Organolithium

reagent

Organolithium reagents are

organometallic compounds that contain
carbon – lithium bonds. They are
important reagents in organic synthesis,
and are frequently used to transfer the
organic group or the lithium atom to the
substrates in synthetic steps, through
nucleophilic addition or simple
deprotonation.[1] Organolithium reagents
are used in industry as an initiator for
anionic polymerization, which leads to the
production of various elastomers. They
have also been applied in asymmetric
synthesis in the pharmaceutical industry.[2]
Due to the large difference in
electronegativity between the carbon atom
and the lithium atom, the C-Li bond is
highly ionic. Owing to the polar nature of
the C-Li bond, organolithium reagents are
good nucleophiles and strong bases. For
laboratory organic synthesis, many
organolithium reagents are commercially
available in solution form. These reagents
are highly reactive, and are sometimes
pyrophoric.
Glass bottles containing butyllithium

sec-Butyllithium aggregate

History and development

Studies of organolithium reagents began
in the 1930 and were pioneered by Karl
Ziegler, Georg Wittig, and Henry Gilman. In
comparison with Grignard reagents,
organolithium reagents can often perform
the same reactions with increased rates
and higher yields, such as in the case of
metalation.[3] Since then, organolithium
reagents have overtaken Grignard
reagents in usage.[4]

Structure
Although simple alkyllithium species are
often represented as monomer RLi, they
exist as aggregates (oligomers) or
polymers.[5] The degree of aggregation
depends on the organic substituent and
the presence of other ligands.[6][7] These
structures have been elucidated by a
variety of methods, notably 6Li, 7Li, and 13C
NMR spectroscopy and X-ray diffraction
analysis.[1] Computational chemistry
supports these assignments.[5]

Nature of carbon-lithium bond

Delocalized electron density in allyllithium reagents

The relative electronegativities of carbon
and lithium suggest that the C-Li bond will
be highly polar.[8][9][10] However, certain
organolithium compounds possess
properties such as solubility in nonpolar
solvents that complicate the issue. [8]
While most data suggest the C-Li bond to
be essentially ionic, there has been debate
as to whether a small covalent character
exists in the C-Li bond.[9][10] One estimate
puts the percentage of ionic character of
alkyllithium compounds at 80 to 88%.[11]

In allyl lithium compounds, the lithium

cation coordinates to the face of the
carbon π bond in an η3 fashion instead of
a localized, carbanionic center, thus,
allyllithiums are often less aggregated
than alkyllithiums.[6][12] In aryllithium
complexes, the lithium cation coordinates
to a single carbanion center through a Li-C
σ type bond.[6][13]
Solid state structures of methyllithium tetramers, n-
butyllithium hexamers and polymeric ladder of
phenyllithium

Solid state structure

Tetrahedron and octahedron metal cores formed by

aggregation of the Li3 triangle - carbanion coordinate
complex[5]

Like other species consisting of polar

subunits, organolithium species
aggregate.[7][14] Formation of aggregates
is influenced by electrostatic interactions,
the coordination between lithium and
surrounding solvent molecules or polar
additives, and steric effects.[7]

A basic building block toward constructing

more complex structures is a carbanionic
center interacting with a Li3 triangle in an
η- 3 fashion.[5] In simple alkyllithium
reagents, these triangles aggregate to
form tetrahedron or octahedron
structures. For example, methyllithium,
ethyllithium and tert-butyllithium all exist in
the tetramer [RLi]4. Methyllithium exists as
tetramers in a cubane-type cluster in the
solid state, with four lithium centers
forming a tetrahedron. Each methanide in
the tetramer in methyllithium can have
agostic interaction with lithium cations in
adjacent tetramers.[5][7] Ethyllithium and
tert-butyllithium, on the other hand, do not
exhibit this interaction, and are thus
soluble in non-polar hydrocarbon solvents.
Another class of alkyllithium adopts
hexameric structures, such as n-
butyllithium, isopropyllithium, and
cyclohexanyllithium.[5]
LDA dimer with THF coordinated to Li cations

Common lithium amides, e.g. lithium

bis(trimethylsilyl)amide and lithium
diisopropylamide, are also subject to
aggregation.[15] Lithium amides adopt
polymeric-ladder type structures in non-
coordinating solvent in the solid state, and
they generally exist as dimers in ethereal
solvents. In the presence of strongly
donating ligands, tri- or tetrameric lithium
centers are formed. [16] For example, LDA
exists primarily as dimers in THF.[15] The
structures of common lithium amides,
such as lithium diisopropylamide (LDA)
and lithium hexamethyldisilazide
(LiHMDS) have been extensively studied
by Collum and coworkers using NMR
spectroscopy.[17] Another important class
of reagents is silyllithiums, extensively
used in the synthesis of organometallic
complexes and polysilane
dendrimers.[7][18] In the solid state, in
contrast with alkyllithium reagents, most
silyllithiums tend to form monomeric
structures coordinated with solvent
molecules such as THF, and only a few
silyllithiums have been characterized as
higher aggregates.[7] This difference can
arise from the method of preparation of
silyllithiums, the steric hindrance caused
by the bulky alkyl substituents on silicon,
and the less polarized nature of Si-Li
bonds. The addition of strongly donating
ligands, such as TMEDA and (-)-sparteine,
can displace coordinating solvent
molecules in silyllithiums.[7]

Solution structure

Relying solely on the structural information

of organolithium aggregates obtained in
the solid state from crystal structures has
certain limits, as it is possible for
organolithium reagents to adopt different
structures in reaction solution
environment.[6] Also, in some cases the
crystal structure of an organolithium
species can be difficult to isolate.
Therefore, studying the structures of
organolithium reagents, and the lithium-
containing intermediates in solution form
is extremely useful in understanding the
reactivity of these reagents. [19] NMR
spectroscopy has emerged as a powerful
tool for the studies of organolithium
aggregates in solution. For alkyllithium
species, C-Li J coupling can often used to
determine the number of lithium
interacting with a carbanion center, and
whether these interactions are static or
dynamic.[6] Separate NMR signals can also
differentiate the presence of multiple
aggregates from a common monomeric
unit.[20]

The structures of organolithium

compounds are affected by the presence
of Lewis bases such as tetrahydrofuran
(THF), diethyl ether (Et2O),
tetramethylethylene diamine (TMEDA) or
hexamethylphosphoramide (HMPA).[5]
Methyllithium is a special case, in which
solvation with ether, or polar additive
HMPA does not deaggregate the
tetrameric structure in the solid state.[7] On
the other hand, THF deaggregates
hexameric butyl lithium: the tetramer is the
main species, and ΔG for interconversion
between tetramer and dimer is around 11
kcal/mol.[21] TMEDA can also chelate to
the lithium cations in n-butyllithium and
form solvated dimers such as [(TMEDA)
LiBu-n)]2.[5][6] Phenyllithium has been
shown to exist as a distorted tetramer in
the crystallized ether solvate, and as a
mixture of dimer and tetramer in ether
solution.[6]
Aggregates of some alkyllithiums in solvents[6]
Solvent Structure

methyllithium THF tetramer

methyllithium ether/HMPA tetramer

n-butyllithium pentane hexamer

n-butyllithium ether tetramer

n-butyllithium THF tetramer-dimer

sec-butyllithium pentane hexamer-tetramer

isopropyllithium pentane hexamer-tetramer

tert-butyllithium pentane tetramer

tert-butyllithium THF monomer

phenyllithium ether tetramer-dimer

phenyllithium ether/HMPA dimer

Structure and reactivity

As the structures of organolithium

reagents change according to their
chemical environment, so do their
reactivity and selectivity.[7][22] One
question surrounding the structure-
reactivity relationship is whether there
exists a correlation between the degree of
aggregation and the reactivity of
organolithium reagents. It was originally
proposed that lower aggregates such as
monomers are more reactive in
alkyllithiums.[23] However, reaction
pathways in which dimer or other
oligomers are the reactive species have
also been discovered,[24] and for lithium
amides such as LDA, dimer-based
reactions are common.[25] A series of
solution kinetics studies of LDA - mediated
reactions suggest that lower aggregates
of enolates do not necessarily lead to
higher reactivity.[17]
Also, some Lewis bases increase reactivity
of organolithium compounds.[26][27]
However, whether these additives function
as strong chelating ligands, and how the
observed increase in reactivity relates to
structural changes in aggregates caused
by these additives are not always
clear.[26][27] For example, TMEDA increases
rates and efficiencies in many reactions
involving organolithium reagents.[7]
Toward alkyllithium reagents, TMEDA
functions as a donor ligand, reduces the
degree of aggregation,[5] and increases the
nucleophilicity of these species.[28]
However, TMEDA does not always function
as a donor ligand to lithium cation,
especially in the presence of anionic
oxygen and nitrogen centers. For example,
it only weakly interacts with LDA and
LiHMDS even in hydrocarbon solvents with
no competing donor ligands.[29] In imine
lithiation, while THF acts as a strong
donating ligand to LiHMDS, the weakly
coordinating TMEDA readily dissociates
from LiHMDS, leading to the formation of
LiHMDS dimers that is the more reactive
species. Thus, in the case of LiHMDS,
TMEDA does not increase reactivity by
reducing aggregation state.[30] Also, as
opposed to simple alkyllithium
compounds, TMEDA does not
deaggregate lithio-acetophenolate in THF
solution.[6][31] The addition of HMPA to
lithium amides such as LiHMDS and LDA
often results in a mixture of
dimer/monomer aggregates in THF.
However, the ratio of dimer/monomer
species does not change with increased
concentration of HMPA, thus, the observed
increase in reactivity is not the result of
deaggregation. The mechanism of how
these additives increase reactivity is still
being researched.[22]

Reactivity and applications

The C-Li bond in organolithium reagents is
highly polarized. As a result, the carbon
attracts most of the electron density in the
bond and resembles a carbanion. Thus,
organolithium reagents are strongly basic
and nucleophilic. Some of the most
common applications of organolithium
reagents in synthesis include their use as
nucleophiles, strong bases for
deprotonation, initiator for polymerization,
and starting material for the preparation of
other organometallic compounds.

As nucleophile

Carbolithiation reactions
As nucleophiles, organolithium reagents
undergo carbolithiation reactions, whereby
the carbon-lithium bond adds across a
carbon-carbon double or triple bond,
forming new organolithium species.[32]
This reaction is the most widely employed
reaction of organolithium compounds.
Carbolithiation is key in anionic
polymerization processes, and n-
butyllithium is used as a catalyst to initiate
the polymerization of styrene, butadiene,
or isoprene or mixtures thereof.[33][34]
Another application that takes advantage
of this reactivity is the formation of
carbocyclic and heterocyclic coumpounds
by intramolecular carbolithiation.[32] As a
form of anionic cyclization, intramolecular
carbolithiation reactions offer several
advantages over radical cyclization. First,
it is possible for the product cyclic
organolithium species to react with
electrophiles, whereas it is often difficult
to trap a radical intermediate of the
corresponding structure. Secondly, anionic
cyclizations are often more regio- and
stereospecific than radical cyclization,
particularly in the case of 5-
hexenyllithiums. Intramolecular
carbolithiation allows addition of the alkyl-,
vinyllithium to triple bonds and mono-alkyl
substituted double bonds. Aryllithiums can
also undergo addition if a 5-membered
ring is formed. The limitations of
intramolecular carbolithiation include
difficulty of forming 3 or 4-membered
rings, as the intermediate cyclic
organolithium species often tend to
undergo ring-openings.[32] Below is an
example of intramolecular carbolithiation
reaction. The lithium species derived from
the lithium-halogen exchange cyclized to
form the vinyllithium through 5-exo-trig
ring closure. The vinyllithium species
further reacts with electrophiles and
produce functionalized cyclopentylidene
compounds.[35]

Addition to carbonyl compounds

Nucleophilic organolithium reagents can
add to electrophilic carbonyl double bonds
to form carbon-carbon bonds. They can
react with aldehydes and ketones to
produce alcohols. The addition proceeds
mainly via polar addition, in which the
nucleophilic organolithium species attacks
from the equatorial direction, and
produces the axial alcohol.[36] Addition of
lithium salts such as LiClO4 can improve
the stereoselectivity of the reaction.[37]

When the ketone is sterically hindered,

using Grignard reagents often leads to
reduction of the carbonyl group instead of
addition.[36] However, alkyllithium reagents
are less likely to reduce the ketone, and
may be used to synthesize substituted
alcohols.[38] Below is an example of
ethyllithium addition to adamantone to
produce tertiary alcohol.[39]

Organolithium reagents are also better

than Grignard reagents in their ability to
react with carboxylic acids to form
ketones.[36] This reaction can be optimized
by carefully controlling the amount of
organolithium reagent addition, or using
trimethylsilyl chloride to quench excess
lithium reagent.[40] A more common way to
synthesize ketones is through the addition
of organolithium reagents to Weinreb
amides (N-methoxy-N-methyl amides).
This reaction provides ketones when the
organolithium reagents is used in excess,
due to chelation of the lithium ion between
the N-methoxy oxygen and the carbonyl
oxygen, which forms a tetrahedral
intermediate that collapses upon acidic
work up.[41]
Organolithium reagents can also react
with carbon dioxide to form carboxylic
acids.[42]

In the case of enone substrates, where two

sites of nucleophilic addition are possible
(1,2 addition to the carbonyl carbon or 1,4
conjugate addition to the β carbon), most
highly reactive organolithium species favor
the 1,2 addition, however, there are several
ways to propel organolithium reagents to
undergo conjugate addition. First, since
the 1,4 adduct is the likely to be the more
thermodynamically favorable species,
conjugate addition can be achieved
through equilibration (isomerization of the
two product), especially when the lithium
nucleophile is weak and 1,2 addition is
reversible. Secondly, adding donor ligands
to the reaction forms heteroatom-
stabilized lithium species which favors 1,4
conjugate addition. In one example,
addition of low-level of HMPA to the
solvent favors the 1,4 addition. In the
absence of donor ligand, lithium cation is
closely coordinated to the oxygen atom,
however, when the lithium cation is
solvated by HMPA, the coordination
between carbonyl oxygen and lithium ion
is weakened. This method generally
cannot be used to affect the
regioselectivity of alkyl- and aryllithium
reagents.[43][44]

Organolithium reagents can also perform

enantioselective nucleophilic addition to
carbonyl and its derivatives, often in the
presence of chiral ligands. This reactivity
is widely applied in the industrial
syntheses of pharmaceutical compounds.
An example is the Merck and Dupont
synthesis of Efavirenz, a potent HIV
reverse transcriptase inhibitor. Lithium
acetylide is added to a prochiral ketone to
yield a chiral alcohol product. The
structure of the active reaction
intermediate was determined by NMR
spectroscopy studies in the solution state
and X-ray crystallography of the solid state
to be a cubic 2:2 tetramer.[45]
SN2 type reactions

Organolithium reagents can serve as

nucleophiles and carry out SN2 type
reactions with alkyl or allylic halides.[46]
Although they are considered more
reactive than Grignards reactions in
alkylation, their use is still limited due to
competing side reactions such as radical
reactions or metal-halogen exchange.
Most organolithium reagents used in a
alkylations are more stabilized, less basic,
and less aggregated, such as heteroatom
stabilized, aryl- or allyllithium reagents.[6]
HMPA has been shown to increase
reaction rate and product yields, and the
reactivity of aryllithium reagents is often
enhanced by the addition of potassium
alkoxides.[36] Organolithium reagents can
also carry out nucleophilic attacks with
epoxides to form alcohols.

As base

Organolithium reagents provide a wide

range of basicity. tert-Butyllithium, with
three weakly electron donating alkyl
groups, is the strongest base
commercially available (pKa = 53). As a
result, the acidic protons on -OH, -NH and -
SH are often protected in the presence of
organolithium reagents. Some commonly
used lithium bases are alkyllithium species
such as n-butyllithium and lithium
dialkylamides (LiNR2). Reagents with bulky
R groups such as lithium diisopropylamide
(LDA) and lithium bis(trimethylsilyl)amide
(LiHMDS) are often sterically hindered for
nucleophilic addition, and are thus more
selective toward deprotonation. Lithium
dialkylamides (LiNR2) are widely used in
enolate formation and aldol reaction.[47]
The reactivity and selectivity of these
bases are also influenced by solvents and
other counter ions.
Metalation

Metalation with organolithium reagents,

also known as lithiation or lithium-
hydrogen exchange, is achieved when an
organolithium reagent, most commonly an
alkyllithium, abstracts a proton and forms
a new organolithium species.

 
 

 
 

(1)

Common metalation reagents are the

butyllithiums. tert-Butyllithium and sec-
butyllithium are generally more reactive
and have better selectivity than n-
butyllithium, however, they are also more
expensive and difficult to handle.[47]
Metalation is a common way of preparing
versatile organolithium reagents. The
position of metalation is mostly controlled
by the acidity of the C-H bond. Lithiation
often occurs at a position α to electron
withdrawing groups, since they are good at
stabilizing the electron-density of the
anion. Directing groups on aromatic
compounds and heterocycles provide
regioselective sites of metalation; directed
ortho metalation is an important class of
metalation reactions. Metalated sulfones,
acyl groups and α-metalated amides are
important intermediates in chemistry
synthesis. Metalation of allyl ether with
alkyllithium or LDA forms an anion α to the
oxygen, and can proceed to 2,3-Wittig
rearrangement. Addition of donor ligands
such as TMEDA and HMPA can increase
metalation rate and broaden substrate
scope.[48] Chiral organolithium reagents
can be accessed through asymmetric
metalation.[49]

Directed ortho metalation is an important

tool in the synthesis of regiospecific
substituted aromatic compounds. This
approach to lithiation and subsequent
quenching of the intermediate lithium
species with electrophile is often better
than the electrophilic aromatic
substitution due to its high regioselectivity.
This reaction proceeds through
deprotonation by organolithium reagents
at the positions α to the direct metalation
group (DMG) on the aromatic ring. The
DMG is often a functional group
containing a heteroatom that is Lewis
basic, and can coordinate to the Lewis-
acidic lithium cation. This generates a
complex-induced proximity effect, which
directs deprotonation at the α position to
form an aryllithium species that can
further react with electrophiles. Some of
the most effective DMGs are amides,
carbamates, sulfones and sulfonamides.
They are strong electron-withdrawing
groups that increase the acidity of alpha-
protons on the aromatic ring. In the
presence of two DMGs, metalation often
occurs ortho to the stronger directing
group, though mixed products are also
observed. A number of heterocycles that
contain acidic protons can also undergo
ortho-metalation. However, for electron-
poor heterocycles, lithium amide bases
such as LDA are generally used, since
alkyllithium has been observed to perform
addition to the electron-poor heterocycles
rather than deprotonation. In certain
transition metal-arene complexes, such as
ferrocene, the transition metal attracts
electron-density from the arene, thus
rendering the aromatic protons more
acidic, and ready for ortho-metalation.[50]

Superbases

Addition of potassium alkoxide to

alkyllithium greatly increases the basicity
of organolithium species.[51] The most
common "superbase" can be formed by
addition of KOtBu to butyllithium, often
abbreviated as "LiCKOR" reagents. These
"superbases" are highly reactive and often
stereoselective reagents. In the example
below, the LiCKOR base generates a
stereospecific crotylboronate species
through metalation and subsequent
lithium-metalloid exchange.[52]

Asymmetric metalation

Enantioenriched organlithium species can

be obtained through asymmetric
metalation of prochiral substrates.
Asymmetric induction requires the
presence of a chiral ligand such as (-)-
sparteine.[49] The enantiomeric ratio of the
chiral lithium species is often influenced
by the differences in rates of
deprotonation. In the example below,
treatment of N-Boc-N-benzylamine with n-
butyllithium in the presence of (-)-
sparteine affords one enantiomer of the
product with high enantiomeric excess.
Transmetalation with trimethyltinchloride
affords the opposite enantiomer.[53]
Enolate formation

Lithium enolates are formed through

deprotonation of a C-H bond α to the
carbonyl group by an organolithium
species. Lithium enolates are widely used
as nucleophiles in carbon-carbon bond
formation reactions such as aldol
condensation and alkylation. They are also
an important intermediate in the formation
of silyl enol ether.

Lithium enolate formation can be

generalized as an acid-base reaction, in
which the relatively acidic proton α to the
carbonyl group (pK =20-28 in DMSO)
reacts with organolithium base. Generally,
strong, non-nucleophilic bases, especially
lithium amides such LDA, LiHMDS and
LiTMP are used. THF and DMSO are
common solvents in lithium enolate
reactions.[54]
The stereochemistry and mechanism of
enolate formation have gained much
interest in the chemistry community. Many
factors influence the outcome of enolate
stereochemistry, such as steric effects,
solvent, polar additives, and types of
organolithium bases. Among the many
models used to explain and predict the
selectivity in stereochemistry of lithium
enolates is the Ireland model.[55]

In this assumption, a monomeric LDA

reacts with the carbonyl substrate and
form a cyclic Zimmerman-Traxler type
transition state. The (E)-enolate is favored
due to an unfavorable syn-pentane
interaction in the (Z)-enolate transition
state.[54]

Addition of polar additives such as HMPA

or DMPU favors the formation of (Z)
enolates. The Ireland model argues that
these donor ligands coordinate to the
lithium cations, as a result, carbonyl
oxygen and lithium interaction is reduced,
and the transition state is not as tightly
bound as a six-membered chair. The
percentage of (Z) enolates also increases
when lithium bases with bulkier side
chains (such as LiHMDS) are used.[54]
However, the mechanism of how these
additives reverse stereoselectivity is still
being debated.

There have been some challenges to the

Ireland model, as it depicts the lithium
species as a monomer in the transition
state. In reality, a variety of lithium
aggregates are often observed in solutions
of lithium enolates, and depending on
specific substrate, solvent and reaction
conditions, it can be difficult to determine
which aggregate is the actual reactive
species in solution.[54]

Lithium-halogen exchange

Lithium-halogen exchange is a metathesis

reaction between an organohalide and
organolithium species. Gilman and Wittig
independently discovered this method in
the late 1930s.[56]

 
 

 
 

(2)

The mechanism of lithium-halogen

exchange is still debated.[57] One possible
pathway involves a nucleophilic
mechanism that generates a reversible
“ate-complex” intermediate. Farnham and
Calabrese were able to isolate “ate-
complex” lithium bis(pentafluorophenyl)
iodinate complexed with TMEDA and
obtain an X-ray crystal structure.[58] The
"ate-complex" further reacts with
electrophiles and provides
pentafluorophenyl iodide and C6H5Li.[58] A
number of kinetic studies also support a
nucleophilic pathway in which the
carbanion on the lithium species attacks
the halogen atom on the aryl halide.[59]
Another possible mechanism involves
single electron transfer and the generation
of radicals. In reactions of secondary and
tertiary alkyllithium and alkyl halides,
radical species were detected by EPR
spectroscopy.[60] However, whether these
radicals are reaction intermediates is not
definitive.[57] The mechanistic studies of
lithium-halogen exchange is also
complicated by the formation of
aggregates of organolithium species.

The rate of lithium halogen exchange is

extremely fast. It is usually faster than
nucleophilic addition and can sometimes
exceed the rate of proton transfer. In the
example below, the exchange between
lithium and primary iodide is almost
instantaneous, and outcompetes proton
transfer from methanol to tert-butyllithium.
The major alkene product is formed in over
90% yield.[61]

Lithium-halogen exchange is very useful in

preparing new organolithium reagents.
Exchange rates usually follow the trend I >
Br > Cl. Alkyl- and arylfluoride are generally
unreactive toward organolithium reagents.
Lithium halogen exchange is kinetically
controlled, and the rate of exchange is
primarily influenced by the stabilities of
the carbanion intermediates (sp > sp2 >
sp3) of the organolithium reagents.[36][48]
For example, the more basic tertiary
organolithium reagents (usually n-
butyllithium, sec-butyllithium or tert-
butyllithium) are the most reactive, and will
react with primary alkyl halide (usually
bromide or iodide) to form the more stable
organolithium species. Therefore, lithium
halogen exchange is most frequently used
to prepare vinyl-, aryl- and primary
alkyllithium reagents. Lithium halogen
exchange is also facilitated when alkoxy
groups or heteroatoms are present to
stabilize the carbanion, and this method is
especially useful for the preparation of
functionalized lithium reagents which
cannot tolerate the harsher conditions
required for reduction with lithium
metal.[48] Substrates such as vinyl halides
usually undergo lithium-halogen exchange
with retention of the stereochemistry of
the double bond.[62]

Below is an example of the use of lithium-

halogen exchange in the synthesis of
morphine. Here, n-butyllithium is used to
perform lithium-halogen exchange with
bromide. The nucleophilic carbanion
center quickly undergoes carbolithiation to
the double bond, generating an anion
stabilized by the adjacent sulfone group.
An intramolecular SN2 reaction by the
anion forms the cyclic backbone of
morphine.[63]

Lithium halogen exchange is a crucial part

of Parham cyclization.[64] In this reaction,
an aryl halide (usually iodide or bromide)
exchanges with organolithium to form a
lithiated arene species. If the arene bears
a side chain with an electrophillic moiety,
the carbanion attached to the lithium will
perform intramolecular nucleophilic attack
and cyclize. This reaction is a useful
strategy for heterocycle formation.[65] In
the example below, Parham cyclization
was used to in the cyclization of an
isocyanate to form isoindolinone, which
was then converted to a nitrone. The
nitrone species further reacts with
radicals, and can be used as "spin traps" to
study biological radical processes.[66]

Transmetalation
Organolithium reagents are often used to
prepare other organometallic compounds
by transmetalation. Organocopper,
organotin, organosilicon, organoboron,
organophosphorus, organocerium and
organosulfur compounds are frequently
prepared by reacting organolithium
reagents with appropriate electrophiles.

 
 

 
 

(3)

Common types of transmetalation include

Li/Sn, Li/Hg, and Li/Te exchange, which
are fast at low temperature.[47] The
advantage of Li/Sn exchange is that the
tri-alkylstannane precursors undergo few
side reactions, as the resulting n-Bu3Sn
byproducts are unreactive toward
alkyllithium reagents.[47] In the following
example, vinylstannane, synthesized from
terminal alkyne, forms vinyllithium through
transmetalation with n-BuLi.[67]

Organolithium can also be used in to

prepare organozinc compounds through
transmetalation with zinc salts.[68]
Lithium diorganocuprates can be formed
by reacting alkyl lithium species with
copper(I) halide. The resulting
organocuprates are generally less reactive
toward aldehydes and ketones than
organolithium reagents or Grignard
reagents.[69]

Preparation
Most simple alkyllithium reagents, and
common lithium amides are commercially
available in a variety of solvents and
concentrations. Organolithium reagents
can also be prepared in the laboratory.
Below are some common methods for
preparing organolithium reagents.

Reaction with lithium metal

Reduction of alkyl halide with metallic

lithium can afford simple alkyl and aryl
organolithium reagents.[36]

 
 

 
 

(4)
Industrial preparation of organolithium
reagents is achieved using this method by
treating the alkyl chloride with metal
lithium containing 0.5-2% sodium. The
conversion is highly exothermic. The
sodium initiates the radical pathway and
increases the rate.[70] The reduction
proceeds via a radical pathway. Below is
an example of the preparation of a
functionalized lithium reagent using
reduction with lithium metal.[71]
Sometimes, lithium metal in the form of
fine powders are used in the reaction with
certain catalysts such as naphthalene or
4,4’-di-t-butylbiphenyl (DTBB). Another
substrate that can be reduced with lithium
metal to generate alkyllithium reagents is
sulfides. Reduction of sulfides is useful in
the formation of functionalized
organolithium reagents such as alpha-
lithio ethers, sulfides, and silanes.[72]

Metalation

See Metalation.(under Reactivity and

applications)

A second method of preparing

organolithium reagents is a metalation
(lithium hydrogen exchange). The relative
acidity of hydrogen atoms controls the
position of lithiation.

This is the most common method for

preparing alkynyllithium reagents, because
the terminal hydrogen bound to the sp
carbon is very acidic and easily
deprotonated.[36] For aromatic
compounds, the position of lithiation is
also determined by the directing effect of
substituent groups.[73] Some of the most
effective directing substituent groups are
alkoxy, amido, sulfoxide, sulfonyl.
Metalation often occurs at the position
ortho to these substituents. In
heteroaromatic compounds, metalation
usually occurs at the position ortho to the
heteroatom.[36][73]

Lithium halogen exchange

See lithium-halogen exchange (under

Reactivity and applications)

A third method to prepare organolithium

reagents is through lithium halogen
exchange.
tert-butyllithium or n-butyllithium are the
most commonly used reagents for
generating new organolithium species
through lithium halogen exchange.
Lithium-halogen exchange is mostly used
to convert aryl and alkenyl iodides and
bromides with sp2 carbons to the
corresponding organolithium compounds.
The reaction is extremely fast, and often
proceed at -60 to -120 °C.[48]

Transmetalation

See transmetalation (under Reactivity and

applications)
The fourth method to prepare
organolithium reagents is through
transmetalation. This method can be used
for preparing vinyllithium.

Shapiro reaction

In the Shapiro reaction, two equivalents of

strong alkyllithium base react with p-
tosylhydrazone compounds to produce the
vinyllithium, or upon quenching, the olefin
product.

Handling
Organolithium compounds are highly
reactive species and require specialized
handling techniques. They are often
corrosive, flammable, and sometimes
pyrophoric (spontaneous ignition when
exposed to oxygen or moisture).[74]
Alkyllithium reagents can also undergo
thermal decomposition to form the
corresponding alkyl species and lithium
hydride.[75] Organolithium reagents are
typically stored below 10 °C. Reactions are
conducted using air-free techniques.[74]
The concentration of alkyllithium reagents
is often determined by titration.[76][77][78]

Organolithium reagents react, often slowly,

with ethers, which nonetheless are often
used as solvents.[79]
Approximate half-lives of common lithium reagents in typical solvents
Solvent/Temp n-BuLi s-BuLi t-BuLi MeLi CH2=C(OEt)-Li CH2=C(SiMe3)-Li

THF/-40 °C 338 min

THF/-20 °C 42 min

THF/0 °C 17 h

THF/20 °C 107 min >15 h 17 h

THF/35 °C 10 min

THF/TMEDA/-20 °C 55 h

THF/TMEDA/ 0 °C 340 min

THF/TMEDA/20 °C 40 min

Ether/-20 °C 480 min

Ether/0 °C 61 min

Ether/20 °C 153 h <30 min 17 d

Ether/35 °C 31 h

Ether/TMEDA/ 20 °C 603 min

DME/-70 °C 120 min 11 min

DME/-20 °C 110 min 2 min <<2 min

DME/0 °C 6 min

See also
HSAB concept
Grignard reagent
Organometallic
 Alkynylation

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