· 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.


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.


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.


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).


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.


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


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


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


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.


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.


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


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


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


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

· 2019-03-09 · 1 organometallic chemistry organometallic reagents play a key role in...

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