carbonyls - aldols Flashcards
(32 cards)
what is the aldol reaction
a key C-C bond forming process between 2 carbonyl species , one acting as the electrophile with its C=O carbon and one as the enolate nucleophile with its α carbon, specifically
under what conditions can the aldol reaction take place?
acid or base catalysis
give 1 structural consequence of the aldol reaction
results in the formation of 2/more stereogenic centres
how does the aldol reaction work under base catalysis?
- base protonates carbonyl group forming enolate little bit at a time (full deprotonated does not occur because equilibrium is so far on the RHS)
- reactive carbonyl immediately reacts with any/all enolate generated, enolate forms C=O bond, nucleophilic C reacts with electrophilic carbonyl C and C=O is broken
- -vely charged O reacts with water, protonating itself into hydroxyl + regenerating base
- forms aldol product
give 1 advantage + 1 disadvantage of base catalysis of aldol reaction
as the base is a catalyst it regenerates itself so only a small amount is needed
however as this process is catalysed by base, it can go on to further react + side reactions
what happens when base re-reacts with aldol product?
- attacks α hydrogen which causes C=O bond to break, via E1cB
- double bond is formed as α proton leaves
-vely charged O reforms C=O and double bond shifts adjacently and hydroxyl group leaves - this forms the dehydration prodcuct
how does the aldol reaction work under acid catalysis?
- protonation via acid to form enol
- protonated carbonyl immediately reacts with enolate generated, enolate forms C=O bond, nucleophilic C reacts with electrophilic carbonyl C and C=O is broken
- deprotonation of carbonyl forms aldol product
give 1 disadvantage of performing the aldol reaction under acidic conditions
the elimination of water to form the dehydration product is easier under acid conditions, via E1 reaction
- OH group on aldol is protonated to H2O+, via E1 it leaves forming carbocation
- loss of proton forms second double bond = enone = dehydration product
is it possible for 2 of the same carbonyl compound undergo the aldol reaction + what is formed + 1 disadvantage?
yes, this is via self condensation = a dimerisation of a single carbonyl compound
- this product can be further deprotonated even if stoichiometry was perfect, leading to byproduct formation
give 2 ways byproduct formation be restricted
- if enolisation can only occur at 1 carbon, onyl 1 product is possible
- using specific enol equivalents which doesn’t allow the formation of certain byproducts, as specific enols are preprepared and then added to electrophilic carbonyl species, this means no base catalyst is needed for reaction therefore cannot go further
what is cross condensation + 1 disadvantage?
when 2 different carbonyl species are reacted together to form the aldol
this means that if both carbonyls can form enolates, there are 4 possible aldol products as there is 1 enolisable prpton per carbonyl and 1 electrophilic carbonyl per carbonyl, this is before considering second enolisations/condensation products
- serious lack of control
how do lithium enolates react to form aldols?
lithium enolates are made via reaction of LDA with ketone at low temperatures
- Li leaves O as C=O bond is formed, β carbon at the end of enolate C=C attacks δ+ C which breaks C=O which bonds with Li
- Li is removed via aq work up forming aldol
give 2 advantages of using lithium enolates for the aldol reaction
- no base in the system so further reactions are prevented
- electrophile is fully controlled as its added in small quantities to the lithium enolate mixture
why can the aldol reaction via lithium enolates be used with aldehydes?
aldehydes cannot be deprotonated under these conditions and if they are, they will be too reactive and self-condense/react
what are the 2 ways silyl enol ethers can be made?
- quench lithium enolate with Me3SiCl
- react ketone with weak base in the presence of Me3SiCl
what extra consideration needs to be made when using silyl enol ethers?
they are less reactive than lithium enolare, meaning electrophiles need to be made moer reactive, done via lewis acid which lowers the LUMO of the carbonyl sufficiently for the reaction to take place
how are intramolecular aldol synthesised?
molecules containing 2 carbonyls can react via the aldol mechanism in the presence of acid or base to form an intramolecular aldol/cyclic aldol
what are 2 similarities of the reactions forming intramolecular aldols and intermolecular aldols?
- process can occur under both acidic + basic conditions
- once enol/enolate forms it will quickly react with ketone
are rings likely to form in aldol reactions?
yes - if it is possible for a ring to form it most likely will form + be the major product,, 5/6 membered rings especially
why are other rings other than 5/6 membered rings less likely to form?
they do exist and can form, however they are much less stable and so more likely to reverse react back into starting products
what is robinson annulation?
a 2 step process for forming 6 membered rings, micheal addition followed by intramolecular aldol reaction, then dehydration
how are 6 membered rings formed via robinson annulation?
micheal addition: ketone + β unsaturated ketone
- ketone is deprotonated in the presence of base to form enolate
- -vely charged O reforms C=O bond causing double bond to attack β carbon of doble bond of β unsaturated ketone, causes C=O bond to break
- C=O bond reforms, double bond of β unsaturated ketone is protonated - generates enolate
aldol formation:
- base attacks α hydrogen, which attacks δ+ C causing C=O to break
- C=O reforms and enol double bond attacks carbonyl bond, causing it to break, this forms new ring
- -vely charged oxygen protonates into OH group
- base attacks α hydrogen which attacks δ+ C causing C=O to break + forms a double bond via E1cB
- C=O reforms, double bond attacks β carbon which causes OH to leave via dehydration
- final dehydrated product is formed
what is the claisen reaction?
the acylation of α carbon via condensation reaction of 2 esters in base - similar to aldol reaction
occurs via ester enolate and forms 1,3 diketone
give 1 limitation of the claisen reaction
similar issues to alcol cross condensation, the 2 esters should have very different reactivities to ensure success of the rection
