carbonyl compounds as electrophiles

how do aldehydes and ketones react as both nucleophiles and electrophiles

what consequence does this have for their reactions

they react as nucleophiles through their enol/enolate forms and as electrophiles through attack at the carbonyl

this means they can undergo self-condensation known as the aldol reaction

overall equation for the aldol reaction of butanal

mechanism + product

comment on equilibrium?

only a small equilibrium population of enolate is formed, but aldehydes + ketones are powerful electrophiles and can trap the enolates

mechanism + product

mechanism + product

where does the name aldol come from

initial adduct from aldehydes is an aldehyde-alcohol (although this name is also used for the reactions of ketones)

mechanism + product

why is this step important

rather than stopping at the aldol, the reaction will usually continue to enolate formation which triggers E1_cb elimination (next step)

mechanism + product

name of mechanism

name of product

what drives this step

E1cb (conjugate base) elimination which gives the stable, conjugated enal product - note this is different to an E2 elimination

OH leaving pushes the elimination despite it being a poor leaving group

mechanism

acid catalysed aldol condensation - what type of acid is needed and why

enols act as electrophiles in the presence of strong acid - strong acid is needed since the enol is not nucleophilic enough to attack the neutral carbonyl so a protonated carbonyl is needed as it is charged and more electrophilic

overall equation for acid-catalysed aldol condensation

step 1 in acid catalysed aldol condensation

next stage of aldol condensation

mechanism + product + conditions

this molecule is a good nucleophile but it is not as reactive as enolates - carbonyls don’t react alone with enols as they are not electrophilic enough but they will when they are catalysed and hence protonated - the second molecule MUST be protonated for the reaction to happen

mechanism + product

mechanism + product

why is this step necessary

makes OH into a viable leaving group

next step in aldol condensation

E1 elimination (part 1)

mechanism + products

full mechanism

what are crossed aldol reactions

reactions where the enolate and carbonyl come from different starting materials

these are much more useful but can lead to problems

when do crossed aldol reactions work and why

only work well when only one partner can form an enolate to prevent a mixture of products from forming, and additionally the compounds are well distinguished as electrophiles as if there are multiple enolates or electrophiles, this will lead to the complex mixture of products

this usually means choosing a monoenolisable or symmetrical ketone and reacting it with a non-enolisable alcohol

show product + conditions and identify nucleophile and electrophile

what makes a position enolisable

the presence of H atoms on a C next door to the carbonyl

how to achieve crossed aldol reactions with problematic carbonyls

irreversibly form the lithium enolate of one carbonyl (usually the ketone) first

show mechanism for the pre-formed lithium enolate

reaction with pentanal

final step of crossed aldol reaction, why done and what is product

final product is not an α,β-unsaturated ketone as the alkoxide group is not a leaving group so cannot eliminate. in order for it to eliminate it would need to be protonated but there is no water or protic solvent to do this

what is step (i)

ketone A, LDA, THF, -78°C

what is step (ii)

add aldehyde B

what is step (iii)

aqueous work-up (add water to quench reaction and convert O-Li to O-H)

overall equation for reaction between these carbonyls

full mechanism for reaction between these carbonyls

for crossed aldol reactions with pre-formed lithium enolates, how can you ensure the crossed-aldol is the only product

prevent equilibrium using solvent and temperature choice

for crossed aldol reactions with pre-formed lithium enolates, whic product is formed

the less hindered/substituted enolate due to kinetic control

alternative approach to pre-formed lithium enolates for problematic crossed aldol reactions

silyl enol ethers - a stable equivalent of enols

how is silicon effective in making silyl enol ethers

forms very strong bonds to oxygen and can be used to trap very small concentrations of enolates formed when using a very weak base

favoured enolate from silyl enol ethers and why

at high temperatures, equilibrium is achieved so the more substituted thermodynamic enolate is favoured and more of this is trapped by the silicon to form more of the more substituted silyl enol ether

why does the conversion from enolate to silyl enol ether work

O-C = ca. 360 kJ mol^-1

O-Si = ca. 450 kJ mol^-1

reagents and conditions for production of silyl enol ethers

explain choice of solvent and temperature

solvent chosen as polar, temp chosen as DMF has high BP

equation for production of silyl enol ethers

what is unusual about this reaction

the nucleophile attacks the O and not the C, which is unusual in organic reactions

complete to show possible products

which is favoured?

left hand product is more substituted and thermodynamic product so it is favoured

conditions for reaction between silyl enol ether and carbonyl

example? how does it react?

silyl enol ethers are not nucleophilic enough to attack a carbonyl compound on their own so the reaction is promoted by Lewis acid catalysts

example = TiCl₄. O donates lone pair to Ti giving it a negative charge (and the O is positive)

product of crossed aldol with silyl enol ethers

non-eliminated aldol adducts, as with pre-formed lithium enolates

first step of crossed-aldol reaction

next step in mechanism

next step in mechanism

name of product

trimethylsilyl ether

how is this final step achieved + how does it work

water workup - hydrolyses ether

how are the products of crossed aldol reactions with LDA vs silyl enol ethers

LDA gives the less-substituted kinetic enolate, whereas silyl enol ethers give the more substituted thermodynamic enolate

what are intramolecular aldol reactions useful for? are they selective?

how are they catalysed?

powerful way to construct rings - selectivity is observed for forming five or six membered rings - smaller or larger rings are disfavoured. this is because five and six membered rings have less strain than smaller rings and are more substituted than larger rings

the reactions work under acid or base catalysis