Carbonyl chemistry- alkylation of enolates Flashcards
Describe the conditions which cause reaction at oxygen of enolate
- Hard electrophiles
- Polar aprotic solvents (DMSO, DMF)
- Large enolate counter ion- not so tightly bound so more naked
Describe the conditions which cause reaction at carbon of enolate
- Soft electrophiles
2. Ethereal solvents (THF, Et2)
How can you alkylate a ketone
- Form an enolate by addition of base
2. Alkylate using R-X
What type of bases can you use and what effect do they have
- Strong base- add base first then electrophile
2. Weak base- add base and electrophile at same time
Why are the electrophile and base added at the same time for when weak bases are used to alkylate
- Only little bits of enolate form at a time so need to add electrophile at same time to catch enolate as fast as you can
What is a common side reaction and when is this an issue
- Multiple alkylation is a common side reaction
2. Issue if excess of bae is employed
What can be alpha-alkylated
- Generally, if you have alpha-protons which are acidic
2. Specific enol equivalents- enol ethers, silyl enol ethers and enamines
What is formed when enamines react with akylating agents
- Final compound is the corresponding ketone not the enamine
What is formed when silyl enol ethers react with alkylating agents
- Corresponding ketone not the silyl enol ether
What alkylating agent is used for silyl enol ethers and how are they prepared
- Tertiary alkyl halides
2. Needs to form a carbocation by reaction with Lewis acid- removes halide
How else can ketones be alkylated
- Using non-nucleophilic bases to form enolates (LDA)
- E.g lithium enolate
- Then add alkyl halide
Why can’t aldehydes be alkylated using lithium enolates
- They are too reactive
2. If lithium enolate formed it will quickly self condense
How can esters be alkylated
- Have alpha protons which are acidic
- Can react with their own enolate- Claisen Condensation
- Need to convert to enolate and keep cold to prevent side reaction
How can carboxylic acids be alkylated
- Acid proton of OH will react first with any base
- Once H has been removed nucleophilic bases can be used and a Iwanow intermediate is formed
- Then the electrophile and H+ is added
What can alpha, beta unsaturated carbonyls act as
- Electrophiles for soft nucleophiles e.g. organo copper/cuprates- Me-Cu
- Can be alkylated by the Me and Cu leaves
- Need soft nucleophile to react at beta carbon
Where do different carbonyl derivatives react in conjugate addition
- Acyl chlorides and more reactive carbonyls always react at C=O
- amines- react at beta carbon
- Ones in the middle react with either
What problems do you get with ketone reduction with hydride sources E.g. NaBH4, EtOH
- Regiochemistry issues- may reduce at C=C or C=O or both
2. Can’t control
How can the reduction of enones be forced at C=O
- Using CeCl3
2. Luche reduction
How can conditions for alpha,beta-unsaturated carbonyls enolate alkylation be used to promote 1,4/Michael addition not 1,2
- Form either Na/K enolates- enamine, silyl enol ether
2. Use stabilised enolates e.g. where they can form hydrogen bonding 6 membered ring
How does enolate addition to carbonyls work in Michael addition
- The beta double bond breaks and attaches to the carbonyl species where the acidic proton is
What reduces the pKa of the alpha-proton
- The presence of additional electron withdrawing group alpha to the carbonyl
- e.g. COR, CO2R, CN etc
What group particularly is important in reducing acidity of alpha-proton
- 1,3-dicarbonyls
- Malonate- double ester
- B-keto-ester
What is the significance of having a low pKa of the alpha hydrogen
- Can now be deprotonated by weak bases e.g. CO32-
What else can happen to 1,3-dicarbonyls
- They can be decarboxylated
Describe how 1,3-dicarbonyls can be decarboxylated e.g. double ester
- First a base is used to hydrolyse both esters
- Forms a double carboxylate intermediate
- Then an acid is added to protonate O-
- Heat added allows CO2 group to be removed and double bond with two alcohols is left
- This can be tautomerised to produce carboxylic acid
