imines and esters as electrophiles

what is reductive amination

formation of substituted amines by a three-component reaction of carbonyl compounds, amines and a reducing agent

how does reductive amination work

the amine and carbonyl condense to form an iminium ion which is more electrophilic and hence reactive towards the nucleophile than the carbonyl alone

conditions

product

mechanism, condition + product

why this works

basis of the Mannich reaction (in terms of iminium ions)

we can harness iminium ion formation to drive carbon-carbon bond formation with enols in a three-component condensation (Mannich)

how are iminium ions generated for Mannich condensation

give specific reagent which works well

why is this done

can be formed in situ from an aldehyde and a secondary amine

formaldehyde is a particularly good aldehyde for this as it is unstable and reacts rapidly with amines

the positive iminium ion is much more reactive towards the low concentration of enol than the neutral aldehyde

which reagent enolises? show the formation of the enol

first stage of mechanism (not enolisation)

next stage of Mannich mechanism

type of product?

aminal would be 2 amines on 1 carbon, so this is a hemiaminal (hydroxy + amine group on same C)

next stage of Mannich mechanism

next stage of Mannich mechanism

type of product?

next stage of Mannich mechanism

final stage of Mannich mechanism

how does intramolecular Mannich condensation happen

cyclic amines can be accessed by tethering two of the components of the Mannich condensation together so that either the iminium formation or the iminium trapping by the enol (or both) are intramolecular

overall equation for Mannich condensation

which type of intramolecular condensation is it

iminium formation is the intramolecular part, iminium trapping by the enol will happen separately

show enol formation for this Mannich condensation

first stage of intramolecular Mannich condensation

next stage of intramolecular Mannich

next stage of intramolecular Mannich

next stage of intramolecular Mannich

next stage of intramolecular Mannich

final stage of intramolecular Mannich

what can happen to the product of the intramolecular Mannich condensation

a second step/intramolecular condensation in which the amine and enol/carbonyl component are in the same molecule and react with the electrophilic aldehyde to form an iminium which undergoes trapping to give a second ring

intramolecular Mannich condensation overall equation

first process/stages in intramolecular Mannh

final stage of intramolecular Mannich

how to identify a product of a Mannich reaction

look for an amine with a 1,3-relationship to a carbonyl

what is Claisen condensation

esters undergo self-condensation in a manner similar to the aldol reaction

base needed for Claisen condensation and why

use an alkoxide base (NOT a hydroxide) matching the ester alkoxy group to prevent trans-esterification

overall equation for Claisen condensation

type of product

β-ketoesters

first step of mechanism

where does eqm lie?

K_eq = ca. 10^-9

small equilibrium population of ester enolate reacts with a second molecule of ester as the electrophile

next step of Claisen

describe product

tetrahedral intermediate - wants to reform C=O

next step of Claisen

next step of Claisen

describe step

this deprotonation is the equilibrium shifting step - K_eq = ca. 10⁵

without this step the reaction does not happen as the product is thermodynamically unfavourable until this point

final step of Claisen

how do we know that the ketoester deprotonation is vital to the Claisen reaction

branched alkyl esters with only one enolisable proton do not give the Claisen product

they cannot do the deprotonation step as the carbon is tetra-substituted

what are crossed Claisen reactions

what is good about them

different esters act as nucleophile and electrophile

potentially more useful as there is a wider range of products

requirements for esters for crossed Claisen reactions

one of the esters needs to be non-enolisable so that there is only one possible nucleophile

the ester acting as the electrophile needs to be more reactive than the nucleophilic ester

overall equation (crossed Claisen condensation)

first step in crossed Claisen

next step in crossed Claisen

why does this step happen this way

next step in crossed Claisen

next step in crossed Claisen

describe this step

this is the eqm shifting deprotonation step

final stage of crossed Claisen

overall crossed Claisen mechanism

give 4 examples of non-enolisable, very electrophilic esters for crossed Claisen reactions

alternative nucleophile to non-enolisable esters for crossed Claisen

ketones

overall eqn for crossed Claisen

first step in crossed Claisen

next step in crossed Claisen

next step in crossed Claisen

next step in crossed Claisen

final stage in crossed Claisen

overall crossed Claisen mechanism

intramolecular Claisen

• name of reaction?

• forms?

• what drives the reaction?

Dieckmann condensation, good way to form rings

reaction is driven by the formation of the stable enolate anion of the ketoester

overall equation for Dieckmann condensation

first step of Dieckmann condensation

why is only one ester group shown to enolise

if eqm constant is 1 in 1 billion to form 1 enolate then it is 1 in 10¹⁸ for both esters to enolise - so safe to show only 1

next stage of Dieckmann condensation

next step in Dieckmann condensation

next step in Dieckmann condensation

final step in Dieckmann condensation

products of non-symmetrical diestere substrates for Dieckmann condensation

give overall equation

mixture of regioisomers is formed

show how the different regioisomers are formed

each different ester can act either as the nucleophile (enolate) or the electrophile