KNOWN AS GRIGNARD REAGENTS GRIGNARD REAGENTS … · Most reactions of Grignard reagents fall into ... Two of the alkyl groups on the 3 o alcohol are identical, ... aldehydes are more

1

GRIGNARD REAGENTSGRIGNARD REAGENTS

ALKYLMAGNESIUM HALIDES, R-Mg-X, ARE

KNOWN AS GRIGNARD REAGENTS.

GRIGNARD REAGENTS ARE PREPARED BY

REACTING ALKYL HALIDES WITH EXCESS

MAGNESIUM METAL IN DRY ALCOHOL-FREE

DIETHYL ETHER OR TETRAHYDROFURAN

(THF). DIETHYL ETHER AND THF ARE

SOLVENTS.O

CH3CH2OCH2CH3

diethyl ether tetrahydrofuran (THF), a cyclic ether

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GRIGNARD REAGENTSGRIGNARD REAGENTS

PREPARATION

R-X + Mg →→→→ R-Mg-X (radical mechanism)

Ease of formation follows the trends shown below

R-I > R-Br > R-Cl.

CH3X > C2H5X >C3H7X

Grignard reagents are usually closely associated

with two molecules of the ethereal solvent in which

they have been prepared. R

Mg

XO

O Et

Et

Et

Et

3

REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS

Most reactions of Grignard reagents fall into

one of two categories.

1. Reactions with compounds containing

active hydrogen, e.g. H2O, ROH.

2. Addition to epoxides and to multiply

bonded groups.C C

O

EPOXIDE

C O C S S O N O C N

4

REACTIONS OF GRIGNARD REAGENTS

1. Reactions with compounds containing active hydrogen, e.g. H2O, ROH.

The Mg-C bond in a Grignard reagent,

e.g. methylmagnesium bromide, is polarized as shown.

The carbon attached to Mg bears a partial negative charge. This carbon is NUCLEOPHILIC, and is subject to attack by electrophiles.

An ELECTROPHILE is a chemical species which seeks electrons.

H

C

H

MgBrHδδδδδδδδ

5


1. Reactions with compounds containing active H, e.g. H2O, ROH.

The carbon bonded to Mg in Grignard reagents is nucleophilic. The hydrogens on the O-H groups in H2O and alcohols (ROH) are effective ELECTROPHILES.

n-octylmagnesium bromide + H2O:

A similar reaction occurs with alcohols, e.g. ethanol:

What would the reaction be with D2O?

HCCH3(CH2)6

HMg

H

OH

HCHCH3(CH2)6

H

OH

MgBrδδδδδδδδ

+Br

HCCH3(CH2)6

HMg

H

OEt

HCHCH3(CH2)6

H

OEt

MgBrδδδδ

δδδδ

Br +

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REACTIONS OF GRIGNARDREACTIONS OF GRIGNARD REAGENTSREAGENTS

2. Addition to epoxides and to carbonyl groups (aldehydes, ketones, esters, CO2).

Experimental procedure

(i) A solution of the epoxide/aldhyde/ketone/

ester in anhydrous Et2O or THF is added

to the Grignard reagent in Et2O or THF.

(ii) After a short time, dilute acid or aqueous

NH4Cl (a proton source) is added to the

reaction mixture. The product of the

reaction is then isolated.

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2. (a) Addition to epoxides.Epoxides, also known as oxiranes, are three-membered cyclic compounds. The ring consists of two carbon atoms and one oxygen atom. The simplest epoxide is

ethylene oxide.

The carbons of the ring can bear substituents other than hydrogen, e.g.

The three-membered ring is highly strained, as the angles between the oxygen and carbon atoms are significantly less than the tetrahedral angle of ~ 109o. Epoxides therefore open readily, and are quite reactive.

CC

O

H

H

H

H

CC

O

H

H

CH3

H

8


2. (a) Addition to epoxides

n-octylmagnesium bromide + ethylene oxide

The product is a 1o alcohol. The carbon chain of the alcohol

is two carbons longer than the carbon chain of the alkyl group in the Grignard reagent.

Grignard reagents react with epoxides →→→→ 1o alcohols, with 2 carbon homologation.

HCCH3(CH2)6

HMg

CH2H2C

OHCCH3(CH2)6

HCH2-CH2-O-MgBr

HCCH3(CH2)6

HCH2-CH2-O-MgBr

(i)

δδδδ

HCCH3(CH2)6

H

δδδδ

(ii)

Br

CH2-CH2-O-HH3O

+ Mg(OH)Br

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2. Addition to carbonyl compounds

The difference in electronegativity between oxygen and carbon causes the carbon-oxygen bond of carbonyl groups to be polarized as shown.

The carbon atoms of carbonyl groups are ELECTROPHILIC, and will be attacked by the nucleophilic carbons of Grignard reagents.

C Oδδδδ δδδδ

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ALDEHYDES react with Grignard reagents to yield 2o

alcohols. An example is this reaction is shown.

n-octylmagnesium bromide + propanal

HCCH3(CH2)6

HMg

C O

H

CH3CH2HCCH3(CH2)6

HMg

C OH

CH3CH2

Br

HCCH3(CH2)6

H

δδδδ

+ Mg(OH)Br

C OH

δδδδ

Br

H

CH3CH2

H3O

δδδδ

(i)

(ii)

δδδδ

11



ALDEHYDES react with Grignard reagents to

yield 2o alcohols. The general reaction is:

KETONES add to Grignard reagents to produce 3o

alcohols. The general reaction is shown.

C O

R''

R'

δδδδ

R

MgC O

R''

R'X H3O(i) (ii)δδδδ

+ Mg(OH)X

R-MgX +

R

C OH

R''R'

C O

H

R'

δδδδ

R

MgC OHR'

X H3O(i) (ii)δδδδ

+ Mg(OH)X

R-MgX + R

C OHHR'

12



An example of the reaction between ketones and Grignard

reagents is the addition of

methylmagnesium bromide to 3-hexanone.

HCH

HMg

C O

CH3CH2

CH3CH2CH2H3C

Mg

C O

CH3CH2

CH3CH2CH2

I

H3C

C OH

CH3CH2

CH3CH2CH2 + Mg(OH)I

δδδδδδδδI

δδδδ

H3O

δδδδ

(ii)

(i)

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2. Addition to carbonyl compounds – esters

The addition of Grignard reagents to esters is illustrated

by the reaction between

ethyl acetate and n-propylmagnesium bromide.

δδδδ δδδδC O

CH3

CH3CH2O

HCCH3CH2

HMgδδδδδδδδ

C O

CH3

EtO

Br

ethyl acetate n-propylmagnesium bromide

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ethyl acetate+ n-propylmagnesium bromide

HCCH3CH2

HMg

C O

CH3

EtOC O

CH3

EtO

HC

CH3CH2 H

Mg

C O

CH3

EtO

PrMgBr

δδδδ

δδδδ

δδδδδδδδBr

Br

electrophilicfairly goodleaving group

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ethyl acetate+ n-propylmagnesium bromide

The initially formed adduct reacts with a second equivalent of the

Grignard reagent. After workup a 3o alcohol is obtained.

Two of the alkyl groups on the 3o alcohol are identical, and

originate from the Grignard reagent.

C O

CH3

EtO

Pr MgBr

HC CH2CH3H

Mg

C O

CH3

PrMgBrH

C CH2CH3H

C OH

CH3

Pr

Pr

δδδδBr

H3O

+ Mg(OH)Br+ EtOMgBr

16



carbon dioxide (dry ice or CO2 gas)

The addition of methylmagnesium iodide to CO2

is illustrative. The product is a carboxylic acid.

The general reaction is:

(i)

H3O(ii)

RMgX CO2 RCOOH + Mg(OH)X

HCH

HMg

C OOC O

O

H3CMg I

δδδδ

C OH

δδδδ

O

I

(i)

H3C

H3O+ Mg(OH)I(ii)

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CARBONYL COMPOUNDSCARBONYL COMPOUNDS1. Acyclic aldehydes and ketones with saturated

carbon chains have the general formula

CnH2nO. They contain the oxo,

or carbonyl group.

2. In aldehydes, one of the

available valencies of the carbonyl carbon is

occupied by a hydrogen, therefore the

aldehyde group always occurs at the end of a

chain.

3. In ketones, R and R’ are alkyl groups,

so the keto group occurs within a chain.

C O

C OR

H

C O

R

R'

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CARBONYL COMPOUNDSCARBONYL COMPOUNDS

4. Bonding

The carbonyl carbon is sp2 hybridized.

In a ketone, it is connected by

two σ (“sigma”) bonds to the

adjacent carbon atoms

by sp2 (C) – sp3 (C) overlap.

A third σ bond connects the

carbonyl carbon to the oxygen

atom by by sp2 (C) –2p (O) overlap.

The π bond is formed by 2p(C) – 2p(O) overlap.

Carbonyl groups are flat. The π electrons are above and below the trigonal plane formed by the sp2 orbitals of the carbonyl carbon.

C

C O

C

C

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6. The electronic configuration of oxygen is

1s2, 2s2, 2p4. Oxygen has six outer sphere electrons,

two of which are involved in covalent bonding to carbon;

the remaining four electrons comprise two unshared

(non-bonded) pairs.

7(a) Oxygen is much more electronegative than carbon.

The carbonyl group is ∴polarized.

C O

C Oδδδδ δδδδ

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7 (b) It is also possible to draw a dipolar resonance form of a carbonyl group.

The structures on either side of a straight

two-headed arrow are resonance forms of the same chemical entity; they differ only the location of electrons, and can be interconvertedby the movement of curly arrows.

A carbonyl group is a HYBRID of the two resonance forms shown.

C O C O

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8. As a result of the high electron density on

the oxygen atom of carbonyl groups,

carbonyl compounds participate in

hydrogen bonding with compounds which

contain active hydrogen.

Aldehydes and ketones of low molecular

weight are therefore soluble in water.

C

O

R R'

H O

H

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CARBONYL COMPOUNDS - nomenclature

To name an aldehyde using the IUPAC system,

the final ‘e’ in the name of the parent alkane is

replaced by ‘al’

C OCH3

H

C OC

H

HCl

H3C

CH3CH CHCHO

ethanal (acetaldehyde)

2-butenal

2-chloropropanal

23

CARBONYL COMPOUNDS - nomenclature

Ketones are named by replacing the ‘e’ in the

name of the parent alkane with ‘one’. If necessary,

the position of the oxo group is indicated by a number.

O

cyclohexanone

O

CCH3 CH2CH2CH3

2-pentanone

O

CCH3 CH3

propanone (acetone)

O

CCH3 CH2CH3

butanone(methyl ethyl ketone)

O

CCH3 C

2,4-pentanedionethe 'e' is retained in dione names

H

H

CCH3

O

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PREPARATION OF CARBONYL COMPOUNDSPREPARATION OF CARBONYL COMPOUNDS

A. Preparation of aldehydes

1.Aldehydes may be prepared by oxidation

of 1o alcohols

2.Reduction of acyl chloride yields aldehydes

H

CR OH

H

[O]C O

R

H

+ "2H"

1o alcohol aldehyde

C OR

Cl

an acyl chloride, also known asan acid chloride

+ "H " C OR

H

+ Cl

aldehyde

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PREPARATION OF ALDEHYDES

1. Oxidation of 1o alcohols: RCH2OH →→→→ RCHO

In general, aldehydes are more easily oxidized than

alcohols.

RCHO →→→→ RCOOH occurs more readily than

RCH2OH→→→→ RCHO.

Therefore, very mild oxidizing agents must by used for

the transformation RCH2OH →→→→ RCHO.

Examples of mild oxidizing agents are:

(a) chromium trioxide-pyridine complex,

CrO3.2py;

(b) manganese dioxide, MnO2

NCrO3 . 2

26

PREPARATION OF ALDEHYDESPREPARATION OF ALDEHYDES1. Oxidation of 1o alcohols: RCH2OH →→→→ RCHO

Mild oxidizing agents

are used.

You are not required to know the mechanisms of these

reactions.

With strong oxidizing agents, e.g. KMnO4, H2CrO4,

1o alcohols are oxidized to carboxylic acids.

H

CR OH

H

C OR

HCrO3.2py

H

CR OH

H

C OR

HMnO2

H

CR OH

H

C OR

HO

carboxylic acid

KMnO4

1o alcohol

27

PREPARATION OF ALDEHYDESPREPARATION OF ALDEHYDES

2. Reduction of acyl chlorides: RCOCl →→→→ RCHO

Lithium tri-t-butoxyaluminum hydride is often used for this reduction.

LiAlH[OC(CH3)3]3 or LiAlH(OtBu)3;

this is a mild hydride reducing agent.

O Al O

H

O

C C

C

CH3

H3C

CH3

CH3

CH3

CH3

H3C

CH3

CH3

Li

28

PREPARATION OF ALDEHYDESPREPARATION OF ALDEHYDES

2. Reduction of acyl chlorides .

A partial, simplified mechanism for this reaction:

C OR

Cl

C OR

H

LiAlH(OtBu)3

C OR

Cl

"H "

C OR

Cl H

Li C OR

H+ LiCl

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KNOWN AS GRIGNARD REAGENTS GRIGNARD REAGENTS … · Most reactions of Grignard reagents fall into ... Two of the alkyl groups on the 3 o alcohol are identical, ... aldehydes are more