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NPTEL – Chemistry – Reagents and Organic reactions, , Module II, , Reduction Reactions, , Lecture 14, 2.1.1 Lithium Aluminum Hydride (LAH), , 2.1.1.1 Introduction, Lithium aluminum hydride (LAH) is a strong reducing agent with chemical formula, LiAlH4. It can reduce a variety of functional groups such as aldehydes, esters,, acids, ketones, nitriles, epoxides and azides. It vigorously reacts with water and, all the reactions are performed in polar aprotic solvents., , 2.1.1.2 Preparation, It was first prepared by treating lithium hydride (LiH) with aluminum chloride, (AlCl3) (Scheme 1)., 4LiH, , +, , AlCl3, , LiAlH4 +, , 3LiCl, , Scheme 1, , In industrial scale, it is prepared from sodium aluminum hydride which is, prepared by reaction of sodium, aluminum and hydrogen at high temperature and, pressure (Scheme 2)., Na + Al +, , 2H2, , NaAlH4, , NaAlH4 + LiCl, , LiAlH4, , + NaCl, , Scheme 2, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 1 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , 2.1.1.3 Reduction of Aldehydes and Ketones, The aldehydes and ketones are reduced to give the corresponding alcohols, when treated with LAH (Scheme 3). For the reduction of aldehydes and ketones,, the reaction is generally performed in ether solvents at low temperature., O, R, , OH, H, , or, , R, , LiAlH4, , O, , O, Br, , H, , OH, R', , R, , or, , R, , OH, , LiAlH4, Me, , R', , Br, , Me, , Et2O, -78 C, Scheme 3, , Mechanism, The hydride from LAH is transferred to the carbonyl group to form alkoxy anion, which then forms complex with aluminum (Scheme 4). Similarly, four hydride, atoms are replaced by four alkoxy groups and the aluminum complex thus, formed is then hydrolyzed by dilute acid to give the desired alcohol., H, , O, O, R, , H, , H, H Al H, H, , H, O Al H, R, H, H H, , R, , H, , R, , O, , O, O Al H, R, H, H H, H, , R, , H, , H, , R, , R, H, O, H, O Al O, R, H, H H, O, H, , R, H, , OH, 4 R, , H, , H, , H3O, , R, , R, H, O, H, H, O Al O, R, H, O, H H, H, R, , Scheme 4, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 2 of 55, , H

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NPTEL – Chemistry – Reagents and Organic reactions, , 2.1.1.4 Reduction of Acids, The acids are often reduced with LAH to prepare the corresponding alcohols, (Scheme 5). The other comparable method for reduction of acid is using BH 3 as, a reducing agent. The three hydride ions are consumed for reducing one acid, group., , O, R, , LiAlH4, , R, , OH, , OH, Me, , Me, O, , LiAlH4, OH, , Et2O, , OH, , Scheme 5, , 2.1.1.5 Reduction of Esters and Amides, The esters and amides are reduced to the corresponding alcohols and amines,, respectively, when treated with LAH (Scheme 6). Each molecule of ester or, amides consumes two molecules of hydride ions., O, O, , R, , R', LiAlH4, , or, , OH + R', , R, or, , O, R, , N, R', , OH, , R', , R, , N, R', , R', , Me, , Me, O O, O, , O, O, Me, , LiAlH4, Et2O, , O, , HO, , OH, O, Me, , O, Me, , Me, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 3 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , LiAlH4, NH, O, , NH, , THF, , OH, , OH, , Me, , Me, Scheme 6, , 2.1.1.6 Reduction of Azides, Nitriles and Nitro Compounds, The azides, nitriles and nitro compounds are reduced to the corresponding, amines in presence of LAH (Scheme 7). The aromatic nitro compounds do not, give the desired amines., R, , N3, or, , LiAlH4, , R C N, or, R, , NH2, , R, , NO2, Scheme 7, , 2.1.1.7 Reduction of Epoxides, The epoxides are reduced to the corresponding alcohols (Scheme 8). The, hydride ion is transferred to the less hindered side of the epoxides., Me LiAlH, 4, O, , O, , HO, , Me, , LiAlH4, , H, CO2Me, , Me, OH, , O, O, , Me, H, , Et2O/THF, 0 C, , O, O, , OH, Scheme 8, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 4 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , O, CN, , LiAlH(OEt)3, , H, , Et2O, Scheme 11, , 2.1.3 Sodium bis(2-Methoxyethoxy)aluminum Hydride (SMEH), [NaAlH2(OCH2CH2OMe)2], Sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) is a commercially, available reducing agent with trade name Red-Al. It is more selective than LAH, and the reduction can be carried out in aromatic hydrocarbons as well as other, ethers solvent (Scheme 12)., M. Gugelchuk, Encyclopedia of Reagents for Organic Synthesis, John Wiley and, Sons., Inc., L. A. Paquette, Ed., New York, 1995, 7, 4518., , R, , R', R', , N, H, , NH2, R NH2, , R, R, CN, , R', R', N R, , R, , O, R, , H2N, , O, , O, R'OH + R, , R, , OH, , OR', , R, , Red-Al, , NO2, , or, R' R, , O, R, , R, , O, O, , OH, , OH, , OH, or, , H, , R, , R', , O, NR'2, , R, R, , O, , O, R, , O, Cl R, R, , OH, , R, , NR'2, , OH, , Scheme 12, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 6 of 55, , R, , H

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NPTEL – Chemistry – Reagents and Organic reactions, , Examples:, OH, , OH, , OH, , OH, , Reduction, +, , +, , Ether, , TMS, , TMS, LAH, SMEAH, , TMS, , TMS, , 19, , 49, , 32, , 100, , 0, , 0, , S. E. Denmark, T. K. Jones, J. Org. Chem. 1982, 47, 4595., OH, , HOH2C, , OH, , OH SMEAH, , OH, , Toluene, , N, , N, , t-Bu, , 30%, , M. Ishizaki, O. Hoshino, Y. Iitaka, J. Org. Chem. 1992, 57, 7285., , O, Me, , O, Me, , SMEAH, , O, , Al, , H, , Me, , THF, , Al, O, , Al, O, , O, Me, , C, Me Al, , Me, , OH, O, Me, , Me, , CH2OH, , O, Al, , Me, Me, , R. B. Gammill, L. T. Bell, S. A. Mizsak, Tetrahedron Lett. 1990, 31, 5301., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 7 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , 2.1.4 Diisobutylaluminum Hydride (DIBAL-H), The diisobutylaluminum hydride (DIBAL-H) is a commercially available selective, reducing agent. It can selectively reduce esters and nitriles to the corresponding, aldehydes. The reaction is carried out in inert and moisture free atmosphere., P. Galatsis, Encyclopedia of Reagents for Organic Synthesis, John Wiley and, Sons, Inc., L. A. Paquette, Ed., New York, 1995, 3, 1908., , 2.1.4.1 Reduction of Esters to Aldehydes, The esters are selectively reduced to the corresponding aldehydes at low, temperature. The DIBAL-H transfer one hydride to the ester group and forms a, tetrahedral intermediate which is stable at low temperature. The hydrolytic work, up of the intermediate gives the desired aldehydes (Scheme 13). The presence, of alkoxy or amino group to the close proximity can stabilize the tetrahedral, intermediate and hence give better result., O, , CO2Me, , CHO, , O, , Toluene -78 C, , Me, , MeO, , DIBAL-H, , Me, , MeO, , Me, Me, O, R, , Me, O, , R', , Me, , Al, H, , Me, , O, , Me, , R, , Me, , Al, , Me, O, , R', , O, H3O, , R, , H, , H, tetrahedral, intermediate, , Scheme 13, , 2.1.4.2 Reduction of Nitriles, The nitriles are selectively reduced to the corresponding aldehydes with one, equivalent of DIBAL-H at low temperature. The use of two equivalent of DIBAL-H, gives the corresponding primary amine., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 8 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , B. Provide mechanism for the following reaction., DIBAL-H, , OH, , CO2Me, THF, , Text Book, M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004., , Lecture 15, 2.1.5 Borohydrides, , Different borohydrides are available depending on the metal cations and ligands, such as sodium borohydride, lithium borohydride, zinc borohydride, lithium or, potassium, , trialkylborohydride, , and, , sodium, , cyanoborohydride., , All, , the, , borohydrides reduce aldehydes and ketones to the corresponding alcohols but, due to its counter cations and ligands it shows some special selectivity towards, some functional groups., , 2.1.5.1 Sodium Borohydride (NaBH4), The sodium borohydride is an ideal reducing agent for the reduction of aldehydes, and ketones to give the corresponding alcohols (Scheme 1). Unconjugated, ketones and aldehydes are rapidly reduced, usually in preference to a, conjugated carbonyl group that may be present elsewhere in the molecules. The, reactions are performed in polar solvents such as THF, DME, diglyme, hydroxyl, solvent and water but the ethanol is the solvent of choice., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 10 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , O, , O, HO, , O, , NaBH4, EtOH/CH2Cl2, , HS, , S, , NH4Cl, , HS, , S, , Scheme 1, , In contrast, in the presence of CeCl3, conjugated ketone is reduced much faster, compared to the normal ketone (Scheme 2). The combination of NaBH4 and, CeCl3 is called Luche reagent and the reaction is known as Luche reduction., O, , OH, Me, , Me, , Me, , NaBH4/CeCl3, CO2Me, MeOH, OH, Me, , O, , Me, , O, , CO2Me, OH, Me, , 91%, Scheme 2, , Proposed Mechanism, The cerium reagent coordinates to the carbonyl, making only a 1,2-addition, possible (Scheme 3)., CeCl3 + NaBH4, Cl, Cl, O Ce, H, , HCeCl2, Cl, Ce Cl, O, H, , R, R, , H3O+, , OH, H, R, , Scheme 3, , The esters react slowly and the carboxylic acids in normal condition do not react, but are reduced to alcohol in presence of catalytic amount of iodine in reflux, condition in THF (Scheme 4). This method provides effective route for the, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 11 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , The zinc borohydride is prepared from zinc chloride and NaBH 4 in ether. It is, most useful for the reduction of, , -unsaturated aldehydes and ketones to give, , saturated alcohols (Scheme 7)., , O, , OH, , OH, Zn(BH4)2, +, , H3O+, , 4%, , 96%, Scheme 7, , 2.1.5.4 Lithium or Potassium Trialkylborohydride, The presence of three alkyl groups in boron atom makes the hydride strongly, nucleophile and hence it is a strong reducing agent compared to other, borohydrides, and it can reduce the aldehydes and ketones even at -78 °C, temperature., , The, , commonly, , used, , trilakylborohydrides, , are, , lithium, , triethylborohydride, Li(Et3BH), and lithium and potassium tri-sec-butylborohydride, (L- and K-Selectrides). The bulky L- and K-selectrides can reduce carbonyl, compound from less hindered side resulting selective products (Scheme 8)., , H, , H, L-Selectride, O, , THF, -78 C, , H, H, , Et, , H, H, , OH, H, Et, H, , H, Scheme 8, , J. L. Hubbard, Encyclopedia of Reagents for Organic Synthesis, John Wiley and, Sons, Inc., L. A. Pauette, Ed., New York, 1995, 5, 3172., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 14 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Problems:, A. Complete the following reactions., OH, , N, 1., , Br, , 2., O, , B. What major products would you expect in the following reactions., O, 1., , OEt, , Ar, , EtOH, -30 oC, , O, , Ph, , O, , NaBH4, , H H, NaBH4, , N, , 2., N, , Br, , O, , EtOH, , Me, , 3., , H, N S, O, O, , O, , NaBH4, THF, , C. Provide mechanistic rational for the following reaction., OH, CCl3, , 3.3 equiv NaOH, 1.5 equiv NaBH4, , CO2H, , t-BuOH, heat, , Text Book, M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 19 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Lecture 16, 2.2 Dissolving Metal Reductions (Na-Liq. NH3, Li-Liq., NH3, etc.), , 2.2.1 Introduction, The solution of alkali metal in ammonia (at -33 °C) can generate solvated, electrons and metal cations., M, , +, , M+ [ H3N, , (NH3)liquid, , e-, , NH3], , solvated electron, , These solvated electrons can reduce conjugated double bonds, triple bonds and, aromatic compounds. Most of the organic compounds are not soluble in liquid, ammonia and, therefore, the compounds are dissolved in THF or Et2O and are, added to the dissolved metal solution., , 2.2.2 Reduction of Conjugated Dienes, The conjugated dienes are readily reduced to the corresponding 1,4-dihydro, compounds with dissolved metal ammonia reagents (Scheme 1)., Me, , Me, , Na, (NH3)liquid, Me, , Me, , Scheme 1, , 2.2.3 Reduction of α,β-Unsaturated Ketones, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 20 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , The α,β-unsaturated ketones could be reduced to the corresponding saturated, carbonyl compounds or alcohols depending on the reaction conditions with, dissolved metal in ammonia (Scheme 2). For examples, the α,β-unsaturated, ketone, cyperone,, , when treated with lithium in ammonia, it gives the, , corresponding saturated ketone but when treated with lithium in ammonia and, ethanol, a good proton source, it gives the corresponding alcohol., Me, , Me, Li, (NH3)liquid, Et2O, then aq. NH4Cl, , O, Me, , Me, , O, , H, Me, , Me, , cyperone, Me, , Me, Li, (NH3)liquid, HO, , EtOH, , O, Me, , Me, , H, Me, , Me, , cyperone, Scheme 2, , Mechanism, The solvated electron is transferred to the conjugated system to give the radical, anion which is protonated by added alcohol or ammonia and then the second, electron transfer generates the enolate anion which on protonation during work, up gives the desired carbonyl compound (Scheme 3)., , Li, (NH3)liquid, Me, , OH, , OH, , Li O, , O, , protonation, Me, , Li O, , Li, (NH3)liquid, Me, , Me, Li, , Me, , aq. NH4Cl, O, , Me, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 21 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Scheme 3, , 2.2.4 Reduction of Aromatic Compounds (Birch Reduction), The reduction of aromatic compounds to 1,4-cyclohexadiene compounds in, presence of alkali metal liquid ammonia and an alcohol is called Birch reduction., A variety of aromatic compounds containing electron donating or electron, withdrawing groups could be readily converted to the corresponding 1,4cyclohexadiene derivatives (Scheme 4)., Li, (NH3)liquid, EtOH, Scheme 4, , The regioselectivity towards the products in Birch reduction of substituted, aromatic compound depends on the nature of the substituent. For example, the, electron donating substituent such as alkyl or alkoxy group remains on the, unreduced carbon where as the electron withdrawing groups such as carboxylic, acid or primary amide remains on reduced carbon almost exclusively (Scheme, 5)., X, X, , X, , Birch reduction, , or, X = -OH, -OR, -NR2,, -SR, -PR2, -alkyl,, -CH2OR, -CH2OH,, - CHO, CO2R, , X = -CO2H, -CONH2, , Scheme 5, , The aldehydes and esters groups are in the electron donation side because, these are reduced to the corresponding alcohols in Birch condition before the, reduction of aromatic ring (Scheme 6). The addition of one or two equivalent of, water or t-BuOH to the NH3 before the addition of metal can preserve the ester, group in Birch reduction., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 22 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , latter takes the second electron and a proton and undergoes elimination of an, alcohol to give aldehydes that further proceeds further reduction to give the, desired alcohol., , O, R, , O, , e, OR', , R, , OH, , EtOH, OR', , R, , e, R, , OR', , O, , OH, , H, , EtOH, R, , OR', , OR', , -HOR', OH, R, , H, , OH, , OH, , EtOH, , R, , H, , R, , O, , EtOH, , e, H, , R, , O, , e, R, , H, , Examples:, CO2Me, CO2H, , CH2OH, , Na, NH3, , CO2H, , alcohol, 72%, , L. A. Paquette, N. A. Nelson, J. Org. Chem. 1962, 27, 2272., Na, EtO2C, , CO2Et, , HOH2C, , CH2OH, , EtOH, 75%, , R. H. Manske, Org. Synth. CV2, 154., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 27 of 55, , H

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NPTEL – Chemistry – Reagents and Organic reactions, , Lecture 17, 2.3 Molecular Hydrogen, , 2.3.1 Introduction, Hydrogen is the most abundant chemical element in the universe with atomic, number 1 and symbol H. It has three isotopes hydrogen 1H, deuterium 2D and, tritium 3T and the 1H is the most abundant (99.98%). The hydrogen 1H and, deuterium 2D are stable isotopes whereas the tritium 3T is a radioactive. In, organic chemistry, hydrogen is used to reduce a variety of functional groups but, the hydrogen gas itself can not reduce any functional groups without a catalyst., , 2.3.2 Reduction of Carbon-Carbon Double Bonds, The reduction of carbon-carbon double bond is academically as well as, industrially important transformation (Scheme 1). The order of hydrogenation of, substituted double bond is 1,1-di > 1,2-di > 1,2-tri > 1,2-tetra substituted., Different metal catalysts have been used for the purpose. Among them, platinum, (Pt), iridium (Ir), ruthenium (Ru), rhodium (Rh), palladium (Pd) and nickel (Ni), catalysts are commonly used., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 30 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Ni Catalysts: C. R. Sarko, M. DiMare, Encyclopedia of Reagents for Organic, Synthesis, John Wiley and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6,, 3701; Pd Catalysts: A. O. King, I. Shinka, Encyclopedia of Reagents for Organic, Synthesis, John Wiley and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6,, 3867; E. M. Leahy, Encyclopedia of Reagents for Organic Synthesis, John Wiley, and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6, 3887; Pt Catalysts: A. O., King, I. Shinka, Encyclopedia of Reagents for Organic Synthesis, John Wiley and, Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6, 4159; 4160; Rh Catalysts: S., Siegel, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons,, Inc., L. A. Paquette, Ed., New York, 1995, 6, 4405; Ru Catalysts: S. Siegel,, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Inc., L., A. Paquette, Ed., New York, 1995, 6, 4410., Platinum oxide (PtO2) also known as Adam’s catalyst is generally used for the, platinum catalyzed hydrogenation reaction. Other catalysts such as Pd on, charcoal,, , Wilkinson’s, , catalyst, , RhCl(PPh3)3,, , Crabtree’s, , catalyst, , [Ir(cod)(PChx3)(py)]PF6, Ru(OAc)2(BINAP), Raney nickel and Nickel boride (Ni2B), are used. These reactions are performed in ethyl acetate, alcohols and acetic, acid as solvents., , Me, , Me, , Me, , CO2H, , Me, , CO2H, , Pt, H2, AcOH, Me, , Me, O, , O, , RhCl(PPh3)3, H2, toluene, , Me, , Joint initiative of IITs and IISc – Funded by MHRD, , Me, , Me, , Page 31 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , 2.3.3 Reduction of Carbon-Carbon Triple Bonds, The carbon-carbon triple bonds are reduced to the corresponding carbon-carbon, single bonds when treated with Pt, Pd, Raney Ni catalysts and molecular, hydrogen (Scheme 3)., OH, , OH, , OH, , OH, , Pt, H2, , Scheme 3, , The carbon-carbon triple bonds are selectively reduced to carbon-carbon double, bonds in the presence of Lindlar catalyst (Pd/CaCO3/PbO) or Rosenmund, catalyst (Pd/BaSO4/quinoline) and molecular hydrogen (Scheme 4). The, hydrogenation of carbon-carbon triple bonds to carbon-carbon double bonds, always takes place from same side of the carbon-carbon triple bond providing, stereo specifically cis alkenes (Z alkenes)., Pd/BaSO4/quinoline, MeO2C, , CO2Me, , H2, MeOH, , MeO2C, , CO2Me, , Pd/CaCO3/PbO, H2, MeOH, Me, , CO2H, , Me, , CO2H, , Scheme 4, , For Lindlar Catalyst, see: Lecture 16, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 33 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , 2.3.4 Reduction of Aromatic Compounds, Reduction of aromatic compounds could be performed with molecular hydrogen, in the presence of metal catalysts such as Pt, Pd, Rh, Ru and Raney nickel, (Scheme 5). The choice of metal catalyst depends on the nature of substrates., For example, the aromatic ring could be selectively reduced in the presence of, an ester or acid group using molecular hydrogen with nickel or platinum catalyst., CO2Et, , Ni, H2, , CO2Et, , 100 atm., 50 C, PtO2, H2, , CO2H, , CO2H, , AcOH, 25 C, Scheme 5, , 2.3.5 Reduction of Aromatic Nitro Compounds, The aromatic nitro compounds can be reduced to give the corresponding amines, when treated with molecular hydrogen in the presence of Pt, Pd or Ni catalyst, (Scheme 6). The reaction is generally performed in methanol, ethanol or ethyl, acetate at ambient temperature., NO2, , Pd/C, H2, , NH2, , EtOAc, rt, Scheme 6, , 2.3.6 Reduction of Acid Chlorides, Acids chlorides undergo reduction to give the corresponding aldehydes in the, presence of molecular hydrogen and palladium catalyst (Scheme 7). When, Pd/BaSO4/quinoline is used as a catalyst along with molecular hydrogen the, reaction is called Rosenmund reaction., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 34 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Problems, Provide suitable reagents/catalysts for the following transformations., , 1., , 2., , NC, , NC, , 3., , OH, , OH, , 4., OH, 5., , CO2H, , 6., , CO2H, , OH, , OH, , 7., , Text Book, M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 38 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Lecture 18, 2.4 Miscellaneous Reducing Agents, , 2.4.1 Tributyltin Hydride (Bu3SnH), Tributyltin hydride (TBTH) is an organotin compound can acts as a reducing, agent when treated with a radical initiator such as azobisisobutyronitrile (AIBN) or, by photo irradiation. It is a colourless liquid and is generally purified by distillation., T. V. Rajanbabu, Encyclopedia of Reagents for Organic Synthesis, John Wiley, and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 7, 5016., , 2.4.1.1 Reductive Dehalogenation, The halogens are removed by TBTH in presence of AIBN in aromatic, hydrocarbon solvent such as benzene, toluene. The AIBN acts as a radical, initiator and needed in catalytic amount (2-5 mol %). The reactivity order of the, halogens is I > Br > Cl and F does not work under these conditions (Scheme 12)., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 39 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Me, Me, NC, , 60 C, , Me, , N N, , 2, , Me, , + N2, , CN, , Me, , NC, , Me, , AIBN, Me, , Me, , H, , +, , CN, , Bu3Sn, , +, , Me, , Me, CN, , Bu, , Bu3Sn, , R, , H, , Bu, Sn Bu, , X, , Bu3SnX + R, , R, Bu, Sn Bu, , + H, , (X = Cl, Br, I), , Bu3Sn + R, , H, , Bu, Scheme 1, , H, , O, , H, , O, , Bu3SnH (1.2 equiv), , Br, , AIBN (0.05 equiv), benzene, , H, , R', , R', R, , Br, , N, H, , H, , Bu3SnH (1.2 equiv), AIBN (0.05 equiv), toluene, 110 C, , R, N, H, , Scheme 2, , 2.4.1.2 Radical Cyclization, The radical cyclization of the suitably substituted halides could be performed in, presence of TBTH to give the desired cyclized products (Scheme 3). The, reaction undergoes via radical pathway., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 40 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , 2.4.2 Diimide (HN=NH), Diimide can be prepared in situ, by the copper-catalyzed oxidation of hydrazine, in the presence of hydrogen peroxide or oxygen as terminal oxidant or the, decomposition of azodicarboxylic acid or sulfonylhydrazines (Scheme 6)., Cu2+, NH2-NH2, , HN=NH, H2O2, heat, , HO2CN NCO2H, O, S NH-NH2, O, , HN NH + CO2, MeOH, SO3H, , heat, HN NH +, Diglyme, Scheme 6, , D. J. Pasto, Encyclopedia of Reagents for Organic Synthesis, John Wiley and, Sons, Inc., L. A. Paquette, Ed., New York, 1995, 3, 1892., The reduction using diimide finds unique applications because:, The reagent is extremely tolerant of other functional groups, The reduction is highly stereoselective and takes place cis-addition, from, the less-hindered face., , H, , H, N N, , H, , H, N N, , H, , H, , Reactivity decreases with increasing substitution about the alkene bond., Alkynes show greater reactivity compared to alkenes., Alkenes with electron withdrawing groups show greater reactivity, compared to those with electron donating groups., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 43 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Text Book, M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004., , Lecture 19, 2.5 Photoreductions and Bio-reductions, , 2.5.1 Photoreduction, The electron transfer to a certain functional groups can be induced by irradiation, with light source. Reductions are possible when a proton source along with a, sensitizer and a source of irradiation are employed. The reduction proceeds via, photo-induced electron transfer (PET)., , 2.5.1.1 Reduction of Carbonyl Compound, The aliphatic and aromatic carbonyl compounds are reduced to a variety of, products depending on the reduction conditions. For examples, the aromatic, ketones, benzophenone or acetophenone, in isopropanol or methanol undergo, photoreduction to give dimeric pinacol in good yield (Scheme 1). In contrast,, benzophenone in isopropanol under reflux condition undergoes photoreduction to, give the secondary alcohol Ph2CHOH., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 48 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , R3N, , hv, , + R3N, H+, , e-, H+, H, , H, , H, , H, , dimerization, , Scheme 6, , 2.5.1.2 Reduction of Aromatic Compounds, The aromatic hydrocarbons such as benzene, biphenyl, naphthalene and, anthracene in their excited states react with amine to give reduced or aminated, products. The reaction involves the transfer of lone pair electron of amine to the, excited state singly occupied molecular orbital of aromatic compound (Scheme, 6)., The excited aromatic compounds could also be reduced by hydride source such, as sodium borohydride, lithium aluminum hydride of metal hydride (Scheme 7)., The reaction may undergo via the following sequences., CN, , CN H H, , CN, hv, , CN, , CN, H3O+, , NaBH4, , Scheme 7, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 51 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , 2.5.2 Bio-reduction, The bio-reduction is one of the important procedures in biological system. There, are mainly two different pathways through which most of the biological reductions, takes place, enzymatic and non-enzymatic reduction. The advantages of these, protocols are, it is very much substrate specific, that they work under ambient, condition in aqueous medium., , 2.5.2.1 Reduction of Carbonyl Group, The reductions of carbonyl groups have been studied most by using different bioreductants such as Baker’s yeast or with reductase enzyme. For example, the, reductions of β-ketoesters have been studied extensively (Scheme 8). The ethyl, acetoacetate could be reduced to give the corresponding 3-hydroxybutyrate. On, the other hand, 4-chloroacetoacetate when reduced with Baker’s yeast, gives the, corresponding, , (S)-alcohol, , with, , opposite, , selectivity., , Therefore,, , the, , stereochemistry of the reduced product depends on the shape and size of the, prochiral starting substrates. It also says that the Baker’s yeast has at least two, different active reducing sites., O, , O, OEt, , Me, , O, Cl, , OH O, , Baker's yeast, , O, , H2O, sucrose, 30 C, , Me, , OEt, , OH O, , Baker's yeast, OEt, , Cl, H2O, sucrose, 30 C, , OEt, , Scheme 8, , The reduction with Baker’s yeast is very much substrate dependant and it works, well with β-keto substrates but it is less selective with other keto-functional, substrates. Therefore, it promoted further study on this subject for better results., For example, a better result has been achieved with lyophilized whole cells of, Rhodococcus ruber DSM 44541, for asymmetric reduction of aryl ketones and, other unfunctional ketones with good enantiomeric excess (Scheme 9)., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 52 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Me, , O, , Me, , Me, , Rhodococcus ruber, Me, , OH, , Me, , phosphate buffer, iPrOH, , Me, , Scheme 9, , Another important microorganism is Geotrichum candidum which can perform the, asymmetric reduction of aliphatic, aromatic and trifluoromethane substituted, ketones with very high enantioselectiovity (Scheme 10)., , O, , OH, , G. candidum, NAD+, , Me, , Me, , Me, , Me, OH, , O, Br, , secondary alcohol, G. candidum, NAD+, , Me, , Br, , Me, , secondary alcohol, OH, , O, , G. candidum, NAD+, CF3, , CF3, , secondary alcohol, , Scheme 10, , The reduction with isolated enzymes have also been studied and the advantage, of this protocol is that it reduces the effect of other interfering enzymes which are, present in a cell but the weak point is that the stability of isolated enzymes and, use of expensive specific co-factor such as NADP (Nicotinamide adenine, dinucleotide phosphate) (Scheme 11)., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 53 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , H2N, , H, O, , HO, , +, , enzyme, R, , R', , R, , O, , N, O, O, P O, OH OH, O, O P, O, O, O, N, , NH2, , O, , +, , R', , N, , N, O, PO3H, , H2N, , OH, , H, , N, , O, O, P O, OH OH, O, O P, O, O, O, N, , O, , O, , N, , HO, NADP+, , NADPH, , N, , N, O, PO3H, , NH2, N, , formate dehydrogenase, HCOO-, , CO2, , Scheme 11, , For an example, the following symmetrical diketone could be reduced by enzyme, horse liver alcohol dehydrogenase (HLADH) to give the corresponding chiral, alcohol with high enantioselectivity (Scheme 12)., H, , O, H, , O, , H, HLADH, cat. NADH, EtOH, phosphate buffer, 30 C, , OH, , O, H, , Scheme 12, , Joint initiative of IITs and IISc – Funded by MHRD, , Page 54 of 55

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NPTEL – Chemistry – Reagents and Organic reactions, , Problems:, A What products would you expect from the following reactions?, O, , O, , 1., , Baker's yest, OEt, , O, Ph, , 2., , light, , O, light, 3., OH, O, , O, OEt, , 4., , Baker's yest, , S, , B. Rationalize the following photoreduction process., OH, , O, Ph, , light, +, NH2, , Ph, , +, NH, , Text Book, M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004., , Joint initiative of IITs and IISc – Funded by MHRD, , Page 55 of 55