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Organometallic
O
lli
Compounds
p
Organometallic
g
Compounds
p
• Organometallic compound: a compound that contains
a carbon-metal
carbon metal bond
• In this chapter, we focus on organometallic
compounds of Mg, Li, and Cu
– these classes illustrate the usefulness of
organometallics in modern synthetic organic
chemistry
– they illustrate how the use of organometallics can
bring about transformations that cannot be
accomplished
li h d in
i any other
h way
Organometallic Reagents
The Key Concepts:
y
p
Make a carbon negatively charged/polarlized so it is nucleophilic. h
d/ l li d it i
l
hili
Reaction with electrophilic carbons can p
make carbon‐carbon bonds.
This is a Big
g Deal!
The First Organometallic Reagents…
Grignard Reagents
• Discovered by Victor Grignard in 1900
– Key factors are ethereal solvent and water‐free conditions
t f
diti
• Awarded Nobel Prize in 1912
Victor Grignard
Grignard, Victor , 1871–1935, French chemist. He shared the 1912 Nobel Prize in Chemistry for his work in organic synthesis based on his discovery (1900) of the Grignard Reagent. He taught at the Univ. of Nancy (1909
Grignard Reagent.
He taught at the Univ. of Nancy (1909–19)
19) and at the Univ. of and at the Univ. of
Lyons (from 1919 until the end of his career). Grignard Reagents
• Grignard reagent: an organomagnesium
compound
– prepared by addition of an alkyl,
alkyl aryl,
aryl or alkenyl
(vinylic) halide to Mg metal in diethyl ether or
THF
Br
1B
1‐Bromobutane
b t
+ Mg
B + Mg
Br
M
Bromobenzene
ether
MgBr
B t l
Butylmagnesium bromide
i
b
id
(an alkyl Grignard reagent)
ether
et
e
M B
MgBr
Phenylmagnesium
bromide
(an aryl Grignard reagent)
An Alternative to Grignard
g
Reagents
g
are Alkyl
y Lithiums
Both are prepared from alkyl, vinyl, and aryl halides under anhydrous conditions
dry ether
+
B
Br
Mgo
n-butyl bromide
M B
MgBr
or
tetrahydrofuran
(THF)
recall: THF =
Grignard Reagent
O
dry ether
Br
n-butyl bromide
+
2 Lio
or
tetrahydrofuran
(THF)
Li
alkyl lithium
+ LiBr
Grignard and Organolithium Reagents
• Given the difference in electronegativity between carbon and magnesium (lithium), the δ‐ and Mg (C‐
g ( ‐Li) bond is polar covalent, with C
)
p
C‐Mg (C
Mgδ+ ( Liδ+ )
– Grignard
Grignard and organolithium reagents behave like and organolithium reagents behave like
carbanions
• Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge
δ-
δ-
δ+
Li
δ+
MgBr
Grignard Reagent
alkyl lithium
Grignard and Organolithium Reagents
• Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative g
charge
– Carbanions are strong bases
Carbanions are strong bases‐‐
‐‐they are easily they are easily q
quenched by even very weak acids (water, alcohols, y
y
(
amines, amides, carboxylic acids, even terminal alkynes). A limitation to utility!
alkynes). A limitation to utility!
pKa = ca. 50
δδ+
MgBr
Grignard
g
Reagent
g
+
δ- δ+
OH
pKa = 16
alkane corresponding
to original alkyl halide
+
O- MgBr+
Grignard and Organolithium Reagents
• Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative g
charge
– Carbanions are strong bases
Carbanions are strong bases‐‐
‐‐they are easily they are easily q
quenched by even very weak acids (water, alcohols, y
y
(
amines, carboxylic acids, amides, even terminal alkynes). A limitation to utility!
alkynes). A limitation to utility!
pKa = ca. 50
δδ+
Li
δ- δ+
NH2
+
alkane corresponding
to original alkyl halide
+
alkyl lithium
pKa = 40
NH- Li+
Limitations
• Can’t make Grignards with acidic or electro‐philic f
functional groups present in the molecule:
i
l
i h
l l
•
R2NH pKa 38‐40
Terminal Alkynes
Terminal Alkynes
pKa 25
ROH
pKa 16‐18
Carbonyls
& Nitros
pKa 11‐27
Grignard and Organolithium Reagents
• Carbanion: an anion in which carbon has
an unshared pair of electrons and bears a
g
charge
g
negative
– Carbanions are also great nucleophiles. This is
the reason for their g
great utility!
y
• Key Point: Grignard and Organolithium Reagents • Great nucleophiles that add efficiently to electrophilic carbons, such as epoxides and carbonyl group of aldehydes, ketones and esters However their basicity can be a
ketones and esters. However, their basicity can be a limitation!
• Epoxides illustrate how many common organic illustrate how many common organic
functional groups contain electrophilic carbons
Grignard and Organolithium Reagents
• Carbanions (nucleophiles) can react with electrophilic carbon centers in favorable cases. The net result is a carbon‐‐carbon bond
carbon
carbon bond‐‐
‐‐a big deal!
a big deal!
• Grignards and organolithium reagents react with many oxygen‐
oxygen
o
yge ‐co
containing electrophiles, but not with alkyl ta
g e ect op es, but ot t a y
halides.
We’llll illustrate this with epoxides.
illustrate this with epoxides
• We
• Recall, acidic protons will “kill” our reagents and/or won’t allow them to be generated in the first place
won’t allow them to be generated in the first place
Grignard reagents react productively with:
formaldehyde to give primary alcohols
aldehydes
ld h d to give
i secondary
d
alcohols
l h l
ketones to give tertiary alcohols
esters to ggive tertiary
y alcohols
CO2 to give acids
epoxides to give primary alcohols
The one we are
choosing for the sake
of initial illustration
Epoxides:
p
The Example
p We Want to Stress
New
C-C
bond
δ- MgBr
δ+
-
O
Considered
R t
Retrosynthetically:
+
OH
O MgBr H O+
3
Dilute
THF
OH
MgBr
+
O
Detailed Mechanism Highlighting Retention of Stereochemistry
New
C-C
bond
Key Points to Note:
Attack at least hindered carbon
M h i
Mechanism
iis SN2-like
lik iin iinitial
iti l step
t
Single enantiomeric product
Chiral center not affected byy reaction
Relief of ring strain helps drive reaction
H3O+ breaks up initial salt
Two More Examples of Additions to Epoxides
1.
δδ+
MgBr
O
δ-
New
CC
C-C
bond
δ+
2. HCl, H2O
OH
Grignard Reagent
1.
δδ+
Li
Organolithium Reagent
O
New
C-C
bond
δ-
OH
δ+
H
H
H
H
2. HCl, H2O
Note: Stereochemistry at
epoxide retained in product
Gilman Reagents
• Lithium diorganocopper reagents, known more
g
commonlyy as Gilman reagents
– prepared by treating an alkyl, aryl, or alkenyl
lithium compound with Cu(I) iodide
diethyl ether
2 CH3 CH2 CH2 CH2 Li + CuI
or THF
Butyllithium
Copper(I)
iodide
( CH3 CH2 CH2 CH2 ) 2 Cu - Li
Lithium dibutylcopper
Lithi
dib t l
(a Gilman reagent)
+
+ LiI
Gilman Reagents
• Coupling with organohalogen compounds
– form new carbon-carbon bonds by coupling with alkyl and
alkenyl chlorides, bromides, and iodides. (Note that this
doesn’t work with Grignard or organolithium reagents.
THEY ARE TOO BASIC AND DO E2 ELIMINATIONS.)
ELIMINATIONS )
R'Br
R
Br + R2 CuLiBr
d iethyl eth er
or THF
R'-R
R
R + RCu + LiBr
•Example
I
1 . Li,
Li pent ane
2 . CuI
2
1-Iod od ecane
d ie
i th
h yll ethe
h r
Br
or THF
2-Methyl-1-dodecen e
CuLi
New
C-C
bond
Gilman Reagents
– coupling with a vinylic halide is stereospecific; the
configuration of the carbon-carbon double bond is
retained
I +
t rans-1-Iodo-1-nonene
rans 1 Iodo 1 nonene
2
CuLi
Lithiu m
dib utylcopper
d iethyl eth er
or THF
New
C-C
C
C
bond
trans -5-Tridecen e
Gilman Reagents
• A variation on the preparation of a Gilman
g is to use a Grignard
g
reagent
g with a
reagent
catalytic amount of a copper(I) salt
CH3 (CH2 ) 7
(CH2 ) 7 CH2 Br
C C
H
H
(Z)-1-Bromo-9-octadecene
Cu+
THF
+ CH3 ( CH 2 ) 4 MgBr
CH3 (CH2 ) 7
(CH2 ) 1 2 CH3
C C
H
H
(Z)-9-Tricos ene
(Muscalu re)
Gilman Reagents
• Reaction with epoxides
– regioselective
g
ring
g opening
p
g ((attack at least
New
hindered carbon)
C-C
O
OH
bond
1 . ( CH 2 =CH) 2 CuLi
2 . H2 O,, HCl
S tyrene oxide
(racemic)
1-Ph enyl-3-buten-1-ol
(racemic)
Interim Summary of Introduction to y
Organometallic Reagents…
Organolithium reagents and Grignard reagents are very basic but also great nucleophiles. They react with
basic but also great nucleophiles. They react with epoxides at the less hindered site to give a two‐carbon chain extended alcohol. They do not couple with alkyl‐, aryl‐, or vinyl halides.
Gilman reagents react with epoxides as do organolithium reagents and Grignard reagents. H
However, they also add to alkyl‐, aryl‐, and vinyl halides th
l
dd t lk l
l
d i l h lid
to make new C‐C bonds.
Feeling Lost?
Fortunately, Dr. Iverson will
i be back on Monday!
Meanwhile….
Back to Grignard Reagents…
• Addition of a Grignard reagent to formaldehyde
followed by H3O+ gives a 1° alcohol
H
H
-
+
CH3CH2 MgBr
C O
H
-
THF
+
g
CH3CH2 C O MgBr
H
H3O
dil.
+
H
+2
CH3CH2 C OH + Mgg
H
• This sequence (mechanism) is general and important!
Gi
Grignard
dR
Reactions
ti
-
+
CH3CH2 MgBr
O C O
-
THF
+
CH3CH2 C O MgBr
O
H3O
+
dil
dil.
These are valuable and important reactions…
Please add to your card stock!
+2
CH3CH2 C OH + Mg
O
Grignard reagents react with esters
δ– R
R'
••
δ+ OCH
3
••
C
MgX O ••
••
R'
diethyl
ether
R
C
••
OCH3
••
•• O •• + MgX
•• –
but species formed is unstable p
and dissociates under the reaction conditions to form a ketone
Grignard reagents react with esters
δ– R
R'
••
δ+ OCH
3
••
C
R'
diethyl
ether
R
OCH3
••
•• O •• + MgX
•• –
MgX O ••
••
this ketone then goes on hi k
h
to react with a second mole of the Grignard
mole of the Grignard reagent to give a tertiary alcohol
C
••
–CH3OMgX
g
R
R'
C
O ••
••
Example
O
CHCOCH
OCH3
2 CH3MgBr + (CH3)2CHC
1. diethyl
y ether
2. H3O+
OH
(CH3)2CHC
CHCCH
CH3
CH3
(73
73%)
%)
Two of the groups attached to the h d
h
tertiary carbon come from the Grignard
from the Grignard reagent
Practice
OH
MgBr
O
+
H
H
Practice
OH
MgBr
O
+
O
MgBr
+
H
H
The Same Chemistry is seen With Organolithium Reagents
O
H2C
CHLi +
CH
1. diethyl ether
2. H3O+
CHCH
OH
CH2
(76
76%)
%)
Practice
O
OH
MgBr
+
O C O