wwu chemistry addition-elimination: nitrogen and phosphorus nucleophiles sections 16.12 - 16.14

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ADDITION-ELIMINATION: ADDITION-ELIMINATION: NITROGEN AND PHOSPHORUS NITROGEN AND PHOSPHORUS

NUCLEOPHILESNUCLEOPHILES

Sections 16.12 - 16.14

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Compounds that bear an amino group

G NH2

form Imines.

The G group can be one of many different possibilities

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Addition-Elimination:The Formation of Imines

+.. HA

+ H2OC O

R

R

C

R

R

N GG NH2

an imine

All of the imine reactions, regardless of G, go by the same mechanism.

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Mechanism of Imine FormationStep 1

+slow.. ..

..+

_..:..

.. ..

..

.. ..

..

Step 2

+ HAfast

+ + A_

H2O+

C OH

R

R

G N

H

H

C O

R

R

C

R

R

NG

H

G N

H

C OH

R

R

G NH2C O

R

R

G N

H

What is the mechanism of this step?

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Mechanism of Imine Formation(Part Two)

Step 3

++ A

_ fast+

..H ANG

H

C

R

R

NG C

R

R

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•This is Addition-Elimination

•The first step is carbonyl addition of an amine, and the second step is a dehydration (elimination) to yield the C=N double bond.

•HA is the catalyst

•Step #1 is rate-determining, unless the amine is very basic (e.g., semicarbazide or aniline), in which case step #2 becomes rate-determining.

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Carbonyl compounds react with:

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Formation of Simple Imines

+ + H2OC O

R

R

NH2 R C N

R

R

R..

an imine

acid

•Aldehydes and ketones react with simple primary amines to yield imines.

•The equilibrium is unfavorable; the products are much less stable than the reactants.

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A Simple Model for Enzyme-Substrate

Binding.

NH2+

O

CR R

N C

R

R

enzyme substrate

enzyme-substrate complex

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H2NCH2

CH2CH2

CH2CH

COH

O

NH2

Lysine

If lysine is part of the protein chain of the enzyme, the terminal amino group is available to bind to carbonyl groups to form an imine.

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•Once the substrate (aldehyde or ketone) is bound to the enzyme, the active site of the enzyme is in a position to react with and modify the substrate.

•At the end of the reaction, because imines come apart easily (remember the “unfavorable” equilibrium?), the modified substrate can dissociate from the enzyme and return to the solution.

•As we can see, often biological substrates possess carbonyl groups so that they can act as a “handle” in enzyme-substrate binding. The carbonyl group may have no other chemical purpose than just this one!

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Formation of Oximes

+ + H2OC O

R

R

NH2 OH C

R

R

N OH..

an oxime

acid

hydroxylamine

•Aldehydes and ketones react with hydroxylamine to yield oximes.

•Oximes are important derivatives in qualitative organic analysis.

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What’s a Derivative?• One of the principal tests for the correct

identification of an unknown compound comes in trying to convert the compound by a chemical reaction into another known compound -- a derivative

• If the melting point of the derivative matches the expected value, according to the literature, then one can assume that the original substance had been correctly identified.

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Formation of Hydrazones

+ + H2O..

a hydrazone

C O

R

R

NH2 NH R C

R

R

N NH Racid

a hydrazine

•Aldehydes and ketones react with substituted hydrazines to yield substituted hydrazones.

•The equilibrium is generally unfavorable.

•Exception: when R is an aromatic ring.

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2,4-Dinitrophenylhydrazones

+

+ H2O

C O

R

R

NH2 NH NO2

NO2

C

R

R

N NH

NO2

NO2

..

a 2,4-dinitrophenylhydrazone

a 2,4-DNP

acid

2,4-dinitrophenylhydrazine

2,4-DNP’s are the most important of all derivatives for aldehydes and ketones.

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Formation of Semicarbazones

+

+ H2O

C O

R

R

NH2 NH C NH2

O

C

R

R

N NH C NH2

O

..

a semicarbazone

acid

semicarbazide

•Aldehydes and ketones react with semicarbazide to yield semicarbazones.

•Semicarbazones are the second-most important of the derivatives of aldehydes and ketones.

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Formation of Phenylhydrazones

C O

R

R

+ NHH2N

HA

C N

R

R

NH + H2O

Phenylhydrazine

a phenylhydrazone

In most cases, the equilibrium is unfavorable. However, this reaction is sometimes used to form derivatives of the sugars.

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As we have already seen, substituted amines can react with aldehydes and ketones to form a variety of products.

Primary amines can yield imines by an addition-elimination process.

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Addition-Elimination:The Formation of Imines

+.. HA

+ H2O

an imine

C O

R

R

C

R

R

N GG NH2

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When secondary amines are allowed to react with aldehydes or ketones, dehydration of the type shown in the elimination step cannot take place (there is no labile hydrogen on the nitrogen atom of the addition product).

CH2 C R

OH

NR' R'

R

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If the starting aldehyde or ketone has an -hydrogen, however, dehydration toward the -carbon can occur, yielding an enamine.

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Formation of Enamines

R C C

H

R

R

OH

H

NRR

R C C

H

R

R

OH2

NRR

R C C

H

R

R

NRR

+ OH

R C C

R

R

NRR

An enamine

Protonated byHOTs catalyst

slow

H

Resonance-stabilized

A proton goes back to the reaction medium

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The equilibrium for the formation of enamine is not favorable. It can be shifted to the right, however, by removing the water by azeotropic distillation as it is formed.

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The enamine is quite nucleophilic, owing to resonance of the type:

C C

R

R

R

N

R'

R'

C C

R

R

R

N

R'

R'

As a consequence of this resonance, the -carbon of an enamine has a great deal of carbanion-like (nucleophilic) character.

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Amines that are used typically to form enamines:

N H

CH2

CH2CH3

CH3

N

H

Diethylamine

Pyrrolidine

N

H

Piperidine

N

O

H

Morpholine

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Nucleophilic Characterof Enamines

C C

R

R R

N

R

R

C C

R

R R

N

R

R: +..

_

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Reactions of Enaminesas Nucleophiles

: +

+

:

+ X_

an iminium salt

C C

R

R R

N

R

R

R X

R C C R

R

R

N

R R

R C C R

R

R

N

R R

SN2

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Hydrolysis of Iminium Salts(Part One)

1)

..

..

+

slow

:+

+

..:

+

..:

2)

+..

+..

:

N

R R

H

R C C R

O

R

R H

R C C R

O

R

R

H H

N

R R

R C C R

O

R

R H

N

R R

H

R C C R

O

R

R H

OH H

N

R R

H

R C C R

R

R

N

R R

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Hydrolysis of Iminium Salts(Part Two)

3)

+..

+ H+

: :

R C C R

O

R

R H

R C C R

O

R

R

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Enamines can react with alkyl halides -- Here’s an example.

Apply the previous mechanisms to this synthesis.

N

O

N

O

CH3

H2O

O

CH3

CH3 I+

from cyclohexanone

H+

HOTs

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Another example:

Try to apply the mechanisms to this synthesis.

N

O

CH2 CH CH2 BrH2O

H+

O

CH2 CH CH2

from cyclohexanone

+HOTs

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In each of these reactions, the enamine, In each of these reactions, the enamine, acting as a nucleophile, displaces the halide acting as a nucleophile, displaces the halide ion from the alkyl halide in an Sion from the alkyl halide in an SNN2 process2 process.

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-Alkylation of a Ketone-Alkylation of a Ketone

CH3 CH2 C CH2

O

CH3

N

H CH3I H2O

H+

CH3 CH2 C CH

O

CH3

CH3

HOTs

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-Alkylation of a Ketone-Alkylation of a Ketone

O N

HBr CH2 C O CH2 CH3

O

H2O

H+

O

CH2

COOCH2CH3

HOTs

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Enamine Reactions -- Summary

O N

R R

N

R R

R

O

R

R XR2NH

+

+

H2O

H

HOTs

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The nucleophilic behavior of enamines has been used to The nucleophilic behavior of enamines has been used to prepare deuterium-labelled ketones.prepare deuterium-labelled ketones.

This reaction demonstrates that enamines are basic.

O

N

O

H

N

O O

N

O

D

D

+

1-Morpholinocyclohexane

D3PO4

D2O

0 °C

+

HOTs

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In the previous examples, we have been using In the previous examples, we have been using nitrogen as the nucleophilic atom.nitrogen as the nucleophilic atom.

Reasoning by analogy and using the periodicity that Reasoning by analogy and using the periodicity that we associate with position in the Periodic Table, what we associate with position in the Periodic Table, what would we predict if phosphorus were the would we predict if phosphorus were the nucleophile?nucleophile?

When phosphorus is the nucleophilic atom, the When phosphorus is the nucleophilic atom, the behavior is similar to that of amines, but there are behavior is similar to that of amines, but there are important differences. important differences.

The chief application of phosphorus chemistry in The chief application of phosphorus chemistry in this type of reaction is in the this type of reaction is in the Wittig reactionWittig reaction..

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The Wittig Reaction

+

:..

:_ +

a betaine

+

an ylide

C O

R1

R2

(C6H5)3P C

R4

R3

R2 C

R1

O

C R4

R3

P(C6H5)3

C

R1

R2

C

R4

R3

O P(C6H5)3This is a type of This is a type of condensation condensation reactionreaction -- we use it to “dock” -- we use it to “dock” two large structures together.two large structures together.

This is another example of This is another example of addition-eliminationaddition-elimination..

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Ylide

• A compound or intermediate with both a positive and a negative formal charge on adjacent atoms.

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Resonance in Ylides

+_..

(C6H5)3P C

R

R

(C6H5)3P C

R

R

The ylide is nucleophilic, owing to the negative The ylide is nucleophilic, owing to the negative charge character on carbon (structure on the charge character on carbon (structure on the right).right).

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Typical Solvents

• Ylides are highly reactive with water, alcohols, acids, carbonyl compounds, and esters.

• So, the solvents must exclude these classes of compounds.

• That limits us to hydrocarbons (and perhaps ethers). Toluene and xylene are used frequently.

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Example of a Wittig Reaction

C O C CH2

O P(C6H5)3

C CH2

(C6H5)3P

+ (C6H5)3P=CH2

+ =O

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Mechanism (???): :

slow+

:..

:_

=

+:

..:

_

:..

+

(C6H5)3P C

R4

R3

R1 C

O

R2

R3

P(C6H5)3

R4

C

C

R4

R3(C6H5)3P

R1 C R2

O

R1 C

O

R2

C R3

P(C6H5)3

R4

O

CR1 R2

C

R1

R2

C

R3

R4

O P(C6H5)3

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Preparation of the Ylide

+ (C6H5)3P+

a phosphonium salt

+ "HX"

base

R1 CH

R2

X (C6H5)3P CH R2

R1

X_

(C6H5)3P C

R2

R1

Typical bases:Typical bases:

•NaOCHNaOCH33

•NaHNaH

•LiCLiC44HH99

This reaction is not stereospecific.This reaction is not stereospecific.

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Preparation of Preparation of trans,transtrans,trans-1,4-Diphenyl-1,3-butadiene-1,4-Diphenyl-1,3-butadiene

CH2 Cl + (C6H5)3P: CH2 P(C6H5)3

Cl

NaOCH3

CH P(C6H5)3

C C

H

H

C O

H

C C

H

C C

H

H

H

C C

H

C C

H

H

H

+

trans,trans trans,cis

Major productMajor product Minor productMinor product

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Green Chemistry ApplicationGreen Chemistry ApplicationCH2 Cl + (C6H5)3P: CH2 P(C6H5)3

Cl

K3PO4

CH P(C6H5)3

C C

H

H

C O

H

C C

H

C C

H

H

H

C C

H

C C

H

H

H

+

trans,trans trans,cis

no solvent!

More More grinding!grinding!

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The Wittig Reaction: A Reminder

+

:..

:_ +

a betaine

+

an ylide

C O

R1

R2

(C6H5)3P C

R4

R3

R2 C

R1

O

C R4

R3

P(C6H5)3

C

R1

R2

C

R4

R3

O P(C6H5)3

This is a type of This is a type of condensation condensation reactionreaction -- we use it to “dock” -- we use it to “dock” two large structures together.two large structures together.