Está en la página 1de 35

Organomagnesium (Grignard)

and organolithium reagents


Different polarization of non-metallic and
organometallic reagents

HO CH3 - I HO - CH3 + I
H3C H3C
H3C
H3N O H3N+ O H2N OH
H3C
H3C H3C

I - CH3 CH3 - M CH3 - CH3 + M + I


CH3
CH3
O CH3 - M O CH3 + M
CH3 CH3
Organometallic reagents (R-M) are not fully
ionic

Metal K Na Li Mg

% Ionic
Character 51 47 43 35

reactivity of organometallic reagents


Ethers are the only solvents for
organomagnesium (Grignard) reagents

X OEt2
Et2O
R - X + Mg RMgX Mg
R OEt2

X = I, Br, Cl

R = alkyl, aryl, alkenyl Et2O X R


Mg Mg
R X
OEt2
Generation of Grignard reagents by
metallation (hydrogen metal exchange)

1
RH + R1MgX RMgX + R H

R-C C-H + C2H5MgBr


R-C C-MgBr + C2H6

+ C2H5MgBr + C2H6
H H H MgBr
Reactivity: magnesium atom is transferred to a
more electronegative atom, as in metallation

ROH + R1MgX RO-MgX + R1H


R2NH + R1MgX R2N-MgX + R1H
R2CO + R1MgX R2R1C-O-MgX

then H+
+ n-BuMgBr n- C6H13OH
O
SN2-type (coupling) reactions
EtMgBr + Br + MgBr

EtO OEt + MgCl(OSO2OEt


MgCl + S
O 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 1,4-
addition to unsaturated carbonyl compounds
+ Et
+
then H
O EtMgBr OH
(from pure Mg)

Et Et
1) EtMgBr +
O 2) H+ O OH
1,4-addition 1,2-addition
EtMgBr
H+

Et 1) Me-I Et
MgBr
O 2) H+ O

intermediate enolate
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

R-Li
H
(any temperature)
N addition N
R
Li

LDA MeI
- 78 oC
N Li N Me
lithiation

LDA: lithium diisopropylamide Li N


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

Br Li
n-BuLi (1.0 equiv)
+ n-BuLi
o
S Et2O, -70 C S

n-BuLi (1.0 equiv)


o + n-BuLi
Br Et2O, -70 C
N N Li
Lithiation and complex induced proximity
effect (CIPE)

n-BuLi D 2O

S Li D
S S

Li
N n-BuLi N
S
O S
O
complex-induced proximity effect
Lithiation and CIPE (contd.)
1) LDA
2) Me3SiCl

N N SiMe3

Me3Si N OMe

N OMe
SiMe3
complex-induced
proximity effect
N OMe
CIPE (contd.)

OH
LDA Li
MeCHO Me
N Cl N Cl N Cl

complex-induced proximity effect


CIPE and transmetallation

t-BuOCOCOBu-t n-BuLi

N N N Li
H
BOC
t-BuO O
Low yield,
(BOC group) many byproducts

(n-Bu)3SnCl

n-BuLi
High yield,
high purity Li Sn(n-Bu)3
N N
BOC BOC
Synthesis of ketones

R Li
O- + R OLi
R-Li O=C=O R Li
O R OLi

H3O+

R
O + 2 LiOH
R
Reaction with unsaturated carbonyl
compounds

1) PhMgBr Ph O
+ Ph Ph
2) H
1,4-addition
O
Ph Ph

1) PhLi OH
2) H+ Ph
Ph
Ph
1,2-addition
Addition reaction to the formal C=N bond of
heteroaromatic compounds
O
Cl CN

N Cl CN
N H
N O
N Cl (DDQ)
N Cl then H2O H
S
N OH
Li Cl CN
S N
n-BuLi N
N Cl Cl CN
N
S OH
Br
S
Addition to heteroaromatic compounds
(contd.)

N Cl N
N
The addition reaction of organometallic reagents
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 Cu O-
R R
-RCu

R H+
O R O-
R2CuLi: reactions with acid chlorides and
epoxides

O Cl O Me

Me
1) (Me2C=CH)2CuLi
2) H+

Me
Me 1) Et2CuLi
OH
O 2) H+ Et
R2CuLi: coupling reactions

Bu2CuLi
C10H21Br C14H30
1-bromodecane tetradecane

Br Bu2CuLi
Drying of diethyl ether (ether or Et2O) and
tetrahydrofuran (THF) for organolithium reactions

EtOEt
diethyl ether O
terahydrofuran

O H2O
O Na
Na O2
Brown mixture
Ph Ph (metal) Ph Ph

benzophenone sodium benzophenone


(colorless) ketyl radical
(intensively violet)
The use of THF

THF must be used below 0 oC. The following reaction


occurs if the temperature is above oC:

n-Bu-Li
Li O
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
Cl CN
H
N N S
then H2O Cl CN
Cl HN N O
1 DDQ
2 Cl

Li OH
S
Cl CN
n-Bu-Li
Cl CN
OH
S
S
N N

Cl
3
Synthesis of 3-butylcyclohexanone

O
O O
H2O

Bu Bu
CuI 4
n-Bu-Li Bu2CuLi
Graduate Studies in Chemistry Competitive stipends and fellowships;
waived tuition; and assisted health
MS and PhD Programs offered in: insurance (PhDs supported: 82)

Analytical Ranked top 10 of 178 by National


Biological / Biochemical Research Council in Student support
and Outcomes and Faculty Diversity
Biophysical / Computational http://www.nap.edu/rdp/
Organic / Medicinal
Masters program ranked number 9 in
the United States (number one in the
For more information: Southeast) by the American Chemical
www.chemistry.gsu.edu Society for MS degrees conferred in
chegsc@langate.gsu.edu 2008-2009
http://pubs.acs.org/cen/email/html/8834acsnews1.html
32
Center for Diagnostics and
Therapeutics

33
34
35