Lecture6: 123.312

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Lecture 6: C-C bond formation
The big one; the all important formation of C-C bonds. Reagents include organometallics and enolates. There will also be a slight detour into the wonderful world of pKa.

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Lecture6: 123.312

  1. 1. FUNCTIONALGROUP 123.312 looked at substrate (R-LG)... INTERCONVERSIONS functional group CHAPTER9 interconversions Nuc R LG R Nuc CHAPTER nine c–c bond formation: previously we looked at enolates the substrate & which leaving groups were good in substitution reactions E 1 2 now look at c-based nucleophiles 3 we’ll concentrate on... enolates formation O O O :base H O pKa = 19 easily prepared by deprotonation of the !- ©alfred sim@flickr hydrogen 4 5 6 enolates stable as electrons spread out... it is easier to deprotonate a 1,3- diketone O O O O O pKa = 9 O O :base H H H two resonance forms. The anion residing on the oxygen contributes the most to the resonance hybrid (or is the more p pKa of acetone is 19 so this is much easier ‘realistic’ if you like) (remember it is a log scale) 7 8 9
  2. 2. resonance stablisation (delocalisation) the normal representation... O O O O O O H H H O O O another question oxygen is more more resonance spread charge over electronegative so forms more stable H more atoms more charge more associated stable with o ©horia varlan@flickr 10 11 12 ...but the majority of neutral MO theory can give us the answer electrphiles react at carbon... O Elec ©e-magic@flickr 13 14 15 overall, there is more charge / carbon has bigger coefficient in carbon has bigger coefficient in electron density on oxygen but... homo homo oxygen has greater soft hard charge overall, but in nucleophile nucleophile the highest occupied (big charge O molecular orbital (HOMO) the carbon has greatest charge O so electrophiles with small volume) little charge & low lying LUMO react at carbon O neutral/weakly highly charged charged electrophiles electrophiles 16 17 18
  3. 3. carbon has bigger coefficient in if you want a good introduction to SOft electrophiles... homo molecular orbital theory (for hard organic chemists not theoreticians soft then ian Fleming’s book is a must nucleophile nucleophile (big charge small volume) O O H3C I CH3 O soft electrophile reacts with soft nucleophile (the in other words it is carbon) iodomethane is considered pearson’s Hard soft soft as iodine is big & acid base at work... diffuse 19 20 21 hard electrophiles... stable as electrons spread out... stability of other O O enolates... Ph pKa = 12.7 O O Me lets get back to deprotonations & O Ph O H H O OEt :base Ph O H O OEt H3C OMs forming enolates pKa = 13 slightly less acidic O O hard electrophile reacts as ester can donate electrons with hard nucleophile (the from oxygen lone pair but very Ph OEt oxygen) hard as charge/electrons little difference concentrated in a small H volume 22 23 24 stability of other O O stability of other O O good indicator of ease of deprotonation enolates... enolates... pKa Ph Ph pKa = 12.7 pKa = 12.7 O O O O O O N N C C N N Ph Ph Ph O Ph O :base :base H H H H H H pKa = 10.2 pKa = 7.7 O O O N C nitro group is strong N nitrile strong electron Ph EWG. Both an inductive & Ph O withdrawing group (EWG) so resonance effect It is a good guide proton more acidic H H but not perfect... 25 26 27
  4. 4. base must have enolate formation which base do we use? conjugate acid with pKa higher than carbonyl O pKa pKa base O H base O H H base > the general formula in english...the base is easy, but... 28 ©marcarena c.@flickr 29 must be more basic! H 30 base must have is ethoxide sufficiently strong? look at pKa... conjugate acid with pKa higher than carbonyl O O pKa pKa O ? O O H OEt OEt OEt > OEt H H > H H H base pKa = 15-16 pKa = 11 conjugate acid of ethoxide the base must want to (ethanol) has a higher pKa than hold on to the proton more than the acid does H 31 32 carbonyl so it will take the proton 33 it is a good choice... can we use what about...? methoxide (Meo-)? O ? O O O O OEt OEt OEt H OEt OEt H H H H start to try & think about the chemistry & not just learn facts 34 35 36
  5. 5. look at pKa... no enolate formation... what about...? KETONE (CONJUGATE ACID OF ENOLATE) IS MORE BASIC (HIGHER pKa than ethoxide/ethanol) so we do not get O deprotonation O x Li ? H OEt > OEt O H OEt O Bu H H H pKa = 15-16 pKa = 26.5 37 38 39 look at pKa... theoretically possible... Text Li Bu O Li Li Li Bu H Bu > O H Bu O H Bu H pKa = 48-51 pKa = 26.5 base has high enough pKa so can cause deprotonation... ©caramdir@flickr problem! 40 41 42 competing addition Li Li O Bu O Li O Bu H H ? the solution start to try & think about the chemistry & not just learn facts 43 44 45
  6. 6. lithium diisopropylamide lithium diisopropylamide lithium diisopropylamide LDA N Li Bu N Li Bu N H Bu N N H H Li pKa = 36 pKa = 48-51 (conjugate Li Li acid) this forms a new we can react non-nucleophilic butyllithium and an amine sterically demanding means it rarely (bulky) base attacks a functional (just look at the pKa) non-nucleophilic group 46 47 48 what about...? look at pKa... deprotonation and no nucleophilic attack O ? Li Li Li N O H NiPr2 Li > O NiPr2 H O N H H pKa = 36 pKa = 26.5 size of lda means it does much higher pKa so not attack carbonyl readily deprotonates ketone therefore... 49 50 51 Silyl enol ethers allow the use of weak bases SiR3 O H R3Si Cl O SiR3 a second O these allow the use of H Et3N: solution a weak base to form the enolate equivalent they rely on the SiR3 strength of the si-O bond O to activate the carbonyl this is an enolate equivalent or a compound that reacts like an enolate 52 53 54
  7. 7. will approach by mechanism... General mechanism reactions substitution Cnuc C LG C C LG Cnuc C C C C C O carbonyl addition O Cnuc C LG C C LG Cnuc C C C alkene addition Cnuc C C C C C ©-andor-@flickr ©Zanthia@flickr 55 56 57 enolates as nucleophiles Enolate alkylation Text Cy(iPr)NLi HMPA / THF Li N N PhO2S O O PhO2S O O Li O O R X Li X R avocados are a I good source of vitamin e in this reaction we form OH the enolate as normal but it is part of a chiral amide O O & this permits control of Xc simple sn2 reactions stereochemistry O vitamin E ©darwin bell@flickr 58 59 60 silyl enol ethers & strong silyl enol ethers & strong electrophiles electrophiles SiR3 Cl AlCl3 O SiR3 Cl AlCl3 we use a Lewis acid here, O O O to form a cation (a strong electrophile) reactions of silyl enol AlCl4 Cl AlCl4 Cl ethers SiR3 SiR3 SiR3 SiR3 O O O O do not need to activate the silyl enol ether if it is reacting with a strong electrophile 61 62 63
  8. 8. ©earl -what i saw 2.0@flickr silyl enol ethers & weak silyl enol this is achieved by attacking the silicon ethers & weak electrophiles electrophilesstrong organometallic reagent or with a an acid SiR3 MeLi O SiR3 MeLi O O O R X R X R R if we react the silyl enol ether with a weak electrophile then we must regenerate the enolate first... SiR3 Me SiR3 Li SiR3 Me SiR3 Li O O O O Li Me R X Li Me R X what about 64 65 ? regioselectivity 66 unsymmetrical ketones can give two products O O O O OEt O OEt OEt R H O LDA and / or how can we control R X O ? regioselectivity by adding a second carbonyl group X R deprot0nation is limited to one position only O O OEt R method 1: Activated starting material R 67 68 69 ...then remove activating group but how do we method 2: selective enolate formation selectively add the O O O O O O O activating group? NaOH OEt O Na R R O note: lovely six-membered kinetic ring with 3 curly arrows. H Organic chemistry does energy repeat the same motif so O often... thermo- H dynamic O O O R heat one product is more O O stable & one product is formed more rapidly CO2 R reaction progress ©Jill Greenseth@flickr 70 71 72
  9. 9. method 2: selective enolate formation formation of thermodynamic enolate formation of thermodynamic enolate O O O O R3Si Cl SiR3 O R3Si Cl SiR3 O O O kinetic NEt3 NEt3 energy O SiR3 SiR3 SiR3 SiR3 SiR3 SiR3 thermo- O !+ O !+ O O !+ O !+ O dynamic or or thus changing how we form the enolate (reagents/ O temperature) we can selectively this is the more silicon activates the carbonyl stable enolate (it is the H H so that we only haveH use H to form either more substituted double !+ NEt3 !+ NEt a weak base to deprotonate !+ NEt !+ NEt 3 3 3 reaction progress bond) 73 74 75 formation of thermodynamic enolate or... then regenerate enolate deprotonation occurs through a cationic transition state that is more OH O OH O R3Si stable if it is spread over a secondary Cl SiR3 O position rather than a primary position minor an alternative major SiR3 Li NEt3 argument is that silyl O MeLi O reagents can react with the R3Si Cl enol & that the more substituted SiR3 SiR3 SiR3 enol is formed in preference O !+ O !+ O or to the terminal enol SiR3 Et3N H SiR3 O O H H finally re-generate the enolate, a process that occurs with retention !+ NEt3 !+ NEt of regiochemistry 3 76 77 78 kinetic enolate kinetic enolate kinetic enolate O O O O O O H H H H H H H H H more acidic more accessible strong base at low statistics bulky base gives good temperature gives good more of these protons selectivity selectivity 79 80 81
  10. 10. O LDA O O LDA O kinetic enolate Lda is bulky & strong base reaction is performed at low temperature O sn2 reaction O O epoxides good electrophiles O as we control alcohol stereochemistry OH OH 82 83

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