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U-M CHEM 216 - Chapter 14 Aldehydes and Ketones - Addition Reactions at Electrophilic Carbons - Part I

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Chem 215-216 HH W11 Notes – Dr. Masato Koreeda - Page 1 of 11. Date: February 17, 2011 Chapter 14 Aldehydes and Ketones: Addition Reactions at Electrophilic Carbons: Part I Overview of Chapter 14 1. Structures of aldehydes and ketones CRR'OR, R' = alkyl, aryl: ketonesR = alkyl, aryl; R' = H: aldehydesδδelectrophilic CAldehyde C=O carbons are lesssterically hindered and more electrophilic compared with the corresponding ketone carbons (i.e., with the same R)lone pair: more basic than C=O π 2. Reactions of aldehydes and ketones with an electrophile and a nucleophile CR'ROσ−frameworklone pairsall of these sigma-bonds and lone pairs on thesame planeEl+with this trajectoryπ-bondingHighest occupied molecular orbitals (HOMOs) of the C=O groupCR'ROemptyanti-bondingorbitalsLowest unoccupied molecular orbital(LUMO)Nu:trajectory ofa nucleophileapproachtrajectory angle of 107°CR'RONuCR'RONusp3between sp2 and sp3;on its way to sp3CRR'OElall atoms including Elon the same planeTwo lone pairs: 3. Activation of RR’C=Z (Z = O and N) with H-A or a Lewis acid → activates C=O toward a nucleophilic addition O OHAbecomes even more δ ; i.e., more electrophilicOHAH ALewis acid (L.A.)OL.A.OL.A.OM(if M+ is used)orChem 215-216 HH W11 Notes – Dr. Masato Koreeda - Page 2 of 11. Date: February 17, 2011 Chapter 14: Overview (continued) 4. Four categories of nucleophilic addition reactions Two classes of nucleophiles: reversible and irreversible OReversible Nu:Irreversible Nu:Type 1H MOHMH3OH2OHOHType 2RORMHORROORHOORHONore.g.,RLi,RMgX(Grignard reagent) Type 3divalent Nu:e.g.,ROH, RSHSN1NRHRE1Type 4 Trivalent Nu:e.g., R-NH2H3OH2Oor ============================================================== I. Nucleophilic Addition Reactions of RR’C=Z (Z: electronegative atom) NaBHHHH- mild reducing agent- relatively stable reagent (against moisture, air)electronegativity values: H 2.1; B 2.0; Al 1.5|Δe.n.| for B-H: 0.1|Δe.n.| for Al-H: 0.61. Sodium borohydride (NaBH4)LiAlHHHH- powerful reducing agent- reacts violently with water, ROH to produce H2 gas- Reactions with LiAlH4 are usually carried out in a polar aprotic solvent such as anhydrous tatrahydrofuran (THF) and anhydrous (diethyl) ether (CH3CH2OCH2CH3)2. Lithium aluminum hydride (LiAlH4) more polarized, more on the Ha stronger H donorOOTHF(diethyl) etherIn addition, the difference in the coordination power of Na+ and Li+ (stronger) on the C=O oxygen further contributes to make the reactivity of LiAlH4 stronger.Reduction with LiAlH4 requires an aqueous (usually acdic) workup.I-1. Irreversible nucleophiles [ H - Type 1; R - Type 2 ](1) Hydride reducing agents: Type 1••Also, the larger size difference between Al-H than B-H makesdissociation of Al-H much easier.4. Diisobutylaluminum hydride (DIBAL or DIBAL-H) - powerful red. agent --reaction needs to be carried out in anhydrous conditions (e.g., anhyd THF or ether).3. Sodium cyanoborohydride [Na(CN)BH3] (much weaker hydride reagent)AlHDIBALChem 215-216 HH W11 Notes – Dr. Masato Koreeda - Page 3 of 11. Date: February 17, 2011 I-1 (1) Hydride reducing agents (cont’d) OOHAlHHHLiH3OOHH+ LiOH + Al(OH)3All of these three Hs could be used in the reduction of a ketone.Reduction with LiAlH4:LiAlH4OLiHAlHHHOLiAlHHHnote: O-Al bond stronger than O-Lihydrolysis**This acid-hydrolysis step may be quite complex, depending upon the stoichiometry betweena ketone and LiAlH4. However, all of those hydrolysis step should involveOHAlXXXHanhyd. aproticsolvent (e.g., THF)X: OH or ORReduction with NaBH4:OOHHNaBH4usually in a proticsolvent (e.g., ethanol)ONaHBHHHONaH OR+ BH3reacts with the solvent 3 x RO-H to formB(OR)3 and 3 x H2Reduction with DIBAL (Al in DIBAL quite Lewis acidic):OOHAlH3OOHH+ Al(OH)3 + 2 (H3C)3CHDIBALOAlhydrolysisanhyd. aproticsolvent (e.g., THF)AlHHOHAlOHAlCHOH2O H2OH2OH3OHHHOHHLi AlH4Na BH4Na OROnot very favorable;Na+ not much Lewis acidicChem 215-216 HH W11 Notes – Dr. Masato Koreeda - Page 4 of 11. Date: February 17, 2011 I-1. Irreversible nucleophiles (cont’d) ++++(b) R nucleophiles: Type 2OCould be sp3, sp2, sp carbanions!!!Grignard reagents (R-MgX)!!!alkyllithium (R-Li) or sodium (R-Na)!!!alkenyl lithium (C=CHLi)!!!alkynyl lithium/sodium or lithium/sodium acetylide (C C-Li; C C-Na)R Manhydrousaprotic solventORMH3OhydrolysisORHM(OH)Grignard reagents: R-MgX (X is usually Br or I, sometimes X=Cl)H3CBrMg*anhydrousTHF or etherδ δδδH3CMg BrδH3C Mg Br2Formally equivalent to:polarization reversal*R XMgR••Mg-Xoxidation #: 0oxiudation #: +2Prepration of Grignard reagents:(i) Alkyl Grignard reagents from R-X(ii) Alkynyl Grignard reagents:CH3C CHpKa ~26H3CCH2MgBrCH3C CMgBrCH3C C MgBrH3C CHHHpKa ~50+CH3C CHnote:Na, liq NH3or NaNH2, liq NH3CH3C CNaBrMgBr(iii) Alkenyl and aryl grignard reagents from their halide precursorsMgusually in anhydrousTHFBr MgBrMganhydrousTHF or ethernote:LiLi-Br2 LialkenyllithiumCyanide carbanion - often reversible nucleophileONaCNH2OOCNNaH3OOHCNelectronegativity values: C (2.5); H (2.1); Li (1.0); Na (0.9); Mg (1.2); Al (1.5); Br (2.8)R-Mg-XChem 215-216 HH W11 Notes – Dr. Masato Koreeda - Page 5 of 11. Date: February 17, 2011 Chapter 14 I-1. Irreversible nucleophiles δδ+ Mg(OH)2(b) R M (Type 2; organometallic reagents) (cont'd)Note: Reactions with epoxidesOHPhMgBrOHPhOHHPhMgBrPhSN2!work-upwithaq NH4Cl**NH4Cl: weakly acdic; pKa ~9.7; commonly used for the work-up of organometallic reactions; the only exception is the work-up of a carboxylate product (you need to acdity the solution to pH~1-2).Ph MgBrOMgBrCOPhOCOPh COO HH3OpH 1-2+ BrpKa 4.2Not with aq NH4Cl! I-2. Reversible nucleophiles Type 3: Divalent nucleophiles (ROH & RSH); requires an acid catalyst Type 4:!!Trivalent nucleophiles (R-NH2 & RR'NH); w/o activation by an acid +Oketoneoxygen atomROH, Hor L.A.OHORORORROH, Hor L.A.H2O+HOaldehydeoxygen atomROH, Hor L.A.HOHORHORORROH, Hor L.A.H2OhemiketalhemiacetalketalacetalTend to be unsatble intermediates!+Oketoneoxygen atomRSH, Hor L.A.OHSRSRSRRSH, Hor L.A.H2O+HOaldehydeoxygen atomRSH, Hor L.A.HOHSRHSRSRRSH, Hor L.A.H2Ohemithioketalhemithioacetalthioketalthioacetal(a) ROH (alcohols)(b) RSH (thiols or mercaptans)meaning"mercury capturers"Chem 215-216 HH W11 Notes – Dr. Masato Koreeda - Page 6 of 11.


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U-M CHEM 216 - Chapter 14 Aldehydes and Ketones - Addition Reactions at Electrophilic Carbons - Part I

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