Transcript ac nancy

Organometallic
Compounds
B.Sc. III
Organic Chemistry
Organometallic Compounds
• Organometallic compound: a compound that contains
a carbon-metal bond
• In this chapter, we focus on organometallic
compounds of Mg, Li, and Zn
– 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 in any other way
Organometallic Reagents
The Key Concepts:
Make a carbon negatively
charged/polarlized so it is nucleophilic.
Reaction with electrophilic carbons
can make carbon-carbon bonds.
This is a Big Deal!
The First Organometallic Reagents…
Grignard Reagents
• Discovered by Victor Grignard
in 1900
– Key factors are ethereal solvent
and water-free conditions
• 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 (1909–19)
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, aryl, or alkenyl
(vinylic) halide to Mg metal in diethyl ether or
THF
Br
+ Mg
1-Bromobutane
Br + Mg
Bromobenzene
ether
MgBr
Butylmagnesium bromide
(an alkyl Grignard reagent)
ether
MgBr
Phenylmagnesium
bromide
(an aryl Grignard reagent)
An Alternative to Grignard Reagents are Alkyl Lithiums
Both are prepared from alkyl, vinyl, and aryl halides under anhydrous conditions
dry ether
+
Br
Mgo
n-butyl bromide
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 C-Mg (C-Li) bond is polar covalent, with
C- and Mg+ ( Li+ )
– Grignard and organolithium reagents behave
like carbanions
• Carbanion: an anion in which carbon has an
unshared pair of electrons and bears a negative
charge


-
-
+
Li
+
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 charge
– Carbanions are strong bases--they are easily
quenched by even very weak acids (water,
alcohols, amines, amides, carboxylic acids,
even terminal alkynes). A limitation to utility!
pKa = ca. 50
+
MgBr
Grignard Reagent
+
- +
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 charge
– Carbanions are strong bases--they are easily
quenched by even very weak acids (water,
alcohols, amines, carboxylic acids, amides,
even terminal alkynes). A limitation to utility!
pKa = ca. 50
+
Li
-  +
NH2
+
alkane corresponding
to original alkyl halide
+
alkyl lithium
pKa = 40
NH- Li+
Limitations
• Can’t make Grignards with acidic or electrophilic functional groups present in the molecule:
•
R2NH
pKa 38-40
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
negative charge
– Carbanions are also great nucleophiles. This is
the reason for their great utility!
• 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 limitation!
• Epoxides 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--a big deal!
• Grignards and organolithium reagents react with
many oxygen-containing electrophiles, but not with
alkyl halides.
• We’ll illustrate this with epoxides.
• Recall, acidic protons will “kill” our reagents and/or
won’t allow them to be generated in the first place
Grignard reagents react productively with:
formaldehyde to give primary alcohols
aldehydes to give secondary alcohols
ketones to give tertiary alcohols
esters to give tertiary alcohols
CO2 to give acids
epoxides to give primary alcohols
The one we are
choosing for the sake
of initial illustration
Epoxides: The Example We Want to Stress
New
C-C
bond
- MgBr
+
-
O
Considered
Retrosynthetically:
+
OH
O MgBr H O+
3
Dilute
THF
OH
MgBr
+
These is an extremely valuable reaction…
O
A Related Example
Detailed Mechanism Highlighting Retention of Stereochemistry
New
C-C
bond
Key Points to Note:
Attack at least hindered carbon
Mechanism is SN2-like in initial step
Single enantiomeric product
Chiral center not affected by reaction
Relief of ring strain helps drive reaction
H3O+ breaks up initial salt
Two More Examples of Additions to Epoxides
1.
+
MgBr
O
-
New
C-C
bond
+
2. HCl, H2O
OH
Grignard Reagent
1.
+
Li
Organolithium Reagent
O
New
C-C
bond
-
OH
+
H
H
H
H
2. HCl, H2O
Note: Stereochemistry at
epoxide retained in product
Gilman Reagents
• Lithium diorganocopper reagents, known more
commonly 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
(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.)
R'Br + R2 CuLiBr
diethyl ether
or THF
R'-R + RCu + LiBr
•Example
I
1 . Li, pent ane
2 . CuI
2
1-Iod od ecane
d ie th yl ethe 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
2
CuLi
Lithiu m
dib utylcopper
d iethyl eth er
or THF
New
C-C
bond
trans -5-Tridecen e
Gilman Reagents
• A variation on the preparation of a Gilman
reagent is to use a Grignard reagent with a
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 ( CH2 ) 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 ring opening (attack at least
New
hindered carbon)
C-C
O
OH
bond
1 . ( CH2 =CH) 2 CuLi
2 . H2 O, HCl
S tyrene oxide
(racemic)
1-Ph enyl-3-buten-1-ol
(racemic)
Interim Summary of Introduction to
Organometallic Reagents…
Organolithium reagents and Grignard reagents are
very 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.
However, they also add to alkyl-, aryl-, and vinyl
halides to make new C-C bonds.
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
+
CH3CH2 C O MgBr
H
H3O
dil.
+
H
+2
CH3CH2 C OH + Mg
H
• This sequence (mechanism) is general and important!
Grignard Reactions
CH3CH2
+
MgBr
O C O
-
THF
+
CH3CH2 C O MgBr
O
H3O
+
dil.
These are valuable and important reactions…
Please add to your card stock!
+2
CH3CH2 C OH + Mg
O
Grignard reagents react with esters
– R
R'
••
+ OCH
3
••
C
MgX O ••
••
R'
diethyl
ether
R
C
••
OCH3
••
• O • + MgX
• •• •–
but species formed is
unstable and dissociates
under the reaction
conditions to form a ketone
Grignard reagents react with esters
– R
R'
••
+ OCH
3
••
C
R'
diethyl
ether
R
OCH3
••
• O • + MgX
• •• •–
MgX O ••
••
this ketone then goes on
to react with a second
mole of the Grignard
reagent to give a tertiary
alcohol
C
••
–CH3OMgX
R
R'
C
O ••
••
Example
O
2 CH3MgBr + (CH3)2CHCOCH3
1. diethyl ether
2. H3O+
OH
(CH3)2CHCCH3
CH3
(73%)
Two of the groups
attached to the
tertiary carbon
come 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
H2 C
CHLi +
CH
1. diethyl ether
2. H3O+
CHCH
OH
CH2
(76%)
Practice
O
OH
MgBr
+
O C O
Other Organometallic Reagents
We can also make R-Zn, R-Sb, R-As, R-Be,
R-Ca, R-Hg, R-Sn,
… reagents. We choose other metals for different degrees of
reactivity and for greater selectivity.
CH3 CH2 I
+
Zn
ether
CH3 CH2 Zn
Organozinc reagents are used in synthesis owing to their greater
selectivity (see J. Vyvyan)
• The first organozinc ever prepared = diethylzinc (Et2Zn), by Edward
Frankland in 1849, was also the first ever compound with a metal to carbon
sigma bond.
• Many organozinc compounds are pyrophoric and therefore difficult to handle.
• Organozinc compounds in general are sensitive to oxidation, dissolve in a
wide variety of solvents where protic solvents cause decomposition.
• In many reactions they are prepared in situ. All reactions require inert
atmosphere: N2 or Ar
• The three main classes of organozincs are: organozinc halides R-Zn-X
with, diorganozincs R-Zn-R, and lithium zincates or magnesium zincates
M+R3Zn- with M = lithium or magnesium Organozinc
Preparations
• Primary and secondary alkylzinc iodides (RZnI) are best prepared by direct
insertion of zinc metal (zinc dust activated by 1,2-dibromoethane or
chlorotrimethylsilane) into alkyl iodides or by treating alkyl iodides with Rieke
zinc. The zinc insertion can tolorate a lot of functional groups, allowing
preparation of polyfunctional organozinc reagents.
Unfunctionalized dialkylzincs (R2Zn) are obtained by transmetalation of zinc
halides, such as ZnCl2, with organolithium or Grignard reagents.
• Iodide-zinc exchange reactions catalyzed by CuI provide a practical way
for preparing functionalized dialkylzincs.
• Diorganozincs are always monomeric, the organozinc halides
form aggregates through halogen bridges
Dialkylzinc (R2Zn)
• Alkyl group exchange between diethylzinc and diiodomethane produces the
iodomethyl zinc carbenoid species, tentatively assigned as EtZnCH2I
(Furukawa’s reagent).
•oxidative addition of Zn metal to diiodomethane affords an iodomethylzinc
iodide, tentatively assigned as ICH2ZnI (Simmons-Smith reagent), which is
used for cyclopropanation of alkenes.
Reaction of Organozinc compounds
The Reformatsky Reaction
• involves condensation of ester-derived zinc enolates with aldehydes or
ketones to give corresponding β-hydroxy esters.
• zinc enolates are generated by addition of an α-haloester in THF, DME,
Et2O, benzene, or toluene to an activated zinc, such as a Zn-Cu couple or
zinc obtained by reduction of zinc halides with potassium (Rieke zinc).
Reactions of functionally substituted RZnI
• application of functionally substituted organozincs allows for
construction of C-C bonds while circumventing tedious protection-
deprotection strategies.
Reactions of functionally substituted RZnI
Note that tosyl cyanide reacts with alkenyl or arylzinc reagents
to provide α,β-unsaturated alkenyl or aromatic nitriles, respectively
Reaction of Organozinc compounds
Cyclopropanation
• Cyclopropane rings are encountered in many natural products
possessing interesting biological activities.
• Cyclopropane moiety represents a useful synthon for further
synthetic transformations.
• In 1958, Simmons and Smith reported that treatment of a zinccopper
couple with diiodomethane in ether produces a reagent that adds to
alkenes to form cyclopropanes.
The cyclopropanation reaction of simple alkenes appears to proceed via
stereospecific syn-addition of a Zn-carbenoid (carbene-like species)
to the double bond without the involvement of a free carbene.
stereospecific syn-addition of Zn-carbenoid to the double bond
Cyclopropanation modifications of Simmons-Smith :
• Furukawa’s reagent, (iodomethyl)zinc derived from diethylzinc and
diiodomethane, or its modification using chloroiodomethane instead of
diiodomethane, allows more flexibility in the choice of solvent.
• The reagent is homogeneous and the cyclopropanation of olefins can be
carried out in noncomplexing solvents, such as dichloromethane or 1,2dichloroethane, which greatly increase the reactivity of the zinc carbenoids.
Directed Simmons-Smith Cyclopropanation
• A particularly interesting aspect of the Simmons-Smith
reaction is the stereoelectronic control exhibited by proximal
OH, OR groups, which favor cyclopropanation to occur from
the same face of the double bond as the oxy substituents.
• order of decreasing directive effects : OH > OR > C=O