Organometa llic Compounds Orggpanometallic Compounds • Organometallic compound: a compound that contains a carbon -metal bond • In this chapter, we focus on organometallic compounds of Mg, Li, and Cu – 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 accomplish ed i n any oth er way Organometallic Reagents

The Key Concepts: Make a carbon negatively chd/llidharged/polarlized so it is nucleop hilic. Reaction with electrophilic carbons can make carbon‐carbon bonds.

This is a Big Deal! 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 Br + Mg MgBr 1‐BbtBromobutane BtlButylmagnesi um bidbromide (an alkyl Grignard reagent) eth er Br + Mg MgBr

Bromobenzene Phenylmagnesium bromide (an aryl Grignard reagent) An Alternative to Grigggnard Reagents are Alk yl Lithiums

Both are prepared from alkyl, vinyl, and aryl halides under anhydrous conditions

dryether + Mgo Br or MgBr tetrahydrofuran n-butyl bromide (THF) Grignard Reagent

recall: THF = O

dryether + 2 Lio Br or Li tetrahydrofuran n-butyl bromide (THF) alkyl lithium + LiBr Grignard and Organolithium Reagents

• Given the difference in electronegativity between carbon and magnesium (lithium), the C‐Mg (C‐Li) bond is polar covalent, with Cδ‐ and Mgδ+ ((LiLiδ+ ) – Grignard and organolithium reagents behave like carbanions

• Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge

- δ- δ + δ+ δ MgBr Li

Grignard Reagent alkyl lithium 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!

δ- pKa = ca. 50 δ+ δ- δ+ alkane corresponding MgBr + OH to original alkyl halide + GrignardReagent pKa = 16

O- MgBr+ 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!

δ- pKa = ca. 50 δ+ δ- δ+ alkane corresponding + Li NH2 to original alkyl halide + alkyl lithium pKa = 40

NH- Li+ Limitations

• Can’t make Grignards with acidic or electro‐philic filfunctional groups present in the molllecule: •

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 negggative charge – Carbanions are also great nucleophiles. This is the reason for their ggyreat 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 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 ooygexygen‐con tainin g eectopelectrophiles, but not with aaylkyl 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 Grignard reagents react productively with:

formaldehyde to give primary alcohols aldeh yd es to gidlhlive secondary alcohols ketones to give tertiary alcohols esters to ggyive tertiary alcohols

CO2 to give acids epoxides to give primary alcohols The one we are choosing for the sake of initial illustration Epppoxides: The Example We Want to Stress New C-C bond + δ- MgBr δ - + O MgBr + OH O H3O THF Dilute

OH MgBr Considered RtRetrosyn- + O thetically: Detailed Mechanism Highlighting Retention of Stereochemistry

New C-C bond

Key Points to Note: Attack at least hindered carbon

MhiMechanism iSNis SN2-like in in itia l s tep 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

1. δ- O New δ- C-C δ+ δ+ bond MgBr 2. HCl, H2O Grignard Reagent OH

New C-C 1. δ- O bond OH δ- + δ+ δ Li H H H H

Organolithium Reagent 2. HCl, H2O 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

diethyl ether 2CH CH CH CH Li + CuI 3 2 2 2 or THF Butyllithium Copper(I) iodide

- + (CH3 CH2 CH2 CH2 ) 2 Cu Li + LiI Lithium dib utyl t lcopper (a Gilman reagent) Gilman Reagents • Coupling with organohalogen compounds – 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.)

diethyl ether R'Br + R CuLiBr R'-R ++RCu LiBr 2 or THF •Example 1. Li, pent ane I CuLi 2. CuI 2 1-Iododecane New diethyl ether C-C Br or THF bond

2-Methyl-1-dodecene Gilman Reagents

– coupling with a vinylic halide is stereospecific; the configuration of the carbon-carbon double bond is retained

+ diethyl ether I CuLi New 2 or THF t rans-1-Iodo-1-nonene Lithium C-C dibutylcopper bond

trans-5-Tridecene Gilman Reagents

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

CH (CH ) 3 2 7 (CH2 ) 7 CH 2 Br Cu+ CC + CH (CH ) Mg Br 3 2 4 THF H H (Z)-1-Bromo-9-octadecene CH3 (CH2) 7 (CH2 ) 12CH3 CC HH (Z)-9-Tricosene (Muscalure) Gilman Reagents

• Reaction with epoxides – regggpgioselective ring opening (attack at least New hindered carbon) C-C bond O OH

1. (CH2 =CH)2 CuLi

2. H2 O, HCl Styrene oxide 1-Phenyl-3-buten-1-ol (racemic) (racemic) 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 alky l‐, aryl‐, and viilnyl ha lides to make new C‐C bonds. Feeling Lost?

Fortunately, Dr. Iverson will be back on Monday! Meanwhile…. Back to Grignard Reagents…

• Addition of a Grignard reagent to formaldehyde + followed by H3O gives a 1° alcohol

H H H - + + +2 - + H3O CH CH MgBr C O CH3CH2 C O MgBr CH3CH2 C OH + Mg 3 2 THF H H dil. H

• This sequence (mechanism) is general and important! GiGrignar dRd Reacti ons

- + + +2 - + H3O CH CH MgBr O CO CH3CH2 C O MgBr CH3CH2 COH+ Mg 3 2 THF O dil. O

These are valuable and important reactions… Please add to your card stock! Grignard reagents react with esters

R' R' •• δ+ OCH3 diethyl δ– •• •• R C ether R C OCH •• 3 + MgX O• •O• MgX •• • •• –

but species formed is unstable and dissociates under the reaction conditions to form a ketone Grignard reagents react with esters

R' R' •• δ+ OCH3 diethyl δ– •• •• R C ether R C OCH •• 3 + MgX O• •O• MgX •• • •• –

–CH OMgX this ketone then goes on 3 to react with a second R mole of the Grignard R' reagent to give a tertiary C alcohol • O• •• Example O

2 CH3MgBr + (CH3)2CHCOCH3 11.. diethyl ether

+ 22.. H3O

Two of the groups OH attachdhed to the tertiary carbon come (CH3)2CHCCH3 from the Grignard reagent CH3 ((7373%)%) Practice

OH

MgBr O + HH Practice

OH MgBr

+ O

O MgBr + H H The Same Chemistry is seen With Organolithium Reagents

O

H2C CHLi + CH

1. diethyl ether

+ 22.. H3O

CHCH CH2

OH (76%) Practice

O

OH MgBr + O CO