24-1 carbon-carbon bond formation and synthesis. 24-2 organometallic compounds recall: two...

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Carbon-Carbon Bond Carbon-Carbon Bond Formation and Formation and

SynthesisSynthesis

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Organometallic CompoundsOrganometallic Compounds

Recall: two extremely important reactions of metals and organometallic compounds:• Oxidative additionOxidative addition:: The addition of a reagent to a metal

center causing it to add two substituents which extract two electrons from the metal and increasing its oxidation state by two.

• Reductive eliminationReductive elimination:: The elimination of two substituents which donate two electrons to the metal center causing the oxidation state of the metal to decrease by two.

MLn + X2 MLn

oxidative addition

reductiveelimination

X

X

electrons move to the X ligands

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Heck ReactionHeck Reaction

Overall: A palladium-catalyzed reaction in which the R group of RX, 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 Reaction (consider the alkene)Heck Reaction (consider the alkene)

• Substitution (H R) is highly regioselective; most commonly at the less substituted carbon of the double bond.

• Substitution is highly stereoselective; the E configuration is often formed almost exclusively.

Br CH2=CHCOCH3

O

COCH3

O

+

Bromobenzene Methyl 2-propenoate(Methyl acrylate)

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

Pd catalystHeck reaction

E

Neither E nor ZLess substituted, H Phsubstitution occurs here.

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Heck Reaction (RX = Haloalkene)Heck Reaction (RX = Haloalkene)

• For RX = haloalkene: Reaction is stereospecific; the configuration of the double bond in the haloalkene is preserved.

IPh

Ph

(Z)-3-Iodo-3-hexene

+

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

Z Z

Styrene


IPh

Ph

(E)-3-Iodo-3-hexene

+

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

E E

Styrene


E

E

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Heck Reaction. Some considerations.Heck Reaction. Some considerations.

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, benzylic, and vinylic iodides, chlorides, bromides, and triflates (CF3SO2O-).

• alkyl halides with an easily eliminated hydrogen are rarely used because they undergo -elimination to give alkenes.

• OH groups and the C=O groups of aldehydes, ketones, and esters are unreactive under Heck conditions.

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Heck Reaction. More…Heck Reaction. More…

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, and

DMSO.• aqueous methanol may also be used.

The ligand• Triphenylphosphine, PPh3, 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 right about the C-C bond

The catalyticcycle of the

Heck reaction

1

2

34

5

oxidativeaddition

syn addition

synelimination

reductiveelimination

Rotation about the C-C bond. This is where the R is swapped in, replacing the H.

L = PPh3

R

Start here

0II

II

II

II

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• The usual pattern of acyclic compounds: replacement of a hydrogen of the double bond with the R group.

• If the R group has no H for syn elimination, then a H may be abstracted elsewhere.

I Pd(OAc)2

(C2H5)3N

PdL2OAcH

H H

+

(racemic)

This H should be brought into position for syn elimination with the Pd. Can’t happen due to cyclohexane ring.

not this conjugated product

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Suzuki CouplingSuzuki Coupling

Suzuki coupling:Suzuki coupling: A palladium-catalyzed reaction of an organoborane (R’-BY2) or organoborate (RB(OMe)2) with an alkenyl, aryl, or alkynyl halide, or triflate (R-X) to yield R-R’.

B

RCH=CHB

X

RCH=CHX

Alkyl-X(Difficult)

RC C XAlkyl B

OrganoboronCompounds

Coupling reagents X = halide or triflate)

R'-BY2 R-X XBY2R-R'PdL4, Base

++Overall:

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• Recall boranes are easily prepared from alkenes or alkynes by hydroboration.

• Borates are prepared from alkyl or aryl lithium compounds and trimethylborate.

+ (Sia)2BHhydroboration

B(Sia)2

H

H

Li B(OMe)3 B(OMe)2 LiOMe+ +

PhCl + Li

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• These examples illustrate the versatility of the reaction.

B(OMe)2N

Br NH2

Ph(OAc)2

Na2CO3 NNH2+

B(Sia)2

H

H

C6H13BrPd(Ph3)4

NaOMe

H

H C6H13

+

B(OMe)2Br

Pd(OAc)2

Et3N+

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Oxid. Addn

Substitution

Transmetalation R1 and OtBu swap

Reductive elimination

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Alkene MetathesisAlkene Metathesis

Alkene metathesis:Alkene metathesis: A reaction in which 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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Alkene MetathesisAlkene 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.

• Catalysts for these reactions are a class of compounds called stable nucleophilic carbenes.

COOEtEtOOC COOEtEtOOC

CH2=CH2+catalyst

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Stable Nucleophilic CarbenesStable Nucleophilic Carbenes

• Carbenes and carbenoids provide the best route to three membered carbon rings.

• Most carbenes are highly reactive electrophiles.

• Carbenes with strongly electron-donating atoms, however, for example nitrogen atoms, are particularly stable.

• Rather than being electron deficient, these carbenes are nucleophiles because of the strong electron donation by the nitrogens.

• Because they donate electrons well, they are excellent ligands (resembling phosphines) for certain transition metals.

• The next screen shows a stable nucleophilic carbene.

H H

R2N NR2

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Nucleophilic CarbeneNucleophilic Carbene

• A stable nucleophilic carbene.

N

NN

N

N

N –

+

–

+

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Alkene Metathesis CatalystAlkene Metathesis Catalyst

• A useful alkene methathesis catalyst consists of ruthenium, Ru, complexed with nucleophilic carbenes 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 metallocarbenoid to the alkene gives a

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

a new alkene.

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RR

M

M

R

R

RR RR

M

R

M

R

RRR

R

R

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Initiation Step

Cycle

start

R'

R'

R''

R''

R' R''

R' R''

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Diels-Alder ReactionDiels-Alder Reaction

Diels-Alder reaction:Diels-Alder reaction: A cycloaddition reaction of a conjugated diene and certain types of double and triple bonds.• dienophile:dienophile: Diene-loving.• Diels-Alder adduct:Diels-Alder adduct: The product of a Diels-Alder

reaction.

Diels-Alder adduct3-Buten-2-one(a dienophile)

1,3-Butadiene(a diene)

+

O O

3-Buten-2-one(a dienophile)

1,3-Butadiene(a diene)

+

O O

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• Alkynes also function as dienophiles.

• Cycloaddition reaction:Cycloaddition reaction: A reaction in which two reactants add together in a single step to form a cyclic product.

Diels-Alder adductDiethyl 2-butynedioate(a dienophile)

+

1,3-butadiene (a diene)

COOEt

COOEt

COOEt

COOEt

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• We write a Diels-Alder reaction in the following way:

• The special value of D-A reactions are that they:

1. form six-membered rings.

2. form two new C-C bonds at the same time.

3. are stereospecific and regioselective.

Note the reaction of butadiene and ethylene gives only traces of cyclohexene.

DieneDieno-phile

Adduct

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• The conformation of the diene must be s-cis.

s-trans conformation

(lower in energy)

s-cis conformation

(higher in energy)

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Diels-Alder Reaction Steric RestrictionsDiels-Alder Reaction Steric Restrictions

• (2Z,4Z)-2,4-Hexadiene is unreactive in Diels-Alder reactions because nonbonded interactions prevent it from assuming the planar s-cis conformation.

(2Z,4Z)-2,4-Hexadiene

s-trans conformation(lower energy)

s-cis conformation(higher energy)

methyl groupsforced closer thanallowed by vander Waals radii

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• Reaction is facilitated by a combination of electron-withdrawing substituents on one reactant and electron-releasing substituents on the other.

CyclohexeneEthylene1,3-Butadiene

200°Cpressure

3-Buten-2-one

140°C+

1,3-Butadiene

O O

+

2,3-Dimethyl-1,3-butadiene

+ 30°C

3-Buten-2-one

O O

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Electron-WithdrawingGroups

Electron-ReleasingGroups

-C N (cyano)

-OR (ether)

-OOCR (ester)

-CHO (aldehyde, ketone)

-COOH (carboxyl)

-COOR (ester)

-NO2 (nitro)

-CH3, alkyl groups

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• The Diels-Alder reaction can be used to form bicyclic systems.

+

roomtemperature

170°CDiene Dienophile

Dicyclopentadiene(endo form)

H

H

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• Exo and endo are relative to the double bond derived from the diene.

the double bondderived fromthe diene

endo (inside)

exo (outside)relative tothe doublebond

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• For a Diels-Alder reaction under kinetic control, endo orientation of the dienophile is favored.

Methyl bicyclo[2.2.1]hept-5-en-endo-2-carboxylate

(racemic)

Methylpropenoate

Cyclopentadiene

+ OCH3

O

H

COOCH3

COOCH3redraw 1 23

45

6

7

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• The configuration of the dienophile is retained.

COOCH3

COOCH3 COOCH3

COOCH3

A cis dienophile)

Dimethyl cis-4-cyclohexene- 1,2-dicarboxylate

+

COOCH3

H3COOC COOCH3

COOCH3

A transdienophile)

Dimethyl trans-4-cyclohexene- 1,2-dicarboxylate

(racemic)

+

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• The configuration of the diene is retained.

CH3

CH3

CH3

O

O

O

O

O

O

O

O

O

H3C

H3C

O

O

OH3C

H3C

CH3

+

+

H

H

H

H

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Mechanism• No evidence for the participation of either radical of

ionic intermediates.• Chemists propose that the Diels-Alder reaction is a

concerted pericyclic reaction.

Pericyclic reactionPericyclic reaction: A reaction that takes place in a single step, without intermediates, and involves a cyclic redistribution of bonding electrons.

Concerted reaction: All bond making and bond breaking occurs simultaneously.

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• Mechanism of the Diels-Alder reaction

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Aromatic Transition StatesAromatic Transition States

Hückel criteria for aromaticity:Hückel criteria for aromaticity: The presence of (4n + 2) pi electrons in a ring that is planar and fully conjugated.

Just as aromaticity imparts a special stability to certain types of molecules and ions, the presence of (4n + 2) electrons in a cyclic transition state imparts a special stability to certain types of transition states.• Reactions involving 2, 6, 10, 14.... electrons in a cyclic

transition state have especially low activation energies and take place particularly readily.

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• Decarboxylation of -keto acids and -dicarboxylic acids.

• Cope elimination of amine N-oxides.

O OH

O

OH

C

O

O

OCO2+

enol ofa ketone

(A cyclic six-membered transition state)

O

heat+

A cyclic six-memberedtransition state

N,N-dimethyl-hydroxylamine

C C

H NCH3

CH3

NCH3

CH3

OHC C

An alkene

+

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• the Diels-Alder reaction

• pyrolysis of esters (Problem 22.42)

We now look at examples of two more reactions that proceed by aromatic transition states:• Claisen rearrangement.• Cope rearrangement.

DieneDieno-phile

Adduct

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Claisen RearrangementClaisen Rearrangement

Claisen rearrangement:Claisen rearrangement: A thermal rearrangement of allyl phenyl ethers to 2-allylphenols.

Allyl phenyl ether

200-250°C

2-Allylphenol

O OH

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Claisen RearrangementClaisen Rearrangement

O

Allyl phenyl ether

heat

OH

o-Allylphenol

O

H

A cyclohexadienone intermediate

keto-enoltautomerism

O

Transition state

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Cope RearrangementCope Rearrangement

Cope rearrangement:Cope rearrangement: A thermal isomerization of 1,5-dienes.

3,3-Dimethyl-1,5-hexadiene

2-Methyl-2,6- heptadiene

heat

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Cope RearrangementCope Rearrangement

Example 24.8Example 24.8 Predict the product of these Cope rearrangements.

(a)

(b)

350°C

OH

H

320°C

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Synthesis of Single EnantiomersSynthesis of Single Enantiomers

• We have stressed throughout the text that the synthesis of chiral products from achiral starting materials and under achiral reaction conditions of necessity gives enantiomers as a racemic mixture.

• Nature achieves the synthesis of single enantiomers by using enzymes, which create a chiral environment in which reaction takes place.

• Enzymes show high enantiomeric and diastereomeric selectivity with the result that enzyme-catalyzed reactions invariably give only one of all possible stereoisomers.

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How do chemists achieve the synthesis of single enantiomers?

The most common method is to produce a racemic mixture and then resolve it. How?• the different physical properties of diastereomeric

salts.• the use of enzymes as resolving agents.• chromatographic on a chiral substrate.

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• In a second strategy, asymmetric inductionasymmetric induction, the achiral starting material is placed in a chiral environment by reacting it with a chiral auxiliarychiral auxiliary. Later it will be removed.

• E. J. Corey used this chiral auxiliary to direct an asymmetric Diels-Alder reaction.

• 8-Phenylmenthol was prepared from naturally occurring enantiomerically pure menthol.

Me

HO

Me Me

Me

HO

Me MePh

8-Phenylmenthol(an enantiomericallypure chiral auxillary)

Menthol(enantiomerically pure)

several steps

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• The initial step in Corey’s prostaglandin synthesis was a Diels-Alder reaction.

• By binding the achiral acrylate with enantiomerically pure 8-phenylmenthol, he thus placed the dienophile in a chiral environment.

• The result is an enantioselective synthesis.

OBn

Me

O

Me MePh

O

ORO

BnO

RO O

OBn

+

Diels-Alder+

Enantiomericallypure

97% 3%

89%

Achiral

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• A third strategy is to begin a synthesis with an enantiomerically pure starting material.

• Gilbert Stork began his prostaglandin synthesis with the naturally occurring, enantiomerically pure D-erythrose.

• This four-carbon building block has the R configuration at each stereocenter.

• With these two stereocenters thus established, he then used well understood reactions to synthesize his target molecule in enantiomerically pure form.

HOH

O

OH

OH

D-Erythrose

24-1 carbon-carbon bond formation and synthesis. 24-2 organometallic compounds recall: two...

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