Dr. Pere Romea Department of Organic Chemistry Sky and Water I Maurits Cornelis Escher, 1938 6. Functional Group Interconversion Organic Synthesis 2014-2015 Autumn Term Carbon Backbone & Functional Groups The synthesis of an organic compound must pay attention to ... Carbon backbone Functional groups (Chapters 2–4 ) Functional Group Interconversion (FGI) I. Nucleophilic Substitutions Electrophilic Additions to C=C Addition-Eliminations on Carboxylic Acids and Derivatives II. Reductions Mechanism!!! III. Oxidations Pere Romea, 2014 2 Nucleophilic Substitutions The nucleophilic substitutions involve the interconversion of functional groups bound to sp3 carbonis + Nu + X X Nu Csp3 RX Electrophile Nucleophile Leaving group Chap. 15 Pere Romea, 2014 3 Nucleophilic Substitutions Two model mechanisms, called SN1 i SN2, are used to explain the nucleophilic substitutions + Nu + X X Nu Unimolecular (SN1) or bimolecular (SN2) nucleophilic substitution? A slightly different model, called SN2’, may be useful in substitutions on allylic substrates X + Nu Nu + X 4 Pere Romea, 2014 Nucleophilic Substitutions and FGI There are three main sources to carry out FGI through nucleophilic substitutions: sulfonates, alcohols, and alkyl halides Nu Sulfonates R–OSO2R’ R–Nu Nu Alcohols R–OH R–Nu Alkyl halides Nu R–X R–Nu X: I, Br, Cl 5 Pere Romea, 2014 Nucleophilic Substitutions and FGI A wide array of structures can be synthesized from sulfonates and alkyl halides through nucleophilic substitution of X = OSO2R, I, Br, Cl in C–C bond forming reactions and FGI R Y R R R OH Y R H2O or OH R N R OR ROH CN or RO R X O N3 O R N O R R 3 O R NH H2S 3 RSH or HS or RS R NH2 R SH Pere Romea, 2014 R SR 6 Nucleophilic Substitutions and FGI How easy is to interconvert sulfonates, alcohols, and alkyl halides? Nu Sulfonates R–OSO2R’ R–Nu Nu Alcohols R–OH R–Nu Alkyl halides Nu R–X R–Nu X: I, Br, Cl 7 Pere Romea, 2014 Alcohols and Sulfonic Esters Conversion of alcohols into sulfonic esters pyridine + RSO2Cl or (RSO2)2O OH CH2Cl2 or Et2O OSO2R 0 °C – rt Mesyl chloride MsCl MeSO2Cl Mesylate Tosyl chloride TsCl p-MePhSO2Cl Tosylate Triflic Anhidride Tf2O (CF3SO2)2O Triflate – Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance OH TsCl, pyr Me Me Me H Me – The reaction does not affect the C–O bond: the configuration of the carbon remains the same – Mesylates and tosylates are largely employed. Triflates are the most reactive sulfonates – Rearrangements of the carbon backbone are not frequent 8 Pere Romea, 2014 Sulfonic Esters and Alkyl Halides Conversion of sulfonate into alkyl halides X OH X SN2 X: Cl, Br, I OH 1) MsCl, Et3N, CH2Cl2 Cl Pr 2) LiCl, DMF Pr 83% Ph 1) TsCl, pyr, CH2Cl2 Ph OH Br 2) LiBr, DMF Ph Ph 89% 1) MsCl, Et3N, CH2Cl2 TBDPSO OH TBDPSO I 2) Lil, acetone 94% 9 Pere Romea, 2014 Alcohols and Alkyl Halides Conversion of alcohols into alkyl halides Sulfonates R–OSO2R’ R’SO2Cl Alcohols R–OH X– ? Alkyl halides R–X X: I, Br, Cl 10 Pere Romea, 2014 Alcohols and Alkyl Halides Conversion of alcohols into alkyl halides OH X X: Cl, Br, I Reagents & Conditions Alcohols Mechanism HCl conc Tert SN1 (racemization) HCl/ZnCl2 (Lucas reagent) Prim & Sec SN2 (inversion) PCl3 Prim & Sec SN2 (inversion) SOCl2, 1,4-dioxane Prim & Sec SN2 + SN2 (retention) SOCl2, non nucleophilic solvent Prim & Sec SN2 (inversion) HBr conc Tert SN1 (racemization) HBr conc, ∆ Prim SN2 PBr3 Prim & Sec SN2 (inversion) P/I2 Prim & Sec SN2 (inversion) 11 Pere Romea, 2014 Alcohols and Alkyl Halides Problem! Too harsh experimental conditions: mixture of mechanisms and transpositions H Br OH OH2 Br SN2 single OH OH2 H Br Br SN1 Br 86% 14% Br Cl H Cl OH OH2 single Pere Romea, 2014 12 Alcohols and Alkyl Halides More selective transformations are required … The most used options are based on the conversion of alcohols into alkoxyphosphonium salts, highly reactive in SN2 substitutions E Ph3P + E–Nu Ph3P Ph3P E + Nu Nu Ph3P E + HO Ph3P O + HE H H Alkoxyphosphonium salt Ph3P O + Nu Ph3P=O + Nu H H Alkoxyphosphonium salt 13 Pere Romea, 2014 Alcohols and Alkyl Halides Ph3P / X2 : Ph3P / I2, Ph 3P / Br2, Ph3P / Cl2 Br – Br Ph3P + Br–Br Ph3P Ph3P Br Br + Br – HBr – Ph3P=O Ph3P Br + HO Ph3P O Br H H Br H SN2 This transformation is very useful for secondary alcohols and those systems that easily produce transpositions, as neopentylic alcohols The control on the configuration is very good. Br Br PBr3 Ph3P/Br2 + + Br OH Br 11% 26% 63% 90% OMe OMe Ph3P, Br2 Ph3P, I2 OH I O O R O O R Imidazole OH Br Et2O, rt 85% 96% 14 OBn OBn Alcohols and Alkyl Halides Since chlorine (Cl2) is a gas difficult to handle .... HO – CCl3 H – Ph3P=O Ph3P + Cl–CCl3 Ph3P Cl Ph3P O Cl – HCl H Cl H carbon tetrachloride O O Cl Cl Ph3P + CCl3 CCl3 Cl Cl Cl hexachloroacetone OH Cl Ph3P/Cl2 Ph3P/CCl4 OH Cl 92% 70% Ph3P/CCl3COCCl3 OH Cl 99% 15 Pere Romea, 2014 Nucleophilic Substitutions and FGI Nu Sulfonates R–OSO2R’ R–Nu Nu Alcohols R–OH R–Nu Alkyl halides Nu R–X R–Nu X: I, Br, Cl 16 Pere Romea, 2014 Carbon Nucleophiles O O O R NH2 R OH R H R Me Amine 1 Carboxylic Acid Aldehyde Methyl ketone Red Hydrolisis Red Hydration + 2+ LiAlH4 H3O DIBALH cat Hg , H 2O R CN R C CH + C + 2 C Attention! Alkyl halides are very useful for R X R OH the construction of C–C bonds 17 Pere Romea, 2014 Nitrogen Nucleophiles: Primary Amines The alkylation of ammonia, NH3, is not easy ... R X – HX NH3 R NH3 X R NH2 Primary Amine + HX R X – HX R NH2 R2 NH2 X R2 NH Secondary Amine + HX R X – HX R2 NH R3 NH X R3 N Tertiary Amine + HX R X R3 N R4 N X Ammonium Salt Such an alkylation only becomes efficient when the resulting amine is much less nucleophile than the initial one, for steric or electronic reasons CO2Et CO2Et CO2Et 1) Br CO Et 1) RCH2Cl 2 NH N 2) NaHCO 2) NaHCO H2N 3 R N 3 H R: C15H31 18 Pere Romea, 2014 Nitrogen Nucleophiles: Primary Amines Potassium phthalimide, PhthNK O O Br Ph NaOH Ph H N N K N 2 Ph 95% O SN2 O Potassium phthalimide, pKa 8.3 Gabriel synthesis of amines – Azide, N3 The azide anion is an excellent nucleophile that participates in a large number of SN2 processes The reduction of the azide group affords a primary amine NaN I 3 N NH Bu Bu 3 Bu 2 DMSO, Δ 90% O O O O 1) MsCl, Et3N OTBDPS OTBDPS 2) NaN3, DMF OH N3 85% 19 Nitrogen Nucleophiles: Primary Amines Mitsunobu conditions: Ph3P / DEAD / HN3 or DPPA [(PhO)2PON3] Ph3P, EtO2C N N CO2Et OH N3 H HN3 o (PhO)2PON3, H Ph3P CO2Et Ph3P CO2Et N N N N EtO2C EtO2C OH Ph3P CO2Et CO2Et H N N O PPh3 + N N EtO2C H EtO2C H O P (PhO)2PO CO2Et CO2Et H CO2Et (PhO)2 N3 HN3 N3 + N N N N N N + N3 DPPA EtO2C H EtO2C H EtO2C H N3 O PPh3 N3 + O=PPh3 H H 20 Pere Romea, 2014 Nitrogen Nucleophiles Reduction Mitsunobu LiAlH4, H 2 cat, Ph3P/H2O Ph3P/DEAD/ HN3 or DPPA O 1 R N R R NH2 R N3 R OH H Amide Amine 1 Azide SN2 SN2 – Phthalimide N3 R X R OSO2R' O O O O Ph3P, DEAD, HN3 O N OH O N N3 CH2Cl2, 0 °C Bn 97% Bn O O O 1) H2, Pd/C, THF/MeOH/TFA, ta O N N Ph H 2) PhCOCl, Et3N, CH2Cl2, 0 °C Bn 97% 21 Oxygen Nucleophiles: Alcohols – The most simple nucleophile: H2O / OH – H2O, OH X OH X: Cl, Br, I This is a rare transformation in which... ... tertiary halides, R3C–X, react with H2O (solvolysis) through SN1 and – ... the secondary and primary ones, R2CH–X i RCH2–X, with OH /H2O through SN2 In both situations E1 and E2 eliminations are competing reactions No eliminations can occur at this benzylic position Me Cl OH Cl2 K2CO3 hν H2O NC NC 85% NC Radical chlorination 22 Pere Romea, 2014 Oxygen Nucleophiles: Ethers Alkoxydes, RO–: Williamson Synthesis RO– X RO SN2 H H X: Cl, Br, I Only on 1ary substrates to avoid E2 eliminations ... and the most successful deconnections are applied to activated systems O 2 O O Ar + XCH2R R1 R2 R1 + MeX o BnX NO2 NO2 O O OH OBu O O BuBr, K2CO3 1) NaH, THF O O O O H2O H 2) BnCl, Δ H HO O BnO O 80% 95% 23 Pere Romea, 2014 Oxygen Nucleophiles: Esters – Carboxilates, RCO2 – RCO2 X RCO2 SN2 H H X: Cl, Br, I, OSO2R They are usually applied to 1ary substrates to avoid E2 eliminations O O OK Br 18-crown-6 O + O 95% O Br Br why KF? O O CO2H O O CO2Me MeI, KF O O O DMF O O O 84% Attention: interconversion of carboxílic acids and derivatives 24 Oxygen Nucleophiles: Esters Mitsunobu conditions: Ph3P / DEAD / RCO2H Ph3P, EtO2C N N CO2Et OH RCO2 SN2 H RCOOH H Ph3P CO2Et Ph3P CO2Et N N N N EtO2C EtO2C OH Ph3P CO2Et CO2Et H N N N N + O PPh3 EtO2C EtO2C H H RCO2H H CO2Et N N RCO2 RCO2 EtO2C H H OH PhCO2 Ph3P, DEAD CO2Me CO2Me O PhCO2H O 25 Pere Romea, 2014 89% Oxygen Nucleophiles Configuration inversion SN2 Hidrolysis – – RCO2 OH OH OSO2R' RCO2 HO H H H H Mitsunobu Hidrolysis – Ph3P/DEAD/RCO2H OH OH RCO2 HO H H H O OH O OH Ph Ph Ph Ph3P, DEAD O2N KOH p-O2NPhCO2H MeOH 99% overall 26 Pere Romea, 2014 Phosphorus Nucleophiles: in Route to Wittig Reactions Phosphines are excellent nucleophiles because they are less basic than amines and the phosphorus atom is very polarizable.