Organomagnesium (Grignard) and organolithium reagents

Organomagnesium (Grignard) and organolithium reagents

Organomagnesium (Grignard)
and organolithium reagents
Different polarization of non-metallic and
organometallic reagents
H3N
H3C
H3C
H3C
H3N+
O
H3C
O
H2N
H3C
I - CH3
O
HO - CH3 + I
CH3 - I
HO
CH3
CH3
CH3 - M
CH3 - M
H3C
CH3 - CH3 + M +
O
CH3
CH3
CH3
I
+ M
OH
Organometallic reagents (R-M) are not fully
ionic
Metal
K
Na
Li
Mg
% Ionic
Character
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reactivity of organometallic reagents
Ethers are the only solvents for
organomagnesium (Grignard) reagents
R - X + Mg
RMgX
Et2O
OEt2
X
Mg
R
OEt2
X = I, Br, Cl
R = alkyl, aryl, alkenyl
Et2O
X
Mg
R
R
Mg
X
OEt2
Generation of Grignard reagents by
metallation (hydrogen – metal exchange)
RH + R1MgX
1
RMgX + R H
R-C C-H + C2H5MgBr
R-C C-MgBr + C2H6
+ C2H5MgBr
H
H
+
H
MgBr
C2H6
Reactivity: magnesium atom is transferred to a
more electronegative atom, as in metallation
• ROH + R1MgX → RO-MgX + R1H
• R2NH + R1MgX → R2N-MgX + R1H
• R2C═O + R1MgX → R2R1C-O-MgX
+ n-BuMgBr
O
then H+
n- C6H13OH
SN2-type (coupling) reactions
Br
EtMgBr +
MgCl +
EtO
O
S
+ MgBr
OEt
+
MgCl(OSO2OEt
O
C5H11-n
MgCl + n-Bu-O-SO2-
Me
+ MgCl(OTs)
Br
Me
Me
Me
Me
Me
1) Mg
2) (MeO)2SO2
Me
Me
+ MgBr(OSO2OMe)
Transition metal ion (e.g. CuBr) mediated 1,4addition to unsaturated carbonyl compounds
O
+
then H
EtMgBr
Et
+
OH
(from pure Mg)
1) EtMgBr
O 2) H+
Et
Et
O
+
1,4-addition
EtMgBr
Et
O
MgBr
intermediate enolate
OH
1,2-addition
H+
1) Me-I
2) H+
Et
O
Organolithium reagents
•
•
Methyllithium CH3-Li
(MeLi)
a strong base and a strong nucleophile
•
•
n-Butyllithium n-C4H9-Li
(n-BuLi)
a strong base and a strong nucleophile
•
•
t-Butyllithium Me3C-Li
(t-BuLi)
a strong base and a strong nucleophile
•
basicity increases in the following order:
•
MeLi < n-BuLi < t-BuLi
Basicity vs. nucleophilicity
•
A basic reagent has a strong
•
affinity for proton (e.g. removal
of proton from a C-H moiety
A nucleophilic reagent has a
strong affinity for carbon in the
molecule (e.g. SN2 reaction at
the carbon atom)
Phenyllithium C6H5-Li
(PhLi)
a strong base and a strong nucleophile
Lithium diisopropylamide
iPr2N-Li (LDA)
a strong base and a relatively weak nucleophile
LDA: lithium diisopropylamide
Li
N
Alkyllithium and aryllithium reagents are strongly basic and
strongly nucleophilic, while lithium amide reagents are
strongly basic and relatively non-nuleophilic
N
R-Li
(any temperature)
addition
H
N
R
Li
MeI
LDA
- 78 oC
lithiation
N
Li
LDA: lithium diisopropylamide
N
Li
N
Me
Generation of organolithium reagents
•
RCl + 2Li
RLi + LiCl
the reaction of alkyl halides with
lithium metal
•
RLi + R1X
R1Li + RX
lithium – halogen exchange in the
reaction of an alkyllithium reagent
and an alkyl halide,
X = I or Br
•
RLi + R1H
RH + R1Li
lithium – hydrogen exchange in
the reaction of an organolithium
reagent with a relatively acidic
hydrocarbon portion of a molecule
(lithiation)
Lithium – halogen exchange
Li
Br
n-BuLi (1.0 equiv)
+ n-BuLi
o
Et2O, -70 C
S
S
n-BuLi (1.0 equiv)
N
Br
+ n-BuLi
o
Et2O, -70 C
N
Li
Lithiation and complex – induced proximity
effect (CIPE)
n-BuLi
S
D 2O
S
Li
S
Li
N
n-BuLi
S
O
complex-induced proximity effect
N
S
O
D
Lithiation and CIPE (contd.)
1) LDA
2) Me3SiCl
N
N
SiMe3
Me3Si
N
N
OMe
SiMe3
complex-induced
proximity effect
N
OMe
OMe
CIPE (contd.)
OH
Li
LDA
N
Cl
N
Cl
complex-induced proximity effect
MeCHO
Me
N
Cl
CIPE and transmetallation
n-BuLi
t-BuOCOCOBu-t
N
H
N
t-BuO
Li
N
BOC
O
Low yield,
many byproducts
(BOC group)
(n-Bu)3SnCl
n-BuLi
High yield,
high purity
N
BOC
Li
N
BOC
Sn(n-Bu)3
Synthesis of ketones
R Li
R-Li O=C=O
R
O- +
Li
O
R OLi
R OLi
H3O+
R
R
O + 2 LiOH
Reaction with unsaturated carbonyl
compounds
1) PhMgBr
2) H
+
Ph O
Ph
Ph
1,4-addition
O
Ph
Ph
1) PhLi
2) H+
OH
Ph
Ph
Ph
1,2-addition
Addition reaction to the formal C=N bond of
heteroaromatic compounds
O
N
N
N
H
N
Cl
then H2O
S
N
CN
Cl
CN
O
Cl
(DDQ)
OH
Li
S
n-BuLi
N
S
N
H
Cl
CN
Cl
CN
N
N
N
S
Br
Cl
Cl
OH
Addition to heteroaromatic compounds
(contd.)
N
N
Cl
N
The addition reaction of organometallic reagents
N
Organocopper (RCu) and lithium
organocuprates (R2CuLi)
• MeLi + CuI → MeCu + LiI
colorless
yellow
• MeLi + MeCu → Me2CuLi
colorless
1,4-addition reaction of R2CuLi
(not reactive enough for a 1,2-addition)
R
R
Cu-
O
R
R
R
Cu
O-RCu
O
H+
R
O-
R2CuLi: reactions with acid chlorides and
epoxides
O
Cl
O
1) (Me2C=CH)2CuLi
Me
Me
2) H+
Me
Me
O
1) Et2CuLi
2) H+
OH
Et
R2CuLi: coupling reactions
C10H21Br
Bu2CuLi
tetradecane
1-bromodecane
Br
C14H30
Bu2CuLi
Drying of diethyl ether (ether or Et2O) and
tetrahydrofuran (THF) for organolithium reactions
EtOEt
diethyl ether
O
Ph
O
terahydrofuran
O Na
Na
Ph
benzophenone
(colorless)
(metal)
Ph
Ph
sodium benzophenone
ketyl radical
(intensively violet)
H2O
O2
Brown mixture
The use of THF
THF must be used below 0 oC. The following reaction
occurs if the temperature is above oC:
n-Bu-Li
O
Li
O
OLi
enolate
ethylene
Titration of organolithium reagents
RLi
CH COOH
CH COO_ Li+
colorless
diphenylacetic acid
RLi
Li
C
COO_ Li+
yellow
Synthesis of 2-chloro-4-(2-thienyl)pyrimidine
O
N
CN
Cl
CN
H
N
then H2O
Cl
1
S
Cl
S
HN
2
O
DDQ
N
Cl
OH
Li
Cl
CN
Cl
CN
n-Bu-Li
S
OH
S
N
N
Cl
3
Synthesis of 3-butylcyclohexanone
O
O
H2O
O
Bu
n-Bu-Li
CuI
Bu2CuLi
Bu
4
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