OrgChem- Chap20 1 Chapter 20 Enolates / Other Carbon Nucleophiles C-C bond formation is very important larger, more complex organic molecule can be made from smaller ones How? carbon nucleophile + carbon electrophile Carbon electrophile: or + - ++ abundant
OrgChem- Chap20 2 How about carbon nucloephile? limited Ex) cyanide ion: M + - CN acetylide ion: ylide: Grignard reagent and organo metallic compound: R-X + 2Li RLi + LiX
OrgChem- Chap20 3 Grignard reagent and organometallic compund are not useful for S N 2 reactions because they are too reactive. For the S N 2 enolates are used Because they are not as reactive as organometallic compunds, then C-C bond through S N 2 can be formed
OrgChem- Chap20 4
Enols and Enolate Anions both are possible under acidic and basic conditions In acidic condition In basic condition
OrgChem- Chap20 6 Equilibrium constants of carbonyl and enol tautomers for base condition Higher value for 1,3-dicarbonyl compoundsdiketone > ketoester > diester
OrgChem- Chap20 7 What kinds of base can we use? Use base whose pK a s of conjugate acids are greater than those of the carbonyl base !
OrgChem- Chap20 8 For Use compunds whose pK a s of conjugate acids are greater than 30 such as Ethoxide can be used (pK a ~ 16) For
OrgChem- Chap Halogenation of the -Carbon The reaction of an aldehyde or ketone with Cl 2, Br 2, or I 2, under either acid or basic condition Both acidic and basis conditions can be used
OrgChem- Chap20 10 Under acidic conditions The presence of the halogens retards the enolation, so the addition of single halogen is possible Examples
OrgChem- Chap20 11 Under basic conditions
OrgChem- Chap20 12 Example
OrgChem- Chap Alkylation of Enolate Anions Enolates from esters, ketones, and nitriles can be used in S N 2 reactions (alkylations). Ex)
OrgChem- Chap20 14 Aldehydes cannot be used in such reactions because they are too reactive (side reactions) 1. Reactions with base No steric hidrance ! 2. Reactions with themselves: Aldol condensation (later) LDA: lithium diisopropylamide It is a very strong base but not very nucleophilic due to the steric hindrance
OrgChem- Chap20 15 To avoid the formation of two products, deprotonation of the ketones must produce a single enolate ion. Examples
OrgChem- Chap20 16
OrgChem- Chap Alkylation of More Stabilized Anions Strong nucleophiles are normally strong bases, then many side reactions are possible. 1.Elimination 2.Unwanted substitution
OrgChem- Chap20 18 Therefore we might need to use less nucleophilic enolates, Then we might need more steps to, still the yield can be higher due to less side reaction. Example Ch 10.2 Ch 10.6
OrgChem- Chap20 19 Ch 10.2
OrgChem- Chap20 20 Ch 10.6 Why?
OrgChem- Chap20 21 This time, ethyl acetoacetate can be used instead of acetone!
OrgChem- Chap20 22 Mechanism
OrgChem- Chap20 23 Example
OrgChem- Chap20 24 Diethyl malonatate can be used instead of acetic acid
OrgChem- Chap20 25
OrgChem- Chap20 26 Preparation of substituted -ketoesters, -diester, and dinitrile without hydrolysis
OrgChem- Chap20 27
OrgChem- Chap The Aldol Condensation (aldehyde + base) cannot be used for the alkylation of alkyl halide, because of the aldol condensation! Carbonyl carbon of aldehyde is much more electrophilic than those of ester, ketone, and nitrile! ester, ketone, and nitrile S N 2
OrgChem- Chap20 29
OrgChem- Chap20 30 If the aldol condensation is conducted under very vigorous conditions (higher temperature, longer reaction time, and/or strong base
OrgChem- Chap20 31
OrgChem- Chap20 32 Ketones As less electrophilic, usually no aldol condensation. However when the product is 5- or 6- membered ring, then aldol condensation occurs!
OrgChem- Chap20 33 Mixed aldol condensation 4 products = 2 acidic compounds x 2 electrophilic compounds
OrgChem- Chap20 34 Use aromatic aldehyde (only electrophilic) to get one product. Product is more favorable: conjugation
OrgChem- Chap20 35
OrgChem- Chap Ester Condensation : enolates with alkyl halide using weak or strong bases depending on the acidity.
OrgChem- Chap : enolate with ester using weaker bases. Ester condensation or Claisen ester condensation 20.5: enolate with aldehyde using weaker bases. Aldol condensation
OrgChem- Chap20 38 Mechanism of the Claisen Ester Condensation Step 4 is the reason why this reaction is possible
OrgChem- Chap20 39 For the compounds with only one on the -carbon, Step 4 is impossible. Then the ester condensation is impossible If stronger base is used, then condensation is possible
OrgChem- Chap20 40 Dieckmann condensatoin Intramolecular ester condensation Mixed ester condensation can be prevented if one of the component acts as only electrophile such as
OrgChem- Chap20 41
OrgChem- Chap Carbon and hydrogen leaving groups A carbanion as a leaving group
OrgChem- Chap20 43 A hydride as a leaving group, Cannizzaro reaction
OrgChem- Chap Enamines In ch 18.8 The enamine can be used as a carbon nucleophile !
OrgChem- Chap20 45 -carbon is nucleophilic, still weaker nucleophile than the enolates. Therefore for S N 2 reaction, the alkyl halide must be very reactive such as:
OrgChem- Chap20 46
OrgChem- Chap Other Carbon Nucleophiles
OrgChem- Chap20 48 Example reaction
OrgChem- Chap20 49 Example reaction
OrgChem- Chap20 50 Other Carbon Nucleophiles
OrgChem- Chap20 51 Using two equivalent of LDA more nucleophic site is reacted
OrgChem- Chap Conjugated Addition 1,2 addition: Grignard reagent, hydride stronger nucleophile 1,4 addition: cyanide, amine less reactive nucleophile or sterically hindered See CH 18.10
OrgChem- Chap20 53 In CH 20 Michael reaction enolate and related carbanion + , -unsaturated carbonyl compound In Michael reaction only catalytic amount of base is needed
OrgChem- Chap20 54 Michael reaction mechanism
OrgChem- Chap20 55 Examples of Michael reaction
OrgChem- Chap20 56 Robinson annulation Michael reaction + aldol condensation
OrgChem- Chap Synthesis Retrosynthetic Arrow
OrgChem- Chap20 58
OrgChem- Chap20 59
OrgChem- Chap20 60
OrgChem- Chap20 61
OrgChem- Chap20 62 Other example
OrgChem- Chap20 63 Summary
OrgChem- Chap20 64
OrgChem- Chap20 65