Components of Organic Chemistry Advanced Org Chem-Carey B Fall 2002 Components of Organic Chemistry Reactions: synthesis Organic compounds Structure Reactivity bonding, conformation, analysis, stereochem. interaction with other molecules: mechanism, dynamic stereochem. Carey B-5ed-Chap 1 Chapter 1

Chapter 1. Alkylation: What to study Advanced Org Chem-Carey B Fall 2002 Chapter 1. Alkylation: What to study Generation of carbon nucleophiles enolate & imine anions: conditions of formation Alkylation: reaction conditions reactivity and structure of carbon nucleophile Selectivity of alkylation regioselectivity & stereoselectivity Carey B-5ed-Chap 1 Chapter 1

Generation & Properties of Enolates Advanced Org Chem-Carey B Fall 2002 Generation & Properties of Enolates Generation of enolates: acid-base reactions deprotonation: stronger bases for enough enolates acidity of C-H (pKa): inductive & resonance;  3 Table 1.1 the more acidic, the faster deprotonation (kinetic) & the more stable carbanion (thermodynamic) bases: HOK, RONa & LDA, L(Na/K)HMDS, Na(K)H, RLi solvents: ROH & ether, THF, DME, DMF, DMSO, PhMe Carey B-5ed-Chap 1 Chapter 1

Deprotonation Equilibrium Advanced Org Chem-Carey B Fall 2002 Deprotonation Equilibrium K K = [A:][BH] / [HA][B:] = [A:]/[HA] x [BH]/[B:] = [A:][H3O+]/[HA] x [BH]/[B:][H3O+] = Ka(HA) / Ka(HB) = 10exp(-pKa(HA) + pKa(HB) ) Ka (HA) = [A:][H3O+] / [HA] Ka (HB) = [B:][H3O+] / [HB] K > 1, when HA is stronger than HB (pKa (HA) < pKa (HB)) DG = - RT ln K < 0; K= 10(-20 + 35) = 1015 Carey B-5ed-Chap 1 Chapter 1

Advanced Org Chem-Carey B Fall 2002 Estimation of pKa Carey B-5ed-Chap 1 Chapter 1

Other Useful Amine Bases Advanced Org Chem-Carey B Fall 2002 Other Useful Amine Bases Carey B-5ed-Chap 1 Chapter 1

Regioselectivity in Enolate Formation Advanced Org Chem-Carey B Fall 2002 Regioselectivity in Enolate Formation Kinetic vs thermodynamic control:  6 top & others kinetic control: rapid, irreversible, quantitative deprotonation more acidic H at the less substituted carbon (bases) aprotic solvent, excess amount of strong bases, more covalent Li-O than Na/K, low temp. & short rxn time thermodynamic control: more stable enolates (equilibration) more substituted & conjugated enolates typical examples:  7-8 Scheme 1.1 conjugated ketones: kinetic (a-C) & thermo (g-C);  13 top Carey B-5ed-Chap 1 Chapter 1

Kinetic vs Thermodynamic Enolates (I) Advanced Org Chem-Carey B Fall 2002 Kinetic vs Thermodynamic Enolates (I) Carey B-5ed-Chap 1 Chapter 1

Stereoselectivity in Enolate Formation Advanced Org Chem-Carey B Fall 2002 Stereoselectivity in Enolate Formation E- vs Z-enolates: closed vs open TS;  9 bottom definition of E & Z: higher priority for the oxygen bonded to metal regardless of the normal priority of the other atom closed TS: kinetic control; Ireland models diastereoselectivity:  10 top;  12 Table 1.2 chelation effect of LHMDS (Z) vs steric effect (E):  12 bot Diastereotopic faces of enolates: si vs re face Enantioselective deprotonation:  13 bottom kinetic resolution: mechanism;  14 top more chiral bases:  13 middle Carey B-5ed-Chap 1 Chapter 1

Stereochemistry of Enolate Formation (I) Advanced Org Chem-Carey B Fall 2002 Stereochemistry of Enolate Formation (I) Carey B-5ed-Chap 1 Chapter 1

Stereochemistry of Enolate Formation (II) Advanced Org Chem-Carey B Fall 2002 Stereochemistry of Enolate Formation (II) Carey B-5ed-Chap 1 Chapter 1

Diastereotopicity of Enolates Advanced Org Chem-Carey B Fall 2002 Diastereotopicity of Enolates Carey B-5ed-Chap 1 Chapter 1

Preparation of Regiospecific Enolates Advanced Org Chem-Carey B Fall 2002 Preparation of Regiospecific Enolates Irreversibility & stability:  15 Scheme 1.2 cleavage of TMS enol ethers and enol acetates separation of isomeric silyl enol ethers:  Scheme 1.2 (C) thermodynamic: R3N at high T & then, TMSCl kinetic: TMSCl/TMSOTf & LDA/ R3N at -78/+20 oC more less substituted enolates: LOBA;  16 top reduction of conjugated ketones:  Scheme 1.2 (D) dissolving metals: Li/Na in liquid NH3;  435 bottom catalytic hydrosilylation: [Pt] / BR3 & R3SiH;  17 top conjugate addition of carbanions: Chap. 8;  17 middle [H-]: L-Selectride® ( 400), retention;  16 bottom Carey B-5ed-Chap 1 Chapter 1

Aggregation Factors in Alkylation of Enolates Advanced Org Chem-Carey B Fall 2002 Aggregation Factors in Alkylation of Enolates Solvent effects:  17 Table 1.3 structure of enolates: aggregates;  19 Fig. 1.2-1.3 highly polar aprotic solvents: ‘naked (bare) ions’;  18 strong solvation to a metal cation & weak to an enolate ion less polar aprotic solvents: lower reactivity but more useful (workup & kinetic enolates); THF, ether, DME enhanced reactivity with chelating additives: TMEDA, HMPA, crown ethers (18-crown-6: K, Na; 12-crown-4: Li);  21 top enhanced alkylation rate:  20 bottom Counter cation: reactivity; K+ > Na+ > Li+ > Mg2+ smaller, harder cations: tightly associated with enolates Carey B-5ed-Chap 1 Chapter 1

Indirect Alkylation of Enolates Advanced Org Chem-Carey B Fall 2002 Indirect Alkylation of Enolates Enolates with two M groups:  22 Scheme 1.3 good (reliable) Nu produced by weak bases: RO- alkylating agents: a-halocarbonyl > benzyl/allyl > 1o halides (sulfonates) > 2o halides, no 3o halides dialkylation: one-pot or stepwise (two-step); side rxns cyclization with dihaloalkanes (entry 6): 3-ring > 5 > 6 > 4 decarboxylation: synthetic equivalents to enolates with one M group;  23 top &  23 Scheme 1.4 dianion of acetoacetic acid: no hydrolysis;  24 top dianions of monoalkyl malonates:  24 middle Carey B-5ed-Chap 1 Chapter 1

Direct Alkylation of Enolates: Ketones Advanced Org Chem-Carey B Fall 2002 Direct Alkylation of Enolates: Ketones No decarboxylation required:  29 Scheme 1.7 quantitative & selective formation of enolates: strong & soluble bases, controlled reaction conditions Stereoselectivity in alkylation of enolates:  29-30 stereoelectronic control: orbital overlap in space axial substitution more favored with R at C-2:  25 middle endocyclic enolates: steric; trans to R on the ring exocyclic enolates: steric or stereoelectronic (axial) bicyclic examples:  26 middle - 27 top acyclic enolates: allylic strain (A1,3);  28 middle conjugated enolates: kinetic a-alkylation;  31 top Carey B-5ed-Chap 1 Chapter 1

Stereoelectronic Control in Enolate Alkylation Advanced Org Chem-Carey B Fall 2002 Stereoelectronic Control in Enolate Alkylation Carey B-5ed-Chap 1 Chapter 1

Alkylation of Other Carbonyls:  34-35 Advanced Org Chem-Carey B Fall 2002 Alkylation of Other Carbonyls:  34-35 Esters & amides: high pKa & condensation (Claisen) strong amide bases at low temp & addition of HMPA nitriles: less self-condensation products malate enolates: chelation control;  33 middle & Fig. 1.5 Aldehydes: undesired aldol condensations rapid & quantitative formation of enolates:  31 bottom better alkylation via enamines or imine anions: Chap. 1.3 carboxylic acids: via dianions;  34 top 1,3-dicarbonyls: different reactivities;  37 Scheme 1.7 Carey B-5ed-Chap 1 Chapter 1

Intramolecular Alkylation of Enolates Advanced Org Chem-Carey B Fall 2002 Intramolecular Alkylation of Enolates Ring size & geometric requirements:  37-38 closeness of electrophilic sites to Nu: 3 > 5 > 6 > 7 > 4 Baldwin’s rule: ease of ring formation; 5-ring vs 6-ring DG‡ = DH‡ (strain factor) - TDS‡ (distance factor); exam!! trajectory of Nu & hybridization of the electrophilic carbon ester enolates: H-eclipsed & R-pseudoequatorial;  38-40 Carey B-5ed-Chap 1 Chapter 1

Favored Trajectory with Electrophiles Advanced Org Chem-Carey B Fall 2002 Favored Trajectory with Electrophiles Carey B-5ed-Chap 1 Chapter 1

Enantioselective Alkylation of Enolates Advanced Org Chem-Carey B Fall 2002 Enantioselective Alkylation of Enolates Facial control with chiral auxiliaries:  41 Evans’ oxazolidinones: Z-enolates;  41 middle acyclic amino alcohols: chelation control;  42 remote control: p-p interaction;  43 top & Scheme 1.9 bicyclic enolates: bicyclic lactams;  45 top & middle other chiral auxiliaries: substrate control & reagent control Carey B-5ed-Chap 1 Chapter 1

Nitrogen Analogs of Enols and Enolates Advanced Org Chem-Carey B Fall 2002 Nitrogen Analogs of Enols and Enolates Imines: azomethines or Schiff bases;  46 top preparation: 1o amines & ketones/aldehydes; dehydration Enamines (vinylamines): 2o amines;  46 middle facile dehydration: TiCl4 or R3Si-NR’2; oxophilic atoms more basic than enols: reactive E+;  46 bot & Scheme 1.10 regio-/stereoselective alkylation: less & trans;  47 bottom Imine anions: metalloenamine;  49 middle structure of azaallyl anions: ionic N atom;  49 Fig. 1.6 more reactive than enolates & less condensation with aldehydes:  50 top & side reactions of enolates Carey B-5ed-Chap 1 Chapter 1

Preparation of Imines & Enamines Advanced Org Chem-Carey B Fall 2002 Preparation of Imines & Enamines Carey B-5ed-Chap 1 Chapter 1

Advanced Org Chem-Carey B Fall 2002 Reaction of Enamines Carey B-5ed-Chap 1 Chapter 1

Possible Side Reactions of Enolates Advanced Org Chem-Carey B Fall 2002 Possible Side Reactions of Enolates Carey B-5ed-Chap 1 Chapter 1

공 부 하 는 방 법 “그저 익숙하도록 읽는 것뿐이다. 글을 읽는 사람이, 비록 글의 뜻은 알았으나, 만약 익숙하지 못하면 읽자마자 곧 잊어버리게 되어, 마음에 간직할 수 없을 것은 틀림없다. 이미 읽고 난 뒤에, 또 거기에 자세하고 익숙해질 공부를 더한 뒤라야 비로소 마음에 간직할 수 있으며, 또 흐뭇한 맛도 있을 것이다.” - 퇴계 이황 (금장태 著) Carey B-5ed-Chap 1