Wht is in Common for the Following Rections, nd ow Do They Work? You should eventully be ble to drw the mechnism for these (nd other) rections 13 Key Intermedite 1 Br-Br N Br 2 C 3 -I Me NMe Me Me C 3 3 NMe 4 2 N 5 Me C 3 Me NMe Me Me C 3 C 3 6 2 C 3 opticlly ctive N C 3 3 C rcemic mixture C 3 4 Things in Common KEY: Deprotontion of n α- hydrogen genertes 1. Formtion of bond to the crbon α to crbonyl ENLATE nion, which is good nucleophile 2. Bsic/nionic rection conditions 3. Involve n electrophile 4. At lest one α to crbonyl is lost
TYPICAL MECANISM: Vi ENLATE Anion 14 = (Aldehyde) = R (Ketone) = R (Ester) R (Bse) Br Br C 2 3 -I 2 Me C 3 Enolte Ion 2 Me (originl stereo forgotten) Under bse conditions, crbonyl compound with n α-hydrogen cn be deprotonted to give resonnce-stblized, deloclized enolte nion, which is nucleophilic t the α-crbon. Norml C- bonds re very non-cidic. But C- bonds α to crbonyl re much more cidic becuse the resulting nion is resonnce stbilized nd is shred by the oxygen. K = 10-20 K = 10-50 Stbilized Unstbilized The α-crbon hs two other ttchments in ddition to the crbonyl nd the shown in this pge. The other ttchments will remin ttched s specttors, nd need to be ccounted for in drwing products. α-ydrogens re only slightly less cidic thn is wter or lcohol hydrogens
15 Acidity Tble Clss Structure K Acid Strength Anion Bse Strength Strong Acids -Cl 10 2 Mx on Top Cl Mx on Bottom Crboxylic Acid R 10-5 R enol 10-10 1,3-Dicrbonyl Me 10-12 Me Wter 10-16 Alcohol R 10-17 R Ketones nd Aldehydes 10-20 Ester Me 10-24 Me Amine (N-) (ipr) 2 N- 10-33 (ipr) 2 N Li LDA Alkne (C-) RC 3 10-50 RC 2 -A B A B- Reltive stbility of nions dicttes equilibrium Notes to remember 1. Crbonyls cidify α- s (nion stbilized) 2. 1,3-Dicrbonyls re much more cidic thn monocrbonyls (nion is more stbilized) 3. Ketones re more cidic thn esters 4. A lower nion on the chrt cn fvorbly deprotonte ny cid tht s higher on chrt. Becuse ny cid-bse equilibrium will lwys fvor the more stble nion. 5. LDA is strong enough to completely deprotonte ketones, esters, or 1,3-dicrbonyls 6. N, NR cn completely deprotonte 1,3-dicrbonyl (but not ketones or esters) 7. N, NR do not completely deprotonte ketones or esters, but do provide usble equilibrium supply of the enolte tht cn procede to product in some rections.
1. Rnk the cidity of the hydrogens t the lbeled positions, 1 being most cidic. Drw the three nions tht would result from deprotiontion t the three spots, nd ny pertinent resonnce structures. b Site : c b c b > > c b c Some resonnce stbiliztion 16 Site b: b c b c b c Excellent resonnce stbiliztion Site c: b c No resonnce stbiliztion 2. For the following compounds, record to wht degree they would be deprotonted by NC 3 or LDA [LiN(iPr) 2 ] respectively. The bsic choices re totlly (>98%), zero (no enolte whtsoever) or slightly (definitely some equilibrium mount, but <10%). A B C LDA: totlly totlly none (no α-) totlly NMe: slightly totlly none (no α-) slightly 3. For the following compounds, rnk them ccording to which would hve the gretest mount of enol isomer present t equilibrium, 1 being most enol, 4 being lest. A B C B (enol stbilized by -bonding; enol lkene stbilized by conjugtion) > A (enol lkene stbilized by conjugtion) > D (no enol stbiliztion, but t lest some enol is possible) > C no enol whtsoever, becuse no α-hydrogens 4. Drw products for the following rections 2 Br 2, 2N 2 1 Cl 2, Br Br D D 2 1. 3 I 2, 3 N, 2 Cl 2. vi I I I nd
5. Keto-Enol Mechnisms. Drw the mechnism for conversion of the keto form to the enol form 17 b. Drw the mechnism for conversion of the enol form to the ketone 6. Drw the mechnism for the following 2 Br 2, N 7. Try to drw the mechnism for the following. NEt, Et
Drw products for the following lkyltion rections, often involving ester hydrolyses nd therml decrboxyltions. 18 8. 1. LDA 2. Me-I 1. LDA 9. 2. Br 1. NEt Et Et 2. Br Et Et 10. 1. NEt 2. Br 11. Et Et 3. NEt 4. BrC 2 C=C 2 Et Et 12. Et Et 1. NEt 2. Br 3., 2, het 1. NEt 2. Br Et 3., 2, het 13. 1. LDA Et 2. Br Et 14.
15. Which of A, B, C, or D is the correct product for the following rection? 1. NC 3 2. C 3 I B, vi the best enolte C 3 C 3 A B C C 3 3 C D 19 Some Synthetic Strtegy Tips Alkyltion resulting eventully in n cid: from 1,3-diester, vi NR, then subsequent ester hydrolysis/decrboxyltion Alkyltion resulting eventully in mono-ester: from ester using LDA Alkyltion resulting eventully in mono-ketone, where unmbiguous deprotontion ws possible: from ketone using LDA Alkyltion resulting in mono-ketone, where unmbiguous LDA deprotontion would not hve been possible: from keto-ester using NR, then subsequent ester hydrolysis/decrboxyltion Provide regents for the following: 1. NEt 16. Et Et 2. C 2 Br 3., 2, het 1. LDA Et 2. BrC 2 C=C 2 Et 17. 18. Which of the following would undergo decrboxyltion? And which would go fstest? A B C D D > A (the 1,3-crbonyl cids tht cn proceed to enol) B nd C won t, not 1,3 D > A becuse enol produced in rte-determining-step is stbilized by conjugtion with the phenyl 19. Drw the mechnism for the following rection. 1. LDA 2. C 3 I C 3
Aldol Exmples: Aldehydes/Ketones s Electrophiles 20 N, 2 N, 2 1. cold wrmup 2. N, 2 cold N, 2 wrmup With ldehydes, you cn usully stop t the β-hydroxy crbonyl stge or proceed on to the α,β-unsturted crbonyl, depending on time nd temperture. NEt, Et NEt, Et 3. et With ketones s electrophiles, the ldol rection to give the β-hydroxy crbonyl is normlly reversible with n unfvorble equilibrium. owever, while it is not possible to isolte high yields of the β-hydroxy ketone, further dehydrtion to give the enone is irreversible nd cn give good yields of the enone. 4. NMe Me 0ºC NMe Me wrmup more time With two different crbonyl compounds, one must function selectively s the enolte precursor, nd the other s the electrophile. Since ldehydes re much more electrophilic, when mixed with ketone the ldehyde will lwys be the electrophile If there re more thn one site where n enolte might form, the most cidic site tht would give stbilized nion will form preferentilly 5. Et NEt Et 0ºC Et NEt Et wrmup more time Et Comments Bsic ne crbonyl functions s the enolte nucleophile, second crbonyl s the neutrl electrophile. The enolte precursor nd the electrophile crbonyl my be the sme (exmples 1-3) or different (exmples 4 nd 5) Loss of n α-, replced by n α,β C-C bond.
21 All of the following molecules cn be mde by n ldol-type rection or n ldol-type condenstion (ldol followed by loss of 2 ). Drw the crbonyl compound or compounds from which ech is derived. exmple: Strtegy: Identify the crbonyl in the product, nd mrk off which re the α nd β crbons. The key bond connection will hve been between the α nd β crbons. β ws originlly crbonyl (the electrophile crbonyl) α originlly hd s (it ws the enolte crbnion) Note: ny ttchments on the α nd β crbons re specttors. If they re there t the end, they must hve been ttched t the beinning 20. 21. (both enolte precursor nd electrophile) 22. 23. 24. Drw the mechnism for the following rection. NMe Me 0ºC
Provide products for the following ldol rections. 22 25. N, 2 cold N, 2 het NMe, Me 26. het 27. NEt Et 0ºC NEt Et het 28. best enolte NEt Et 0ºC NEt Et het 29. enolte leding to 5-ring N 2 cold N 2 hot NC 3 NC 3 30. enolte leding to 6-ring C 3 cold C 3 hot 31. Drw the mechnism for phse one nd then phse two of the rection in problem 28.
Provide products for the following Clisen rections. 23 NC 3 Me C 3 Me 32. NEt 33. Et Et Et 1. NMe, Me 2. 34. Me 2. NMe 3. BrC 2 C=C 2 Me 3. Me 35. Me 1. NMe, Me 2. NMe 3. BrC 2 C=C 2 4., 2, het Me 4. 36. Me 1. NC 3, C 3 Me 2., 2, het Me 2. 37. Me Me NMe Me Me 38. Me NMe Me
Drw the product, regent, or strting mteril for the following Wittig rections. 24 Combo 1: 3 P 39. Combo 2: P 3 40. Br 1. 3 P 2. BuLi 3. Benzldehyde 1. 2 Cr 4 2. 41. Br P 3 P 3 1. PBr 3 2. P 3 3. BuLi 4. cetone 42.
25 Generl Routes to Mke Alkenes Wittig Rections. o Very generl o Useful for mking more elborte orgnics, becuse two subcomponents cn be coupled to mke lrger product. o Techniclly longer nd more difficult thn n ldol condenstion, so should not be used to mke enones when n ldol condenstion could be used insted. Aldol Condenstions. o Gret for mking enones (α,β-unsturted crbonyls). But limited to mking enones. o If you see n enone trget, mke vi ldol condenstion. o Useful for mking more elborte orgnics, becuse two subcomponents cn be coupled to mke lrger product. Elimintion rections (from either hlides or lcohols). o Not useful for building up crbon chin lengths. Simply involves trnsforming one functionl group into nother. 43. For the following lkenes, which method should you use, nd wht would be the immedite precursors tht would be suitble? Aldol Wittig or P 3 3 P 44. Synthesis design. Design syntheses of the following products, strting from lcohols of 4 crbons or less. Some key reminder rections: PCC for oxidizing 1º lcohols to ldehydes 2 Cr 4 for oxidizing 2º lcohols to ketones PBr 3 for converting 1º or 2º lcohols to bromides needed for mking Wittig regents NMe Me het (sme thing) PCC PCC 3 P or 1. PBr 3 2. P 3 3. BuLi P 3 1. PBr 3 2. P 3 3. BuLi 2 Cr 4
Generl: Enones s Electrophiles. Nucleophiles tht ttck enones must chooe between: Crbonyl ddition β-addition 26 Crbonyl Addition Alkoxide Formtion versus "-Addition Enolte Formtion Crbonyl ddition normlly domintes with: RMgBr RLi NB 4 LiAl 4 LiCCR β- ddition normlly domintes with: enoltes of dicrbonyls sometimes enoltes of monocrbonyls (but not lwys) Cuprtes (R 2 CuLi) Prep: 2RBr 1. 4 Li 2. 1 CuI R 2 CuLi Drw the Products for the following Michel rections 45. NEt Et Et Et Et Et NEt Et Et 3 C Et 46. 47. NEt Et het, long time -drw in the initil product, second product, nd third product
27 48. Drw the mechnism for the following rection. (Clisen rection). NC 3 Me C 3 Me 49. Drw the mechnism for the following rection (Michel rection). Et Et NEt Et Et Et 50. Drw the mechnism for the following rection. (Robinson cycliztion, involving sequentil Michel rection, ldol rection, β hydroxyketone dehydrtion.) NEt Et het, long time C vi nd B A