15 15-1 Organic Chemistry William H. Brown & Christopher S. Foote.

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Organic Organic Chemistry Chemistry

William H. Brown &William H. Brown &

Christopher S. FooteChristopher S. Foote

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OrganometallicOrganometallicCompoundsCompounds

Chapter 15Chapter 15

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Organometallic CompoundsOrganometallic Compounds Organometallic compound:Organometallic compound: a compound that

contains a carbon-metal bond We focus on organometallic compounds of Mg,

Li, Cu, Zn, Pd, and Ru• 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

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Organometallic CompoundsOrganometallic Compounds Oxidative addition:Oxidative addition: a reagent adds to a metal or

metal compound, causing its coordination to increase by two

Reductive elimination:Reductive elimination: a reagent is eliminated from a metal compound, causing its coordination to decrease by two

Ligand:Ligand: a Lewis base bonded to a metal in a coordination compound

MLn + X2 MLn

oxidative addition

reductiveelimination

X

X

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Grignard ReagentGrignard Reagent Grignard reagent:Grignard reagent: an organomagnesium

compound• prepared by addition of an alkyl, aryl, or alkenyl

(vinylic) halide to Mg metal in diethyl ether or THF

Mg+1-Bromobutane Butylmagnesium bromide

(an alkyl Grignard reagent)

etherBr MgBr

+ etherMgBr MgBr

Bromobenzene Phenylmagnesiumbromide

(an aryl Grignard reagent)

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RMgX and RLiRMgX and RLi Grignard reagents dissolve as coordination

compounds solvated by ether• ethylmagnesium bromide, EtMgBr

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RMgX and RLiRMgX and RLi Organolithium reagents

• prepared by reaction of an alkyl, aryl, or alkenyl halide with lithium metal

Cl + +1-Chlorobutane Butyllithium

pentane2Li LiClLi

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RMgX and RLiRMgX and RLi The carbon-metal bonds in RMgX and RLi are

polar covalent

2.5 - 1.2 = 1.32.5 - 1.0 = 1.5

2.5 - 1.5 = 1.02.5 - 1.6 = 0.92.5 - 1.8 = 0.7

2.5 - 1.9 = 0.6

Difference inElectronegativity

C-MBond

Percent Ioniccharacter*

6052403628

24

C-LiC-MgC-AlC-ZnC-Sn

C-Hg

*Percent ionic character = EC - EM

ECx 100

2.5 - 1.9 = 0.6 24C-Cu

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RMgX and RLiRMgX and RLi RMgX and RLi are valuable in synthesis as

nucleophiles• the carbon bearing the halogen is transformed from an

electrophile to a nucleophile

• their most valuable use is addition to the electrophilic carbon of a C=O group to form a new carbon-carbon bond

Br -C Br

CH3CH2CH2

HH

C -

CH3CH2CH2

HH

Mg2+δ+ δ-

carbon is anelectrophile

carbon is anucleophile

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RMgX and RLiRMgX and RLi Reaction with protic acids

• RMgX and RLi are strong bases

CH3CH2 -MgBr H-OH

CH3CH2-H Mg2+ + OH- + Br-

Weaker base

Stronger base

Weaker acid

Stronger acid

pKa 51

pKa 15.7

+

+δ+δ-

pKeq = -35

δ-δ+

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RMgX and RLiRMgX and RLi Reaction with protic acids

• RMgX and RLi react readily with these proton donors

1° and 2°Amines

Alcohols

Water Phenols Thiols Carboxylicacids

pKa 4-5pKa 8-9pKa 9-10pKa 15.7

pKa 16-18pKa 38-40R2 NH

ArOH RSH RCOOH

ROH

HOH

RC CH

Terminalalkynes

pKa 25

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RMgX and RLiRMgX and RLi Reaction with oxiranes (epoxides)

• reaction of RMgX or RLi with an oxirane followed by protonation increases chain length by two carbons

+

HClH2O

MgBr O

O-MgBr+OH

Butylmagnesiumbromide

Ethyleneoxide

A magnesium alkoxide

1-Hexanol

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RMgX and RLiRMgX and RLi Reaction with oxiranes (epoxides)

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

MgBr

H2O

HCl

Methyloxirane(Propylene

oxide)

A magnesiumalkoxide

1-Phenyl-2-propanol

+

Phenyl-magnesium

bromide

OHO-MgBr+

O

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Gilman ReagentsGilman Reagents Lithium diorganocopper reagents, known more

commonly as Gilman reagents• prepared by treating an alkyl, aryl, or alkenyl lithium

compound with Cu(I) iodide

2CH3CH2CH2CH2Li + CuIor THF

diethyl ether

(CH3CH2CH2CH2)2Cu- Li + + LiI

Butyllithium Copper(I) iodide

Lithium dibutylcopper (a Gilman reagent)

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Gilman ReagentsGilman Reagents Coupling within organohalogen compounds

• form new carbon-carbon bonds by coupling with alkyl chlorides, bromides, and iodides

or THF

diethyl etherR'Br + R2CuLiBr R'-R + RCu + LiBr

[CH3(CH2)8CH2]2CuLi Br

CH2(CH2)8CH3 CH3(CH2)8CH2Cu

2-Methyl-1-dodecene

+or THF

diethyl ether

+

Lithium didecylcopper2-Bromopropene

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Gilman ReagentsGilman Reagents• coupling with a vinylic halide is stereospecific; the

configuration of an alkene is retained

C C

H

H I

(CH3CH2CH2CH2)2CuLi

CH3(CH2)6

C C

H

H CH2CH2CH2CH3

+or THF

diethyl ether

E-1-Iodo-1-nonene

E-5-Tridecene

CH3(CH2)6

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Gilman ReagentsGilman Reagents A variation on the preparation of a Gilman

reagent is to use a Grignard reagent with a catalytic amount of copper(I) salt

C C

(CH2)7CH2Br

H H

CH3(CH2)7

CH3(CH2)4MgBrCu+

THF

CH3(CH2)7

C C

(CH2)12CH3

H H

+

(Z)-1-Bromo-9-octadecene

(Z)-9-Tricosene(Muscalure)

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Gilman ReagentsGilman Reagents Reaction with epoxides

• regioselective ring opening

Styrene oxide 1-Phenyl-3-buten-1-ol

1. (CH2=CH)2CuLi

2. H2O, HCl

O OH

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Heck ReactionHeck Reaction A palladium catalyzed reaction in which the

carbon group of a haloalkene or haloarene is substituted for a vinylic H of an alkene

R-XH

B

RBH+ X-

+ Pd catalyst+

+

Alkene BaseHaloalkeneor Haloarene

Conjugate acidof the base

Substitutedalkene

Heck reaction

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Heck ReactionHeck Reaction• substitution is highly regioselective; at the less

substituted carbon• substitution is highly stereoselective; where E,Z

isomerism is possible in the product, the E configuration is often formed almost exclusively

Br CH2=CHCOCH3

COCH3

O

+

BromobenzeneMethyl 2-propenoate(Methyl acrylate)

Methyl (E)-3-phenyl-2-propenoate(Methyl cinnamate)

Pd catalystHeck reaction

O

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Heck ReactionHeck Reaction• reaction is stereospecific with regard to the

haloalkene; the configuration of the double bond is retained

I

(Z)-3-Iodo-3-hexene

+

(1E,3Z)-1-Phenyl-3-ethyl-1,3-hexadiene

Z

Z

Phenylethene(Styrene)

Pd catalystHeck reaction

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Heck ReactionHeck Reaction The catalyst

• most commonly Pd(II) acetate• reduced in situ to Pd(0)

• reaction of Pd(0) with good ligands gives PdL2

The organic halogen compound• aryl, heterocyclic, and vinylic iodides, chlorides, and

bromides• alkyl halides with an easily eliminated hydrogen are

rarely used because they undergo -elimination to give alkenes

• OH group, C=O groups of aldehydes & ketones, and esters unreactive under Heck conditions

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Heck ReactionHeck Reaction The alkene

• the less the crowding on the alkene, the more reactive it is

The base• triethylamine, sodium and potassium acetate, and

sodium hydrogen carbonate are most common

The solvent• polar aprotic solvents such as DMF, acetonitrile,

DMSO• aqueous methanol may also be used

The ligand• triphenylphosphine is one of the most common

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BH+ X-

B:

R-X

L2Pd

HX

L2Pd

X

H

L2PdX

R

R3 R

R2R4

R3 R2

HR4

L2Pd H

R3 RR4 R2

X

L2Pd R

R3 R2R4 H

X

rotation about the C-C bond by 60°

The catalyticcycle of the

Heck reaction

1

2

34

5

oxidativeaddition

syn addition

synelimination

reductiveelimination

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Heck ReactionHeck Reaction• the usual pattern of acyclic compounds is replacement

of a hydrogen of the double bond with an R group• if the organopalladium group attacks a double bond so

that the R group has no syn H for syn elimination, then the double bond may shift

I Pd(OAc)2

(C2H5)3N+

PdL2OAcH

H H Formed as aracemic mixture

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Carbenes and CarbenoidsCarbenes and Carbenoids Carbene, RCarbene, R22C:C: 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

• methylene prepared in this manner is so nonselective that it is of little synthetic use

:H2CH2C N N+ hν

N N+

Methylene( the simplest

)carbene

:::

:

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Carbenes and CarbenoidsCarbenes and Carbenoids Dichlorocarbene

• prepared by treating chloroform with potassium tert-butoxide

CHCl3 (CH3)3CO-K+

Cl2C: (CH3)3COH

+

+

Trichloromethane(Cloroform)

Potassiumtert-butoxide

Dichloro-carbene

tert-Butylalcohol

+ K+Cl-

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Carbenes and CarbenoidsCarbenes and Carbenoids Dichlorocarbene

• reacts with alkenes to give dichlorocyclopropanes

Cl2C:

Dichloro-carbene

+

A dichloro-cyclopropane

CCl2

H

H

HCCl3(CH3)3CO-K+

H

Cl

ClH

cis-3-Hexene

+

cis-1,1-Dichloro-2,3-diethylcyclopropane

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Carbenes and CarbenoidsCarbenes and Carbenoids Simmons-Smith reaction

• a way to add methylene to an alkene to form a cyclopropane

• generation of the Simmons-Smith reagent

• this organozinc compound reacts with a wide variety of alkenes to give cyclopropanes

CH2I2 Zn(Cu) ICH2ZnI+ diethyl etherDiiodo-methane

Iodomethylzinc iodide(Simmons-Smith reagent)

Zinc-coppercouple

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Carbenes and CarbenoidsCarbenes and Carbenoids Simmons-Smith reagent

+ CH2I2Zn(Cu)

diethyl ether+ ZnI2

Methylene-cyclopentane

Spiro[4.2]heptane

O

CH2I2Zn(Cu)

O

CH2

H

H

ZnI2+diethyl ether

+

2-Cyclohexenone Bicyclo[4.1.0]-heptan-2-one

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Carbenes and CarbenoidsCarbenes and Carbenoids Simmons-Smith reaction

• the organozinc compound reacts with an alkene by a concerted mechanism

CH2

I

ZnIZnI2 H2C+

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Stable Nucleophilic CarbenesStable Nucleophilic Carbenes Stable nucleophilic carbenes

• certain carbenes with strongly electron-donating groups are particularly stable

• their stability is enhanced by bulky groups that hinder self-reactions; one such group is the 2,4,6-trimethylphenyl group

• rather than behaving as electron-deficient reagents like most carbenes, these compounds are nucleophiles because of the strong electron donation by the nitrogens

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Stable Nucleophilic CarbenesStable Nucleophilic Carbenes• this carbene is stabilized by the electron-donating

nitrogens and the bulky 2,4,6-trimethylphenyl groups

N

N

N

N+

N

N+:::

:

: :

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Ring-Closing Alkene MetathesisRing-Closing Alkene Metathesis Alkene metathesis reaction:Alkene metathesis reaction: two alkenes

interchange carbons on their double bonds

• if the reaction involves 2,2-disubstituted alkenes, ethylene is lost to give a single alkene product

catalystA A

A A

B B

B B

+

A A

B B

B B

A A

+

catalystA A

H H

B B

H H

+

A A

B B

+ CH2=CH2

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Ring-Closing Alkene MetathesisRing-Closing Alkene Metathesis• a useful variant of this reaction uses a starting

material in which both alkenes are in the same molecule, and the product is a cycloalkene

COOEtEtOOC COOEtEtOOC

CH2=CH2+catalyst

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Ring-Closing Alkene MetathesisRing-Closing Alkene Metathesis• a particularly useful alkene methathesis catalyst

consists of ruthenium, Ru, complexed with a nucleophilic carbene and another carbenoid ligand. In this example, the other carbenoid ligand is a benzylidene group.

RuCl

Cl

C6H5

NN RR

NN RR

nucleophiliccarbenes

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Ring-Closing Alkene MetathesisRing-Closing Alkene Metathesis Like the Heck reaction, alkene metathesis

involves a catalytic cycle• addition of a metalocarbenoid to the alkene gives a

four-membered ring• elimination of an alkene in the opposite direction gives

a new alkene

R1

[M]

R1

R2

R1

[M]R2

R1

[M]R2

A metallacycle

R1 R1++

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Prob 15.9Prob 15.9 Complete these reactions involving Gilman reagents.

Br +(a) etherCuLi2

Br+(b) ether2

CuLi

(c) +ether

I CuLi2

+(d) C

H

Cl

H3C

C C

H

H CH2

CuLi

2

ether

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Prob 15.13Prob 15.13 Show reagents to synthesize this target molecule from

cyclohexane.

O

Br

OH

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Prob 15.14Prob 15.14 Complete these equations.

diethyl ether(a)CH3CH2CH2C CH CH3CH2MgBr+

(b)

O

CH2I2Zn(Cu)

+diethyl ether

(c) CHBr3+ (CH3)3CO-K++

CH2I2Zn(Cu)

(d) +diethyl ether

O

CH2I2Zn(Cu)

+diethyl ether

(e) CH=CH2

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Prob 15.15Prob 15.15 Account for the stereospecificity of this reaction.

CH2I2Zn(Cu)

+ diethyl ether

H

H

OH OHH

H

CH2

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Prob 15.18Prob 15.18 Account for the stereospecificity of this Heck reaction;

that is, that the E alkene is formed exclusively.

C6H5Br+

C6H5 OCH3

O

Pd(OAc)2, 2Ph3P

(CH3CH2)3NOCH3

O

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Prob 15.19Prob 15.19 Account for the formation of these isomeric alkenes in

this Heck reaction.

(E)-3-Hexene

C6H5Br+

C6H5+

C6H5

(Z)-3-Phenyl-3-hexene

(E)-4-Phenyl-2-hexene

Pd(OAc)2, 2Ph3P

(CH3CH2)3N

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Prob 15.20Prob 15.20 Complete these Heck reactions.

(a)

(b)

2C6H5CH=CH2 + II

CH2=CHCOCH3

O

+I

Pd(OAc)2, 2Ph3P

(CH3CH2)3N

Pd(OAc)2, 2Ph3P

(CH3CH2)3N

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Prob 15.21Prob 15.21 Account for the formation of 3-phenylcyclohexene and

the fact that no 1-phenylcyclohexene is formed.

Pd(OAc)2, 2Ph3P

(CH3CH2)3N+

C6H5

C6H5I

C6H5

3-Phenylcyclohexene(the only product)

+

1-Phenylcyclohexene(not formed)

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Prob 15.22Prob 15.22 Account for the formation of this product and the cis

stereochemistry of its ring junction.

Pd(OAc)2, 2Ph3P

(CH3CH2)3NI

COOMe COOMe

H86%

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Prob 15.23Prob 15.23 Account for the formation of the following product,

including the cis stereochemistry at the ring junction.R

TfO

R

H

Pd(OAc)2, (R)-BINAP

K2CO3

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Prob 15.24Prob 15.24 Show how Exaltolide can be synthesized from the given

starting material. Give the structure of R.

OR

O

O

O

O

O

Exaltolide

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Prob 15.25Prob 15.25 Propose a synthesis of spiro[2.2]pentane from organic

compounds of three carbons or less.

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Prob 15.26Prob 15.26 Predict the product of each alkene metathesis reaction.

O

OAcOAc 5 mole % Ru catalyst

CH2Cl2, 40°C, 30 min

5 mole % Ru catalyst

CH2Cl2, 40°C, 30 min

OO

(a)

(b)

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OrganometallicOrganometallic

CompoundsCompoundsEnd Chapter 15End Chapter 15