· 2019-03-09 · 1 organometallic chemistry organometallic reagents play a key role in...
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Organometallic Chemistry (Part-I)
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Organometallic Chemistry
Organometallic reagents play a key role in carbon-carbon bond forming
reactions which are the backbone of organic synthesis. The reactivity of an
organometallic reagent generally increases with the ionic character of the
carbon-metal bond and is related to the electronegativity. It means difference
between the carbon atom and the metal centre.
The percent ionicity (ionic character) is related to the difference between the
electronegativity values of the atoms of the C-Metal bond. These are estimated
values, which are affected by the nature of the substituents on carbon.
Nevertheless, they indicate that the C-Li, C-Mg, C-Ti, and C-A1 bonds are more
ionic than C-Zn, C-Cu, C-Sn, and C-B, which form mainly covalent bonds with
carbon. Manipulation of certain organometallic reagents requires special
technique.
Electronegativity values and Ionic characters Element Li Mg Ti Al Zn Cu Si Sn B C
Electronegativity
0.97
1.23
1.32
1.47
1.66
1.75
1.74
1.72
2.01
2.50
% Ionicity 43 35 30 22 15 12 12 11 6
Organolithium Reagents
Organolithium reagents react with a wide variety of organic substrates to form
carbon-carbon bonds and serve as precursors for the preparation of other
organometallic reagents.
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Preparation of the Organolithium reagents
1. Organolithium from Alkyl halide and Lithium metals:
The scope of this method is broad and is especially suited for the preparation of
alkyl-Halides and Lithium Metal and aryllithiums. It is, however, less general than
the corresponding method for preparing Grignard reagents in that allylic,
benzylic, and propargylic halides cannot be successfully converted into the
corresponding organolithiums because they tend to undergo Wurtz coupling, in
which the lithium reagents initially formed react competitively with the R-X to
produce homocoupled products.
2Li LiI
2Li
LiI
Important points to consider when preparing and using organolithiums are:
✓ Atmosphere: Reactions with organolithium compounds must be carried out
in an inert atmosphere (Argon and Helium are best; Nitrogen tarnishes
lithium metal by forming lithium nitride).
✓ Nature of the halide: Bromides generally are best; iodides have a tendency
to undergo the Wurtz reaction. With chlorides, use Li containing 1-2% Na.
✓ Purity and physical state of the metal: The metal surface should be clean
and have a large surface area. Li wire typically is flattened with a hammer
and then cut into small pieces. Li dispersions in mineral oil may be employed
in place of Li wire. The oil is removed by washing with hydrocarbon solvents
such as n-hexane.
✓ Solvent: Most R-Li reagents are prepared in hydrocarbon solvents. However,
phenyllithium, methyllithium, and vinyllithiumn, which are almost insoluble
in hydrocarbon solvents, are quite soluble in Et2O.
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n-BuLi, sec-BuLi, and t-BuLi react at room temperature with Et2O and THF, so
they must be used at low temperature in these solvents.
✓ Analysis of organolithium reagents: Many procedures are reported for the
analysis of organometallic reagents. Out of that, titration of the
organolithium reagent with the 1M solution of 2 butanol in xylene in
presence of 2, 2 bipyridyl as a catalyst was used in toluene at room
temperature. We can easily determine the strength of the reagent before
use.
✓ Organolithium aggregation: Organolithium associate in solution to form
oligomeric species in which the monomeric units are held together via
multicentre bonding. Coordinating solvents such as Et2O and THF influence
their aggregation and reactivity.
MeLi in Et2O – tetrameric nBuLi in hexane – hexameric
in THF – tetrameric in THF tetrameric + dimeric
✓ Reactivity: The basicity of organolithium reagents decreases with increasing
stability of the carbanion moiety (e.g., t-BuLi > s-BuLi > n-BuLi).
Organolithium reagents exhibit reactivities similar to those of Grignard
reagents, with the notable exception that they react with CO2 to produce
ketones on workup, whereas Grignard reagents furnish carboxylic acids.
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Working at lower temperature or generating the organolithium in the presence
of the electrophile (Barbier-type reaction) are the good conditions for the
preparation of functionally substituted organolithiums to overcome the issue of
high reactivity of the organolithiums.
2. Organolithium via Lithium Halogen Exchange
This reaction proceeds in the forward direction when the new lithium reagent
RLi formed is a weaker base (more stable carbanion) than the starting
organolithium R'Li. The method is best suited for exchanges between Csp3-Li
(stronger base) and Csp2-X to give alkenyllithiums, Csp2Li (weaker base).
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A problem encountered in the preparation of alkenyllithiums via lithium-
halogen exchange may be the coupling of the newly formed alkyl halide (e.g. n-
BuBr) with the alkenyl lithium.
n-BuLiTHF
-78 °C
n-BuBr
The alkylation problem can be circumvented by using two equivalents of t-BuLi.
The second equivalent of t-BuLi is involved in the dehydrohalogenation (E2
reaction) of the t-BuBr formed in situ.
t-BuLi
Pentane
THF
-78 °C
t-BuBr
(1st eq)
t-BuLi
(2nd eq)
E+
3. Aryl lithium Reagents
Metal-halogen exchange is the alternative on metal-hydrogen exchange and
which serves the more selectivity. The lithium-halogen exchange reaction is very
fast, even at low temperatures, particularly in electron donating solvents.
Therefore, competitive alkylation and metal-hydrogen exchange (metalation)
reactions are usually not a problem. Caution should be used when employing
TMEDA (tetramethyl ethylene diamine) as a promoter for metal-halogen
exchange reactions, since it accelerates metalations more than it does metal-
halogen exchange.
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nBuH
n-BuLi
metalation
slow
n-BuLi
metal halogen
exchane
fast nBuBr
4. Organolithiums via Lithium-Metal Exchange Allylic, Benzylic, and Propargylic lithium reagents can be synthesized by Trans
metalation more easily than the other methods. The allylic Grignard reagent into
the corresponding allylic lithium reagent involves two metal-metal exchanges.
These reactions proceed in the forward direction because
(1) In the Mg-Sn exchange, the more electropositive Mg preferentially exists as
the more ionic salt MgBrCl, and
(2) In the Sn-Li exchange, the more electropositive Li is associated with the more
electronegative allylic ligand.
ENMg=1.23
Ph3SnCl
THF
-MgBrClENSn=1.72
PhLi
ENSn=1.72
Ph4Sn
(ppt)
5. Organolithium via Lithium-Hydrogen Exchange (Metalation) Metal-hydrogen exchange provides a universal route to organo lithium
compounds. The tendency to form the C-Li bond depends on the stability of the
R group as a negative ion. The most important measure of stability is the acidity
of the corresponding carbon acid.
The following factors influence the acidity of C-H bonds:
✓ Hybridization (s character of the C-H bond)-higher % s character, lower pKa
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PKa (sp3C-H - 50, sp2 C=C-H -44, sp –25)
✓ Effect of substitution-lower carbanion stability, higher pKa
Carbanion stability: RCH2- > R2CH- > R3C -
✓ Resonance-an adjacent electron withdrawing group, lower pKa
Alkyl lithium and Arylithium Reagents for Metalation The certain solvents such as THF (tetrahydrofuran), DME (dimethoxymethane),
diglyme (diethylene glycol dimethyl ether), and various additives can greatly
alter the reactivity of the organolithium reagents. The addition of chelating
agents such as TMEDA (tetramethyl ethylenediamine), HMPA
(hexamethylphosphoramide, potential carcinogen), tertiary amines, crown
ethers, and t-BuO-K+ increases the basicity and/or the nucleophilicity of
organolithiums.
For example, TMEDA or HMPA function to deoligomerize the hexameric n-BuLi
in hexane to the kinetically more reactive monomer by coordination of the Li+
atom. These strong complexing agents generally are used in stoichiometric
amounts or in slight excess. An excellent replacement solvent for the
carcinogenic HMPA in a variety of reactions is DMPU
TMEDA HMPA DMPU 16 crown 4 ether
The commonly used lithium dialkylamides are LDA (lithium diisopropylamide),
LTMP (lithium 2,2,6,6-tetramethylpiperidide), and LHMDS (lithium
hexamethyldisilazide). They are available by reacting the appropriate amine
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with an organolithium reagent in Et2O or in THF solvent, as shown for the
preparation of LDA.
Chemo selectivity
The choice of the metalating agent is especially crucial when the substrate
molecule contains functional groups that can be attacked by bases and
nucleophiles, as is usually the case.
R2NLi (e.g., LDA) are non-nucleophilic, strong bases.
RLi are powerful nucleophiles as well as strong bases
Interestingly, R2NLi reagents are generally more effective metalating agents
than the thermodynamically more basic RLi reagents.
Benzylic Metalation
The preparation of benzyl lithium from benzyl halides and alkyl lithium is not
feasible because the benzyllithium initially formed reacts with the starting
benzyl halides, producing 1,2 diphenylethane. Metalation of toluene with n-BuLi
in the presence of TMEDA at 30 °C results in a 92 : 8 ratio of benzyl lithium and
ring metalated products. Metalation of toluene with n-BuLi in the presence of
potassium tert-butoxide, and treatment of the resultant organopotassium
compound with lithium bromide, affords pure benzyllithium in 89% yield.
Alternatively, benzyllithiums are accessible by cleavage of alkyl benzyl ethers
with lithium.
nBuLi, TMEDA
30 °C, 2h
n-BuLi, t-BuOK -LiBr
-KBr
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Allylic Metalation
The reaction of allylic organometallics with electrophilic reagents is a very
important tool for the formation of carbon-carbon bonds in acyclic systems and
for controlling their organometallic (2-butenylmetal) species undergo a 1,3-shift
of the metal at room temperature. For the stereocontrolled use of allylmetals in
synthesis, it is important to avoid their equilibration.
M= Li, MgX, ZnX, BR2, AlR2, TiL3, ZrL3
L= Ligand
Treatment of propene or isobutylene with n-BuLi in Et2O in the presence of
TMEDA provides a convenient route to allyllithium and methallyllithium,
respectively
n-BuLi
TMEDA
Et2O
n-C5H11Br
The rate of deprotonation of weakly acidic compounds by alkyllithium may be
changed by several orders of magnitude simply by altering the cation. Potassium
tertbutoxide activates n-butyllithiuim (Schlosser's "super base"), allowing
metalation of allylic C-H bonds of olefins in the low acidity range (pKa-40)
Although the true nature of the Super Base is not known, it is probably an
organopotassium/lithium alcoholate aggregate.
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n-BuLi, THF
KOt-Bu
-90 to -20 °C
Crotyllithium and crotylpotassium compounds can assume either the endo or
exo configuration. Due to their planarity, both forms are stabilized by electron
delocalization. While equilibration of the endo-and exo-forms of crotyllithium is
very fast, the corresponding potassium reagents are stable and may be
intercepted with electrophiles. However, after several hours, the
crotylpotassium compounds also equilibrate, surprisingly favoring the endo-
form over the sterically less hindered exo-form.
n-BuLi, THF
KOt-Bu
-78 to -20 °C
E+
n-BuLi, THF
KOt-Bu
-78 to -20 °C
E+
endo
exo
Crotyllithium reagents are ambident nucleophiles and can react with
electrophiles either at the α- or γ-carbon. The regiochemistry of attack depends
on many factors, such as structure, the electrophile, and the solvent. Generally,
unhindered carbonyl compounds preferentially add to crotyllithiums at the γ-
position.
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Allylic potassium organometallics derived from BuLi-t-BuOK react with
electrophiles predominantly at the α-position.
n-BuLi, THF
KOt-Bu
-45 °C
E+
Protons attached to sp2 carbons are more acidic than protons attached to
nonallylic sp3 Substituted Alkenes carbons. Also, the inductive effect of a
heteroatom further increases the acidity of an adjacent sp2 C-H bond, facilitating
α-lithiation. The relative activating effect of heteroatoms is sulfur > oxygen >
nitrogen. Thus, treatment of 2-ethoxy-1-(pheny1thio)ethylene
with t-BuLi results in exclusive lithiation at the phenylthio substituted carbon.
t-BuLi
THF
E+
Metalation of dihydropyran with n-BuLi in the presence of TMEDA occurs at the
α-vinylic position rather than at the allylic position. Abstraction of an allylic
proton proceeds at a slower rate than abstraction of the vinylic proton of the
sp2-carbon bonded to the inductively electron-withdrawing oxygen.
n-BuLi
TMEDAhexane
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Metalation of methyl vinyl ether or phenyl vinyl sulfides furnishes a α-metalated
vinyl ether or vinyl sulfide, respectively. These carbanions represent acyl anion
equiv.
n-BuLi OR LDA
THF
t-BuLi, pentane
t-BuLi, THF, TMEDA
-65 °C
Ortho-Metalation of Substituted Benzenes and Hetero aromatic compounds
Direct metalation of certain aromatic substrates permits regioselective
preparation of substituted benzene derivatives and heterocycles.
Coordination of the lithium reagent with the nitrogen or oxygen holds the
organolithium in proximity to the orthohydrogens.
n-BuLi E+
RLiSlow E+
X= -NR2, -OR, -CH2OR, -CH2NR2, -CH(OR)2, -CONR2
E+ = CO2, DMF, RCHO, R2CO, epoxides, primary alkyl halides
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Because of the greater coordinating ability of nitrogen as compared to oxygen,
treatment of p-methoxy-N,N-dimethyl benzyl amine with BuLi results in
metalation ortho to the –CH2NMe2 However, in the presence of the strongly
complexing TMEDA, coordination of lithium with the nitrogen of –CH2NMe2 is
suppressed. In this case, the most acidic proton ortho to the -OMe group is
removed preferentially.
n-BuLi
TMEDA
Et2O
Hexane
n-BuLi
Hexane
58% 80%
Metalation of the heteroaromatic compound’s furan and thiophene with
alkyllithium reagents furnishes the corresponding 2-lithio derivative.
For example,
The treatment of 2 methylfuran with t-BuLi in THF, followed by electrophile to
get alkylation product.
t-BuLi
THF, -25 °C
E+
Sulfur is more effective than oxygen in stabilizing an adjacent carbanion. Thus,
using an equimolar mixture of furan and thiophene, the thiophene is selectively
metalated when using one equivalent of n-BuLi.
BuLi
1 eq
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Reaction with Alkyne
n-BuLi react with acetylene to generate the carbanion and followed by trapped
with the electrophile can be used for the further derivatization.
(Stronger acid)
n-BuLi
THF, -78 °Cn-Bu-H
(Weaker acid)
R=Alkyl
E+
Michael addition
Conjugate Addition Reactions of the organolithium reagent was observed in the
very sterically hindered esters.
1. RLi, THF
-78 °C
2. MeOH
workup