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Functional Group Transformations Study Guide, Exercises Solution - Organic Chemistry, Exercises of Organic Chemistry

Functional Group Transformations Solutions

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Download Functional Group Transformations Study Guide, Exercises Solution - Organic Chemistry and more Exercises Organic Chemistry in PDF only on Docsity! Massachusetts Institute of Technology Organic Chemistry 5.511 September, 2007 Prepared by Julia Robinson Problem Set 1 Functional Group Transformations Study Guide SOLUTIONS Part I - Functional Group Interconversions and Protective Group Chemistry R-OH S O O Cl Me (1) S O O O+ Me H R N ROTs Tosylate formation Mesylate formation S O O Cl CH2 H NEt3 H2C S O O HO R H2C S O O O R H MsOR (2) In order to convert a primary alcohol to the corresponding nitrile, the alcohol must first be converted to a sulfonate or halide. DMSO is superior to ethanol as a solvent for the conversion of primary sulfonates or halides to the corresponding nitriles because DMSO solvates cations selectively, resulting in more nucleophilic anions. (3) R OH O R Cl O(COCl)2 O O O Cl O RCl- When the pre-formed carboxylate salt is used, these conditions are essentially neutral. O O O Cl O Cl R O O O ClR Cl O + CO2 + CO + Cl- (4) C NN Cy Cy R O OH C N-N Cy Cy O R O+H C NHN Cy Cy O R O HO R' O R OR' O HN NH CyCy + (5) OH CH2N2 OCH3 Alcohols do not work for this reaction because their pKa is too high... they do not protonate the diazomethane as phenol does in order to make the activated methylating species. C- H H N+ N H O Ph H3C N+ N O-Ph PhOCH3 + N2 (6) OCH3 OHBBr3 CH2Cl2 Ph O CH3 BBr3 Ph O+ CH3 B- Br Br Br Ph O+ CH3 BBr2 Br- Ph O BBr2 + H3CBr 3 H2O Ph OH + B(OH)3 + 2 HBr (7) R O OMe R OH O O CN CN Cl Cl O O CN CN Cl Cl R O Ar H O OH CN CN Cl Cl R O Ar OH OH CN CN Cl Cl R O Ar OH R OH H O Ar + H2O H2O O SMeOH NaH, NaI, ClCH2SCH3, DME HgCl2, H2O, CH3CN MTM ether OSit-BuMe2OH TBSCl, DMAP, Et3N, CH2Cl2 TBAF, THF O O OH OH TBDMS ether acetonide BF3.Et2O, CH2Cl2 OMe pTsOH, MeOH O O CH3 OH MOM ether MeO OMe , CH2Cl2 BF3.Et2O, 4A sieves PPTS, tBuOH, Δ O OCH2PhOH BOM ether BOMCl, iPr2NEt, CH2Cl2 H2, Pd/C, EtOAc O OMe OH , iPr2NEt, CH2Cl2 DDQ, CH2Cl2 Cl OMe PMB ether S O O HS OH , BF3.OEt2, CH2Cl2 HgCl2, H2O, CH3CN hemithioketal NHCO2t-BuNH2 Boc2O, NaOH, H2O TFA, CH2Cl2 Part II - Oxidation Methods (1) Swern oxidation of a secondary alcohol (2) Transition state for epoxidation of an alkene with a peracid (3) Reaction of enol ethers with peracids such a m-CPBA (the “Rubottom Oxidation”) produce α-silyloxy ketones (usually hydrolyzed in situ or during workup to the α-hydroxy derivatives). However, oxidation with DMDO often allows isolation of the epoxides. Provide a mechanism for each transformation and explain the different outcome of the reactions. O OH RO Cl O Cl O S+ Me Me O- O O Cl O S+ Me Me Cl- S+ Me Me Cl R R' OH R R' O+ S+ Me Me H NEt3 R R' O S+ Me C H2 H NEt3 R R' O S+ Me -CH2 H R R' O Me S Me O + R TMSO R' Rubottom oxidation: O O H ArO O R OTMS R' O OAr H O+ R OTMS R' H R O OH R' SiMe3 O R OTMS R' O R OH R' Oxidation with DMDO: R TMSO R' O OMe Me TMSO R' OR Me O Me + Peracid epoxidation results in the formation of a carboxylic acid which protonates the epoxide, leading to epoxide-opening and 1,4-silyl migration. Epoxidation with DMDO occurs under neutral conditions, so the epoxide does not open. (4) Oxone = 2 KHSO5 . KHSO4 . K2SO4 (5) Ground state oxygen Excited state "singlet" oxygen (6) A photosensitizer is a compound that absorbs light and is promoted to an excited state, then transfers that excitation to triplet oxygen in order to form singlet oxygen and regenerate the ground-state photosensitizer. This is the most common method for generation of singlet oxygen. (7) Selenium dioxide oxidation of alkenes to allylic alcohols (8) Ozonolysis of a simple alkene in dichloromethane O O O O CH2 R Se O O H Se O H R O = Se R HO O R OSeOH R OH solvolysis O O+ O- O O O O O O O O O O O O ene reaction [2,3] sigmatropic rearrangement [4+2] cycloaddition [4+2] cycloreversion [4+2] cycloaddition PPh3 O O O PPh3 O O O PPh3 Provide detailed conditions for effecting each of the following transformations. CHO CO2H CH2OH CHO 5 methods: 1. PCC, CH2Cl2 2. (COCl)2, DMSO, CH2Cl2; Et3N 3. CrO3 . pyr2, CH2Cl2 4. Dess-Martin periodinane*, CH2Cl2 5. TEMPO (cat), NaOCl, CH2Cl2 OH O Ph Ph Ocat. PdCl2CuCl2 O O OH H2O, O2 DMF PCC CH2Cl2 KHMDS; N O Ph SO2Ph NaOCl2, NaH2PO4 aq. tBuOH * O I O AcO OAcOAc Part III - Reduction Methods (1) Crabtree's catalyst is especially useful for hydroxyl-directed hydrogenations because the hydroxyl group coordinates very strongly to the cationic iridium center. Ir PCy3 N + PF6- (2) R O N R'' R' LiAlH4 R N R'' R' R O N R'' R'H- R OH N R'' R' R N+ R'' R' H- R N R'' R' Amines are the products of this reaction because R2N- is a terrible leaving group compared to HO-, so the iminium is formed rather than the aldehyde, and the iminium is reduced to the amine. (3) In reduction of ketones and aldehydes the reactivity order is Zn(BH4)2 > NaBH4 > NaBH3CN because zinc is a stronger Lewis acid than sodium, and the cyano group of NaBH3CN reduces the nucleophilicity of the hydrides due to its electron-withdrawing effect. (4) Diborane reduces carboxylic acids to alcohols but reacts very slowly with carboxylic esters because diborane reacts with carboxylic acids to give a triacyloxyborane intermediate via protonolyis of the B-H bonds. In this intermediate the carbonyl exhibits enhanced reactivity towards the reducing agent because (5) DIBAL reduction of esters to aldehydes without over-reduction to alcohols O OR Al H O- H OR workup Al+iBu iBu O H At low temperatures the hemi-acetal intermediate is stable and does not collapse to the aldehyde until workup, preventing over-reduction. 3 RCO2H + BH3 (RCO2)3B + 3H2 R O O B CO2R CO2R R O O B CO2R CO2R the ester oxygen donates some electron density to the boron, decreasing donation to the carbonyl, and thus increasing the electrophilicity of the carbonyl compared to an ester carbonyl. (6) Esters react slowly with borane and alane (AlH3) but tertiary amides and lactams are reduced smoothly to amines because borane and alane form a Lewis acid-base complex with the carbonyl of the amide or lactam and then deliver the hydride in an intramolecular fashion. The carbonyl oxygen of tertiary amides and lactams are more Lewis basic than the carbonyl oxygens of esters because nitrogen is more electron-donating than oxygen, so the Lewis acid-base adduct forms more readily with tertiary amides and lactams. (7) Suggest several reagents that effect selective 1,2-reduction of conjugated enones to produce allylic alcohols and explain why these reagents favor 1,2-reduction while the use of NaBH4 and LiAlH4 often leads to mixtures of 1,2 and 1,4-addition products. NaBH4 + CeCl2 (Luche reduction), DIBAL, and 9-BBN all give exclusive carbonyl reduction because the reactivity of the carbonyl group is enhanced by Lewis acid complexation at oxygen, and these reagents are more Lewis acidic than sodium borohydride and lithium aluminum hydride. (8) The reduction of propargylic alcohols with Red-Al to (E)-allylic alcohols: (9) OH 1. NaH, CS2, MeI 2. nBu3SnH, AIBN, PhH, reflux OH NaH O- C S S O S S- H3C I O S SMe O S SMe Sn(nBu)3 SMe S O Sn(nBu)3 H Sn(nBu)3 Sn(nBu)3 Sn(nBu)3 OH NaH2Al(OR)2 Al- H OH RO H2O HO trans addition
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