wb-2008-ureg-1-gen li mg - uni- · pdf file• organolithium reagents react with a wide...

Organometallic ChemistryOrganometallic Chemistry

Worawan BhanthumnavinDepartment of Chemistry

Chulalongkorn UniversityBangkok 10330, Thailand

Given as part of the 6th semester organic chemistry courseat 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 CompoundsOrganometallic 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 CompoundsOrganometallic 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

• 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

Alkyl metals – polarized R-M

Polarized bond

• For organometallics with the same metal component, reactivity increases with decreasing “s” character.

Reactivity- the carbanion part

• Alkyl groups: slightly electron donating• They destabilize the carbanion; therefore reactivity increases


• Electron withdrawing groups help to stabilize the negative charge therefore decrease reactivity.


• Reactivity is determined by nature of organometallic species;• Both carbanion and metal parts contribute to reactivity.


• 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 ENdifference 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,

Reactivity- the metal part

M-C bond strengths

Materials covered here:

• Organolithium• Organomagnesium• Organozinc• Organocopper• Organoboron• Organosilicon

Organometallic compounds

• 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

Organolithium compounds (RLi)

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)


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


Transmetallation• RMgX is less reactive than RLi


• Comparing to GrignardRLi- 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

RLi- Preparations

• 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.

Organolithiums via Lithium–Halogen ExchangeRLi- Preparations

• 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.


– 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 formedin situ.


– (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)


– Alkenyllithium reagents: used for stereospecific syntheses of alkenes and functionally substituted alkenes.


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.


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.

Organolithiums via Lithium–Metal ExchangeRLi- Preparations

• Transmetalation: used to prepare allylic, benzylic, and propargylic lithium reagents (difficult to obtain by other routes)

• conversion of readily available allylic Grignard into the allyliclithium 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.

Organolithiums via Lithium-Hydrogen ExchangeRLi- Preparations

• 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


• 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

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 (hexamethylphosphoramide), 3o amines, crown ethers, and t-BuOKincreases 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


Chemoselectivity• choice of the metalating agent is very crucial when substrate

molecule contains functional groups that can be attacked by


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.


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.


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 metalationAllylic 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 alkyllithiumsmay be changed by several orders of magnitude by altering the cation. Potassium tert-butoxide activates n-butyllithiumallowing metalation of allylic C–H bonds of olefins in the low acidity range (pKa ~ 40).

Alkyllithium and aryllithium reagents for metalationortho-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 metalationortho-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 metalationortho-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 orbitalssince 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 (butylatedhydroxytoluene, BHT esters) and 2,6-di-tert-butyl-4-methoxyphenyl esters (butylated hydroxyanisole; BHA esters).

• The Grignard reaction, reported in 1900 by Victor Grignardprovides the synthetic chemist with one of the most powerful tools for connecting carbon moieties.

• RMgX also serve as precursors for the preparation of other organometallic reagents

Organomagnesium compounds (RMgX)

Victor GrignardDeveloper of Grignard ReagentNobel Prize in Chemistry (1912)

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 surfacearea.

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.

• 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 Grignardreaction 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 carbanionmoiety as R–H and hydrolytic workup leads to the starting ketone.


• 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 enolizationproducts.


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.


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