sign in sign up
<<
Home , Alkylation, Grignard reaction, Grignard reagent, Metalation, Transmetalation

OrganometallicOrganometallic 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

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

• ? Organometallic 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 OrganometallicOrganometallic Compounds Compounds • Compounds that contain a Metal-Carbon bond

• e.g. Tetraethyllead – as additive in • General formula R-M (R = , M = metal) • The C-M bond is a polarized covalent bond OrganometallicOrganometallic Compounds Compounds

• Great source for anionic carbon species ()

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 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 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 – 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 , and of complexes with solvent if 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 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 and Li-H exchange () reactions: usually not a problem.

– Caution: when using TMEDA (tetramethylethylenediamine) as a promoter for Li-X exchange, since it accelerates 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 . RLi- Preparations Organolithiums via Lithium–Metal Exchange • : 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 . 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 . • most important measure of stability is acidity of corresponding

carbon . 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

– —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 ), and various additives can greatly alter their reactivity. • addition of chelating agents: TMEDA, HMPA (hexamethyl phosphoramide), 3o , 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 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 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

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 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 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 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- (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 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 where approach to the 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 , reported in 1900 by provides the synthetic chemist with one of the most powerful tools for connecting carbon moieties.

Victor Grignard Developer of (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” 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 or , 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 , 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 > >

• 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 , 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. • -Mg exchange functionalized ArI and heteroaryl iodides: produce functionalized Grignard reagents at low temperature.