Organometallic Chemistry

Worawan Bhanthumnavin
Department of Chemistry
Chulalongkorn University
Bangkok 10330, Thailand

Given as part of the 6th semester organic chemistry course

at the University of Regensburg (May 2008)
Under the ASEM-DUO Thailand 2007 exchange program

General, organolithium, organomagnesium

Organometallic Chemistry

• Organic Chemistry:
– Covalent C-X bonds
– Rigid coordination geometries
– Fixed oxidation state

• ? Organometallic Chemistry ?

• Inorganic Chemistry / Coordination Chemistry

– Mainly ionic M-X bonds
– versatile and often fluxional coordination geometries
– multiple oxidation states
Organometallic Chemistry

• Organic Chemistry:
– Covalent C-X bonds
– Rigid coordination geometries
– Fixed oxidation state

• ? Organometallic Chemistry ?

• Inorganic Chemistry / Coordination Chemistry

– Mainly ionic M-X bonds
– versatile and often fluxional coordination geometries
– multiple oxidation states
 Organometallic Compounds
• Compounds that contain a Metal-Carbon bond

• e.g. Tetraethyllead – as additive in Gasoline

• General formula R-M (R = alkyl, M = metal)
• The C-M bond is a polarized covalent bond
 Organometallic Compounds

• Great source for anionic carbon species (carbanions)

C with a nagative charge??

• Useful but restricted to one carbon homologations

• Is that all we have for C-C bond formation?
C-C bond formation
Alkyl metals – polarized R-M
• Especially true for organometallic compounds
containing the more electropositive metals, i.e. alkali
and alkaline earth metals.
• Metal = Li, Na, K (alkali metals)
Mg (alkaline earth metals)
• Other examples:
Ti Cr Mn Fe Co Ni Cu Zn
Zr Ru Pd Hg
OS Pt
Polarized bond
Polarized bond
Reactivity- the carbanion part
• For organometallics with the same metal component, reactivity
increases with decreasing “s” character.
Reactivity- the carbanion part
Reactivity- the carbanion part

• Alkyl groups: slightly electron donating

• They destabilize the carbanion; therefore reactivity increases
Reactivity- the carbanion part
• Electron withdrawing groups help to stabilize the negative
charge therefore decrease reactivity.
Reactivity- the carbanion part
• Reactivity is determined by nature of organometallic species;
• Both carbanion and metal parts contribute to reactivity.
Reactivity- the metal part
• The larger the difference in electronegativity between the
• metal and the organic parts, then the less covalent (more
• ionic) is the bond and the greater the reactivity.
Reactivity- the metal part
• Reactivity of RM generally increases with the ionic character
of the C-M bond
• Percent ionicity (ionic character) is related to the EN
difference of the C–M bond
• Estimated values, affected by the nature of the substituents on
carbon.

• C–Li, C–Mg, C–Ti, and C–Al bonds are more ionic than C–Zn,
C–Cu, C–Sn, and C–B,
M-C bond strengths
Organometallic compounds

Materials covered here:

• Organolithium
• Organomagnesium
• Organozinc
• Organocopper
• Organoboron
• Organosilicon
 Organolithium compounds (RLi)
• Organolithium reagents react with a wide variety of organic
substrates to form carbon-carbon bonds

• RLi serve as precursors for the preparation of other

organometallic reagents
Organometallic Preparations
In general:
• Reductive replacement (like Grignard synthesis)

• Metal – hydrogen exchange (deprotonation; because lots

of organometallics are commercially available)
Organometallic Preparations
In general:
• Metal – halogen exchange

• Metal – metal exchange (Transmetallation)

Organometallic Preparations
Transmetallation
• direct metallations involving the metal and an organic halide
are usually quite problematic:
– If proceeds too vigorously: dangerous
– If proceeds far too slowly: not practical for synthesis use
Organometallic Preparations
Transmetallation
• RMgX is less reactive than RLi
RLi- Preparations
• Comparing to Grignard
RLi- Preparations
• prepared in a similar way to Grignard reagents
• but reaction of Li with organic halides: much more vigorous
and even dangerous
• the same orders of reactivity apply for the different types of
halide and carbon unit
• all lithiations of alkyl halides tend to be carried out on the
chlorides in hexane solvent,

• lithiations of alkenyl halides use chlorides or bromides in

THF
• lithiations of aryl halides use bromides in THF
• main problem with RLi: also reacts with starting alkyl halide!!!
- fortunately chloride and bromide are pretty much
unreactive at low temperatures with n-RLi
RLi- Preparations
• for tert-RLi the problem is considerable and special methods
of preparation are required
• aryl halides (ArX) do not react with the corresponding
aryllithium (ArLi), so ArLi can be prepared from the chloride
or the bromide in THF

• the actual structure of the organolithium unit consist of

aggregates of 2, 3 or 4 molecules, and of complexes with
solvent if ethers are used
 RLi- Preparations
Organolithiums from alkyl halides and Li metal

• especially suited for preparation of alkyl and aryllithiums.

• however, less general than the corresponding method for
preparing Grignard reagents in that allylic, benzylic, and
propargylic halides tend to undergo Wurtz coupling, in which
the lithium reagents initially formed react competitively with the
R–X to produce homocoupled products.
 RLi- Preparations
Organolithiums via Lithium–Halogen Exchange

• Reaction proceeds in forward direction when new RLi formed is

a weaker base (more stable carbanion) than the starting RLi.
• Method is best suited for exchanges between Csp3–Li (stronger
base) and Csp2–X to give alkenyllithiums, Csp2–Li (weaker
base).

™ Alkenyllithium Reagents
– A problem encountered in preparation of alkenyllithiums via
lithium-halogen exchange may be coupling of newly formed
alkyl halide (e.g., n-BuBr) with alkenyllithium.
RLi- Preparations
Organolithiums via Lithium–Halogen Exchange
– solved by using 2 equiv. of tert-butyllithium (t-BuLi)
– The second equivalent of t-BuLi is involved in the
dehydrohalogenation (E2 reaction) of the t-BuBr formed
in situ.
RLi- Preparations
Organolithiums via Lithium–Halogen Exchange
– (E)- and (Z)-alkenyllithiums: configurationally stable at low
temperatures.
– The preparation of certain (Z)-alkenyllithiums should be
carried out in Et2O rather than in THF.
– When working at –100 °C or below, solvent should be the
Trapp mixture (a 4 : 1 : 1 mixt. of THF : Et2O: n-pentane)
RLi- Preparations
Organolithiums via Lithium–Halogen Exchange

– Alkenyllithium reagents: used for stereospecific syntheses

of alkenes and functionally substituted alkenes.
RLi- Preparations
Organolithiums via Lithium–Halogen Exchange
™ Aryllithium Reagents
– efficient route to aryllithiums and heteroaromatic lithium
reagents that are inaccessible by Li-H exchange.
– very fast, even at low temp, particularly in e-donating
solvents. Therefore, competitive alkylation and Li-H
exchange (metalation) reactions: usually not a problem.

– Caution: when using TMEDA (tetramethylethylenediamine) as a

promoter for Li-X exchange, since it accelerates metalations more than
it does metal-halogen exchange.
RLi- Preparations
Organolithiums via Lithium–Halogen Exchange
™ Aryllithium Reagents
– Also works for heteroatomatics

– Functionally substituted ArLi such as lithiobenzonitrile and

lithionitrobenzene are only stable at low temperature and
thus require trapping with a reactive electrophile.
RLi- Preparations
Organolithiums via Lithium–Metal Exchange
• Transmetalation: used to prepare allylic, benzylic, and
propargylic lithium reagents (difficult to obtain by other routes)

• conversion of readily available allylic Grignard into the allylic

lithium reagent involves two metal-metal exchanges.
• reactions proceed in 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.
RLi- Preparations
Organolithiums via Lithium-Hydrogen Exchange

• metalation: Metal-hydrogen exchange provides a general

route to organolithium compounds.
• tendency to form the C–Li bond (and thus reactivity) depends
on stability of the R group as a negative ion.
• most important measure of stability is acidity of corresponding
carbon acid. 2–3 pKa unit difference is sufficient to drive the
reaction to completion (98%), though greater pKa difference is
desirable
RLi- Preparations
Organolithiums via Lithium-Hydrogen Exchange
• factors influencing C–H bonds acidity :

– Hybridization (s character of the C–H bond)—higher % s

character, lower pKa
– pKa: C–H ~ 50 C=C–H ~44 C≡C–H ~ 25
– Effect of substitution—lower carbanion stability, higher pKa
– Carbanion stability: RCH2- > R2CH- > R3C-
– Resonance—adjacent e-withdrawing group, lower pKa

– Acidity of decreases in the following order:

R = CHO > C(O)R > CO2R > C(O)NR2 ~ CO2 > SO2R > Ph ~C=C
RLi- Preparations
Organolithiums via Lithium-Hydrogen Exchange
Alkyllithium and aryllithium reagents for metalation
• solvents such as THF, DME (dimethoxyethane), diglyme
(diethyleneglycol dimethyl ether), and various additives can
greatly alter their reactivity.
• addition of chelating agents: TMEDA, HMPA (hexamethyl
phosphoramide), 3o amines, crown ethers, and t-BuOK
increases basicity and/or nucleophilicity of organolithiums.
• TMEDA or HMPA deoligomerize hexameric n-BuLi in hexane
to kinetically more reactive monomer by coordination of Li+.
• DMPU (N,N-dimethylpropyleneurea): a good replacement
solvent for the carcinogenic HMPA
Alkyllithium and aryllithium reagents for metalation
• The commonly used lithium dialkylamides are LDA (lithium
diisopropylamide),LTMP (lithium 2,2,6,6-tetramethylpiperidide),
and LHMDS (lithium hexamethyldisilazide).
• available by reacting the appropriate amine with RLi reagent in
Et2O or in THF solvent
Alkyllithium and aryllithium reagents for metalation

™Chemoselectivity
• choice of the metalating agent is very crucial when substrate
molecule contains functional groups that can be attacked by
Alkyllithium and aryllithium reagents for metalation

™Chemoselectivity
• Interestingly, R2NLi reagents are generally more effective
metalating agents than the thermodynamically more basic RLi.
• The increased kinetic basicity of heteroatom bases may be
rationalized by the availability of free electron pair, which
permits formation of a four-centered transition state, thus
avoiding the free carbanion.

• similar transition state has been proposed for deprotonation of

ketones by R2NLi.
Alkyllithium and aryllithium reagents for metalation
™Benzylic Metalation
• preparation of benzyllithium from benzyl halides and RLi 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 benzyllithium 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.
Alkyllithium and aryllithium reagents for metalation
™Allylic Metalation
• reaction of allylic organometallics with electrophilic reagents is
a very important tool for C-C bond formation in acyclic systems
and for controlling their stereochemistry.
• Crotyl organometallic (2-butenylmetal) species undergo a 1,3-
shift of the metal at room temp.
• For stereocontrolled use of allylmetals in synthesis, it is
important to avoid their equilibration.
Alkyllithium and aryllithium reagents for metalation
™Allylic Metalation
• Treatment of propene or isobutylene with n-BuLi in Et2O in the
presence of TMEDA: convenient route to allyllithium and
methallyllithium, respectively.

• deprotonation rate of weakly acidic compounds by alkyllithiums

may be changed by several orders of magnitude by altering the
cation. Potassium tert-butoxide activates n-butyllithium
allowing metalation of allylic C–H bonds of olefins in the low
acidity range (pKa ~ 40).
Alkyllithium and aryllithium reagents for metalation
™ortho-metalation of substituted benzene
• Direct metalation of certain aromatic substrates permits
regioselective preparation of substituted benzene
• replacement of Csp2–H by organolithium reagents occurs at
ortho-position to a functional group with nonbonding e-, such
as N or O. Coordination of the Li reagent with N or O holds the
organolithium in proximity to the orthohydrogens
Alkyllithium and aryllithium reagents for metalation
™ortho-metalation of substituted benzene
• Because of the greater coordinating ability of nitrogen as
compared to oxygen, treatment of p-methoxy-N,N-
dimethylbenzylamine with n-BuLi results in metalation ortho to
the –CH2NMe2.
• However, in the presence of the strongly complexing TMEDA,
coordination Li with N of –CH2NMe2 is suppressed. In this
case, the most acidic proton ortho to the –OMe group is
removed preferentially.
Alkyllithium and aryllithium reagents for metalation
™ortho-metalation of heteroaromatic compounds
• Metalation of furan and thiophene with alkyllithium reagents
furnishes the corresponding 2-lithio derivatives.
• Example: treatment of 2-methylfuran with t-BuLi in THF,
followed by alkylation of the organolithium intermediate

• 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.
Metalation of 1-Alkynes
(Preparation of Lithium Alkynylides)

• filled sp orbital is lower in energy than filled sp2 or sp3 orbitals

since it is closer to the positively charged nucleus

• greater acidity to acetylene and 1-alkynes (pKa 24–26): bases

such as RLi, lithium dialkylamides, NaNH2 in liq. NH3, and
EtMgBr may be used to generate the alkynyl anions
Conjugate addition of lithium reagents
• RLi and ArLi usually attack C=O of α, β-unsat. carbonyl (1,2-
addition)
• conjugate addition (1,4-addition) is observed with very
hindered esters where approach to the carbonyl group is
impeded,
• Example: in 2,6-di-tert-butyl-4-methylphenyl esters (butylated
hydroxytoluene, BHT esters) and 2,6-di-tert-butyl-4-
methoxyphenyl esters (butylated hydroxyanisole; BHA esters).
 Organomagnesium compounds (RMgX)
• The Grignard reaction, reported in 1900 by Victor Grignard
provides the synthetic chemist with one of the most powerful
tools for connecting carbon moieties.

Victor Grignard
Developer of Grignard Reagent
Nobel Prize in Chemistry (1912)

• RMgX also serve as precursors for the preparation of other

organometallic reagents
RMgX- Preparations
™Alkyl Grignard reagents are prepared by the reaction of an
alkyl chloride, bromide, or iodide with
(1) “activated” magnesium turnings in Et2O or THF solvent

or (2) with Rieke magnesium. Although it is also in the metallic

state, Rieke magnesium differs from the bulk metal by being in
the form of highly reactive small particles with a large surface
area.
RMgX- Preparations
™Alkenyl and phenyl Grignard
• usually prepared from the corresponding bromides or iodides in
THF. In Et2O, Grignard reagents derived from (E)- and (Z)-
alkenyl halides are configurationally unstable, producing
mixtures of isomers.
RMgX- Preparations
™Allylic Grignard prepared from allylic halides and Mg, are
often accompanied by allylic halide coupling products.
• solved by using highly reactive Rieke-Mg or
• mixing the allylic halide, the aldehyde or ketone, and Mg
together (Barbier-type reaction). As Grignard reagent forms, it
reacts immediately with the electrophile before couple with
unreacted allylic halide.
RMgX- Preparations
™Alkynyl Grignard
• obtained by deprotonation of 1-alkynes with EtMgBr in THF.
• For prep. of ethynylmagnesium bromide (HC≡CMgBr), a
solution of ethylmagnesium bromide in THF is slowly added to
a cooled solution of THF containing the acetylene.
 RMgX- Preparations
• actual mechanism(s) for the formation of the reagents and their
structures are still not completely understood (although 100
years have passed since Grignard published the preparation of
ethereal solutions of organomagnesium halides!)
• The overall reaction for the formation of Grignard reagents
involves an insertion of magnesium into the carbon-halogen
bond via an oxidative addition, thereby changing its oxidation
state from Mg(0) to Mg(II).

• It is generally accepted that the structure of RMgX can be

represented by the Schlenk equilibrium.
Reactions of Grignard with carbonyl compounds
• Grignard reagents are capable of Nu- addition to hetero double
bonds such as those in carbonyl compounds. The carbonyl
reactivity toward Grignard reagents decreases in the order

aldehyde > ketone > ester > amide

• high reactivity of Grignard reagents toward carbonyl groups is

due primarily to the polarization of the C=O π-bond and the
weak C–Mg bond.
• Additions of Grignard reagents to carbonyl groups may proceed
either via a polar-concerted or a stepwise electron-transfer
mechanism.
Reactions of Grignard with carbonyl compounds
• possible mechanistic scheme for the polar-concerted reaction
of a Grignard reagent with an aldehyde or a ketone

• Coordination of the Lewis acidic magnesium to the Lewis basic

carbonyl oxygen further polarizes the carbonyl group while
enhancing the nucleophilicity of the R group.
Utilization of Organomagnesium reagents
• Organomagnesium reagents react with a wide variety of
organic substrates to form carbon-carbon bonds
Utilization of Organomagnesium reagents
• In spite of versatility and broad synthetic utility of the Grignard
reaction for C-C bond formation, it is often accompanied by
competing side reactions such as enolization, reduction, or
aldol condensation of the carbonyl substrate.
• Organomagnesium compounds can act not only as
nucleophiles, but also as bases
• It can convert ketones with enolizable hydrogens to the
corresponding magnesium enolates. Loss of the carbanion
moiety as R–H and hydrolytic workup leads to the starting
ketone.
Utilization of Organomagnesium reagents
• If the Grignard reagent has H in the β-position, reduction of the
C=O group by hydride transfer may compete with the addition
reaction

• To suppress these side reactions, use the smallest-possible

group for the Grignard reagent, or use the corresponding
lithium reagents, which give less reduction and enolization
products.
Utilization of Organomagnesium reagents
Utilization of Organomagnesium reagents
™Limitations
• Certain functional groups present in a molecule interfere with
the preparation of Grignard reagents.
• –NH, –OH, and –SH groups will protonate the Grignard reagent
once it is formed.
• C=O and CN groups attached to molecule containing the
halogen substituent will undergo addition reactions.
• iodine-Mg exchange functionalized ArI and heteroaryl iodides:
produce functionalized Grignard reagents at low temperature.