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Chapter 14: Organometallic Compounds - Reagents with -metal bonds 14.1: Organometallic Nomenclature (please read)

H H C C - + H3CH2CH2CH2C-Li (H3C)2Cu Li H MgBr Butyllithium vinylmagnesium bromide Dimethylcopper

14.2: Carbon-Metal Bonds in Organometallic Compounds

C X C MgX

- + !+ !- ! ! _ C X C MgX C

Alkyl halides: : react with 302

Alkyl halides will react with some metals (M0) in or THF to form organometallic reagents 14.3: Preparation of Organolithium Compounds Organolithium Compounds

2 Li(0) R-X R-Li + LiX

- + ! ! _ very strong bases C Li C very strong organolithium reagents are most commonly used as very strong bases and in reactions with carbonyl compounds

M(0) H O R-X R-M 2 R-H + M-OH 303

1 14.4: Preparation of Organomagnesium Compounds: Grignard Reagents Mg(0) R-X R-MgX () THF R-X can be an alkyl, vinyl, or (chloride, bromide, or iodide)

Solvent: diethyl ether (Et2O) or (THF)

H CH C CH CH 3 2 O 2 3 O

diethyl ether (Et2O) tetrahydrofuran (THF)

Alcoholic and water are incompatible with Grignard reagents and organolithium reagents. Reactivity of the alkyl halide: -I > -Br > -Cl >> -F

alkyl halides > vinyl or aryl halides 304

The or alkyl halides can not contain functional groups that are electrophilic or acidic. These are incompatible with the formation of the organomagnesium or .

Grignard reagents will deprotonate

0 _ Mg + H3O HO Br HO MgBr O H HO H _ BrMg

Other incompatible groups:

-CO2H, -OH, -SH, NH2, CONHR ()

Reactive functional groups: , , , amides, halides,

-NO2, -SO2R, nitriles

305

2 14.5: Organolithium and Organomagnesium Compounds as Brønsted Bases - Grignard reagents (M = MgX) and organolithium reagents (M = Li) are very strong bases.

R-M + H2O R-H + M-OH pKa pKa

(CH3)3C-H 71 H2N-H 36

H3CH2C-H 62 H C C H 26

H3C-H 60 Water 16 H H C C 45 H H H H

H H 43 H H are very weak ; their conjugate bases are very strong bases. 306

Lithium and THF + R C C H H3C-H2C-H2C-H2C-Li R C C Li + H3C-H2C-H2C-H2C-H terminal butyllithium pK > 60 lithium a (pKa ~ 26)

THF + R C C H H3C-H2C-MgBr R C C MgBr + H3C-H2C-H ethylmagnesium magnesium bromide acetylide 14.6: Synthesis of Alcohols Using Grignard Reagents Grignard reagents react with aldehydes, ketones, and esters to afford alcohols

MgX MgX ! - + O O ether O H3O OH ! + R: C C C C R R

307

3 Grignard reagents react with . . .

(H2C=O) to give primary alcohols

Br 0 1) H2C=O Mg , ether MgBr + 2) H3O OH

aldehydes to give secondary alcohols O OH Br Mg0, ether MgBr 1) H + 2) H3O ketones to give tertiary alcohols OH H H 0 H H O Mg , ether 1) C C C C + H Br H MgBr 2) H3O esters to give tertiary alcohols O C OH OCH2CH3 0 2 Mg , ether 1) C CH 2 H C-Br 2 H C-MgBr 3 3 3 CH3 + 2) H3O 308

14.10: Preparation of Tertiary Alcohols From Esters and Grignard Reagents - mechanism:

O 1) THF OH + C 2) then H3O + C OCH2CH3 2 H3C-MgBr CH3 CH3

Reaction of Grignard reagents with CO2 (Lab, Chapter 19.11) _ O O O OH Br MgBr + Mg(0) O=C=O H3O

ether 309

4 14.7: Synthesis of Alcohols Using Organolithium Reagents Organolithium reagents react with aldehydes, ketones, and esters in the same way that Grignard reagents do. Li + O ether O H3O OH + R-Li C C C R R 14.8: Synthesis of Acetylenic Alcohols

+ R C C H + NaNH2 R C C Na + NH3

pKa~ 26 pKa~ 36

+ R C C H + H3C(H2C)H2C-Li R C C Li + H3C(H2C)CH3

pKa > 60

+ R C C H + H3CH2C-MgBr R C C MgBr + H3CCH3

pKa > 60

310

Recall from Chapter 9.6

_ THF Na + + R C C CH R + NaBr R1 C C R2-H2C-Br 1 2 2 SN2 acetylide anion 1° alkyl halide new C-C bond formed

Acetylide anions react with ketones and aldehydes to form a C-C bond; the product is an acetylenic (propargyl) alcohols

OH O THF _ + + R1 C C C R1 C C MgBr C + R3 R2 R3 then H3O R2 acetylenic

311

5 14.9: Retrosynthetic Analysis - the process of planning a synthesis by reasoning backward from the the target to a starting compound using known and reliable reactions.

“it is a problem solving technique for transforming the structure of a synthetic target molecule (TM) to a sequence of progressively simpler structures along the pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis.” The transformation of a molecule to a synthetic precursor is accomplished by: Disconnection: the reverse operation to a synthetic reaction; the hypothetical cleavage of a bond back to precursors of the target molecule. Interconversion (FGI): the process of converting one functional group into another by substitution,

addition, elimination, reduction, or oxidation 312

Each precursor is then the target molecule for further retrosynthetic analysis. The process is repeated until suitable starting materials are derived.

Target Precursors Precursors Starting molecule 1 2 materials

Prepare (Z)-2-hexene from acetylene

Z-2-hexene

2-Phenyl-2-propanol OH CH3 CH3

313

6 14.11: Synthesis Using Organocopper Reagents

ether H3C _ + 2 CH3Li + CuI Cu Li + LiI H3C Gilman's reagent (dimethylcuprate, dimethylcopper lithium)

- R2CuLi = R strong nucleophiles Nucleophilic substitution reactions with alkyl halides and sulfonates () H C(H C) H C-I + (H C) CuLi H C(H C) H C-CH 3 2 8 2 3 2 ether 3 2 8 2 3 + CH3Cu + LiI

SN2 reaction of cuprates is best with primary and secondary alkyl halides; tertiary alkyl halides undergo E2 elimination.

314

Vinyl and aryl (but not acetylenic) cuprates

(0) Br 4 Li , ether Li CuI 2 2 CuLi 2

Br Li CuLi 4 Li(0), ether CuI 2 2

THF CuLi + OTs 2

CuLi THF + I 2

315

7 Reaction of cuprates with aryl and vinyl halides

H H (H3C)2CuLi double bond geometry I CH3 is preserved H H

Br CH2CH2CH3 (H3CH2CH2C)2CuLi

14.13: and Carbenoids : highly reactive intermediate, 6-electron species. The carbon is sp2 hybridized; it possesses a vacant hybridized p-orbital and an sp2 orbital with a non-bonding pair of electrons

316

Generation and Reaction of Dihalocarbenes:

CHCl3 + KOH Cl2C: + H2O + KCl dichlorocarbene Carbenes react with to give .

Cl Cl H H CHCl3, KOH H H R R R R

cis- cis-

Br Br H R CHBr3, KOH H R R H R H

trans-alkene trans-cyclopropane The reaction takes place in a single step. There is NO intermediate. As such, the geometry of the alkene is preserved in the product. Groups that are trans on the alkene will end up trans on the cyclopropane product. Groups that are cis on the alkene will end up cis on the cyclopropane product. 317

8 14.12: An Organozinc Reagent for Cyclopropane Synthesis Simmons-Smith Reaction ether CH2I2 + Zn(Cu) I-CH2-Zn-I = H2C: carbene H CH2I2, Zn(Cu)

ether H The geometry of the alkene is preserved in the cyclopropanation reaction. CH I , Zn(Cu) H H 2 2 H H R R ether R R

cis-alkene cis-cyclopropane

CH I , Zn(Cu) H R 2 2 H R R H ether R H

trans-alkene trans-cyclopropane 318

14.14: Transition-Metal Organometallic Compounds (please read) 14.15: Homogeneous Catalytic (please read)

H2, Pd/C - The catalyst is insoluble in the reaction media: heterogeneous , interfacial reaction

H2, (Ph3P)3RhCl - The catalyst is soluble in the reaction media: homogeneous catalysis. 14.16: (please read) 14.17: Ziegler-Natta Catalysis of Alkene Polymerization (please read)

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