Chapter 4. Electrophilic Additions Advanced Org Chem-Carey B Fall 2002 Chapter 4. Electrophilic Additions regioselective non-stereoselective regioselective stereoselective regioselective stereoselective Carey B-Chap 4-5ed Chapter 4

Addition of Hydrogen Halides: HX Advanced Org Chem-Carey B Fall 2002 Addition of Hydrogen Halides: HX Markovnikov’s rule: regioselectivity;  290 top more stable at more substituted C:  290 middle slower reaction for mono/disubstituted alkenes: addition of silica or alumina in CH2Cl2 to SOCl2 or (COCl)2 in situ generation of HCl: TMSCl & H2O;  291 top rearrangements & solvent participation:  291 middle stereochemistry: depends on stability of carbocations anti: 2-butenes, 1-Me-cyclopentene ( 291 bottom) syn: conjugated alkenes & reaction conditions  292 Table 4.1 entries 1 & 10 Carey B-Chap 4-5ed Chapter 4

General Mechanism of Polar Addition Advanced Org Chem-Carey B Fall 2002 General Mechanism of Polar Addition free carbocation: AdE2 syn/rac ion-pair: AdE2 simultaneous: AdE3 anti  292 middle Carey B-Chap 4-5ed Chapter 4

Addition of H2O & Oxygen Nucleophiles Advanced Org Chem-Carey B Fall 2002 Addition of H2O & Oxygen Nucleophiles Hydration: addition of H2O with strong acids good for 3o alcohols: Markownikoff’s rule;  293 top Addition of ROH & RCO2H:  293 bottom in the presence of strong acids: HBF4 TFA: acid-catalyst & addition Not much synthetic utility due to strongly acidic conditions and rearrangement products Carey B-Chap 4-5ed Chapter 4

Oxymercuration: Addition of OH & Hg+ Advanced Org Chem-Carey B Fall 2002 Oxymercuration: Addition of OH & Hg+ Mild conditions & less rearrangements mercurinium ion: Markownikoff’s rule;  294 bottom nucleophiles: oxygen/nitrogen;  299 Scheme 4.1 demercuration: reductive cleavage;  295 top NaBH4: free-radical intermediate;  295 middle Na(Hg) in protic solvents: retention;  295 middle reactivity of alkenes:  296 middle stereochemistry: anti addition;  296 bottom allylic strain & directing effect:  296 bottom neighboring-group participation:  297 middle Carey B-Chap 4-5ed Chapter 4

Addition of Halogens: X2 (I) Advanced Org Chem-Carey B Fall 2002 Addition of Halogens: X2 (I) Bridged halonium ions: anti addition;  298 bot syn addition: a Ph substituent;  300 top Cl2: similar to Br2 but more syn products;  300 bot carbocation intermediates:  301 top synthesis of halohydrins: in aq. DMSO;  302 middle in-situ generation of HOX: HOd-Xd+;  303 top mild halogen sources: NBS/NCS, pyr•HBr3, R4N+Br3-, dioxane-Br2, tetrabromocyclohexadienone ( 304 bot), NIS, [pyr-I-pyr]+BF4-, [coll-I-coll]+PF6-;  305 Table 4.2 Carey B-Chap 4-5ed Chapter 4

Addition of Halogens: X2 (II) Advanced Org Chem-Carey B Fall 2002 Addition of Halogens: X2 (II) Addition of F2: highly reactive & ionic intermed. nearly no selectivity: in favor of syn;  303 middle other fluorinating reagents:  303 bot & 304 top Iodination: not useful;  304 middle Other reagents: X+-Y-;  306 Scheme 4.2 similar mechanism to halogenation: halonium bridged (symmetric/unsymmetrical) cationic intermediates Markovnikov regioselectivity anti stereoselectivity due to the bridged intermediates Carey B-Chap 4-5ed Chapter 4

Addition of Sulfur & Selenium Advanced Org Chem-Carey B Fall 2002 Addition of Sulfur & Selenium Electrophilic S & Se agents:  308 Scheme 4.3 bridged intermediates: S & Se;  307 middle anti-Markownikoff regioselectivity: more stronger C-S bonds & less electrophilic sulfurane;  310 top anti stereoselectivity: neither rearrangement nor syn rearrangement possible with LiClO4 addition of RSeX: anti-Markownikoff but equilibration selenylation with external Nu;  309 bot – 310 top Carey B-Chap 4-5ed Chapter 4

Electrophilic Cyclization Advanced Org Chem-Carey B Fall 2002 Electrophilic Cyclization Baldwin’s rule:  311 top preferred: 5-exo over 6-endo; 5-endo over 4-exo Iodocyclization reactions:  317-8 Scheme 4.4 good electrophiles with intramolecular nucleophiles cyclization under basic conditions: kinetic, anti & exo thermodynamic control: no base;  313 top depending on conformations:  313 bot &  314 top other Nu & further reactions:  315 top amides:  316 middle & bottom Cyclization with Other electrophiles: Se/S/Hg  322-3 Scheme 4.5 &  327 Scheme 4.6 Carey B-Chap 4-5ed Chapter 4

Electrophilic Substitution at a-C to Carbonyls Advanced Org Chem-Carey B Fall 2002 Electrophilic Substitution at a-C to Carbonyls a-Halogenation of ketones:  329 bottom electrophilic addition of enols/enolates:  328 bottom monohalogenation: CuBr2/CuCl2;  330 top polyhalogenation: haloform reactions;  329 top a-fluoroketones: 1-F-4-OH-DABCO;  331 top halogenation of reactive enols:  330 middle a-Halogenation of carboxylic acids:  331 mid Hell-Volhard-Zelinsky reaction: P(red) & Br2 a-Substitution of S & Se:  332 Scheme 4.7 facile elimination of oxides: a,b-unsaturated carbonyls Carey B-Chap 4-5ed Chapter 4

Addition to Allenes & Alkynes Advanced Org Chem-Carey B Fall 2002 Addition to Allenes & Alkynes Allenes: addition to terminal C;  333 bottom internal C: less stable due to orthogonal p orbitals HX: protonation at the terminal carbon;  334 middle protonation at the sp carbon: Ph, 1,1-diMe;  334 mid Alkynes: less reactive than alkenes 10 kcal/mol less stable vinyl cations than alkyl cations HBr: anti & Markownikoff selectivity:  335 top rate & selectivity increase with R4N+Br- in TFA:CH2Cl2 HCl: syn (kinetic) to anti (thermodynamic);  335 mid Carey B-Chap 4-5ed Chapter 4

Advanced Org Chem-Carey B Fall 2002 Addition to Alkynes Addition of Cl2: depends on the substrate in AcOH: syn to 1-pentyne/hexyne & anti to 2/3-butyne vinyl cation vs cyclic chloronium ion:  336 bottom addition of Br2: vinyl cation vs cyclic bromonium ion Addition of H2O: equivalent to -C(O)CH2- addition of AcOH:  335 middle Hg2+-catalyzed hydration:  336 Scheme 4.8 Addition of RSeY: anti,  337 top aryl alkynes: regioselective than alkyl alkynes Carey B-Chap 4-5ed Chapter 4

Hydroboration: Addition of H-BR2 Advanced Org Chem-Carey B Fall 2002 Hydroboration: Addition of H-BR2 Electrophilic BR3: (BH3)2;  337 middle Regioselectivity:  338 Table 4.3 B to the less substituted carbon: R2Bd+–Hd- (r = -0.5) alkylboranes: more selective;  338 middle &  339 top Stereoselectivity: syn & concerted;  339 mid Reversibility: to the terminal isomer;  343 bot intramolecular mechanism possible:  343 bottom facile migration with bulky boranes:  343 middle Carey B-Chap 4-5ed Chapter 4

Stereoselectivity of Boranes Advanced Org Chem-Carey B Fall 2002 Stereoselectivity of Boranes Carey B-Chap 4-5ed Chapter 4

Other Hydroboration Reagents Advanced Org Chem-Carey B Fall 2002 Other Hydroboration Reagents Haloboranes: ClBH2, BrBH2, Cl2BH, Br2BH more regioselective & similar reactivity to (BH3)2 further transformations possible:  340 top Oxygenated boranes: less reactive but selective catecholborane & pinacolborane:  340 bottom activated by additives: 10-20% of DMA in CH2Cl2 catalytic activation: Wilkinson’s catalyst [ClRh(PPh3)3] metal-catalyzed hydroboration:  341 top selectivity: depends on metals;  341 middle & bottom Carey B-Chap 4-5ed Chapter 4

Useful Hydroboration Reagents Advanced Org Chem-Carey B Fall 2002 Useful Hydroboration Reagents Carey B-Chap 4-5ed Chapter 4

Reactions of Organoboranes (I) Advanced Org Chem-Carey B Fall 2002 Reactions of Organoboranes (I) Conversion into alcohols:  344 bottom concerted migration: retention;  348 Scheme 4.9 anti-Markownikoff regioselectivity: entries 1-4 other oxidants: H2O2 & NaOH, O2, Na2CO4, R3N+-O- migratory aptitude: 3o > 2o > 1o carbon Reactions to ketones/aldehydes:  345 top other oxidants: PCC, TPAP & R3N+-O-; entries 5-7 to carboxylic acids: terminal alkenes;  345 middle Carey B-Chap 4-5ed Chapter 4

Transformation of Boranes: Alcohols (I) Advanced Org Chem-Carey B Fall 2002 Transformation of Boranes: Alcohols (I) Carey B-Chap 4-5ed Chapter 4

Reactions of Organoboranes (II) Advanced Org Chem-Carey B Fall 2002 Reactions of Organoboranes (II) Conversion into amines: concerted mechanism H2N-Cl/-OSO3H: 1o amines;  345 bottom R’-N3 & RBCl2: 2o amines;  346 top 2o amines: Cl-NHR’ & R3B;  346 middle Transformation into halides:  346 bottom reactive with base & halogen: Br2 & NaOMe Reactions with CO: depending on the conditions 3o/2o/1o alcohols, ketones/aldehydes Carey B-Chap 4-5ed Chapter 4

Reactions with CO (I): General Advanced Org Chem-Carey B Fall 2002 Reactions with CO (I): General Carey B-Chap 4-5ed Chapter 4

Enantioselective Hydroboration Advanced Org Chem-Carey B Fall 2002 Enantioselective Hydroboration Chiral boranes: from terpenes;  347 bottom terpenes: both enantiomers, low but >99% ee purity Enantioselection with (Ipc)2BH:  349 bottom Z-1,2-alkenes: 75-90% ee; E-1,2-alkenes: 5-30% ee with IpcBH2 & recycle of a-pinene:  350 middle syntheses of chiral alcohols and amines:  351 mid transition metal for enantioselectivity:  342 bottom Carey B-Chap 4-5ed Chapter 4

Hydroboration of Alkynes Advanced Org Chem-Carey B Fall 2002 Hydroboration of Alkynes syn Addition to alkynes: Z-dialkylalkenes Reactive with (BH3)2: polymeric byproducts use of R2BH: catecholborane; syn,  352 top anti addition of HBr to alkynes: Br2;  352 middle Br2BH•SMe2 & pinacolborane: E-iodide;  352 bottom from catecholboranes & I2:  239 bottom 9-BBN for internal alkynes: Z-alkenes;  353 top Carey B-Chap 4-5ed Chapter 4

Carbo(Hydro)metallation: Al, Zr Advanced Org Chem-Carey B Fall 2002 Carbo(Hydro)metallation: Al, Zr R(H)AlR2: less reactive than boranes terminal/strained alkenes & alkynes:  353 bottom less electronegative Al: [-CH3] in Me3Al vs [+CH3] in Me3B effective catalyst: [(Cp)2ZrX2];  355 bottom enantioselectivity & activation:  356 top &  357 bottom functionalization of intermediates:  356 Scheme 4.10 HZrCl(Cp)2: Cl2Zr(Cp)2 & M-H;  357 top internal alkynes: equilibration to the less hindered one alkenes: less reactive & isomerization;  357 bottom Carey B-Chap 4-5ed Chapter 4