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Home , Gilman reagent, Grignard reagent, Organozinc compound

Organic Lecture Series

OrganometallicOrganometallic CompoundsCompounds (Chapter 15)

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Organic Lecture Series Organometallic compound

• Organometallic compound: a compound that contains a -metal bond • The focus will be on organometallic compounds of Mg, Li, and Cu – these classes illustrate the usefulness of organometallics in modern synthetic organic – the use of organometallics can bring about transformations that cannot be accomplished in any other way

2 Organic Lecture Series

Organometallic reagents have 2 general types of reactions: 1. As Strong bases (Bronsted-Lowry) 2. As nucleophilic reagents.

Regard the group as “R-”

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Organic Lecture Series Grignard Reagents

• : an organomagnesium compound – prepared by addition of an alkyl, aryl, or alkenyl (vinylic) to Mg metal in diethyl or THF

4 Organic Lecture Series

Preparation of Grignard reagents:

ether Br + Mg MgBr 1-Bromobutane Butylmagnesium bromide (an alkyl Grignard reagent)

ether Br+ Mg MgBr

Bromobenzene (an aryl Grignard reagent)

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Organic Lecture Series

• Grignard reagents dissolve as coordination compounds solvated by ether – ethylmagnesium bromide, EtMgBr

6 Organic Lecture Series Organolithium reagents

• Organolithium reagents – prepared by reaction of an alkyl, aryl, or alkenyl halide with metal

pentane Cl + 2LiLi + LiCl 1-Chlorobutane Butyllithium

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Organic Lecture Series The carbon-metal bonds in RMgX and RLi are polar covalent

C-M Difference in Percent Ionic Bond character* C-Li 2.5 - 1.0 = 1.5 60 Increasing Ionic C-Mg 2.5 - 1.2 = 1.3 52 Character C-Al 2.5 - 1.5 = 1.0 40 C-Zn 2.5 - 1.6 = 0.9 36 C-Sn 2.5 - 1.8 = 0.7 28 Stronger C-Cu 2.5 - 1.9 = 0.6 24 C-Hg 2.5 - 1.9 = 0.6 24

EC -EM *Percent ionic character = x 100 EC 8 Organic Lecture Series • Reaction with proton donors: – RMgX and RLi are strong bases

δ- δ+ δ+ δ- + 2+ - - pK = -35 CH3 CH 2 -MgBr + H-OH CH3 CH 2 -H Mg ++OH Br eq Stronger pKa 15.7 pKa 51 Weaker base Stronger Weaker base acid acid – they react readily with these proton acids

R2 NHRC CH ROH HOH ArOH RSH RCOOH pKa 38-40 pKa 25 pKa 16-18 pKa 15.7 pKa 9-10 pKa 8-9 pKa 4-5 1° and 2° Terminal Water Phenols Carboxylic Amines acids

This is often an undesired side reaction-to be avoided!! 9

Organic Lecture Series Organometallic reagents have 2 general types of reactions: 1. As Strong bases (Bronsted-Lowry) 2. As nucleophilic reagents:

CH3 CH2 CH2 MgBr

Regard the alkyl group as “R-”

10 Organic Lecture Series Organometallic reagents • RMgX and RLi are valuable in synthesis as – the carbon bearing the is transformed from an to a nucleophile

carbon is an carbon is a electrophile nucleophile H H H δ+ δ- H CBr C - Mg 2+ Br -

CH3 CH2 CH2 CH3 CH2 CH2

– their most valuable use is addition to the electrophilic carbon of C=O groups of , , carboxylic , and acid chlorides to form a new carbon-carbon bonds 11

Organic Lecture Series General Reactions of Grignard Reagents

O OH 1) R" Mg X C C + R R(H) 2) H3O R R(H) R"

12 Organic Lecture Series

• Reaction with oxiranes (epoxides) – reaction of RMgX or RLi with an oxirane followed by protonation gives a primary with a carbon chain two longer than the original chain

MgBr + O

Butylmagnesium bromide oxide

O MgBr + OH A 1-Hexanol

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Organic Lecture Series • Reaction with oxiranes (epoxides)

– the major product corresponds to SN2 attack of RMgX or RLi on less hindered carbon of the epoxide

MgBr + O Phenyl- Methyloxirane magnesium (Propylene oxide) bromide (racemic)

HCl - + O MgBr H2 O OH A magnesium 1-Phenyl-2-propanol alkoxide (racemic) 14 A Simple Example: Organic Lecture Series MgBr O O H OH

H 3 C CH3 H 3 C CH3

CH3 CH2 CH2 CH3 CH2 CH2 MgBr alkoxide

O H

H C CH H 2 O 3 3 MgBrOH Mg(OH)2 CH3 CH2 CH2 alcohol 15

Organic Lecture Series 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

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

- + (CH3 CH2 CH2 CH2 ) 2 Cu Li + LiI Lithium dibutylcopper (a ) 16 Organic Lecture Series Coupling within organohalogen compounds – form new carbon-carbon bonds by coupling with alkyl chlorides, bromides, and iodides

diethylether R'Br + R CuLi R'-R ++RCu LiBr 2 or THF

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Organic Lecture Series Coupling within organohalogen compounds – form new carbon-carbon bonds by coupling with alkenyl chlorides, bromides, and iodides

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1. Li, pentane I CuLi 2. CuI 2 1-Iododecane diethyl ether Br or THF

2-Methyl-1-dodecene 18 Organic Lecture Series coupling with a vinylic halide is stereospecific: the configuration of the carbon-carbon double bond is retained

diethyl ether I + CuLi 2 or THF trans-1-Iodo-1-nonene Li thi u m dibutylcopper

trans-5-Tridecene

R R

+ R2CuLi etherorTHF X R 19

Organic Lecture Series

• A variation on the preparation of a Gilman reagent 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)

20 Organic Lecture Series Carbenes &

• Carbene, R2C: a neutral molecule in which a carbon atom is surrounded by only six valence electrons • Methylene, the simplest carbene – prepared by photolysis or thermolysis of diazomethane

: + h : ν H2 CNN H2C: + :NN: Methylene (the simplest carbene) – methylene prepared in this manner is so nonselective that it is of little synthetic use

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Organic Lecture Series Carbenes & Carbenoids

Dichlorocarbene – prepared by treating chloroform with potassium tert-butoxide

- + + - CH Cl3 + (CH3 )3 CO K Cl 2 C:+ ( CH3 ) 3 COH+ K Cl Trichloromethane Potassium Dichloro- tert-Butyl (Cloroform) tert-butoxide carbene alcohol

22 Organic Lecture Series Dichlorocarbene reacts with to give dichlorocyclopropanes

H

Cl2C: + CCl2 H Dichloro- A dichloro- carbene cyclopropane

- + (CH3 ) 3CO K Cl + HCCl3 H H cis- 3-Hexene Cl cis- 1,1-Dichloro- 2,3-diethylcyclopropane 23

Organic Lecture Series

• Simmons-Smith reaction – a way to add methylene to an to form a cyclopropane – generation of the Simmons-Smith reagent

CH I + Zn( Cu) ICH ZnI 2 2 diethyl ether 2

Diiodo- -copper Iodomethylzinc iodide couple (Simmons-Smith reagent) – this reacts with a wide variety of alkenes to give cyclopropanes

(prepared by: Zn dust; CuCl & heat) 24 Organic Lecture Series Simmons-Smith reaction: the organozinc compound reacts with an alkene by a concerted mechanism*

I

CH2 ZnI2 + H2C I Zn

*concerted mechanism-one in which there is simultaneous bond breaking and bond formation.

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Organic Lecture Series Uses of the Simmons-Smith reagent:

Zn(Cu) + CH2I2 + ZnI2 diethyl ether Methylene- Spiro[4.2]heptane cyclopentan e

O O H Zn(Cu) + CH2I2 CH + ZnI2 diethyl ether 2 H 2-Cyclohexenone Bicyclo[4.1.0]heptan-2-one

26 Organic Lecture Series Example of a drug which has a cyclopropane moiety:

Naltrexone

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•Sedation •Analgesia •Euphoria •Constipation (GI) opioid receptor antagonist used primarily in •Respiratory depression the management of alcohol dependence •Addiction liability and opioid dependence. 27