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 LiAlH + 3LiCl 4 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 LiAlH + NaCl 4 Scheme 2 Joint initiative of IITs and IISc – Funded by MHRD Page 1 of 55 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 OH R H LiAlH R H or 4 or O OH R R' R R' O OH LiAlH4 Br Br Me Et O, -78 C Me 2 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. R R O H O H R H O H H H O H O R H R H H H Al H O Al H O Al H O Al O R H R H H R H R H H H H H H H O R H R H R OH H O H H3O H 4 R H O Al O H R O H H H H R Scheme 4 Joint initiative of IITs and IISc – Funded by MHRD Page 2 of 55 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 BH3 as a reducing agent. The three hydride ions are consumed for reducing one acid group. O LiAlH4 R OH R OH Me Me O LiAlH4 Et2O OH 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 R' R O R OH + R' OH or LiAlH4 or O R' R' R N R N R' R' Me Me O O LiAlH HO OH O O 4 Et2O O O O O Me Me Me Me Joint initiative of IITs and IISc – Funded by MHRD Page 3 of 55 NPTEL – Chemistry – Reagents and Organic reactions LiAlH4 NH NH THF O 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 R NH2 or R NO 2 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 Me LiAlH4 O OH HO O Me Me LiAlH4 H O H O Et2O/THF O 0 C O CO2Me OH Scheme 8 Joint initiative of IITs and IISc – Funded by MHRD Page 4 of 55 NPTEL – Chemistry – Reagents and Organic reactions 2.1.2 Lithium Trialkoxyaluminum Hydride [LiAlH(OR)3] 2.1.2.1 Introduction Though LAH is a powerful reducing agent but is less selective. The reactivity and selectivity can be modified by replacing the three hydride ion with alkoxy groups such as tert-butoxy or ethoxy group. The resulting reagents are less reactive but more selective than LAH. 2.1.2.2 Preparation The lithium trialkoxyaluminum hydride can be prepared by treating LAH with the alcohol and better to prepare in situ prior to use (Scheme 9). 3 t-BuOH LiAlH(Ot-Bu)3 or LiAlH4 + or + 3H2 LiAlH(OEt)3 3 EtOH Scheme 9 2.1.2.2.1 Lithium tri-t-Butoxyaluminum Hydride [LiAlH(Ot-Bu)3] This is less reactive compared to LAH and reduces aldehydes and ketones to alcohols and acid chlorides to aldehydes (Scheme 10). The other functional groups such as acids, amides and nitriles do not react or react very slowly. O O LiAlH(Ot-Bu) Cl 3 H diglyme, -78 C NC NC Scheme 10 2.1.2.2.2 Lithium tri-Ethoxyaluminum Hydride [LiAlH(OEt)3] Lithium tri-ethoxyaluminum hydride is comparatively stronger reducing agent than lithium tri-t-butoxyaluminum hydride (Scheme 11). It can reduce amides and nitriles to the corresponding aldehydes in good yield. Joint initiative of IITs and IISc – Funded by MHRD Page 5 of 55 NPTEL – Chemistry – Reagents and Organic reactions O CN LiAlH(OEt)3 H Et O 2 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 NH R' 2 R NH R 2 R' N H R R R' O NO2 CN R R' H N N R 2 O O O or OH OH R OR' R R' R H or R'OH + R OH Red-Al R R' R H O O O R R O NR'2 R O O R Cl R OH R OH R NR'2 R OH Scheme 12 Joint initiative of IITs and IISc – Funded by MHRD Page 6 of 55 NPTEL – Chemistry – Reagents and Organic reactions Examples: OH OH OH OH Reduction + + Ether TMS TMS TMS TMS LAH 19 49 32 SMEAH 100 0 0 S. E. Denmark, T. K. Jones, J. Org. Chem. 1982, 47, 4595. OH OH HOH2C OH SMEAH OH N Toluene N t-Bu 30% M. Ishizaki, O. Hoshino, Y. Iitaka, J. Org. Chem. 1992, 57, 7285. O Al O Al O H Al Me O SMEAH Me O Me O C Me THF Me Me Al O OH Al O Me Me Me CH2OH 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 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. CO Me DIBAL-H CHO O 2 O Me Toluene -78 C Me MeO MeO Me Me Me O O Me Me Al Al O H3O R' Me R H R O Me H Me R' R O 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 NPTEL – Chemistry – Reagents and Organic reactions Me Me H H CN DIBAL-H CHO CH2Cl2, -78 C Me Me Scheme 14 Examples: O O O ClH C O ClH2C DIBAL 2 iPrOH, PPTS 79% J. L. Vicario, A. Job, M. Wolberg, M. Muller, D. Enders, Org. Lett. 2002, 4, 1023. O O O DIBAL O PhH CN CHO 80% R. V. Stevens, L. E. Dupree, P. L. Lowenstein, J. Org. Chem. 1972, 37, 977. Problems A. How will you carry out the following reduction reactions using aluminum hydride based reagents? CHO CH2OH 1. Ph Ph CHO CH2OH 2. Ph Ph O O H 3. NMe2 4. CN CHO 5. CO2Me CHO Joint initiative of IITs and IISc – Funded by MHRD Page 9 of 55 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.