Download GRIGNARD REAGENTS

GRIGNARD 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.
CH3CH2 O CH2CH3
diethyl ether
O
tetrahydrofuran
(THF), a cyclic ether
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GRIGNARD 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
Et
they have been prepared.
O Et
R
Mg
X
O Et
Et
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REACTIONS 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
EPOXIDE
O
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.
H
H
δ
C
δ
MgBr
H
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.
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REACTIONS 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:
O
H
H
CH3(CH2)6
C
Hδ
H
H
Mg Br
δ
CH3(CH2)6
H
O
H
CH + MgBr
A similar reaction occurs with alcohols, e.g. ethanol:
O
H
H
CH3(CH2)6
C
δ
H
Et
H
Mg Br
δ
What would the reaction be with D2O?
CH3(CH2)6
H
O
Et
CH + MgBr
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REACTIONS OF GRIGNARD REAGENTS
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
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reaction is then isolated.
REACTIONS 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. H
H
C C
H
O H
The carbons of the ring can bear substituents other than
hydrogen, e.g.
H
CH
H
C C
O H
3
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
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open readily, and are quite reactive.
REACTIONS OF GRIGNARD REAGENTS
2.
(a)
Addition to epoxides
n-octylmagnesium bromide + ethylene oxide
H2C CH2
O
H
(i) CH3(CH2)6 C
Mg Br
Hδ
δ
H
CH3(CH2)6 C CH2-CH2-O-MgBr
H
H
H3O
(ii) CH3(CH2)6 C CH2-CH2-O-MgBr
H
H
CH3(CH2)6 C CH2-CH2-O-H
H
+ Mg(OH)Br
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.
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REACTIONS 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.
δ
C
δ
O
The carbon atoms of carbonyl groups are
ELECTROPHILIC, and will be attacked by the
nucleophilic carbons of Grignard reagents.
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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
H
CH3CH2
H
CH 3(CH 2)6 C
Hδ
δ
C
H
δ
O
(i)
CH3CH2 C
H
CH 3(CH2)6
Mg Br
δ
H
CH3CH2 C
H
CH 3(CH2)6
C
H
O
OH
C Mg Br
H
(ii) H3O
+ Mg(OH)Br
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REACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds
ALDEHYDES react with Grignard reagents to
yield 2o alcohols. The general reaction is:
H
R-MgX +
R'
δ
C
δ
O
R' H
C O Mg X
R
(i)
(ii) H3O
R' H
C OH
R
+ Mg(OH)X
KETONES add to Grignard reagents to produce 3o
alcohols. The general reaction is shown.
R''
R-MgX +
R'
R''
δ
C
δ
O
(i)
R'
R
C O Mg X
R''
(ii) H3O
R'
C OH
R
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+ Mg(OH)X
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.
CH3CH2
δ
δ
C
O
CH3CH2CH2
H
H C
Mg I
Hδ
δ
CH3CH2
(i)
CH3CH2CH2 C
H3C
O
Mg
(ii) H3O
CH3CH2
CH3CH2CH2 C OH + Mg(OH)I
H3C
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I
REACTIONS 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.
CH3
δ
C
CH3CH2O
δ
O
CH3
C
EtO
ethyl acetate
O
H
CH3CH2 C MgBr
Hδ δ
n-propylmagnesium bromide
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REACTIONS OF GRIGNARD REAGENTS
2. Addition to carbonyl compounds – esters
ethyl acetate+ n-propylmagnesium bromide
CH3
δ
O
δ C
EtO
H
CH3CH2 C
Mg Br
δ
H
δ
CH3
CH3
EtO C
H
C
CH3CH2 H
O
C
EtO
MgBr
Pr
O
MgBr
electrophilic
fairly good
leaving group
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REACTIONS 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.
CH3
CH3
EtO
C
Pr
Br
O
MgBr
H
Mg
C CH2CH3
δ H
O
H3O
H MgBr
C CH2CH3
H
+ EtOMgBr
Pr
C
CH3
Pr C OH
Pr
+ Mg(OH)Br
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REACTIONS 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.
O
C
O
H
H
C
Hδ
Mg I
δ
O
O
(i)
C
H3C
O
Mg I
(ii) H3O
C
OH
+ Mg(OH)I
H3C
The general reaction is:
RMgX
(i) CO2
(ii) H3O
RCOOH + Mg(OH)X
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CARBONYL COMPOUNDS
1. Acyclic aldehydes and ketones with saturated
carbon chains have the general formula
CnH2nO. They contain the oxo,
C O
or carbonyl group.
R
C O
2. In aldehydes,
one of the
H
available valencies of the carbonyl carbon is
occupied by a hydrogen, therefore the
aldehyde group always occurs at the end of a
chain.
R
3. In ketones, R' C O R and R’ are alkyl groups,
so the keto group occurs within a chain.
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CARBONYL COMPOUNDS
4.
C
Bonding
The carbonyl carbon is sp2 hybridized.
C
In a ketone, it is connected by
two σ (“sigma”) bonds to the
C
adjacent carbon atoms
O
by sp2 (C) – sp3 (C) overlap.
A third σ bond connects the
C
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.
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CARBONYL 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;
C
O
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
δ
O
δ
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CARBONYL COMPOUNDS
7 (b) It is also possible to draw a dipolar
resonance form of a carbonyl group.
C
O
C
O
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 interconverted
by the movement of curly arrows.
A carbonyl group is a HYBRID of the two
resonance forms shown.
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CARBONYL 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.
O
H
H
C
R
O
R'
Aldehydes and ketones of low molecular
weight are therefore soluble in water. 21
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’
CH3
C O
ethanal (acetaldehyde)
H
Cl
H3C
H
C
2-chloropropanal
C O
H
CH3CH CHCHO 2-butenal
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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
CH 3
cyclohexanone
CH 3
O
C
CH 2CH 2CH 3
2-pentanone
O
O
C
C
CH 2CH 3
butanone
(methyl ethyl ketone)
CH 3
O
C
CH 3
CH 3
propanone
(acetone)
O
H
C
CH 3
C
H
2,4-pentanedione
the 'e' is retained in dione names
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PREPARATION OF CARBONYL COMPOUNDS
A. Preparation of aldehydes
1.Aldehydes may be prepared by oxidation
H
H
of 1o alcohols
[O]
R
C OH
H
C O + "2H"
R
1o alcohol
aldehyde
2.Reduction of acyl chloride yields aldehydes
R
R
C O + "H "
Cl
an acyl chloride,
also known as
an acid chloride
C O + Cl
H
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
→ RCHO.
RCH2OH→
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 . 2
CrO3.2py;
(b) manganese dioxide, MnO2
N
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PREPARATION OF ALDEHYDES
1.
Oxidation of 1o alcohols: RCH2OH → RCHO
H
Mild oxidizing agents
CrO3.2py
R C OH
are used.
H
R
H
C OH
MnO2
H
C O
R
H
C O
R
H
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.
R
H
C OH
H
1o alcohol
KMnO 4
R
C O
HO
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carboxylic acid
PREPARATION OF ALDEHYDES
2. Reduction of acyl chlorides: RCOCl → RCHO
Lithium tri-t-butoxyaluminum hydride is often used
for this reduction.
CH3
H3C C O
H
Li
CH3
Al O C CH3
O
CH3
CH3
H3C C CH3
CH3
LiAlH[OC(CH3)3]3 or LiAlH(OtBu)3;
this is a mild hydride reducing agent.
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PREPARATION OF ALDEHYDES
2. Reduction of acyl chlorides
R
LiAlH(OtBu)3
C O
.
R
C O
H
Cl
A partial, simplified mechanism for this reaction:
R
C
Cl
R
O
C
Cl
H
O Li
R
C O
H
+ LiCl
"H "
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