ADDITION-ELIMINATION: NITROGEN AND PHOSPHORUS NUCLEOPHILES

Sections 16.12 - 16.14

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Compounds that bear an amino group

G
form Imines.

NH2

The G group can be one of many different possibilities

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Addition-Elimination: The Formation of Imines

G .. NH2 R + R C O HA R an imine R C N G + H2O

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

Mechanism of Imine Formation

Step 1 R G .. NH2 + R C .. O .. H slow G R + N C H R .. _ O .. : R G .. N H C R .. OH ..

Step 2 R G .. N H C R .. OH .. fast + HA G + N H C R

R + H2 O +

_ A

What is the mechanism of this step? WWU Chemistry

Mechanism of Imine Formation (Part Two)

Step 3 R G + N H C R _ + A fast .. N R C R + H A

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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

R C R O .. + H2N R acid R an imine R C N R + H2O

Aldehydes and ketones react with simple primary amines to yield imines. The equilibrium is unfavorable; the products are much less stable than the reactants. WWU Chemistry

A Simple Model for Enzyme-Substrate Binding.

O NH2 enzyme + R C R substrate

R N C R enzyme-substrate complex

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O H 2N CH 2 CH 2 CH 2 CH 2 CH NH 2 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.

C OH

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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! WWU Chemistry

Formation of Oximes
R C R O + .. H2 N OH acid R an oxime R C N OH + H2O

hydroxylamine

Aldehydes and ketones react with hydroxylamine to yield oximes. Oximes are important derivatives in qualitative organic analysis. WWU Chemistry

Whats 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
R C R O + .. H2N NH R R a hydrazone R acid C N NH R + H2O

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. WWU Chemistry

2,4-Dinitrophenylhydrazones
NO2 R C R O + .. H2N NH NO2 acid

2,4-dinitrophenylhydrazine
NO2 R C R N NH NO2 + H2O

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

a 2,4-dinitrophenylhydrazone a 2,4-DNP

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Formation of Semicarbazones
R C R O + .. H2N O NH C NH2 acid

semicarbazide
R C R a semicarbazone N O NH C NH2 + H2O

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
R C R Phenylhydrazine R C N NH a phenylhydrazone + H 2O O + H 2N NH HA

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 additionelimination process.

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Addition-Elimination: The Formation of Imines

R G .. NH2 + R C O HA R an imine R C N G + H2O

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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).

OH R CH2 C N R' R'

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

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Formation of Enamines
H R C R H N R R H R C C R R C R R C N R R + H N R R R An enamine A proton goes back to the reaction medium O H OH C Protonated by HOTs catalyst R slow R H C R R OH2 C N R R

Resonance-stabilized

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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:

R' R C R C R R N R' R C C R R' N R'

As a consequence of this resonance, the a-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:

CH3 CH2 N CH3 CH2 Diethylamine H N H Piperidine O N H Pyrrolidine N H Morpholine

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Nucleophilic Character of Enamines

R R C R C R R :N R R .. C _ R +N C R R

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Reactions of Enamines as Nucleophiles

R R C R R X + X C R :N R R R C R an iminium salt _ R +N C R R R R C R R :N C + R R

SN2

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Hydrolysis of Iminium Salts (Part One)

1) R R R C R H 2) R R R C R +N C :O .. R H R H R R C R C +O .. R H + R N .. R H +N slow C .. O .. R R C R H H C +O : H R R C R C :O .. R H R R R R N: R R +N R H

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Hydrolysis of Iminium Salts (Part Two)

3) R R C R C +O .. R H R R C R C :O : R + + H

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N CH3 H2O H+

O CH3

HOTs + CH3 I

from cyclohexanone

Enamines can react with alkyl halides -- Heres an example. Apply the previous mechanisms to this synthesis.

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Another example:
O N O CH2 CH + CH2 CH CH2 Br H2O HOTs H+ CH2

from cyclohexanone

Try to apply the mechanisms to this synthesis.

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In each of these reactions, the enamine, acting as a nucleophile, displaces the halide ion from the alkyl halide in an SN2 process.

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O CH3 CH2 C CH2 CH3

N H HOTs CH3I H2O H+

O CH3 CH2 C CH CH3 CH3

a-Alkylation of a Ketone

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O O N H HOTs CH3 CH2 O C H2O H+ CH2 O O Br CH2 C O CH2 CH3

a-Alkylation of a Ketone WWU Chemistry

Enamine Reactions -- Summary

R O N R R +N R R2NH HOTs R X R

H2O H+ O R

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The nucleophilic behavior of enamines has been used to prepare deuterium-labelled ketones.
O O D3PO4 D2O + N H HOTs N 0 C D O O

+ 1-Morpholinocyclohexane N D

This reaction demonstrates that enamines are basic. WWU Chemistry

In the previous examples, we have been using nitrogen as the nucleophilic atom. Reasoning by analogy and using the periodicity that we associate with position in the Periodic Table, what would we predict if phosphorus were the nucleophile? When phosphorus is the nucleophilic atom, the behavior is similar to that of amines, but there are important differences.

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

R1 C R2 an ylide O + (C6H5)3P C R4 R3 R2 R1 C : O: .. _ R3 C R4 P(C6H5)3 + a betaine

R1

R3 C R4 + O P(C6H5)3

This is a type of condensation reaction -- we use it to dock two large structures together. This is another example of addition-elimination.

C R2

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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
R (C6H5)3P C R _ R .. C R

+ (C6H5)3P

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

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

+ (C6H5)3P=CH2

C O

CH2 P(C6H5)3

CH2

(C6H5)3P=O

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Mechanism (???)
:O: C R1 R2 R3 (C6H5)3P C R4 slow .. _ :O : R1 C + (C6H5)3P C R4 R2 R3 _ .. + : O : P(C6H5)3 C R3

R1 C

R2 R4

R1 O P(C6H5)3 + C R2 C

R3 R4

.. :O R1 C

P(C6H5)3 C R3

R2 R4

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Preparation of the Ylide

R2 R1 CH X + (C6H5)3P R1 + (C6H5)3P CH R2 _ X a phosphonium salt

Typical bases: NaOCH3 NaH LiC4H9

(C6H5)3P C R2 + "HX" base R1

This reaction is not stereospecific.

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Preparation of trans,trans-1,4-Diphenyl-1,3-butadiene
CH2 Cl + (C6H5)3P: H H C C H C O NaOCH3 CH2 P(C6H5)3 Cl

CH

P(C6H5)3

H H C C C H trans,trans C H + H C

H C C H trans,cis C

Major product

Minor product

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Green Chemistry Application

CH2 Cl + (C6H5)3P: H H C C H C O K3PO4 no solvent! CH2 P(C6H5)3 Cl

More grinding!

CH

P(C6H5)3

H H C C H trans,trans C C H + H C

H C C H trans,cis C

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The Wittig Reaction: A Reminder

R1 C R2 an ylide O + (C6H5)3P C R4 R3 R2 R1 C : O: .. _ R3 C R4

P(C6H5)3 + a betaine

R1 C R2 C

R3 + R4 O P(C6H5)3

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

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