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
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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
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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
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REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS
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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REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS
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
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REACTIONS OF GRIGNARD REAGENTS
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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REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS
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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REACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds
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
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REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds
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'
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REACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds
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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REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS
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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REACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds – esters
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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REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds – esters
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
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REACTIONS OF GRIGNARD REAGENTSREACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds
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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CARBONYL COMPOUNDSCARBONYL COMPOUNDS
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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CARBONYL COMPOUNDSCARBONYL COMPOUNDS
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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CARBONYL COMPOUNDSCARBONYL COMPOUNDS
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
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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
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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
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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
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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