Organometallic Compounds B.Sc. III Organic Chemistry

Organometallic Compounds Organometallic compound: a compound that contains a carbon-metal bond In this chapter, we focus on organometallic compounds of Mg, Li, and Zn these classes illustrate the usefulness of organometallics in modern synthetic organic chemistry they illustrate how the use of organometallics can bring about transformations that cannot be accomplished in any other way

Organometallic Reagents The Key Concepts: Make a carbon negatively charged/polarlized so it is nucleophilic. Reaction with electrophilic carbons can make carbon-carbon bonds. This is a Big Deal!

Grignard Reagents Discovered by Victor Grignard in 1900 The First Organometallic Reagents… Grignard Reagents Discovered by Victor Grignard in 1900 Key factors are ethereal solvent and water-free conditions Awarded Nobel Prize in 1912 Victor Grignard Grignard, Victor , 1871–1935, French chemist. He shared the 1912 Nobel Prize in Chemistry for his work in organic synthesis based on his discovery (1900) of the Grignard Reagent. He taught at the Univ. of Nancy (1909–19) and at the Univ. of Lyons (from 1919 until the end of his career).

Grignard Reagents Grignard reagent: an organomagnesium compound prepared by addition of an alkyl, aryl, or alkenyl (vinylic) halide to Mg metal in diethyl ether or THF ether B r + M g M g B r 1-Bromobutane Butylmagnesium bromide (an alkyl Grignard reagent) ether B r + M g M g B r Bromobenzene Phenylmagnesium bromide (an aryl Grignard reagent)

An Alternative to Grignard Reagents are Alkyl Lithiums Both are prepared from alkyl, vinyl, and aryl halides under anhydrous conditions

Grignard and Organolithium Reagents Given the difference in electronegativity between carbon and magnesium (lithium), the C-Mg (C-Li) bond is polar covalent, with C- and Mg+ ( Li+ ) Grignard and organolithium reagents behave like carbanions Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge 23 23 23

Grignard and Organolithium Reagents Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge Carbanions are strong bases--they are easily quenched by even very weak acids (water, alcohols, amines, amides, carboxylic acids, even terminal alkynes). A limitation to utility! 23 23 23

Grignard and Organolithium Reagents Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge Carbanions are strong bases--they are easily quenched by even very weak acids (water, alcohols, amines, carboxylic acids, amides, even terminal alkynes). A limitation to utility! 23 23 23

Limitations Can’t make Grignards with acidic or electro-philic functional groups present in the molecule: R2NH pKa 38-40 Terminal Alkynes pKa 25 ROH pKa 16-18 Carbonyls & Nitros pKa 11-27

Grignard and Organolithium Reagents Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge Carbanions are also great nucleophiles. This is the reason for their great utility!

Key Point: Grignard and Organolithium Reagents Great nucleophiles that add efficiently to electrophilic carbons, such as epoxides and carbonyl group of aldehydes, ketones and esters. However, their basicity can be a limitation! Epoxides illustrate how many common organic functional groups contain electrophilic carbons 23 23 23

Grignard and Organolithium Reagents Carbanions (nucleophiles) can react with electrophilic carbon centers in favorable cases. The net result is a carbon-carbon bond--a big deal! Grignards and organolithium reagents react with many oxygen-containing electrophiles, but not with alkyl halides. We’ll illustrate this with epoxides. Recall, acidic protons will “kill” our reagents and/or won’t allow them to be generated in the first place 23 23 23

Grignard reagents react productively with: formaldehyde to give primary alcohols aldehydes to give secondary alcohols ketones to give tertiary alcohols esters to give tertiary alcohols CO2 to give acids epoxides to give primary alcohols The one we are choosing for the sake of initial illustration

Epoxides: The Example We Want to Stress New C-C bond d+ d- Considered Retrosyn- thetically: These is an extremely valuable reaction…

Detailed Mechanism Highlighting Retention of Stereochemistry A Related Example Detailed Mechanism Highlighting Retention of Stereochemistry New C-C bond Key Points to Note: Attack at least hindered carbon Mechanism is SN2-like in initial step Single enantiomeric product Chiral center not affected by reaction Relief of ring strain helps drive reaction H3O+ breaks up initial salt

Two More Examples of Additions to Epoxides New C-C bond New C-C bond Note: Stereochemistry at epoxide retained in product

Gilman Reagents Lithium diorganocopper reagents, known more commonly as Gilman reagents prepared by treating an alkyl, aryl, or alkenyl lithium compound with Cu(I) iodide

Gilman Reagents Coupling with organohalogen compounds Example form new carbon-carbon bonds by coupling with alkyl and alkenyl chlorides, bromides, and iodides. (Note that this doesn’t work with Grignard or organolithium reagents. THEY ARE TOO BASIC AND DO E2 ELIMINATIONS.) Example New C-C bond

Gilman Reagents coupling with a vinylic halide is stereospecific; the configuration of the carbon-carbon double bond is retained New C-C bond

Gilman Reagents A variation on the preparation of a Gilman reagent is to use a Grignard reagent with a catalytic amount of a copper(I) salt

Gilman Reagents Reaction with epoxides regioselective ring opening (attack at least hindered carbon) New C-C bond

Interim Summary of Introduction to Organometallic Reagents… Organolithium reagents and Grignard reagents are very basic but also great nucleophiles. They react with epoxides at the less hindered site to give a two-carbon chain extended alcohol. They do not couple with alkyl-, aryl-, or vinyl halides. Gilman reagents react with epoxides as do organolithium reagents and Grignard reagents. However, they also add to alkyl-, aryl-, and vinyl halides to make new C-C bonds.

Back to Grignard Reagents… Addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol This sequence (mechanism) is general and important! 24 24 24

Grignard Reactions These are valuable and important reactions… Please add to your card stock!

Grignard reagents react with esters OCH3 •• R' diethyl ether d+ R C OCH3 •• d– R MgX C + O O •• • • MgX • • •• – but species formed is unstable and dissociates under the reaction conditions to form a ketone 23

Grignard reagents react with esters OCH3 •• R' diethyl ether d+ R C OCH3 •• d– R MgX C + O O •• • • MgX • • •• – –CH3OMgX this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol C O R R' • • •• 23

Example O + 2 CH3MgBr (CH3)2CHCOCH3 1. diethyl ether 2. H3O+ Two of the groups attached to the tertiary carbon come from the Grignard reagent OH (CH3)2CHCCH3 CH3 (73%) 26

Practice

Practice

O + H2C CHLi CH 1. diethyl ether 2. H3O+ CHCH CH2 (76%) OH The Same Chemistry is seen With Organolithium Reagents O + H2C CHLi CH 1. diethyl ether 2. H3O+ CHCH CH2 (76%) OH

Practice

Other Organometallic Reagents We can also make R-Zn, R-Sb, R-As, R-Be, R-Ca, R-Hg, R-Sn, … reagents. We choose other metals for different degrees of reactivity and for greater selectivity. Organozinc reagents are used in synthesis owing to their greater selectivity (see J. Vyvyan)

• The first organozinc ever prepared = diethylzinc (Et2Zn), by Edward Frankland in 1849, was also the first ever compound with a metal to carbon sigma bond. • Many organozinc compounds are pyrophoric and therefore difficult to handle. • Organozinc compounds in general are sensitive to oxidation, dissolve in a wide variety of solvents where protic solvents cause decomposition. • In many reactions they are prepared in situ. All reactions require inert atmosphere: N2 or Ar • The three main classes of organozincs are: organozinc halides R-Zn-X with, diorganozincs R-Zn-R, and lithium zincates or magnesium zincates M+R3Zn- with M = lithium or magnesium Organozinc

Preparations • Primary and secondary alkylzinc iodides (RZnI) are best prepared by direct insertion of zinc metal (zinc dust activated by 1,2-dibromoethane or chlorotrimethylsilane) into alkyl iodides or by treating alkyl iodides with Rieke zinc. The zinc insertion can tolorate a lot of functional groups, allowing preparation of polyfunctional organozinc reagents.

Unfunctionalized dialkylzincs (R2Zn) are obtained by transmetalation of zinc halides, such as ZnCl2, with organolithium or Grignard reagents. • Iodide-zinc exchange reactions catalyzed by CuI provide a practical way for preparing functionalized dialkylzincs. • Diorganozincs are always monomeric, the organozinc halides form aggregates through halogen bridges

Dialkylzinc (R2Zn) • Alkyl group exchange between diethylzinc and diiodomethane produces the iodomethyl zinc carbenoid species, tentatively assigned as EtZnCH2I (Furukawa’s reagent). oxidative addition of Zn metal to diiodomethane affords an iodomethylzinc iodide, tentatively assigned as ICH2ZnI (Simmons-Smith reagent), which is used for cyclopropanation of alkenes.

Reaction of Organozinc compounds The Reformatsky Reaction • involves condensation of ester-derived zinc enolates with aldehydes or ketones to give corresponding β-hydroxy esters. • zinc enolates are generated by addition of an α-haloester in THF, DME, Et2O, benzene, or toluene to an activated zinc, such as a Zn-Cu couple or zinc obtained by reduction of zinc halides with potassium (Rieke zinc).

Reactions of functionally substituted RZnI • application of functionally substituted organozincs allows for construction of C-C bonds while circumventing tedious protection-deprotection strategies.

Reactions of functionally substituted RZnI Note that tosyl cyanide reacts with alkenyl or arylzinc reagents to provide α,β-unsaturated alkenyl or aromatic nitriles, respectively

Reaction of Organozinc compounds Cyclopropanation • Cyclopropane rings are encountered in many natural products possessing interesting biological activities. • Cyclopropane moiety represents a useful synthon for further synthetic transformations. • In 1958, Simmons and Smith reported that treatment of a zinccopper couple with diiodomethane in ether produces a reagent that adds to alkenes to form cyclopropanes.

The cyclopropanation reaction of simple alkenes appears to proceed via stereospecific syn-addition of a Zn-carbenoid (carbene-like species) to the double bond without the involvement of a free carbene.

stereospecific syn-addition of Zn-carbenoid to the double bond

Cyclopropanation modifications of Simmons-Smith : • Furukawa’s reagent, (iodomethyl)zinc derived from diethylzinc and diiodomethane, or its modification using chloroiodomethane instead of diiodomethane, allows more flexibility in the choice of solvent. • The reagent is homogeneous and the cyclopropanation of olefins can be carried out in noncomplexing solvents, such as dichloromethane or 1,2-dichloroethane, which greatly increase the reactivity of the zinc carbenoids.

Directed Simmons-Smith Cyclopropanation • A particularly interesting aspect of the Simmons-Smith reaction is the stereoelectronic control exhibited by proximal OH, OR groups, which favor cyclopropanation to occur from the same face of the double bond as the oxy substituents. • order of decreasing directive effects : OH > OR > C=O