidsalcohols

amines alkynescarboxylic acidsatmosperic moisture

Any -O-H, -S-H, or -N-H bonds are sufficiently acidic to react.

CH3 CH2 CH CH3

Br

CH3 CH2 CH CH3

Mg

CH3 CH2 CH CH3

D

Mg

ether

Br

D2O

This is not a stereospecific synthetic method.

A DELIBERATE SOURCE OF PROTONS OR DEUTERIUMA DELIBERATE SOURCE OF PROTONS OR DEUTERIUM

( or H2O)

R

R+S

C

A

BC

:

Grignard reagents lose stereochemistry (racemize) when madefrom an enantiomerically pure alkyl halide.

INVERSIONS OF THE GRIGNARD REAGENTINVERSIONS OF THE GRIGNARD REAGENT

Organolithium compounds also usually loose stereochemistry,however, some RLi compounds retain configuration at low temp-eratures (-60 oC or below), where the rate of inversion is slow.

C

A

BC

: MgX+

A

CBC

X*

chiral halide

scramblesstereochemistry

SYNTHESIS OF ALCOHOLS ANDSYNTHESIS OF ALCOHOLS AND CARBOXYLIC ACIDSCARBOXYLIC ACIDS

+..

:.. MgX+

R MgX R C

R

R

O

_

H2O

R C OH

R

R

O

CR R

ether

Reaction with Carbonyl Reaction with Carbonyl CompoundsCompounds

Just as with alkyllithiums ( RLi ):

• formaldehyde primary alcohols• other aldehydes secondary alcohols• ketones tertiary alcohols• carbon dioxide carboxylic acids

Read the following section only from Chap 16 (16.7)

REACTION WITH CARBON DIOXIDEREACTION WITH CARBON DIOXIDE

R-Mg-X + O=C=O R-C-O- MgX+

O

R-COOH

H3O+

ether

CH2 Br CH2 MgBr CH2 COOHMg

1) CO2

2) H3O+ether

(s)

STARTING HALIDES STARTING HALIDES YOU CANNOT USEYOU CANNOT USE

NOTE TO STUDENTS

CAUTIONCAUTIONMost Grignard and Alkyllithium compounds are not stablecompounds. You cannot buy them, and you must make them and use them immediately.

Therefore, I will expect you to show the reaction that forms these reagents in any synthesis problem.

Do not “pull a Grignard or Alkyllithium out of your hat”

you must show how it is made from a halide.

RX RMgXMg

ether (CH3)2C=O

Also ….. do not forget the hydrolysis step with H3O+

etc

THESE REACTIONS DON’T WORK …. WHY NOT?THESE REACTIONS DON’T WORK …. WHY NOT?

CH CH

CH3

CH2 MgBr

OH

CH3

O

MgBr

CH MgBr

CH3

HOOC

Mg

Mg

Mg

ether

ether

ether

CH CH

CH3

CH2 Br

OH

CH3

O

Br

CH Br

CH3

HOOC

INTERFERING GROUPS !